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This textbook, now appearing in its 5th, fully updated, and expanded edition, has become widely known as the

best exposition available on the topic of hyperbaric medicine and the wide range of applications of hyperbaric

oxygen (HBO) techniques. In addition to explaining the basic principles of HBO therapy and its application in

carbon monoxide poisoning, decompression sickness, and diving medicine, the textbook looks objectively

and critically at its use in numerous other areas, such as stroke, CNS and neurological disorders, traumatology

and wound healing, infectious diseases, rehabilitation and sports medicine, plastic surgery, emergency

medicine, obstetrics, and cancer treatment. With over 1,700 up-to-date references and an extensive index,

the volume is not just a textbook suitable for those seeking an introduction to this expanding field, but also

an invaluable resource for specialists.

What reviewers say:

“Logically organized… well-researched… critical scrutiny of the evidence and a balanced approach are main-

tained throughout… The completeness and currency of the clinical information will be useful to clinical

investigators and to practicing hyperbaric medicine specialists.”

(G.B. Hayes, in Journal of Intensive Care Medicine)

“Well set out and easily readable… a comprehensive book… well-written, and the information is accurate.”

(P. Moore, in Anaesthesia and Intensive Care)

“This excellent and comprehensive text remains probably the standard work… an essential reference text.”

(N.K. Cooper, in Journal of the Royal Army Medical Corps)

“The experts who have made such superb contributions to [this book] are the world leaders in their fields.”

(Prof. James F. Toole, MD)

“A uniquely up-to-date and comprehensive overview.”

(Prof. H. Wassmann, MD)

Textbook of

n Thorough, comprehensive, objective

n The essential reference for all who use HbO

n numerous illustrations, unique full-color SpecT scans

n internationally renowned contributors

ISBN 978-0-88937-361-7

k. k. Jain

Hyperbaric Medicine

5th revised and updated edition

Textbook ofHyperbaric Medicine

HHPUB 361 Jain HBO5 3-2-2_RZ.indd 1 11.03.2009 10:45:01

About the Author

K.K. Jain, MD, is a neurosurgeon and has held fellowships and teaching positions at Harvard, UCLA, and the University of Toronto. Hehas been a visiting professor in several countries and served in the US Army with the rank of Lieutenant Colonel. He wrote the Handbookof Laser Neurosurgery based on his experience in microsurgery and lasers. He has been active in the field of hyperbaric medicine since1976, starting with the application of this technique to stroke patients.The author of 15 books (including Oxygen in Physiology & Medicine,Textbook of Gene Therapy, and Handbook of Nanomedicine), Prof. Jain, in addition to his activities in biotechnology, serves as a consultantin hyperbaric medicine.

With contributions by

S.A. Baydin MD

Director General, Institute of HyperbaricMedicine and Techniques,Post Box 853Moscow, 119435 Russia(Chapter 29, Pediatric Surgery)

J. Bookspan, PhDTemple University and Jefferson Medical College,Philadelphia, PA, USA(Chapter 23, Headache)

T.M. Bozzuto, DOMedical Director, Phoebe Wound Care & Hyperbaric CenterPhoebe Putney Memorial HospitalAlbany, GA, USA(Chapter 41, United States)

F.K. Butler, Jr., MDCAPT MC USN (Ret)Chairman, Committee on Tactical Combat Casualty CareDefense Health BoardPensacola, FL, USA(Chapter 32, Ophthalmology)

E.M. Camporesi, MDProfessor and Chairman, Dept. of AnesthesiologySUNY, Syracuse, New York(Chapter 38, Anesthesia)

C.E. Fife, MDAssociate Professor of AnesthesiologyMemorial Hermann Center for Hyperbaric MedicineHouston, Texas 77030, USA(Chapters 14, Chronic Lyme Disease; 23, Headache)

W.P. Fife, PhDProfessor of Hyperbaric Medicine (Emeritus)Texas A & M UniversityCollege Station, Texas, USA(Chapter 14, Chronic Lyme Disease)

P.G. Harch, MDDirector, Dept. of Hyperbaric MedicineLSU School of Medicine at New OrleansHarvey, LA, USA(Chapters 19, Anoxia and Coma; 22, Cerebral Palsy; 44, Appen-dix)

P.B. James, MDProfessor Emeritus, Wofson Institute of Occupational HealthMedical SchoolNinewells, Dundee, UK(Chapters 10, Decompression Sickness; 21, Multiple Sclerosis;44, Appendix)

H. Murphy-Lavoie, MDAssistant Residency DirectorEmergency Medicine Residency

Associate Program DirectorHyperbaric Medicine FellowshipLSU School of Medicine/MCLNONew Orleans, LA, USA(Chapter 32, Ophthalmology)

R.A. Neubauer, MD†Director, Ocean Hyperbaric CenterFort Lauderdale, FL, USA(Chapters 19, Anoxia and Coma; 21, Multiple Sclerosis;22 Cerebral Palsy; 44, Appendix)

V. NeubauerOcean Hyperbaric CenterFort Lauderdale, FL, USA(Chapter 22, Cerebral Palsy)

M.H. SukoffClinical Professor of NeurosurgeryUniversity of CaliforniaIrvine, CA, USA(Chapter 20, Neurosurgery)

H. TakahashiProfessor and ChairmanDepartment of Hyperbaric MedicineUniversity of Nagoya School of MedicineShowa-Ku, Nagoya 466–8560Japan(Chapter 43, Japan)

K. Van Meter, MDChief, Section of Emergency MedicineClinical Professor of Medicine, Section of Emergency MedicineLSU Health Sciences Center in New OrleansHarvey, LA, USA(Chapter 39, Emergency Medicine)

J.M. Uszler, MDProfessor of Nuclear MedicineSanta Monica-UCLA Medical CenterSanta Monica, CA, USA(Chapter 44, Appendix)

H.A. Wyatt, MD, PhDClinical Instructor of MedicineLSU Health Sciences CenterDepartment of Medicine and Division of Hyperbaric MedicineMarrero, LA, USA(Chapter 37, Organ Transplants)

H. Yagi, MDDirector, Hyperbaric MedicineFukuoka Yagi Kosei-Kai Hospital(2–21–25, Maidashi, Higashi-Ku,Fukuoka, Japan(Chapter 43, Japan)

Textbook ofHyperbaric MedicineFifth revised and updated edition

K. K. Jain, MD

Library of Congress Cataloguing-in-Publication Data

is available via the Library of Congress Marc Databaseunder the LC Control Number 2008938004

National Library of Canada Cataloguing in Publication

Jain, K. K. (Kewal K.)Textbook of hyperbaric medicine / K.K. Jain.—5th ed.

Includes bibliographical references and index.ISBN 978-0-88937-361-7

1.Hyperbaric oxygenation. I.Title.

RM666.O83J35 2009 615.8’36 C2008-906643-X

Copyright © 2009 by Hogrefe & Huber Publishers

PUBLISHING OFFICESUSA: Hogrefe Publishing, 875 Massachusetts Avenue, 7th Floor Cambridge, MA 02139

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No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by anymeans, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written per-mission from the publisher.

Printed and bound in GermanyISBN 978-0-88937-361-7

To my wife Verena and my children Eric, Adrian, and Vivien Jainfor their patience during the preparation of this work

Table of Contents

Foreword by J. Toole IX

Foreword to the Third Edition by E. Teller X

Preface to the Fifth Edition XII

Preface to the Fourth Edition XII

Preface to the Third Edition XIII

Preface to the Second Edition XIII

Preface to the First Edition XIV

PART I: Basic Aspects

1. The History of Hyperbaric Medicine 3

2. Physical, Physiological, and Biochemical Aspects of Hyperbaric Oxygenation 9

3. Effects of Diving and High Pressure on the Human Body 21

4. Physical Exercise Under Hyperbaric Conditions 31

5. Hypoxia 37

6. Oxygen Toxicity 47

7. Hyperbaric Chambers: Equipment, Technique, and Safety 59

8. Indications, Contraindications, and Complications of HBO Therapy 75

9. Drug Interactions with Hyperbaric Oxygenation 81

PART II: Clinical Applications

10. Decompression Sickness 87

11. Cerebral Air Embolism 103

12. Carbon Monoxide and Other Tissue Poisons 111

13. HBO Therapy in Infections 135

14. HBO Therapy in Chronic Lyme Disease 149

15. HBO Therapy in Wound Healing, Plastic Surgery, and Dermatology 157

16. HBO Therapy in the Management of Radionecrosis 177

17. The Use of HBO in Treating Neurological Disorders 189

18. The Role of Hyperbaric Oxygenation in the Management of Stroke 205

19. HBO Therapy in Global Cerebral Ischemia/Anoxia and Coma 235

20. HBO Therapy in Neurosurgery 275

21. HBO Therapy in Multiple Sclerosis 291

22. HBO in the Management of Cerebral Palsy 299

23. HBO Therapy in Headache 311

24. HBO Therapy in Cardiovascular Diseases 319

25. HBO Therapy in Hematology and Immunology 339

26. HBO Therapy in Gastroenterology 347

27. HBO and Endocrinology 357

28. HBO and Pulmonary Disorders 361

29. HBO Therapy in Pediatric Surgery 367

30. Hyperbaric Oxygenation in Traumatology and Orthopedics 375

31. HBO Therapy in Otolaryngology 387

32. HBO Therapy and Ophthalmology 399

33. Hyperbaric Oxygenation in Obstetrics and Neonatology 421

34. Hyperbaric Oxygenation in Geriatrics 425

35. HBO as an Adjuvant in Rehabilitation and Sports Medicine 431

36. The Role of HBO in Enhancing Cancer Radiosensitivity 435

37. HBO Therapy and Organ Transplants 443

38. Anesthesia in the Hyperbaric Environment 447

39. HBO in Emergency Medicine 453

40. Hyperbaric Medicine as a Specialty: Training, Practice, and Research 483

41. Hyperbaric Medicine in the United States 491

42. Hyperbaric Medicine in Japan 495

43. Hyperbaric Medicine in the Rest of the World 499

PART III: Appendix, Bibliography, Index

44. Appendix: Diagnostic Imaging and HBO Therapy 505

45. Bibliography 521

46. Index 571

VIII

Foreword

James F. Toole, MD

Teagle Professor of NeurologyDirector, Cerebrovascular Research CenterWake Forest University School of Medicine, Winston-Salem, NC

Slowly but surely, hyperbaric medicine is becoming an es-tablished treatment modality for a variety of medical dis-orders, despite the rocky road that it has sometimes had totravel over the years. In some ways, I feel that the need foroxygen in medical treatments is akin to man’s basic re-quirement for water and food, and I also think it is fair tosay that the logic and utility of hyperbaric oxygen treat-ment now seem to be almost as undeniable as these basicrequirements are.

It is certainly the case that, from time immemorial, rem-edies learned by trial and error have been handed downthrough the generations – with the result that many roots,berries, fruits, and leaves, as well as special waters contain-ing minerals have been advocated throughout history fortheir curative powers. More recently, however, evidence-based medicine has come to the fore, demanding higherstandards of evidence from basic and clinical/research tri-als and objective statistical results. One of the first instancesof such objective studies in my lifetime was when AustinBradford Hill and Richard Doll (Doll 2003) convinced col-leagues to allocate patients with pulmonary tuberculosisrandomly to prove the efficacy of streptomycin, althoughtheir trial followed a tradition started 200 years earlier byLinde, who provided citrus fruits aboard some, but not allships in the British Navy to test whether they would preventscurvy (Moberg & Chon 2000).

By means of prospective trials, it has been found thatvarious “established” therapies can be detrimental for somediseases, while being clearly beneficial for others. This isprecisely the case with hyperbaric medicine now: while ahyperoxic environment for newborn babies can lead to ret-rolental fibroplasia with blindness, there is also convincingevidence that hyperbaric treatments provide clear benefitsin diseases such as various neurological disorders, stroke,cerebral ischemia, and wound healing. And, of course,those of us who have worked in high-altitude environ-ments know the very short time window during which thehuman brain can function in hypoxic conditions. It neverceases to astonish me what a wide range of effects (benefi-

cial or toxic) a seemingly innocuous substance such as ox-ygen can have in various circumstances.

By and large, the experts who have made such superbcontributions to the Textbook of Hyperbaric Medicine arethe world leaders in their fields. With their help, Dr. Jainhas expanded his already outstanding book into a com-pendium of multi-authored chapters (containing over2,000 references) covering areas of medicine as disparateas wound healing, gastrointestinal disorders, trauma, andobstetrics. Of particular interest in this edition are the ex-tensive discussions of cerebral circulation and its disor-ders, as well as of stroke, diving accidents, and neurosur-gery.

For an earlier edition, Dr. Jain enlisted a remarkableForeword by Professor Edward Teller (see next page), whobegan by stating “Hyperbaric medicine is new and con-troversial” and that we live “in an age that has the habitof treating progress with suspicion,” and then went on topose the question, “But what is the innovator to do?” Healso raised the age-old problem of the ethics of the dou-ble-blind trial, and cautioned us to be aware of the poten-tial danger of high-pressure treatment for too long a pe-riod, in the same way that drug treatments at too highdosages bear clear risks. The field of hyperbaric medicinehas indeed been subject to an at times intense debate, butmuch progress has been made since Professor Teller orig-inally wrote his words (and will, I am sure, continue to bemade in the future), on the basis of mutual respect, un-derstanding, and cooperation, while also submitting be-liefs to randomized trials.

Professor Teller wrote then: “It is not entirely impossiblethat, perhaps sometime in the next decade, professors ofmedicine will have difficulty in explaining why treatmentwith oxygen was not widely adopted much earlier.” Reflec-ting today on these words by an elder statesman whose sci-entific observations went unheeded early on, we can safelyconclude that the uphill battle for acceptance of hyperbaricoxygen as therapy now rests on a solid foundation. Thissolid foundation is described comprehensively and clearly

IX

within this outstanding text, in which the assembled ex-perts provide a fair and balanced summary of the literatureand evidence. And it also means that the “decade of HBO”to which Professor Teller indirectly referred has now come.

References

Doll R (2003). The evolution of the controlled trial. The EighteenthJohn P. McGovern Award Lecture, delivered at the Thirty-ThirdMeeting of the American Osler Society, Edinburgh, Scotland, May23.

Moberg CL, Chon ZA (Eds.). (1990). Launching the antibiotic era.Personal accounts of the discovery and use of the first antibiotics.New York: Rockefeller University Press.

Foreword to the Third Edition

Edward Teller†

Formerly Director Emeritus Lawrence Livermore National Laboratories, California &Senior Research Fellow Hoover Institution, Stanford University, Stanford, CA

Hyperbaric medicine is new and controversial. Indeed,since it is new, it must be controversial in an age that hasthe habit of treating progress with suspicion. But what isthe innovator to do? If he applies a new and safe procedureto patients, and the procedure appears to be successful, hissuccess might well be denigrated as anecdotal. Will he beallowed to run a double blind experiment in which half ofthe patients are denied the benefits of what appears to be acure? It is an age-old problem that has grown sharper inthe course of time.

Hyperbaric medicine grew out of the problems encoun-tered by divers exposed to high pressures. The treatment ofdisturbances due to bubbles which develop during rapid de-compression was the natural connection between high pres-sure and medicine. This limited application of a medical pro-cedure is, of course, widely accepted. But its extension tocounteract the damage due the air bubbles resulting fromother causes, such as those accidentally introduced duringmedical treatment, is less generally recognized.

What is attempted in this book is a detailed and criticaltreatment of a large subject. If thorough discussion willlead to some consensus, the subject could grow very muchlarger. Indeed, oxygen, which in the form of hyperbaric ox-ygen (HBO) is called a drug, is the most natural of all drugs.

The first problem we must face is the danger of highpressure treatment used at excess pressure for too long aperiod, or in conjunction with the wrong kind of drug. Ox-ygen indeed has toxic effects. Furthermore, the delivery ofthe pressurized gas to the patient may be mishandled. Aproperly extensive discussion is devoted to such dangers,which are completely avoidable.

Perhaps the most natural use of HBO is to counteractcarbon monoxide poisoning. The best known effect of car-bon monoxide is to replace oxygen by being more firmlybound to hemoglobin. But, of course, high pressure oxygencan drive out the carbon monoxide and produce a cure inan understandable fashion.

A little harder to grasp is why pure oxygen at two atmo-spheres of pressure (which is ten times as concentrated asthe natural occurrence) should have any general uses. In-deed, under normal circumstances, the hemoglobin in ar-terial blood is 97 percent saturated with oxygen. Are weexerting ourselves to supply the remaining 3 percent? Theanswer, of course, is no. Oxygen is also soluble in blood. Attwo atmospheres of pressure, oxygen can be dissolved intothe plasma at several times normal levels, and can signifi-cantly improve tissue oxygenation. This is important be-cause hemoglobin, while more eager to take up oxygen, isalso more reluctant to part with it. The oxygen dissolved inthe plasma, having a higher chemical potential, is pushedout from the capillaries and into the surrounding tissue.From there, it can spread small distances by diffusion.

Even in the blood itself, the dissolved oxygen may helpthe white blood cells in their phagocytic activity. Bacteriathemselves may react in a variety of ways. It appears thatmany can use oxygen at normal pressures, but are damagedby oxygen at higher pressures. In the case of anaerobic bac-teria, oxygen can act in a powerful way to stop the infection.In combination with other methods, HBO clearly appearseffective in cases of gangrene.

But more is involved than the straightforward destruc-tion of the pathogen. The natural healing process may also

X

be assisted by the presence of oxygen. This obviouslyshould be the case when hyperbaric treatment counteractson oxygen deficiency. Many injuries involve the destructionof capillaries, the means of delivering oxygen. Under suchcircumstances, healing is itself tied to revascularization ofthe damaged tissue. But growth of the requisite capillariesis in turn tied to the oxygen supply. This relationship canexplain why in the case of many slow healing wounds, HBOseems to have a strong positive effect. Very much more canand should be done to extend the study of the speed ofhealing to the more normal cases.

In the human body, 20 percent of the oxygen consump-tion occurs in 3 percent of the body mass: the brain. Thisis also the region most sensitive to a deficiency of oxygen,which can produce dramatic results. Indeed, surgical meth-ods on the carotid artery are often used to relieve oxygendeficiency to the brain. It seems logical that in HBO wehave a tool that can serve a similar purpose. This might beparticularly important in the case of stroke, a high-rankingcause of death and disability. It is clearly worthwhile to ex-plore whether and to what extent disability can be reducedor avoided by prompt use of hyperbaric treatment. If theblood supply to a small region of the brain is reduced, reliefmight come from the diffusion of oxygen into the ischemicregion from neighboring capillaries.

For all new medical techniques, scientific evidence is de-manded. Yet medicine is still partly an art, as well as a dra-matically advancing science. Therefore in the complicatedquestions of life, disease, and recovery, it is sometimes hard

to distinguish between the fight against the causes of a dis-ease, and our efforts to aid toward the reassertion of overallhealth. There are good indications that HBO is helpful inmany diseases, such as multiple sclerosis and osteomyelitis.One may mention these two applications because, in theformer, earlier recognition of the disease made possible bythe use of magnetic resonance imaging has made earlytreatment a better possibility, and seems to have given a realchance for help from HBO. In the latter case, osteomyelitis,the location of the disease is the bone, where oxygen is usu-ally not amply available.

As members of the scientific community we are all nat-urally tempted to theorize, as long as a glimmer of a theorymight be perceived. This book proceeds, however, alongstrictly step by step empirical lines. Case after case, the var-ious pathologies are reviewed. In each situation, it is care-fully stated to what extent the evidence merely indicates aconclusion, and to what extent the conclusion can beproved. In the present stage of HBO, it is a certainty thatthere will be considerable criticism. On the other hand,those who disagree are likely at the same time to disagreeamong themselves. I believe that the result will be not onlycritical reflection, but also more experimentation, more re-views, more understanding, and more progress. It is notentirely impossible that, perhaps sometimes in the next de-cade, professors of medicine will have difficulty in explain-ing why the treatment with oxygen was not widely adoptedmuch earlier.

XI

Preface to the Fifth Edition

K.K. Jain

American College of Hyperbaric Medicine

Almost 20 years have passed since the first edition of theTextbook of Hyperbaric Medicine was written, and since thepublication of the 4th revised edition in 2004, there hasbeen a considerable increase of research and developmentin applications of hyperbaric oxygen. Of the more than1200 publications relevant to hyperbaric medicine during2004–2008, approximately 300 have been selected and ad-ded to the list in this book, whilst a corresponding numberof older references have been deleted to maintain the bib-liography at 2000 entries. Several older publications havebeen retained for their historical interest, and some of thesehave indeed become classics.

There is an ever increasing use of hyperbaric oxygen forneurological disorders. Other areas of expansion includeapplications in ophthalmology and the chapter on this hasbeen rewritten and expanded by Frank Butler and HeatherMurphy-Lavoie. A new chapter by Alan Wyatt on the role

of hyperbaric oxygen in organ transplantation has been ad-ded as well as a chapter on the treatment of chronic lymedisease by William Fife and Caroline Fife.

Multimodality treatment is required in some complexdisorders and hyperbaric oxygen has been combined withnew advances in drug treatment and surgical procedures aswell as with complementary medicine techniques such asacupuncture. As other new technologies such as those formanipulating stem cells develop, their interaction with hy-perbaric oxygen is being studied. Hyperbaric oxygen mayprove to be a useful adjunct to stem cell-based therapeuticsand regenerative medicine.

I would like to thank the editorial staff at Hogrefe &Huber Publishers, particularly the Publishing Manager,Robert Dimbleby, for their help and encouragement duringthis revision.

Preface to the Fourth Edition

K.K. Jain

American College of Hyperbaric Medicine

The textbook has been revised in accordance with the pro-gress made in hyperbaric medicine during the past fouryears. There were over 1000 publications relevant to hyper-baric medicine during 1999–2002. Approximately 200 ofthese were selected and a corresponding number of olderreferences were deleted to keep the total number of refer-ences in the bibliography to 2000. The number of clinicaltrials for various applications in hyperbaric oxygen therapyhas increased. These are included wherever the publishedresults are available. As personalized medicine is develop-ing, it will be applied to hyperbaric oxygenation as well. Itis already obvious that patients require an individualizedapproach in hyperbaric therapy protocols. The dose of ox-

ygen, pressure, and duration of treatment need to be deter-mined for each patient individually. It is difficult to reachany conclusions from clinical trials about a particular pres-sure of oxygen or even a range for a broad diagnostic cat-egory with many variants among patients that determinethe response.

Applications in neurological disorders are developing fur-ther and space devoted to this area has been increased. A newchapter by Neubauer and Harch has been added on the treat-ment of cerebral palsy with hyperbaric oxygenation.

I wish to thank the publishing directors of Hogrefe Pub-lishers and their Editor, Mr. Robert Dimbleby, for their helpand encouragement throughout the period of revision.

XII

Preface to the Third Edition

K.K. Jain

American College of Hyperbaric Medicine

Hyperbaric medicine continues to make progress. The tex-tbook has been revised and expanded with inclusion of newcontributors. We are fortunate to have an article from Prof.Hideyo Takahashi of Japan describing the state of develop-ment of hyperbaric oxygen therapy in Japan.

As in the previous edition, objective judgment has beenexercised in deciding to include various reports and studieson this subject. There are more than 200 publications everyyear on hyperbaric medicine, and all the publications can-not be included in references. The bibliography alreadycontains more than 2000 entries. Most of the older refer-ences have been retained because of their historical value.

Much of the original material still holds its value and hasalso been retained. Simply because no new work has beendone in some areas does not mean that these indicationsfor HBO are no longer valid. Research in hyperbaric med-icine continues to be limited by lack of funding. However,

the technique is available for clinical application in certaincases when the need arises and often a precedence in thatarea helps. Well-documented anecdotal reports have ateaching value, and this has been utilized in the textbook.This is particularly so in the case of emergency medicineand treatment of hypoxemic/ischemic encephalopathies,where it would be practically impossible to conduct con-trolled studies.

Much of the expansion of hyperbaric oxygen therapy isin the area of neurological disorders, which is reflected inthe increased number of chapters devoted to this area. Thisapplication of hyperbaric oxygen holds the greatest prom-ise for the future for diseases of the nervous system.

I wish to thank the publishing directors of Hogrefe &Huber and their Editor, Mr. Robert Dimbleby, for theirhelp and encouragement throughout the period of prep-aration.

Preface to the Second Edition

K.K. Jain

American College of Hyperbaric Medicine

A great deal of progress has taken place in Hyperbaric Med-icine since the publication of the first edition. This has ne-cessitated a thorough revision of the book and inclusion ofnew contributors. Some of the outdated references were re-moved and new ones have been added, bringing the totalabout 1800 entries. I have tried to keep my judgment objec-tive and this is helped by the fact I have no involvement inthe political and financial aspects of hyperbaric medicine.

In spite of this critical revision and corrections, I ampleased to state that a great deal of the old stuff still holdsits value. Use of hyperbaric oxygen therapy in neurologicaldisorders continues to expand and required a chapter on

neurosurgery, for which I was fortunate to have the collab-oration of Dr. Michael Sukoff of the United States, who hasdone much of the pioneer work in this field. The chapteron pediatric surgery by Prof. Baydin from Russia is a usefulnew addition. With the inclusion of unpublished work onthe role of neuropeptides in oxygen therapy (Prof. G.T. Ni)from China, the book is now truly international.

I wish to thank the publishing directors of Hogrefe &Huber Publishers for their help and encouragementthroughout the period of revision. Countless other col-leagues also helped and their names are too numerous tolist here.

XIII

Preface to the First Edition

K.K. Jain

American College of Hyperbaric Medicine

This book goes considerably beyond the scope of the Hand-book of Hyperbaric Oxygen Therapy, which was written byme, and published by Springer Verlag in 1988. In addition,with the many rapid developments in this field, the Hand-book has already become remarkably outdated. Our use ofthe word “textbook” in the title of the present work is inkeeping with the increasing worldwide recognition of thisbranch of medicine, and the need for a definite and inclu-sive source covering this body of knowledge, as it exists to-day.

In practice hyperbaric medicine of course involves mo-stly the use of hyperbaric oxygen, i.e., oxygen under pres-sure greater than atmospheric. As a result, this field over-laps with diving medicine in the areas of

• the effect of high pressure on the human body• physical exercise under hyperbaric environments• air embolism• decompression sickness

I have made no attempt to intrude any further into divingmedicine, as there are several excellent textbooks on thatsubject. In addition, the use of normobaric oxygen has been

discussed elsewhere in a 1989 title by K.K. Jain, Oxygen inPhysiology and Medicine.

I have written this current work in a textbook style, andthere is more discussion on the pathophysiology of diseasesand the rational basis of hyperbaric oxygen than in theHandbook. Extensive and up-to-date references have beenassembled as an integral part of this project, and these totalabout 1,500.

The highlights of this present effort are the newly docu-mented effectiveness of hyperbaric oxygen therapy in therehabilitation of stroke patients, and the validation of thesegains via the iofetamine scan technique. This same methodhas also been used to document the improvement in mul-tiple sclerosis patients undergoing hyperbaric oxygen ther-apy.

In the preparation of this work I was considerably aidedby the capable and cooperative management effort provid-ed by the two directors of the Hogrefe & Huber publishingcompany. The execution of a project involving this degreeof both scope and detail is certainly an exercise in team-work between author and publisher, and it was a pleasureto have shaped the production in a creative and timelymanner.

XIV

Chapter 1The History of Hyperbaric Medicine

PART I:

BASIC ASPECTS

1The History ofHyperbaric Medicine

K.K. Jain

This chapter reviews the historical relationship between hyperbaric therapy and diving medicine,recounting the important stages in the development of compressed gas technology and a few of themore interesting early attempts to utilize it for medical purposes. The sections involved are:

Hyperbaric Therapy and Diving Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4The Development of Hyperbaric Air Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5The Development of Hyperbaric Oxygen Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Hyperbaric Therapy and DivingMedicine

As is well known, the origins and development of hyper-baric medicine are closely tied to the history of diving med-icine. While the attractions of the deep are easily under-stood, it was the various unpleasant physical consequencesof venturing beneath the surface of the world’s oceans thatled directly to the many applications of compressed-gastherapy in modern medicine. Although scientifically basedapplications of hyperbaric technology are a relatively re-cent development, the use of compressed gas in medicineactually has ancient roots.

The origin of diving is not known, but it was recognizedas a distinct occupation as far back as 4500 B. C. However,since humans can only hold their breath for a few minutes,unaided dives are limited to depths of less than about 30meters. The first use of actual diving equipment to extendthe limits of underwater activity is attributed in legend tonone other than Alexander the Great, who, in 320 B. C., issaid to have been lowered into the Bosphorus Straits in aglass barrel (see Figure 1.1), which purportedly gave him asecret weapon in the siege of Tyre.

Around the year 1500, Leonardo Da Vinci made sketchesof a variety of diving appliances, without developing anyfor practical use. It was not until 1620 that the Dutch in-ventor Cornelius Drebbel developed the first true divingbell. His device was extremely limited, especially by its sim-ple air supply that delivered air pressurized at only one at-mosphere, but it was certainly the forerunner of all sub-mersible vehicles.

In 1691 Edmund Halley, after whom the comet isnamed, advanced diving bell technology by devising a

method of replenishing the air supply using weighted bar-rels (Smith, 1986). This was followed in the next two cen-turies by the development of compressed-air diving hel-mets and suits – which made it possible to remain underwater for an hour or more.

Even though the duration of dives had been extended,divers were still limited to the same shallow waters as be-fore. Undersea pioneers had quickly discovered the ear-drum-rupturing effects of increasing water pressure. Thoseattempting to venture even deeper in diving bells also

Figure 1.1Alexander the Great was said to have been lowered into the Bospho-rus Straits in a glass barrel. Note that the candles are lighted and if,indeed, Alexander went into this barrel, he was lucky to survive. Theillustration is redrawn from a thirteenth century manuscript in theBurgundy Library in Brussels, and is reproduced courtesy of Dr. E.B. Smith (1986).

Table 1.1Some Important Benchmarks in the History of Diving Medicine in Relation to Hyperbaric Medicine

4500 BC Earliest records of breathholding dives for mother-of-pearl400 BC Xerxes used divers for work on ships and for salvaging sunken goods. Dives were for 2–4 min and to a depth of 20–30 m320 BC First diving bell used by Alexander the Great300 BC Aristotle described the rupture of the eardrum in divers1670 Boyle gave the first description of the decompression phenomenon as “bubble in the eye of a snake in vacuum”1620 Cornelius Drebbel developed a one-atmosphere diving bell, basically the forerunner of all modern submarines1691 Edmund Halley improved bell technology by devising a method to replenish air supply in the diving bell1774 Freminet, a French scientist, reached a depth of 50 ft (2.5 ATA) and stayed there for 1 h using a helmet with compressed

air pumped through a pipe from the surface1830 Cochrane patented the concept and technique of using compressed air in tunnels and caissons to balance the pressure

of water in soil1841 Pol an Watelle of France observed that recompression relieved the symptoms of decompression sickness1869 Publication of Twenty Thousand Leagues under the Sea, a science fiction novel by Jules Verne; contains a description of

diving gears with air reserves1871 Paul Bert showed that bubbles in the tissues during decompression consist mainly of nitrogen1920 Use of gas mixtures for diving (heliox); diving depth extended to 200 m1935 Behnke showed that nitrogen is the cause of narcosis in humans subjected to compressed air above 4 ATA1943 Construction of aqua lung by Cousteau; diving at 200 bar possible1967 Founding of Undersea Medical Society, USA

4 Chapter 1

quickly learned about the best-known medical problem as-sociated with diving: decompression sickness. It was notuntil the middle of the nineteenth century that the effec-tiveness of countering decompression sickness with hyper-baric recompression was finally discovered (see Table 1.1).Although recompression in air was utilized first, hyper-baric oxygen (HBO) is now used, and this is the principalconnection between diving medicine and the other formsof HBO therapy.

The Development of HyperbaricAir Therapy

The first documented use of hyperbaric therapy actuallyprecedes the discovery of oxygen. The British physicianHenshaw seems to have used compressed air for medicalpurposes in 1662. The chamber he developed was an air-tight room called a “domicilium,” in which variable climat-ic and pressure conditions could be produced, with pres-sure provided by a large pair of bellows. According to Hen-shaw, “In times of good health this domicilium is proposedas a good expedient to help digestion, to promote insensi-ble respiration, to facilitate breathing and expectoration,and consequently, of excellent use for the prevention ofmost afflictions of the lungs.” There is, however, no accountof any application of Henshaw’s proposed treatment, andthere were no further developments in the field of hyper-baric therapy for nearly two centuries.

In the nineteenth century there was a rebirth of interestin hyperbaric therapy in France. In 1834 Junod built a hy-perbaric chamber to treat pulmonary afflictions usingpressures of two to four absolute atmospheres (ATA). In1837 Pravaz built the largest hyperbaric chamber of thattime and treated patients with a variety of ailments. Fon-taine developed the first mobile hyperbaric operating the-ater in 1877 (Figure 1.2), and by this time hyperbaric cham-bers were available in all major European cities. Interest-ingly, there was no general rationale for hyperbarictreatments, and prescriptions therefore varied from one

physician to another. (In those days no methods were avail-able to estimate the partial pressure of oxygen in blood,which at 2 ATA of air is about double that at sea level. Incomparison, if pure oxygen is breathed at 2 ATA, the partialpressure of oxygen in the arterial blood is twelve timeshigher than normal.)

Figure 1.2Fontaine’s mobile operating room of1877. Note the manual nature of thecompressor apparatus and the anesthe-sia gas container and mask in the cham-ber. (Photo courtesy of Dr. Baixe, Tou-lon, France.)

Figure 1.3Title page of the 2nd edition (1868) of the book by Bertin on thetreatment of diseases by compressed air.

The History of Hyperbaric Medicine 5

During the second half of the nineteenth century, hyper-baric centers were advertised as being comparable to healthspas. Junod referred to his treatment as “Le Bain d’air com-primé” (the compressed-air bath). In 1855 Bertin wrote abook on this topic (the title page is shown in Figure 1.3) andconstructed his own hyperbaric chamber (Figure 1.4). The

literature on hyperbaric medicine up to 1887 was reviewedby Arntzenius and contains a remarkable 300 references.

The first hyperbaric chamber on the North American con-tinent was constructed in 1860 in Oshawa, Ontario, Canada,just east of Toronto. The first such chamber in the UnitedStates was built by Corning a year later in New York to treatnervous disorders. The chamber that received the most pub-licity, however, and was the most actively used, was that ofCunningham in Kansas City in the 1920s (Sellers, 1965). Hefirst used his chamber to treat the victims of the Spanish in-fluenza epidemic that swept the USA during the closing daysof the First World War. Cunningham had observed that mor-tality from this disease was higher in areas of higher elevation,and he reasoned that a barometric factor was therefore in-volved. Cunningham claimed to have achieved remarkableimprovement in patients who were cyanotic and comatose.In 1923, the first recorded hyperbaric chamber fire occurredat Cunningham’s sanatorium. He had installed open gasburners under the tank to keep it warm in winter and some-one turned the flame the flame too high so that it scorchedthe interior insulation. The patients were evacuated safely.However, one night a mechanical failure resulted in a com-plete loss of compression and all his patients died. This trag-edy was a sobering lesson but ultimately did not deter DrCunningham. His enthusiasm for hyperbaric air continued,and he started to treat diseases such as syphilis, hypertension,diabetes mellitus, and cancer. His reasoning was based on theassumption that anaerobic infections play a role in the etiol-ogy of all such diseases. In 1928, in Cleveland, Cunninghamconstructed the largest chamber ever built – five stories highand 64 feet in diameter (Figure 1.5). Each floor had 12 bed-rooms with all the amenities of a good hotel. At that time itwas the only functioning hyperbaric chamber in the world.

As the publicity surrounding his treatments grew, DrCunningham was repeatedly requested by the Bureau ofInvestigations of the American Medical Association (AMA)to document his claims regarding the effectiveness of hy-perbaric therapy. Apart from a short article in 1927, how-ever, Cunningham made no efforts to describe or discusshis technique in the medical literature. He was eventually

Figure 1.4Hyperbaric chamber constructed by Bertin in 1874.

Table 1.2Landmarks in the History of Hyperbaric (Compressed) Air Therapy

1662 Henshaw used compressed air for the treatment of a variety of diseases1834 Junod of France constructed a hyperbaric chamber and used pressures of 2–4 ATA to treat pulmonary disease1837 Pravaz of France constructed the largest hyperbaric chamber of that time and used it to treat a variety of ailments1837–1877 Construction of pneumatic centers in various European cities, e.g., Berlin, Amsterdam, Brussels, London, Vienna, Milan1860 First hyperbaric chamber on the North American continent in Oshawa, Canada1870 Fontaine of France used the first mobile hyperbaric operating theater1891 Corning used the first hyperbaric chamber in the USA to treat nervous disorders1921 Cunningham (USA) used hyperbaric air to treat a variety of ailments1925 Cunningham tank was the only functional hyperbaric chamber in the world1928 Cunningham constructs the largest hyperbaric chamber in the world; American Medical Association condemns Cun-

ningham’s hyperbaric therapy1937 The Cunningham chamber is dismantled for scrap metal

6 Chapter 1

Figure 1.5Cunningham's giant steel ball hyper-baric chamber built in 1928 in Cleve-land, Ohio. It was six stories high andcontained 72 rooms. (Photo courtesy ofDr. K.P. Fasecke.)

Table 1.3Landmarks in the Development of Hyperbaric Oxygen (HBO) Therapy

1775 Discovery of oxygen by Priestley1789 Toxic effects of oxygen reported by Lavoisier and Seguin, who discouraged use of HBO1796 Beddoes and Watt wrote the first book on medical applications of oxygen1878 Bert (father of pressure physiology) placed oxygen toxicity on a scientific basis; recommended normobaric but not hyperbaric

oxygen for decompression sickness1895 Haldane showed that a mouse placed in a jar containing oxygen at 2 ATA failed to develop signs of carbon monoxide

intoxication.1937 Behnke and Shaw first used HBO for treatment of decompression sickness1938 Ozorio de Almeida and Costa (Brazil) used HBO for treatment of leprosy1942 End and Long (USA) used HBO for treating experimental carbon monoxide poisoning in animals.1954 Churchill-Davidson (UK) used HBO to enhance radiosensitivity of tumors1956 Boerema (The Netherlands) father of modern hyperbaric medicine, performed cardiac surgery in a hyperbaric chamber1960 Boerema showed life can be maintained in pigs in the absence of blood by using HBO1960 Sharp and Smith become the first to treat human carbon monoxide poisoning by HBO1961 Boerema and Brummelkamp used hyperbaric oxygen for treatment of gas gangrene; Smith et al. (UK) showed the protective

effect of HBO in cerebral ischemia1962 Illingworth (UK) showed the effectiveness of HBO in arterial occlusion in limbs1963 First International Congress on Hyperbaric Medicine in Amsterdam1965 Perrins (UK) showed the effectiveness of HBO in osteomyelitis1966 Saltzman et al (USA) showed the effectiveness of HBO in stroke patients1970 Boschetty and Cernoch (Czechoslovakia) used HBO for multiple sclerosis1971 Lamm (FRG) used HBO for treatment of sudden deafness1973 Thurston showed that HBO reduces mortality in myocardial infarction1970s Extensive expansion of hyperbaric facilities in Japan and the USSR1980s Development of hyperbaric medicine in China1983 Formation of the American College of Hyperbaric Medicine (founder/president, late Dr. Neubauer of Florida)1986 Undersea Medical Society (USA) adds the word hyperbaric to its name and is called UHMS. Reached a membership of 2000

in 60 countries1987 Jain (Switzerland) demonstrated the relief of spasticity in hemiplegia due to stroke under hyperbaric oxygenation; HBO integrated

with physical therapy1988 Formation of the International Society of Hyperbaric Medicine2001 The Undersea & Hyperbaric Medical Society established a clinical hyperbaric facility accreditation program in the USA.

The History of Hyperbaric Medicine 7

censured by the AMA in 1928, in a report that stated: “Un-der the circumstances, it is not to be wondered that theMedical Profession looks askance at the ‘tank treatment’and intimates that it seems tinctured much more stronglywith economics than with scientific medicine. It is the markof the scientist that he is ready to make available the evi-dence on which his claims are based.”

Dr Cunningham was given repeated opportunities topresent such evidence but never did so. A more detailedaccount of Cunningham’s story and the history of hyper-baric medicine is to be found in Trimble (1974). The Cun-ningham chamber was dismantled for scrap in 1937, whichbrought to a temporary end the era of hyperbaric air ther-apy for medical disorders.

The Development of HyperbaricOxygen Therapy

Oxygen was not “discovered” until 1775, when the Englishscientist Joseph Priestley isolated what he called “dephlogis-

ticated air.” A more detailed history of the applications ofoxygen since that time can be found in Jain (1989b). Al-though hyperbaric air had been used as early as 1662, oxygenwas not specifically added to early hyperbaric chambers.Thetoxic effects of concentrated oxygen reported by Lavoisierand Seguin in 1789 were reason enough for hesitation to useit under pressure. Beddoes and Watt, who wrote the firstbook on oxygen therapy in 1796, completely refrained frommentioning the use of oxygen under pressure. Paul Bert, thefather of pressure physiology, discovered the scientific basisof oxygen toxicity in 1878 and recommended normobaric,but not hyperbaric, oxygen for decompression sickness.

The potential benefits of using oxygen under pressurefor the treatment of decompression sickness were firstrealized by Dräger, who in 1917 devised a system for treat-ing diving accidents (Figure 1.6). For some unknownreason, however, Dräger’s system never went into produc-tion. It was not until 1937 – the very year that Cunning-ham’s “air chamber” hotel was demolished – that Behnkeand Shaw actually used hyperbaric oxygen for the treat-ment of decompression sickness. The age of HyperbaricOxygen (HBO) therapy had finally arrived.

Figure 1.6Sketch of the 1917 Dräger 2 ATA systemfor diving accidents, including oxygenbreathing system. (Photo courtesy ofDr. Baixe, Toulon, France.)

8 Chapter 1

Chapter 19HB O Therapy in Global Cerebral Ischemia/Anoxia and Coma

HBO Therapy in GlobalCerebral Ischemia/Anoxiaand Coma

Paul G. Harch and Richard A. Neubauer†

Hyperbaric oxygen therapy has been used in a number of conditions characterized by global ischemia(as opposed to focal ischemia of stroke), and anoxia, and leading to impairment of consciousness.Conditions such as coma due to brain injury and anoxia associated with drowning and hanging arediscussed under the following headings:

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Rational Basis of HBO Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237Review of Animal Experimental Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254Review of Human Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

19

Introduction

For a discussion of the effectiveness of hyperbaric oxygen(HBO) therapy in global cerebral ischemia/anoxia and co-ma, we define HBO as a medical treatment that uses highpressure oxygen as a drug by fully enclosing a person oranimal in a pressure vessel and then adjusting the dose ofthe drug to treat pathophysiologic processes of the diseases.Like all drugs, the dose of HBO is crucial and should becustomized to each patient’s response. It is dictated by thepathological target and is determined by the pressure ofoxygen, duration of exposure, frequency, total number oftreatments, and timing of the dose in the course of the dis-ease. As diseases and their pathologies evolve, different dos-es of HBO are required at different times. In addition, pa-tients have individual susceptibility to drugs, manifest side-effects and toxicity. Unfortunately, the ideal dose of HBOin acute or chronic global ischemia/anoxia and coma is un-known. The studies reviewed below suggest higher pres-sures (2 ATA or higher) and lesser numbers of treatmentsvery early in the disease process whereas lower pressures(2 ATA or lower) and a greater number of treatments havebeen used as the brain injury matures. While this generaltrend seems justified, the absolute or effective pressures de-livered to the patients in these reports may be slightly lessthan what is stated since many studies do not specify theHBO delivery system that was employed. For example, anoxygen pressurized chamber has an effective HBO pressureequal to the plateau pressure administered during the treat-ment, whereas an air pressurized chamber in which oxygenis administered by aviators mask can achieve a far lowereffective HBO pressure, depending on the fit of the maskand the amount of its air/oxygen leak. In the later cases, thedose of oxygen is less. This concept is particularly impor-tant when analyzing the studies in this chapter performedprior to the late 1980s when the aviator mask dominateddelivery systems in multiplace chambers.

In reviewing the data in this chapter, it is surprising thatHBO has not enjoyed widespread use for neurological dis-eases in the United States. This has been partly due to in-stitutional reservations and overt therapeutic nihilism forneurological injuries, both of which are presently waning.To assume that HBO could have efficacy and benefit whenliberally applied to various “accepted” indications, yet havenone in the great majority of neurological conditions isperplexing. After all, the brain is enclosed within the samebody in the same pressure vessel and is exposed to the sameelevated oxygen pressure. To justify this distinction, onewould have to postulate that an entire set of pathophysio-logical processes of brain that are insensitive to HBO anddistinct from those in the rest of the body’s organ systemswhich are sensitive to HBO and to which we routinely ap-ply HBO. This is illogical and unlikely. Such reasoning isindefensible when one considers the “accepted” neurolog-

ical indications include carbon monoxide poisoning, braindecompression sickness, cerebral air embolism, brain ab-scess, and cyanide poisoning. We conclude that HBOshould benefit other hypoxic/ischemic conditions of thebrain, provided the dose is correct, i.e., target specific.

Other reasons for nonrecognition of HBO in neurolog-ical conditions concern methodologies. The standard forproof in scientific medicine has been the randomized pro-spective controlled double-blinded clinical trial. Whilesome of the studies in this chapter meet this rigor (exceptfor double-blinding), many do not. Some are randomized,prospective, and controlled and thus exceed the quality ofstudies used to sanction reimbursement for some HBO in-dications. Other studies are uncontrolled series, case-con-trolled, or individual cases. All of this clinical data, in con-junction with the animal data, makes a strong case for atleast attempting HBO in what are otherwise untreatableconditions with debilitating, tragic, and expensive out-comes, especially when the visual medium is used to provesingle-case causality (Kiene & von Schön-Angerer 1998;Harch 1996). In addition, case-controlled series withchronic neurological maladies make powerful statementsof efficacy from the statistical (Glantz 1992) and logicalperspectives where the counterargument of placebo effectis minimized (Kienle & Kiene 1996). If these considerationsare kept in mind when analyzing this chapter, it appearsthat the bulk of data is solidly in favor of a beneficial effectof HBO in global ischemia/anoxia and coma.

Pathophysiology

The effect of global ischemia/hypoxia on the brain has beendiscussed in Chapter 5. Oxidation of glucose is the primaryenergy source for the brain. Deprivation of oxygen causesdeep psychological unresponsiveness in 8 s while glucoseand energy stores take a few minutes to exhaust (Plum &Pulsinelli 1992). Global deprivation of oxygen delivery canbe achieved by reduction in blood flow (ischemia), oxygen(hypoxia/anoxia), or both (hypoxic or anoxic ischemia).Unfortunately, clinical syndromes and animal models arerarely pure and often result from combinations or sequenc-es and varying degrees and durations of hypoxia/anoxiaand ischemia. Since the insult, oxygen deprivation, is sim-ilar whether by lowered blood flow or oxygen content thetwo are often considered as a single type of insult and thisconcept will be followed in this chapter.

Global ischemia/anoxia is a severe transient insult to thebrain that causes a stereotypic pathophysiology character-ized by reperfusion hyperemia followed by progressiveischemia which is often heterogeneous (Safar 1986; Dirnagl1993). The extent of injury is governed by a complex inter-play of patterns of systemic and local respiratory and cir-culatory function and selective vulnerability of cells (Mey-

236 Chapter 19

Authorsand year

Diagnosis No. ofpatients

Length of coma/neuro insult pre-hyperbaric oxygentherapy (HBOT)

Timing of HBOT HBOT protocol Results and conclusions

2nd Inter-nationalSympo-sium onHyperbaricOxygen-ation andthe BrainInjuredChild (au-thors: Neu-bauer,Harch,Chavdarov,Lobov, Zer-bini) 2001

Chronic brain injury:Great majority of pa-tients were cerebral pal-sy or global ischemia, an-oxia and coma.Variety of tests per-formed including physi-cal exam, laboratory test-ing and functional brainimaging with SPECT.

361 (?) Vast majority < 10years of age

1.5–2 ATA oxy-gen/60–90 min q.d. tob.i.d., × 1 to > 500 treat-ments (rare case)

Average 50% of patients withnoticeable improvements indifferent tests

Golden etal 2002

Chronic neurologicaldisorders: CP 30%, TBI26%, anoxic/ischemicencephalopathy 16%,CVA 12%, lyme disease6%, other 10%. MeasureSPECT pre, after at least15 HBOTs, and after acourse of at least 50HBOTs.

50 (25 un-der 18years oldand 25over 18years old)

Unknown Average 5–1/3years postinsult

HBOT1.25–2.5 ATA/60 min b.i.d.(12 × per week)

Improvement in SPECT fromfirst to last scan for both hemi-spheres and cortex with the3rd SPECT showing more im-provement than the 2ndSPECT, which was improvedover the 1st. Main increase inblood flow didn’t occur untilafter 2nd SPECT scan and asubstantial number of treat-ments (> 15). No change inblood flow to the pons andcerebellum.

Hardy et al(E) 2002

Cerebral palsy.Psychometric testing preand post treatment.

75 (?) 3–12 years of age.No average age giv-en.

Control 1.3 ATA air/60 minat depth q.d., 5 days perweek × 40.HBOT 1.75 ATA oxy-gen/60 min at depth q.d., 5days per week × 40.

Better self-control and signifi-cant improvements in audito-ry attention, and visual work-ing memory both groups. Nodifference between groups.Sham group significantly im-proved on 8 dimensions ofparent rating scale vs. 1dimension in HBO. Nochange in verbal span, visualattention, and processingspeed in either group.

Muira et al(E) 2002

Overdose with loss ofconsciousness and cya-nosis x unknownamount of time. Second-ary deterioration fifteendays later with akineticmutism. Measure EEG,MRI, MRS, and SPECT.

1 (?) 50 days HBO 2.0 ATA/90 min, 5days a week × 71

Progressive improvementthrough 33 Rxs. Deteriorationwith strange behavior by 47thRx. 52nd Rx disoriented, rest-less, and agitated with de-creased memory. Excitabilityby 71st Rx requiring Valium,Tegretol, and Haldol. Behaviorimproved post HBOT but dis-orientation and amnesia wors-ened. Nine months later pa-tient better than pre-HBO.MRI, MRS, and EEG trackedpatients course.

Waalkes etal (E) 2002

Cerebral anoxia: 8 withCP, 1 near-drowning.Measured GMFM, spas-ticity, WEEFIM, videoexams, parent question-naire, and time spent inany 24-hr. period bycaregivers.

9 (?) 6.4 years averageage

1.7 ATA oxygen/60 minq.d., five days a week × 80

58% average improvement inGMFM, minimal improve-ment WEEFIM, no changespasticity. Significant reduc-tion in time spent with care-giver in 24-h period. Patientsstill improving at end of study.

Table 19.2 continued

HBO Therapy in Global Cerebral Ischemia/Anoxia and Coma 253

Gunther (2004) experiment the results were interesting be-cause they suggested equal sensitivity of pathological tar-gets to both HBO and NBO very early after ischemia (5minutes), but only HBO had a positive effect after 30 min-utes of ischemia. In addition, only the HBO dosage had anyeffect on morphology regardless of early or later initiation.These results reinforce the points made in the introductionto this chapter about hyperbaric dosage differences withevolving pathology and the possible difference in efficacyof HBO depending on the route of delivery. The dose byaviator mask is lower than by oxygen hood or in a pureoxygen environment. Similarly, the dose of HBO in tissueslices is markedly different when 1 ATA and 3 ATA oxygenare used. Lastly, the study by Mink and Dutka (1995b) hadconflicting results with a simultaneous decrease in brainvascular permeability and blood flow while somatosensoryevoked potentials were unchanged. This implies concomi-tant beneficial and detrimental effects which are difficultto explain without more data.

The five Van Meter et al studies (1988, 1999, 2001a,2001b, and 2008) are unique in that they showed resusci-tation of animals using HBO, rather than delivering HBOafter resuscitation as in the Rosenthal article. These com-bined experiments were dose-response evaluations of HBOat 1.0, 2.0, 2.8, 4.0, and 6.0 ATA. The swine study provedthe ability of 4 ATA HBO to resuscitate animals after25 min of cardiac arrest, simultaneously truncating whiteblood cell-independent brain lipid peroxidation. This is thelongest successful arrest/resuscitation reported in the med-ical literature and has profound implications for applica-tion to human cardiac arrest (see Chapter 39, HBO inEmergency Medicine). In 12 of the 16 studies the benefit

of HBO was generated with one treatment, in 2 studies with3 treatments, and in the remaining two studies with 7 treat-ments. No consensus emerges for the ideal dose of HBOafter complete global ischemia, but the Van Meter dose-re-sponse study suggests that HBO at 4 to 6 ATA was effectivein resuscitating animals with cardiac arrest. More impor-tantly, in the sixteen studies, a beneficial effect on globalischemia, anoxia, and coma was demonstrated even whenthe ischemic insult was as long as one hour (two studies)and the delay to treatment as long as six hours after theischemic insult. When metabolic parameters only are con-sidered the delay to treatment can be as long as 24 h (Zhou2003).

The results are similarly impressive and uniformly positivein the group of incomplete global ischemia/anoxia experi-ments. As in the complete models no consensus emerges asto best HBO pressure, duration, frequency, or number oftreatments, but there maybe an intervention time limit of 6hfor improvement in behavioral/neurological outcomes.Shiokawa et al (1986) demonstrated an improvement in sur-vival with 2 ATA HBO for only 30 min, with best results atthree hours post-insult as opposed to one hour. Weinstein etal (1986) achieved an 84% reduction in mortality with a15 min 1.5 ATA treatment and Grigoryeva (1992) demon-strated a superior effect of 1.2 ATA/30 min over2 ATA/60 min on survival and preservation of neuronal tran-scription. Yaxi et al (1995) and Yiqun et al (1995) bothshowed improvements in brain enzymatic function from asingle HBO treatment at 2.5 ATA with the Yaxi article sug-gesting a minimum 20–40 min duration of HBO exposurefor efficacy. Kondo et al (1996), meanwhile, showed that re-petitive HBO at 2 ATA/60 preserves hippocampal neurons

Authorsand year

Diagnosis No. ofpatients

Length of coma/neuro insult pre-hyperbaric oxygentherapy (HBOT)

Timing of HBOT HBOT protocol Results and conclusions

Golden(2006)

Chronic brain injury(Children: CP 29%, TBI26%, HIE 17%, Stroke12%, Lyme 7%, other9%; adults: TBI 26%,stroke 26%, anoxia 21%,hypoxia 7%, other 20%.

21 chil-dren, 21adults,each com-pared to 42untreatedbrain in-jured andnormalchildren oradults. Pro-spective,non-ran-domized.

Not stated. Static level of func-tion for at least 1year, but many pa-tients were yearspost insult. Adultswere at least 2ypost insult.

Not stated, but HBOT pro-tocol well known at thisclinic: 1.15–(<)2.0 ATA/60qd-bid. Children: avg. 28Rx’s in 28 days. Adults: avg.35 Rx’s in 35d.

Children: significant improve-ment in measures of daily liv-ing, socialization, communica-tion, and motor skills.Adults: significant improve-ments on all neuropsychologi-cal measures, including atten-tion, motor, tactile, receptive& expressive language, wordfluency, and immediate anddelayed memory

Senechal(2007)

Cerebral palsy Review ofliterature

Not mentioned Years post insult All published HBOT stud-ies. Compared HBOT stud-ies using the Gross MotorFunctional Measures(GMFM) outcome to stand-ard therapies using theGMFM

Significantly greater rate ofGMFM improvement com-pared to all but one studywhich used dorsal rhizotomy.HBOT was the only therapythat also improved cognition.

Table 19.2 continued

254 Chapter 19

detail in the chapter on cerebral palsy. In short, improve-ments in gross motor functional measures were the high-est, fastest, and most durable in HBOT studies comparedto studies using the GMFM for other types of therapieswith the exception of two dorsal rhizotomy studies. Thesecond important addition is the Golden study (2006), acontrolled nonrandomized study of HBOT in a group ofchildren and adults with chronic stable brain injury. Bothgroups showed significant improvements in nearly allmeasures after 28–35 HBO treatments at low pressure.

In conclusion, additional experience with HBO in chronicglobal ischemia, anoxia and coma that was supported bySPECT, standardized motor, and psychometric testing hasaccumulated in the past five years, strongly suggesting a pos-itive trophic effect of HBO. These results are underpinned bythe addition of the sole animal study in the literature thatdemonstrated a highly correlated improvement in vasculardensity and cognition using an HBO protocol originally de-signed for humans and used in many of the human studiesabove (Harch 2007). This animal study strongly reinforcesthe human studies, especially in TBI, and argues for furtherapplication of HBO to other chronic forms of brain injury.

Case Studies

To illustrate the effect of HBO in both acute and chronicglobal cerebral ischemia/anoxia and coma several casestreated by these authors are presented below. In each casethe visual medium of SPECT brain blood flow imagingon a high resolution scanner (7 mm; Picker Prism 3000)registers in a global fashion the neurocognitive clinicalimprovement experienced by the patients and witnessedby the authors. The SPECT brain scans presented beloware CT technology with the patient’s left brain on thereader’s right and vice versa, with the 30 frame images reg-istering transverse slices from the top of the brain in theleft upper corner to the base of the brain in the lower rightcorner. Images are approximately 4 mm thick. Brainblood flow is color coded from white-yellow to yellow toorange to purple, blue and black from highest brain bloodflow to lowest. Normal human brain shows predominant-ly yellows and oranges, but, more importantly, has a fairlysmooth, homogeneous appearance. The companionimage (B) to the 30 slice transverse set of images is athree-dimensional surface reconstruction of the trans-verse images. Abnormalities in perfusion are registered asdefects and as coarseness of the brain’s surface.

Patient 1: HBO Treatment for Coma Due to TraumaticBrain Injury

A 19-year-old male was inadvertently ejected from a motorvehicle at 65 mph with impact on the left frontal/parietal

region of the skull. Within one-half hour Glascow comascale was 6–7 and the patient was ventilator dependent. CTof the brain revealed diffuse edema, midline shift, petechialhemorrhages, subarachnoid hemorrhage, small subduralhematoma, and basilar skull fracture. HBO was given 19 hpost injury at 1.75 ATA/90 bid. On the first treatment thepatient began to fight the ventilator. Initial SPECT brainimaging obtained five days post injury on a single-headlow-resolution scanner was “normal.” Repeat SPECTimaging on a triple-head high -resolution scanner occurred30 days post injury (Figure 19.1, A and B) and now clearlydemonstrated the significant injury to the left frontal areaas well as the contra coup injury to the right parietal/oc-cipital area characterized by luxury perfusion. Nine dayslater and two hours after a fifth additional HBO, SPECTwas repeated (Figure 19.2, A and B) and showed a dramatic“filling in” of the injured areas thus giving functional neu-rophysiological support to the clinical decision to continueHBO. The patient, meanwhile, progressed rapidly on twicedaily HBO for four weeks with often new neurological orcognitive findings occurring in the chamber and then con-tinued on HBO 4 times a day for seven weeks, at which timehe was conversant and independently ambulatory withslight spasticity. At 11 weeks the patient was transferred toa rehabilitation center and his HBO discontinued by thenew medical team. SPECT imaging at this time (Figure19.3, A, B, and C) registers the patient’s clinical progresswith a persistent increase in flow to the left frontal regionwhile some deterioration occurs to the area of previousluxury perfusion on the posterior right. The patient madetransient limited initial progress at the rehabilitation centerthen quickly leveled off cognitively while his spasticity andbalance worsened. Three months after discontinuance ofHBO the patient’s father requested further HBO and repeatSPECT brain scan (Figure 19.4, A and B), psychometric,and motor testing were obtained. SPECT now demon-strates a significant deterioration in the right frontal andposterior areas, while the left frontal normalization per-sists. The right posterior area has infarcted on simulta-neous MRI. To assess recoverable brain tissue the patientunderwent a single 1.75 ATA/90 min HBO followed bySPECT imaging (Figure 19.5, A and B); SPECT showed im-provement in the right frontal and parietal/occipital lesionsalong the ischemic penumbral margins. HBO was resumedfor an additional 80 treatments, once/day at 1.75 ATA/90 min. The patient made a noticeable improvement incognition (40 percentile gain in written computationalmathematics), insight (the patient now verbalized for thefirst time the understanding that he had sustained a braininjury and could no longer aspire to be a surgeon), andbalance (improvement in gait and progression from a 3-wheel tricycle to a 2-wheel bicycle). HBO (188 treatmentstotal) was discontinued when the patient desired enroll-ment in remedial courses at a community college. SPECTimaging at this time (Figure 19.6, A and B) shows improve-

HBO Therapy in Global Cerebral Ischemia/Anoxia and Coma 259

balance (improvement in gait and progression from a 3-wheel tricycle to a 2-wheel bicycle). HBO (188 treatmentstotal) was discontinued when the patient desired enroll-ment in remedial courses at a community college. SPECTimaging at this time (Figure 19.6, A and B) shows improve-ment in perfusion in the ischemic penumbral areas of theright-sided lesions. The left hemisphere remains intact. Insummary, HBO, when reinstituted following SPECT and

relapse after discontinuation of HBO, prevented furtherdeterioration and improved SPECT image as well as neu-rocognitive function in TBI, demonstrating the benefit ofHBO in the chronic stage of TBI

Patient 2: Near Drowning, Chronic Phase

The patient is a 4-year-old male who was found at the bot-tom of a swimming pool after an estimated 5 min of sub-

Figure 19.1AHMPAO SPECT brain imaging, trans-verse slices, one month post injury. Notesevere reduction in left frontal, parietal,and temporal brain blood flow with lux-ury perfusion in the right occipital pa-rietal region.

Figure 19.1BFrontal projection three-dimensionalsurface reconstruction of Figure 19.1A.Non cerebral uptake is shown in scalpand neck soft tissues.

260 Chapter 19

Conclusions

There are several causes of coma and global cerebral ische-mia/anoxia. HBO has been used in a variety of animalmodels and in over 2500 patients with these conditionsworldwide. Although HBO protocols have varied, the re-sults have been remarkably consistently positive with im-provement in a variety of physiological and biochemical

measures and outcomes, the most important of which wasimprovement in overall clinical condition and conscious-ness. This consistent success rate suggests a generic effectof HBO on common brain pathophysiological processes atdifferent stages in global ischemia/anoxia and coma. Im-portantly, this review excluded thousands of cases of acutecarbon monoxide (CO) coma in the medical literaturetreated with HBO because of the confusion over HBO ef-

Figure 19.5BRight lateral projection three dimen-sional surface reconstruction of Figure19.5A.

Figure 19.5AHMPAO SPECT brain imaging, trans-verse slices, 2 hours following singleHBO at 1.75 ATA/90min. Note im-provement in the right frontal and pos-terior defects.

HBO Therapy in Global Cerebral Ischemia/Anoxia and Coma 265

Tex

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This textbook, now appearing in its 5th, fully updated, and expanded edition, has become widely known as the

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Hyperbaric Medicine

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