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Hyperbaric Oxygen
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--r_i1_k·_n_an_a1_i1_1_11_1,_1_i1_in_c_h_a1_1_11_1a_ic_in_a_ _ Hyperbarlc Oxygen* A Therapy In Search of Diseases Genevieve Gabb;t and Eugene D. Robin, M.D.:j:
T
here appears to be a continual proliferation ofhyperbaric oxygen (HBO) units in the US. 1 The list of so-called indications for its use, past and present, is overwhelming. There is a wide spectrum ofanalyses cited to support the use of HBO in given diseases. These range from serious, thoughtful attempts to rationalize a given use; other analyses border on medical charlatanism. 1 There is a striking dearth of data derived from acceptable clinical trials to support these rationalizations. It is not practical to review the massive literature completely. Herein we provide a historic perspective concerning various indications for HBO use during the past several decades; evaluate the evidence supporting its current use in various disorders; analyze one major driving force for the proliferation of uses and indications, money; review the nature of patient risks associated with the use of HBO; and make some suggestions for dealing with the issues raised by HBO. The overall conclusion is that the world of HBO is a microcosm reflecting many of the problems which plague the macrocosm of medicine. PAST AND PRESENT INDICATIONS
Tu.hie I lists 132 past or present indications for the use of HBO. We provide the list in its entirety§ because we have not been able to find a similar attempt in the recent literature. The list includes indications that are not exclusively American. For example, HBO is used extensively in Eastern Europe. No analysis of most non-American indications was attempted. In assembling the list, several obvious conclusions emerged. The broad range of conditions speaks for itself. HBO has been and continues to be regarded as a form of near-universal treatment. Some indications arose as a result of assumed pathophysiologic considerations, some indications were generated for pragmatic reasons, and for some indications, it was (is) not possible to trace the reasons for the use of HBO.
*From Stanfurd University Medical Center, Stanfurd, Califumia. tMedical student. tProfessor of Medicine and Physiology. §We do not guarantee that the list is complete. We thought that assembling this list might be helpful to future medical historians. Reprint requests: Dr. Robin, Anatomy Bldg, Room 169, Stanford Unlverdty School of Medlclne, Stanford 94305-5070
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Table 1-Varioua Indicationa Uaedfor HBO 7reatment during the ftJet Few Decada Radiation necrosis Decompression sickness Gas embolism Soft tissue infection, due to mixed aerobic and anaerobic organisms Soft tissue necrosis Bacteroides infection Compromised skin grafts or Raps Fungal infections Mucormycosis Anemia from exceptional blood loss Carbon tetrachloride poisoning Fractures Lepromatous leprosy Meningitis Radiation myelitis, cystitis, enteritis Retinal artery insufficiency Chronic brain ischemia Senility Multi-infarct dementia Infant cardiac surgery Chronic ulcers Peripheral vascular disease Diabetic neuropathy Acute endocarditis Hearing loss due to acoustic trauma Cortical blindness Cellulitis Infected pacemaker Hurlers syndrome Postcardiac arrest Scleroderma Mycobacterium tuberculosis Abscess, intraabdominal or intracranial
Asthma Pneumomediastinum Hanging Thrombophlebitis
Hyperbarlc 0 2 : A~
Lyell's syndrome*
co poisoning
Gas gangrene Osteomyelitis (refractory) Crohns disease Cyanide poisoning Crush injury with traumatic ischemia Alzheimers disease Brain edema Thermal bums Head and spinal injury Bone grafts Frostbite Cerebrovascular accidents Hydrogen sulfide poisoning Cancer therapy Pse11domembranous colitis Sickle cell crisis Multiple sclerosis Pyoderma gangrenosum Acute myocardial infarction Carotid aneurysm Aortic aneurysm Anaerobic infections Postcardiac surgery Pulmonary insufficiency Arteriosclerosis Causalgia Collagen vascular diseases Postoperative confusion 'Ihwmatic amputation Pulmonary emboli Drowning Moyamoyat Surgical empyema Pharyngeal fistula Brain cyst Stenotic valvular heart disease Tetanus Intestinal obstruction Continued In Seard! ol Dile.- (Gabb, Robin}
Table 1, continued Necrotizing f8sciitis Postepileptic headaches Radiation pneumonia Balloon aspiration Migraine Allergic reaction Quadriplegia Dust-induced bronchitis Gastroduodenal ulcer Facial neuritis Late pregnancy toxemia Liver failure Closed chest trauma Emphysema Paralytic ileus Bendu-Osler Weber disease Perirectal fistula Necrobiosis lipoidic diabeticorum Black lung disease Allergies Myositis Colitis Cerebral vasospasm Malignant otitis extema Acute hearing loss Pneumatosis cystoides intestinales Maxillofacial phlegmon Cochlear vestibular syndrome
Viral encephalitis Bites Buergers disease Vascular headache Precardiac surgery 'Ihlcheal fistula Vertigo Rheumatoid arthritis Preservation of youthfulness Viral hepatitis Habitual abortion Sodium nitrite poisoning Diabetes mellitus Fouriers gangrene* Acute pancreatitis Organophosphate poisoning Perianal hidradenitis supprativa Organ preservation Muscular dystrophy Poor circulation Cirrhosis of the liver Epilepsy Pulmonary hypertension Lung lavage Revasculari7.ation Chronic coronary artery disease Periodontosis
*Lyells syndrome: toxic epidermal neeiWysis round in lymphoproliferative disease tMoyamoya: sudden cerebral vascular insufficiency with a specific arteriographic pattern :t:Fouriers gangrene: idiopathic gangrene of the scrotum
Applications of HBO, not uncommonly, arise as a result of medical adventurism, therapy in search of diseases. A unit is available at a given facility. A patient enters with a given disease for which treatment is unsatisfactory. Why not try HBO? There is also a dynamic flux involving its use for specific indications. Most of these seem to go through a typical evolution in which there is an initial increase in use characterized by great enthusiasm and widespread use followed by, perhaps, a realization that HBO is not effective, followed by a gradual decline in use. For example, in the 1960s, HBO was touted as an effective antidote for senility which encompassed a spectrum of patients ranging from those with senile dementia to benign senile forgetfulness, and HBO was used in large numbers of older patients. 3•4 This treatment, over the course of several decades, gradually fell into disrepute as a cure for aging although, even in the early 1980s, some patients continued to be treated for senility. 1 There has been no mechanism for memory, ie, to record previous errors so that current HBOers can learn from the mistakes of the past. In fact, a discredited or abandoned use of HBO is seldom, if ever, provide
With rare exceptions, the potential risks of HBO have been (are) ignored or underplayed. With rare exceptions, physicians using the equipment have had little or no personal experience in conducting appropriate clinical trials nor have they demonstrated substantial interest in testing the safety and efficacy of HBO. Increasingly, there have been formal expressions of the desirability of controlled prospective randomized clinical trials. These expressions almost assume the form of a catechism (see below); the clinical trials are not conducted. The activities of HBOers have ranged from serious attempts to rationalize HBO use, by groups such as the Undersea Medical Society, to impulsive and poorly conceived thrusts. Risk-benefit analysis has been strikingly absent. In brie( the history of the use of HBO is not qualitatively different than the history of many therapeutic attempts in medicine. 7•8 The overall point is that, with only rare exception, the history of the use of HBO has been characterized by unscientific, uncritical pragmatism. Baromedicine has also been characterized by a spirit of medical adventures, a willingness to try this therapy in a wide variety of disorders with minimal careful analysis; HBO often is a form of treatment in search of diseases. Tuble 2 lists various disease states for which HBO is currently recommended (with various degrees of enthusiasm by baromedical experts). In general, these conditions are third party reimbursable which plays some role in the degree of enthusiasm. As indicated in the table, for only one disorder, decompression sickness, is there an overwhelming clinical experience and acceptable clinical trials which demonstrate efficacy. For only a few of these conditions is the incidence in the general population of sufficient magnitude to represent an overwhelming health problem. For many of the entities there are effective alternative forms of treatment. In addition to lack of studies indicating benefits, for most of the entities the risks have not been carefully quantitated. The data do not suggest that most present uses of HBO therapy are more clearly established now than in the past several decades. .
Decompression Sickness The use of hyperbaric chambers during ascent from deep diving represents the most clearly and perhaps only validated use of hyperbaric therapy. Proof of efficacy has been established as a result of extensive pragmatic studies by the US Navy as well as other organizations. 8 A series of tables has been developed for the estimation of safe periods of gradual decompression. There is not only an extensive clinical experience, but the clinical experience embodies some elements of alternating single-patient clinical trials. 10.u Symptoms indicating too rapid decompression are rapidly alleviated by recompression at a higher pressure. It should be emphasized that no similar clinical experience or trial supports the use of HBO for the treatment of most forms of intravascular aeroembolism, as that arising during cardiac surgery or during scuba diving. HBO is used to decrease intravascular bubble size and to increase the driving pressure for oxygen into tissue and cells. There are many factors which determine outcome in these patients, such as the time between embolism and the time of treatment. Thus, claiDJS that aggressive HBO treatment is effective from CHEST I 92 I 6 I DECEMBER, 1987
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Table 1-Cummt "Strong" lnJicalioru for the Use
0 (no)
Extensive Favorable Clinical
Experience
± 0 0 0 0 0 0 0
0 0
0 0
Alternative Forms of 'Iieatment Available
very low very low moderate if smoke inhalation included low moderate moderate very low moderate high high high
0 ±
+ + + + + + + + + ±
low
+ 0
high
± (possibly)
minutes to hours after gas embolism would require an acceptable clinical trial for evaluation. No such data are available.
Carbon Monoxide Poisoning This entity is currently cited as the indication par e.rcel-
lence for the use of HBO treatment. It has been established
that HBO reduces blood concentrations of carboxyhemoglobin more rapidly than is effected by breathing 100 percent oxygen at ambient pressure (carboxyhemoglobin half-life at room air: 5 hours and 20 minutes; carboxyhemoglobin halflife at 100 percent oxygen breathing: 90 minutes; and carboxyhemoglobin half-life under HBO: 23 minutes). s It is by no means established that this decrease in half-life results iii improved outcome. It is not at all certain that HBO improves oxygen delivery to the brain and myocardium, which depends not only on the Pa01 but also on the rate of organ blood flow. Nor is there evidence indicating that HBO reduces cerebral edema by brain vasoconstriction. Even if the latter two mechanisms operate, whether these are translated into a better outcome for patients would require independent documentation. None has been provided. The lack of acceptable evidence of efficacy of HBO in CO poisoning has been noted elsewhere. 11 One interesting claim, unsupported by 6rm evidence, is that HBO therapy may improve brain function hours to days after the acute event when blood concentrations of CO are minu~e. The worlds record is the report of a patient who responded to HBO therapy nearly two months after carbon monoxide intoxication. 13 Needless to say, no firm evidence is available to support this claim. Perhaps the claim is accurate and HBO reverses some mysterious biochemical alteration related to CO poisoning, but in the absence of firm evidence, this claim cannot be accurately evaluated. The indications for treatment have been broadened to include suspected CO poisoning even in the absence of detectable CO-Hb levels," and subacute sequelae of established CO poisoning. 15 The most mysterious fact about the use of HBO in CO poisoning is the failure to carry out animal trials in primates. The
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+ 0 0
+ 0 0 0 0 0 0 0 0 0 0
Incidence in General Hospital Population
organimtion of such trials would be relatively simple. Carbon monoxide can be administered with great accuracy; quantitation of carboxyhemoglobin levels is simple; outcome as a function of no treatment, treatment with 100 percent oxygen and with HBO could easily be compared. It would be possible to determine whether late application of HBO reverses brain injury even when significant blood levels of CO are no longer present Finally, the quantitative risks associated with HBO could be determined. The total funds required to carry out these studies would be substantially less than maintaining numerous HBO units in various communities.
Gas Gangrene and Other Anaerobic Infections The modem revival of the use of HBO stemmed &om a report by Brummelkamp and colleagues» in the 1960s. They treated 26 patients with clostridial infection and reported that 25126 patients were cured and 21/26 patients survived. Needless to say, the study was uncontrolled. Even the simple expedient ofcomparing the outcome ofpatients receiving 100 percent oxygen with those on HBO was not considered; nor has it been since. Controlled studies or not, the use of HBO was widely applied to patients with clostridial disease. There may be a subgroup of patients with clostridial infection who may have improved outcome on HBO used as an adjuvant to surgery and antibiotics. This favorable response is by no means universal. 11•11 How these patients would respond on 100 percent oxygen at ambient pressures is not known. One could hardly use this small group of patients to justify the organization of HBO units in the community. In fact, before general clinical application to the treatment of gangrene, a controlled trial of HBO in treating clostridial infection would be desirable. The clinical experience with non-clostridial anaerobic infections or mixed infections does not suggest that the use of HBO has a favorable risk-benefit balance. 11 Oateomyelitis The first report of the use of HBO to treat osteomyelitis (OM) was in 1965. 19 Five cases ofchronic OM were described Hyperbarlc ~:A
Therapy In Semdl of Dile.- (Babb, Robin)
and all were noted to have "responded to treatment with HBO at 2 ATA given fur various periods." The report was remarkable as in only one of the five cases were antibiotics used as part of the treatment. Since then, numerous studies evaluating the use of HBO to treat chronic OM in animals and humans have been reported. Two separate animal experiments have compared the effect of treatment with HBO versus nontreatment on established OM in rats and rabbits, respectively. 111•11 Both experiments demonstrated that those animals treated with HBO had a significant increase in the healing of OM compared with those animals given no treatment. More specifically, 'Iliplett et al11 round a significant improvement in the healing of sinuses, reduced fracture mobility and improved histologic appearance in their group of HBO-treated rabbits. However, these experiments did not include an antibiotic treatment group, or antibiotic and HBO treatment group. In 1978, Mader et al11 compared the effect of fuur treatment programs on established OM in the long bone of a rabbit. Their treatment groups were: no treatment, HBO alone, antibiotic alone, and HBO and antibiotic in combination. They found significant dift"erences in outcome between the control animals and all treatment groups; however, there was no difference between any one of the three treatment groups. They concluded that HBO did not appear to be synergistic or additive with cephalothin (the antibiotic used) in the treatment of OM.
Several large series of patients with refractory OM, treated with HBO in combination with surgery and antibiotics, have been reported. a.u.-.111.rr These uncontrolled trials show success rates of 63 percent to &5 percent. However, important criticisms should be made of these trials. In one study the duration of previous infection ranged from one week to 20 years. 11 OM ofone weeks duration can hardly be described as chronic. rr The studies are, without exception, lacking in control groups, the intention being that each patient should act as his/her own "historic control." It is impossible to know if the surgical and medical aspects of the combined HBO treatment program are identical to those employed befure HBO was commenced. One study stated, " ... the absence of medical records prevented precise documentation of the adequacy of previous treatment." That being so, the ability of a patient to stand as his or her own historic control is in doubt. Moreover, the use ofhistoric controls are notoriously unreliable. In conclusion, the current evidence fur the efficacy of HBO as an adjuvant in the treatment of refractory OM is drawn from animal studies where HBO-treated groups ofanimals are compared with those given no treatment, and uncontrolled human case studies. As such, it would seem that the claim that HBO is "rational, scientific and proven therapy fur chronic refractory OM" is, at best, premature and probably unfuunded. •
Selected Mycotic Infections The use of HBO in any mycotic infection has never been adequately documented. In fact, with the availability of current antifungal agents, the use of HBO must be considered particularly unscientific. ·
Cyanide Poisoning This is a rare furm of poisoning, and the death rate is estimated at between 80 to 400 cases per 10 million population.• Presumably, HBO could compete with CN· binding to cytochrome 88a·30 Animal studies do not indicate efficacy. 31 The case reports from human cases are equally unimpressive. •:1.1 There is an excellent non-toxic therapeutic agent, hydroxycobalamine, :w and it is diflicult to escape the conclusion that the use of HBO as a furm of therapy in the case of CN· poisoning stems from the Sir Edmund Hillary dictum (who climbed Mt. Everest because "the mountain was there"): "the HBO chamber is there."
Brain Edema with and without Head '.lrauma Rationales fur the use of HBO include reductions in intracranial pressure because of cerebral vasoconstriction and enhanced brain oxygen supply. The lack of good experimental evidence ofbenefit and the problems ofoxygen toxicity have made the use of this method almost, but not entirely, obsolete. 311 A prospective, randomized trial of 30 patients eliminated from consideration the least sick patients and the most sick patients. This left eight controls and seven HBO-treated patients to be analyzed. There was no significant dift"erence in survival in the two groups. These results would seem to be unpromising and at variance with the conclusions drawn by the investigators: Based on the experience in the literature cited previously and on our own Initial aperlence, we hope in the future to convincingly demonstrate that the treatment ofsevere bnin-injured patients with HBO will result in an overall bene&cial response in tenns of longterm functional recovery and decreased mortality rates. 311
Thermal Burns Only one hyperbaric chamber consistently uses HBO fur burns, and has treated over a thousand patients. The rational fur its use is based on enhancement of leukocyte bacteriocidal activity and enhancement ofwound healing. There have been no controlled clinical trials and one is left to wonder how patient or family permission was obtained to treat these patients.
Anemia from Exceptional Blood Lou This treatment is suggested fur the most part when blood transfusions are not acceptable fur religious reasons. The theory is that enough oxygen can be physically dissolved in the plasma to supply metabolic needs. Obviously, the efficacy has not been put to any type of critical scrutiny.
Enhancement of Wound Healing The rationale is that HBO increases the bacteriocidal activity of leukocytes and improves oxygen supply to poorly vascularized tissue. Increasing tissue Po1 may enhance collagen synthesis by fibroblasts. No acceptable clinical trials are available.
Radiation Necrosis This area of disease may become the gas gangrene of the 1980s. Progressive proliferative endoarteritis may result from
high doses of ionizing radiation. The primary tissues involved include bone (osteoradionecrosis) and soft tissues. Dating back to 1973, clinical observations suggested that HBO treatCHEST I 92 I 8 I DECEMBER, 1887
1077
ment was valuable iOr partially ischemic, hypoxic bone and soft tissue lesions. 37 The putative mechanisms iOr improvement included the ability of HBO to stimulate fibroblastic proliferation and enhance collagen synthesis and capillary angiogenesis. 38 The major iOrm iOr treatment bas been osteoradionecrosis involving the head. One randomi7.ed prospective clinical trial has been reported. The issue was whether HBO could prevent the development of osteoradionecrosis of the mandible after tooth removal in a high-risk patient population. In the group of patients receiving HBO, there were signi&cantly fewer tooth socket wounds that tailed to heal as compared to a group ofpatients receiving penicillin without HBO. 38 No controls using 100 percent oxygen at ambient pressures were studied. The clinical trial studied a highly speciali7.ed and circumscribed problem: the rate ofresolution of tooth socket healing after radiation. The number of such patients in the general population must be very small. For example, in one major center over a 15-year period, a total of 101 patients were treated. 40 The extrapolation of these favorable results to the general problem of radiation necrosis is neither medically nor scientifically justified. In fact, therapeutic and prophylactic attempts to deal with radiation necrosis in other areas, in an uncontrolled study fraught with polypharmacy, did not provide striking evidence of efficacy. The sites which were treated included the chest wall, the pelvis and lumbar area, the spinal cord, the brain, and the larynx. 41 'Ibis scanty data base is now being extrapolated to consider the use of prophylactic HBO in all or most patients receiving high doses of therapeutic radiation. The patient population iOr such treatment would be very large. What proportion of these patients would develop clinically signi&cant radiation necrosis is unknown. Whether HBO would be effective prophylactically is also not established. Tu implement such a proposal without a prior controlled, prospective randomi7.ed clinical trial would be to repeat the errors of the past. It is useful to describe two examples of more or less discredited indications iOr the use of HBO. Senility
The possibility of improving cognitive function in the senile by HBO bas been a pragmatic indication iOr widespread use of HBO iOr a number of years. 'Ibis approach was provided a scientific rationale and some experimental support by studies reported in the late 1960s. 4 The scientific rationale was that HBO increases oxygen supply to a brain with a deficient cerebral circulation. The experimental studies consisted of comparing several tests of cognitive function in 13 aged subjects with chronic brain syndrome subjected to hyperbaric 100 percent oxygen with five similar subjects subjected to 2.5 atmospheres of 10 percent oxygen. Thirty treatments of90 minutes each were provided iOr 30 days and three tests of cognitive function were applied beiOre and 24 hours after the last treatment administered by an examiner who was blinded as to which breathing mixture bad been used in which subject. It was reported that there was a remarkable and signi&cant improvement in the test scores of treated patients compared to those who breathed an ambient-ail'-like gas mixture.
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Several aspects of these studies warrant comment. The majority of the patients almost certainly did not have cerebral arteriosclerosis as the basis of their chronic brain state. An accurate diagnosis of the majority of patients was almost certainly Alzheimer's disease, a fact which was not appreciated in 1969." Thus, assuming that the treatment worked, it was not because cerebral vascular insufficiency was being temporarily alleviated twice a day iOr 180 minutes. Thus, at most, the treatment "worked" iOr the wrong reasons. The putative benefit of the treatments continued iOr 24 hours after the HBO treatment bad ceased. 'Ibis would require that the cause ofany benefitwas a mechanism unknown then and currently unknown. The sensitivity and speci&city and depth of resolution of the three psychologic tests administered to test the ~ tiveness of HBO treatment are essentially unknown. It is probable that the tests were inadequate to test cognition accurately and quantitatively. Rather than stimulating an adequate clinical trial embracing an adequate number of patients with accurately diagnosed cognitive disorders, the results stimulated mass use of HBO treatment in the senile (aged). Masses ofsenior citi7.ens were lined up to have their senility treated. The complications resulting from HBO in this group of patients are essentially undescribed. By 1983 the practice bad largely faded from use as a iOrm of treatment of senility in the US, although iOur patients with Alzheimer$ disease were treated in 1985. 1 No results are available. It is probable that the gradual abandonment of HBO treatment iOr senility was related to lack of effectiveness. It is, of course, barely possible that some subgroup of patients was benefitted by the treatment to account iOr the results of the early clinical trial. H so, then a potentially beneficial iOrm of treatment bas been abandoned because of inadequate scientific validation. . The point is that the existing lack of scientific rigor not only leads to the use ofineffective treatment, but could also lead to premature abandonment of effective iOrms of treatment. Thus, the use of HBO in the treatment of Alzheimer$ disease remains an unsettled issue. While it is our opinion that an adequate clinical trial will fiUl to show benefit, the use of HBO remains a iOrmal scientifically and medically unsettled issue. Multiple Scleroris (MS)
The suggestion that HBO might be useful in the treatment of MS originally rose in 1970 in Czechoslovakia.• Animal studies were reported which suggested that HBO ameliorated experimental allergic encephalomyelitis in guinea
pigs." 'Ibis was iOllowed by a series of uncontrolled clinical trials suggesting partial to complete remission in human subjects with MS treated with HB0. 44 The major impetus to its widespread use stemmed from the results of a small "controlled" trial reporting benefit and published in a prestigious medical journal. 'Ibis study noted objective improvement in 12of17 patients treated with HBO and in one of 20 patients treated with placebo (p<0.001). Improvement was transient in seven of the patients treated with oxygen and long lasting in &ve patients. The authors themselves recognjzed the inadequacy
"°
of this study; however, the peer reviewers did not. 45 This report was greeted with enthusiasm and, fullowing publication, numerous patients with MS in the US and UK were placed on HBO therapy. In 1983, over 1,300 patients with MS were treated, and in 1984, over 1,100 patients were treated in the US alone. 1 The initial clinical trial stimulated a series of randomized, prospective, controlled clinical trials. At least nine have been published between 1985 and 1986. None has shown efficacy. - Simply stated, there is overwhelming scientific evidence that HBO does not work. But that is not the end of the story. There has been a spate of letters to the editors of various medical journals by protagonists. An organization called the Association fur Research into MS (not to be confused with the Multiple Sclerosis Society) was (is) soliciting money in order to establish hyperbaric chambers. The truly convinced remain convinced, and it will be some time befure HBO use in MS suffers the same fate as oil of evening primrose and snake venom in the treatment of MS. At least in the US, enthusiasm fur this furm of treatment appears to be abating.
How
MANY PATIENTS
ARE TREATED
WITH
HBO?
The magnitude of usage from 1977 to 1985 may be judged from the fullowing figures. A total of 36,937 patients were reported being treated. 1 Of these, 17,885 (49 percent) were treated fur indications fur which there is substantial current enthusiasm and 18,912 (51 percent) were treated fur indications of various degrees of dubiousness. RISKS OF
HBO
With few exceptions, the potential risks of HBO treatment have not received substantial emphasis. In qualitative terms, a number of risks have been described and these are summarized in Table 3. Briefly stated, these risks arise from high barometric pressures during the process of compression; from responses to high oxygen tensions such as brain and lung injury; from gas embolism arising during the process of decompression; from chamber accidents arising from fire (several deaths, including a patient and attendants during a fire in Germany); and from several furms of toxicity, the mechanisms of which are unknown, including myopia and increases in refractive error lasting fur weeks to months, anxiety, nausea and vomiting. Contraindications to the use of HBO are said to include pneumothorax, severe obstructive pulmonary disease, pulmonary blebs and bullae, optic neuritis, acute viral infections and inability to equali7.e middle ear pressures. 114 The precise quantitative extent of the risks associated with HBO will require appropriate clinical trials. Some estimate can be derived from the literature. In an early series of 445 patients, minor complications related to barotrauma occurred in about 30 percent of the patients, convulsions occurred in 2 percent, and psychologic symptoms occurred in about 20 percent. 1111 In a series of 88 patients, there were eight grand mal seizures and in one patient the convulsions persisted and the patient died. ia In another series of87 patients, barotrauma occurred in 28 percent of the patients; anxiety was noted in 43 percent. Dyspnea and chest pain occurred in 18 percent of the pa-
tients, neurologic symptoms occurred in 10 percent, and 5 percent had grand mal fits. 17 In a series of 109 patients treated over a 15-year period, major complications included 2 percent with convulsions; one of these patients suffered a stroke and one an acute myocardial infarction. Minor complications resulting from barotrauma occurred in about 2 percent of the patients. 40 Tu the extent that these data are representative, severe CNS manifestations occur in 1 to 2 percent of treated patients, symptomatic barotrauma in perhaps 15-20 percent of patients, and optic symptoms in perhaps 20 percent of patients. Death attributed to HBO (aside from deaths resulting from fire) is very rare. In summary, then, HBO is not as safe or benign as might be inferred from past and present descriptions of the procedure. ECONOMICS
As A DRIVING PRESSURE
Evidence is abundant that increased use of HBO is closely coupled to a desire fur increased profits. This is not a new development When HBO was thought to be a useful furm of treatment fur multiple sclerosis, the number of private (fur profit) HBO units in the UK increased. As aptly stated by Bates,
There is, of coune, the inevitable fact that the provision of these chambers represents a significant investment in personal eJIOrt, time and money which it will be so hard to accept has been fruitless.•
Current classifications ofthe validity ofthe use of HBO fur various conditions suggest that so-called category 1 diseases are covered by third-party carriers-other categories are not sr The importance of clinical trials is asserted to be based on obtaining evidence which will increase insurance payments fur HBO: Third party insurers who pay fur major medical treatment today have
Table 3-Knmon .Riab tfHBO Therapg Barotrauma from increased barometric pressure (Compression manifestation) ears
sinuses middle ear hemorrhage deafness Oxygen toxicity
brain
convulsions and sequelae other CNS manifestation lung pulmonary edema, hemorrhage, respiratory fi.ilure pulmonary oxygen toxicity Decompression sickness pneumothoru nitrogen emboli-CNS, joints, etc. Fire huard patients medical attendants
Mechanism unknown myopia
fatigue headaches vomiting claustrophobia
CHEST I 92 I 8 I DECEMBER, 1987
1079
to be convinced of scientific validity and we don't always have documented proof[ofHBO efficacy]. We need well-controlled animal work and prospective clinical studies to document who and fur what disorders this therapy should be used. 58
Just how much money has been expended by patients on HBO? Assuming that an average course of treatment is two months and that the treatment cost is $1,0
The medical literature involving HBO contains more than 12 references during the past 15 years commenting on the desirability of adequate and appropriate clinical trials of one disease or another. Despite these sentiments, little has been done. There are a number of problems. One is the sheer magnitude of the various disorders fur which HBO is used. A second problem is that, by dint of training, experts in HBO are not trained or experienced in the organization and implementation of appropriate clinical trials. A third problem is that clinical trials, to paraphrase the immortal words of Willie Sutton, is "not where the money is." A need for appropriate clinical trials can be derived by analyzing the system of classification suggested by the Hyperbaric Medicine Society fur summarizing the status of various indictions fur HBO. 81 Category 1: conditions fur which HBO treatment is known to be effective (and is third-party reimbursable). 1080
Given the lack of acceptable data showing efficacy fur most of these conditions, the word "known" is a substantial oveJ'o statement. At best, most conditions in this category represent a consensus opinion by workers using HBO based on pragmatic and uncritical considerations. Category 2: conditions fur which HBO treatment is unproved clinically or experimentally and is not reimbursable. This category raises even more sharp issues than category 1. If the treatment is experimental, is infurmed consent obtained from the patient or his surrogate to permit the use of the patient in an experiment? (Parenthetically, not to obtain infurmed consent in most legal jurisdictions represents a furm of malpractice.) Are patients required to pay fur experiments perfurmed on them? If so, what is the justification? Are such studies on patients really scientific experiments? What are the hypotheses which are tested? What controls are used? What quality control measures are used to ensure high standards and unifurmity of data collection? What mechanisms are used fur critical evaluation of the data and interpretation of the data? Or is HBO treatment usually a pragmatic, uncritical, unstructured effort? WHAT MIGHT BE DONE
A starting point might be to select one or two conditions fur appropriate clinical trials; fur example, the treatment of CO poisoning and the prophylaxis of radiation necrosis might be suitable areas. While these trials are being conducted, a voluntary or mandated moratorium on the random use of HBO could be suggested or enfurced. A national conference on the application of risk-benefit analysis to HBO, sponsored by the Hyperbaric Medical Committee of the Undersea Medical Society, might be useful. Physicians referring patients fur HBO therapy should be aware of the major uncertainties. SUMMARY
The application of HBO to the therapy of various human diseases developed over a 300 year period. Like most of medicine, the basis of these applications was and continues to be pragmatic in nature, and involves uncritical and untested judgments. The possibility of risks bas been undeJ'o stated and possible benefits have been overstated. Individual physicians offering HBO and organized groups, such as the Undersea Medical Society, advocating its use may well be highly motivated, well meaning, and sincerely convinced that HBO is an important therapeutic approach. It may be that, buried among the host of indications, will be some disorders fur which HBO is uniquely and highly effective. Ifso, the present nonsystem fur evaluating responses to HBO will require modification, so that these potentially valuable additions to therapeutics are not lost. Because of its almost global application to a wide variety of diseases, HBO therapy lends itself easily to medical adventurism (therapy in search of a disease) and economic exploitation. If there is some patient benefit to come from the experience of the last 300 years, changes in approach, initiated by· baromedical devotees or by medicine generally, or resulting from pressures outside of medicine, will be required. Hyperbarlc Oa: A~
In Sellrd1 al Dile-. (Gabb, Robin)
REFERENCES
1 National Hyperbaric Registry, Maryland Institute fur Emel'gency Medical Services, April, 1986 2 Lamy ML, Banquet MM. Application opportunity fur OHP in a general hospital: A two year experience with a monoplace oxygen chamber in hyperbaric medicine. Proceedings of the Fourth International Congress. Wada J, Iwa 1; eds, Baltimore: Williams and Willdns 1970 3 Levine ER. Discussion. Ibid, 451 4 Jacobs EA, Winter P, Alvis HJ, Small SM. Hyperoxygenation effect in cognitive functioning in the aged. Ibid, 449-52 5 Feldmeier JJ, Workman WT. The USAF hyperbaric chamber: A look through the porthole. Military Med 1983; 148:118-21 6 O'Quigley S. Hyperbaric oxygen therapy. Irish Med J 1983; 76: 193-94 7 Robin ED. Saltern pla& boni quam mall efficen conanl: At least try to do more good than harm. Pharos 1987; 50:40-44 8 Robin ED. Iatroepidemics: A probe to examine systematic preventable errors in (chest) medicine. Am Rev Respir Dis 1987; 135:1152-56 9 US Navy Diving Manual, Navships. Washington, DC: US Government Printing Office, 1963; 250-538 10 Guyatt G, Sackett D, 'Jlaylor W. Roberts R, Pugsley S. Determining optimal therapy: Randomi7.ed trials in individual patients. N Engl Med 1986; 314:889-92 11 McLeod RS, Cohen Z. 'Jlaylor DW. Cullen JB. Single-patient randomi7.ed clinical trial. Lancet 1986; 1:907-09 12 Olson KR. Carbon monoxide poisoning: Mechanisms, presentation and controversies in management. J Emerg Med 1984; l: 233-43
13 Thompson RA. Carbon monoxide poisoning: 'li'eatment with hyperbaric oxygen. Arimnia Med 1984; 41:21-22 14 Ackerman WE ill. Hyperbaric oxygen therapy as treatment fur carbon monoxide poisoning. J Kentucky Med Assoc 1985; 83: 401-03 15 Myers RAM, Snyder SK, Emhoff TA. Suhacute sequelae of carbon monoxide poisoning. Ann Emerg Med 1985; 14:1163-67 16 Brummellcamp WH, Boermea I, Hoogendijk I. 'li'eatment of clostridial infections with hyperbaric oxygen drenching. Lancet 1963; 1:235-38 17 Ellis ME, Mandal BK. Hyperbaric oxygen treatment: Ten years experience of a regional infectious diseases unit. J Infect Dis 1983; 6:17-28 18 Darke SC, King AM, Slack WK. Gas gangrene and related infection: Classification, clinical features and etiology, management and mortality. A report of 88 cases. Br J Surg 1977; 64: 104-12 19 Slack WK, Thomas DA, Perrins D. Hyperbaric oxygenation in chronic osteomyelitis. Lancet 1965; 2:1093-04 20 Hamblen DL. Hyperbaric oxygenation: Its effect on experimental staphylocoocal osteomyelitis in rats. J Bone Joint Surg 1968; 50A:ll29 21 1iiplett RC, Bronham GB, Gillmore JD, Lorber M. Experimental mandibular osteomyelitis: Therapeutic trials with hyperbaric oxygen. J Oral Muillofac Surg 1982; 40:640-46 22 Mader J1; Guckian JC, Glass DL, Reinarz JA. Therapy with hyperbaric oxygen fur experimental osteomyelitis due to Staphylocoocal aureus in rabbits. J Infect Dis 1978; 138:312-18 23 Depenbusch FL, Thompson RE, Hart GB. Use of hyperbaric oxygen in the treatment of refractory osteomyelitis: A preliminary report. J 'Ii'auma 1972; 12:807-12 24 Bingham EL, Hart GB. Hyperbaric oxygen treatment of refractory osteomyelitis. Postgrad Med 1977; 61:70-3 25 Morrey BF, Dunn JD, Heimbach RD, Davis JD. Hyperbaric oxygen and chronic osteomyelitis. Clin Orthopaedics and Rel Res 1979; 144:121-27
26 Eltorai I, Hart GB, Strauss MB. Osteomyelitis in the injured spinal cord: A review and a preliminary report on the use of hyperbaric oxygen therapy. Paraplegia 1984; 22:16-24 27 Davis JC, Heckman JD, DeLee JC, Busbvld FJ. Chronic nonhematogenous osteomyelitis treated with adjuvant hyperbaric oxygen. J Bone Joint Surg 1986; 68:1210-17 28 Anonymous. Medicine under glass: Hyperbaric therapy gets a new lease on life. Colorado Med 1984; 81:167-70 29 Chen KK, Rose CL. Nitrite and thiosulf8te in cyanide poisoning. JAMA 1952; 149:113-19 30 Graham DL, Laman D, Theodore J, Robin ED. Acute cyanide poisoning complicated by lactic acidosis and pulmonary edema. Arch Intern Med 1977; 137:1051 31 Way JL, End E, Sheehy MH. Effects ofoxygen on cyanide intoxication rv. Hyperbaric oxygen. Tuxicol Appl Pharmacol 1972; 22:415-21 32 Bismuth C, Cantineau JP, Pontal P. Priorite de I'oxygenation dans l'intoxication cyanhydrique. J Toxicol Med 1984; 4:107-21 33 Litovitz TL, Larkin RF, Myers RAM. Cyanide poisoning treated with hyperbaric oxygen. Am J Emerg Med 1983; 1:94-101 34 Cottrell JE, Casthal P, Brodie JD. Prevention of nitroprussideinduced cyanide toxicity with hydroxocobalamine. N Engl J Med 1978; 298:809-11 35 Dearden NM. Management of raised intracranial pressure after severe head injury. Br J Hosp Med 1986; 36:94-103 36 Rockswold CL, Ford SE. Preliminary results of a prospective randomi7.ed trial fur treatment of severely brain-injured patients with hyperbaric oxygen. Minnesota Med 1985; 68:533-35 37 Green'WOOd Tw, Gilchrist AC. Hyperbaric oxygen and -wound healing in postirradiation head and neck surgery. Br J Surg 1973; 60:394-97
38 Hunt TIC, Pai MK. The effect ofvarying ambient oxygen tensions on -wound metabolism and collagen synthesis. Surg Gynecol Obstet 1972; 135:561-67 39 Marx RE, Johnson RP, Kline SN. Prevention of osteoradionecrosis: A randomi7.ed prospective clinical trial of hyperbaric oxygen versus penicillin. JADA 1985; 111:49-54 40 Giebfried JW, Lawson W. Biller HF. Complications ofhyperbaric oxygen in the treatment of head and neck disease. Otolaryngol Head Neck Surg 1986; 94:508-12 41 Farmer JC Jr; Shelton DL, Bennedest PD, Angellilo JD, Hudson WR. 'li'eatment of radiation-induced tissue injury by hyperbaric oxygen. Ann Otol Rhinol Laryngol 1978; 87:707-15 42 Roth M, Tomlinson BE, Blessed G, Correlations between scores fur dementia and counts of senila plaques in cerebral grey matter of elderly subjects. Nature 1966; 209:109-10 43 Boschetty V. Cernoch J. Aplikase kysliuku m pretlalru nekterych. Neurologickych Anemocneni 1970; 53:298-302 44 Neubauer RA. Exposure of multiple sclerosis patients to hype... baric oxygen at 1.5--2 ATA: A preliminary report. J Fla Med Assoc 1980; 67:498-504 45 Fisher BH, Marks M, Reich T. Hyperbaric-oxygen treatment of multiple sclerosis: A randomi7.ed, placebo controlled double blind study. N Engl J Med 1983; 108:181-86 46 Barnes MP, Cartlidge NEF, Bates D, French JM, Shaw DA. Hyperbaric oxygen and multiple sclerosis: Short-term results ofa placebo-controlled, double-blind trial. Lancet 1985; 1:297-300 47 Neiman J, Nilsson B~ Barr PO, Perrins DJD. Hyperbaricoxygen in chronic progressive multiple sclerosis: Visual evoked potentials and clinical effects. JNeurol Neurosurg Psychiatry 1985; 48: 497-500 48 Wiles CM, Clarke CRA, Irwin HP, Edgar EF, Swan AV. Hype.,. baric oxygen in multiple sclerosis: A double blind trial. Br Med J 1986; 292:367-71 49 Harpur GD, Suke R, Bass BH, Martin MJ, Bull SB, Reese L, et al. Hyperbaric oxygen therapy in chronic stable multiple sclerosis: Double-blind study. Neurology 1986; 36:988-91 CHEST I 92 I 6 I DECEMBER. 1967
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50 Erwin CW, Massey EW, Brendle AC, Shelton DL, Bennett PB. Hyperbaric oxygen inHuences on the visual evoked potentials in multiple sclerosis patients. Neurology 1985; 35(Suppl 1):104 51 Murthy KN, Maurice PB, Wilmeth JB. Double-blind randomized study of hyperbaric oxygen 9HBOO versus placebo in multiple sclerosis (MS). Ibid 52 Massey EW, Shelton DL, Pact V, Greenberg J, Erwin W. Saltzman H, et al. Hyperbaric oxygen in multiple sclerosis: Doubleblind crossover study of 18 patients. Ibid 53 Siddharthan R, Sheremata WA, Defurtuna S, Suant A, Sheldon J. Multiple Sclerosis (MS): Correlation of magnetic resonance imaging with cerebrospinal fluid findings. Ibid 54 Davis JC, Dunn JM, Heimbach RD. Indications fur hyperbaric oxygen therapy. Texas Med 1980; 76:44-7 55 Slack WK, Gillian C, Harison HER, Cockerill G, O'Connor R. Analysis of complications of hyperbaric oxygen therapy in 455
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56 57
58 59 60 61
patients treated in single-person hyperbaric oxygen chambers. In: Proceedings of the Fourth International Congress on Hyperbaric Medicine. Wada J, Iwa 'I; eds. Baltimore: Williams and Wilkins 1970; 305-09 Bates D. Hyperbaric oxygen in multiple sclerosis: Discussion paper. J R Soc Med 1986; 79:535-37 Myers RAM, Schnitzer BM. Hyperbaric oxygen use update 1984. Postgraduate Med 1984; 76:83-95 Heimback RD. Quoted in Medical News. JAMA 1981; 246:1058 Marx RE. Letter to the editor. J Oral Maxillofiic Surg 1984; 42: 141-42 Califano JA Jr. Americas health care revolution. New York: Random House, 1986:104-05 Hyperbaric Committee of the Undersea Medical Society, revised classification, 1983
Hyperbaric <>t: A Therapy In Sean:h of D1seaaes (Gabb, Robin)
1iia
-
--==-
--r_i1_k·_n_an_a1_i1_1_11_1,_1_i1_in_c_h_a1_1_11_1a_ic_in_a_ _ Hyperbarlc Oxygen* A Therapy In Search of Diseases Genevieve Gabb;t and Eugene D. Robin, M.D.:j:
T
here appears to be a continual proliferation ofhyperbaric oxygen (HBO) units in the US. 1 The list of so-called indications for its use, past and present, is overwhelming. There is a wide spectrum ofanalyses cited to support the use of HBO in given diseases. These range from serious, thoughtful attempts to rationalize a given use; other analyses border on medical charlatanism. 1 There is a striking dearth of data derived from acceptable clinical trials to support these rationalizations. It is not practical to review the massive literature completely. Herein we provide a historic perspective concerning various indications for HBO use during the past several decades; evaluate the evidence supporting its current use in various disorders; analyze one major driving force for the proliferation of uses and indications, money; review the nature of patient risks associated with the use of HBO; and make some suggestions for dealing with the issues raised by HBO. The overall conclusion is that the world of HBO is a microcosm reflecting many of the problems which plague the macrocosm of medicine. PAST AND PRESENT INDICATIONS
Tu.hie I lists 132 past or present indications for the use of HBO. We provide the list in its entirety§ because we have not been able to find a similar attempt in the recent literature. The list includes indications that are not exclusively American. For example, HBO is used extensively in Eastern Europe. No analysis of most non-American indications was attempted. In assembling the list, several obvious conclusions emerged. The broad range of conditions speaks for itself. HBO has been and continues to be regarded as a form of near-universal treatment. Some indications arose as a result of assumed pathophysiologic considerations, some indications were generated for pragmatic reasons, and for some indications, it was (is) not possible to trace the reasons for the use of HBO.
*From Stanfurd University Medical Center, Stanfurd, Califumia. tMedical student. tProfessor of Medicine and Physiology. §We do not guarantee that the list is complete. We thought that assembling this list might be helpful to future medical historians. Reprint requests: Dr. Robin, Anatomy Bldg, Room 169, Stanford Unlverdty School of Medlclne, Stanford 94305-5070
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Table 1-Varioua Indicationa Uaedfor HBO 7reatment during the ftJet Few Decada Radiation necrosis Decompression sickness Gas embolism Soft tissue infection, due to mixed aerobic and anaerobic organisms Soft tissue necrosis Bacteroides infection Compromised skin grafts or Raps Fungal infections Mucormycosis Anemia from exceptional blood loss Carbon tetrachloride poisoning Fractures Lepromatous leprosy Meningitis Radiation myelitis, cystitis, enteritis Retinal artery insufficiency Chronic brain ischemia Senility Multi-infarct dementia Infant cardiac surgery Chronic ulcers Peripheral vascular disease Diabetic neuropathy Acute endocarditis Hearing loss due to acoustic trauma Cortical blindness Cellulitis Infected pacemaker Hurlers syndrome Postcardiac arrest Scleroderma Mycobacterium tuberculosis Abscess, intraabdominal or intracranial
Asthma Pneumomediastinum Hanging Thrombophlebitis
Hyperbarlc 0 2 : A~
Lyell's syndrome*
co poisoning
Gas gangrene Osteomyelitis (refractory) Crohns disease Cyanide poisoning Crush injury with traumatic ischemia Alzheimers disease Brain edema Thermal bums Head and spinal injury Bone grafts Frostbite Cerebrovascular accidents Hydrogen sulfide poisoning Cancer therapy Pse11domembranous colitis Sickle cell crisis Multiple sclerosis Pyoderma gangrenosum Acute myocardial infarction Carotid aneurysm Aortic aneurysm Anaerobic infections Postcardiac surgery Pulmonary insufficiency Arteriosclerosis Causalgia Collagen vascular diseases Postoperative confusion 'Ihwmatic amputation Pulmonary emboli Drowning Moyamoyat Surgical empyema Pharyngeal fistula Brain cyst Stenotic valvular heart disease Tetanus Intestinal obstruction Continued In Seard! ol Dile.- (Gabb, Robin}
Table 1, continued Necrotizing f8sciitis Postepileptic headaches Radiation pneumonia Balloon aspiration Migraine Allergic reaction Quadriplegia Dust-induced bronchitis Gastroduodenal ulcer Facial neuritis Late pregnancy toxemia Liver failure Closed chest trauma Emphysema Paralytic ileus Bendu-Osler Weber disease Perirectal fistula Necrobiosis lipoidic diabeticorum Black lung disease Allergies Myositis Colitis Cerebral vasospasm Malignant otitis extema Acute hearing loss Pneumatosis cystoides intestinales Maxillofacial phlegmon Cochlear vestibular syndrome
Viral encephalitis Bites Buergers disease Vascular headache Precardiac surgery 'Ihlcheal fistula Vertigo Rheumatoid arthritis Preservation of youthfulness Viral hepatitis Habitual abortion Sodium nitrite poisoning Diabetes mellitus Fouriers gangrene* Acute pancreatitis Organophosphate poisoning Perianal hidradenitis supprativa Organ preservation Muscular dystrophy Poor circulation Cirrhosis of the liver Epilepsy Pulmonary hypertension Lung lavage Revasculari7.ation Chronic coronary artery disease Periodontosis
*Lyells syndrome: toxic epidermal neeiWysis round in lymphoproliferative disease tMoyamoya: sudden cerebral vascular insufficiency with a specific arteriographic pattern :t:Fouriers gangrene: idiopathic gangrene of the scrotum
Applications of HBO, not uncommonly, arise as a result of medical adventurism, therapy in search of diseases. A unit is available at a given facility. A patient enters with a given disease for which treatment is unsatisfactory. Why not try HBO? There is also a dynamic flux involving its use for specific indications. Most of these seem to go through a typical evolution in which there is an initial increase in use characterized by great enthusiasm and widespread use followed by, perhaps, a realization that HBO is not effective, followed by a gradual decline in use. For example, in the 1960s, HBO was touted as an effective antidote for senility which encompassed a spectrum of patients ranging from those with senile dementia to benign senile forgetfulness, and HBO was used in large numbers of older patients. 3•4 This treatment, over the course of several decades, gradually fell into disrepute as a cure for aging although, even in the early 1980s, some patients continued to be treated for senility. 1 There has been no mechanism for memory, ie, to record previous errors so that current HBOers can learn from the mistakes of the past. In fact, a discredited or abandoned use of HBO is seldom, if ever, provide
With rare exceptions, the potential risks of HBO have been (are) ignored or underplayed. With rare exceptions, physicians using the equipment have had little or no personal experience in conducting appropriate clinical trials nor have they demonstrated substantial interest in testing the safety and efficacy of HBO. Increasingly, there have been formal expressions of the desirability of controlled prospective randomized clinical trials. These expressions almost assume the form of a catechism (see below); the clinical trials are not conducted. The activities of HBOers have ranged from serious attempts to rationalize HBO use, by groups such as the Undersea Medical Society, to impulsive and poorly conceived thrusts. Risk-benefit analysis has been strikingly absent. In brie( the history of the use of HBO is not qualitatively different than the history of many therapeutic attempts in medicine. 7•8 The overall point is that, with only rare exception, the history of the use of HBO has been characterized by unscientific, uncritical pragmatism. Baromedicine has also been characterized by a spirit of medical adventures, a willingness to try this therapy in a wide variety of disorders with minimal careful analysis; HBO often is a form of treatment in search of diseases. Tuble 2 lists various disease states for which HBO is currently recommended (with various degrees of enthusiasm by baromedical experts). In general, these conditions are third party reimbursable which plays some role in the degree of enthusiasm. As indicated in the table, for only one disorder, decompression sickness, is there an overwhelming clinical experience and acceptable clinical trials which demonstrate efficacy. For only a few of these conditions is the incidence in the general population of sufficient magnitude to represent an overwhelming health problem. For many of the entities there are effective alternative forms of treatment. In addition to lack of studies indicating benefits, for most of the entities the risks have not been carefully quantitated. The data do not suggest that most present uses of HBO therapy are more clearly established now than in the past several decades. .
Decompression Sickness The use of hyperbaric chambers during ascent from deep diving represents the most clearly and perhaps only validated use of hyperbaric therapy. Proof of efficacy has been established as a result of extensive pragmatic studies by the US Navy as well as other organizations. 8 A series of tables has been developed for the estimation of safe periods of gradual decompression. There is not only an extensive clinical experience, but the clinical experience embodies some elements of alternating single-patient clinical trials. 10.u Symptoms indicating too rapid decompression are rapidly alleviated by recompression at a higher pressure. It should be emphasized that no similar clinical experience or trial supports the use of HBO for the treatment of most forms of intravascular aeroembolism, as that arising during cardiac surgery or during scuba diving. HBO is used to decrease intravascular bubble size and to increase the driving pressure for oxygen into tissue and cells. There are many factors which determine outcome in these patients, such as the time between embolism and the time of treatment. Thus, claiDJS that aggressive HBO treatment is effective from CHEST I 92 I 6 I DECEMBER, 1987
1075
Table 1-Cummt "Strong" lnJicalioru for the Use
0 (no)
Extensive Favorable Clinical
Experience
± 0 0 0 0 0 0 0
0 0
0 0
Alternative Forms of 'Iieatment Available
very low very low moderate if smoke inhalation included low moderate moderate very low moderate high high high
0 ±
+ + + + + + + + + ±
low
+ 0
high
± (possibly)
minutes to hours after gas embolism would require an acceptable clinical trial for evaluation. No such data are available.
Carbon Monoxide Poisoning This entity is currently cited as the indication par e.rcel-
lence for the use of HBO treatment. It has been established
that HBO reduces blood concentrations of carboxyhemoglobin more rapidly than is effected by breathing 100 percent oxygen at ambient pressure (carboxyhemoglobin half-life at room air: 5 hours and 20 minutes; carboxyhemoglobin halflife at 100 percent oxygen breathing: 90 minutes; and carboxyhemoglobin half-life under HBO: 23 minutes). s It is by no means established that this decrease in half-life results iii improved outcome. It is not at all certain that HBO improves oxygen delivery to the brain and myocardium, which depends not only on the Pa01 but also on the rate of organ blood flow. Nor is there evidence indicating that HBO reduces cerebral edema by brain vasoconstriction. Even if the latter two mechanisms operate, whether these are translated into a better outcome for patients would require independent documentation. None has been provided. The lack of acceptable evidence of efficacy of HBO in CO poisoning has been noted elsewhere. 11 One interesting claim, unsupported by 6rm evidence, is that HBO therapy may improve brain function hours to days after the acute event when blood concentrations of CO are minu~e. The worlds record is the report of a patient who responded to HBO therapy nearly two months after carbon monoxide intoxication. 13 Needless to say, no firm evidence is available to support this claim. Perhaps the claim is accurate and HBO reverses some mysterious biochemical alteration related to CO poisoning, but in the absence of firm evidence, this claim cannot be accurately evaluated. The indications for treatment have been broadened to include suspected CO poisoning even in the absence of detectable CO-Hb levels," and subacute sequelae of established CO poisoning. 15 The most mysterious fact about the use of HBO in CO poisoning is the failure to carry out animal trials in primates. The
1078
+ 0 0
+ 0 0 0 0 0 0 0 0 0 0
Incidence in General Hospital Population
organimtion of such trials would be relatively simple. Carbon monoxide can be administered with great accuracy; quantitation of carboxyhemoglobin levels is simple; outcome as a function of no treatment, treatment with 100 percent oxygen and with HBO could easily be compared. It would be possible to determine whether late application of HBO reverses brain injury even when significant blood levels of CO are no longer present Finally, the quantitative risks associated with HBO could be determined. The total funds required to carry out these studies would be substantially less than maintaining numerous HBO units in various communities.
Gas Gangrene and Other Anaerobic Infections The modem revival of the use of HBO stemmed &om a report by Brummelkamp and colleagues» in the 1960s. They treated 26 patients with clostridial infection and reported that 25126 patients were cured and 21/26 patients survived. Needless to say, the study was uncontrolled. Even the simple expedient ofcomparing the outcome ofpatients receiving 100 percent oxygen with those on HBO was not considered; nor has it been since. Controlled studies or not, the use of HBO was widely applied to patients with clostridial disease. There may be a subgroup of patients with clostridial infection who may have improved outcome on HBO used as an adjuvant to surgery and antibiotics. This favorable response is by no means universal. 11•11 How these patients would respond on 100 percent oxygen at ambient pressures is not known. One could hardly use this small group of patients to justify the organization of HBO units in the community. In fact, before general clinical application to the treatment of gangrene, a controlled trial of HBO in treating clostridial infection would be desirable. The clinical experience with non-clostridial anaerobic infections or mixed infections does not suggest that the use of HBO has a favorable risk-benefit balance. 11 Oateomyelitis The first report of the use of HBO to treat osteomyelitis (OM) was in 1965. 19 Five cases ofchronic OM were described Hyperbarlc ~:A
Therapy In Semdl of Dile.- (Babb, Robin)
and all were noted to have "responded to treatment with HBO at 2 ATA given fur various periods." The report was remarkable as in only one of the five cases were antibiotics used as part of the treatment. Since then, numerous studies evaluating the use of HBO to treat chronic OM in animals and humans have been reported. Two separate animal experiments have compared the effect of treatment with HBO versus nontreatment on established OM in rats and rabbits, respectively. 111•11 Both experiments demonstrated that those animals treated with HBO had a significant increase in the healing of OM compared with those animals given no treatment. More specifically, 'Iliplett et al11 round a significant improvement in the healing of sinuses, reduced fracture mobility and improved histologic appearance in their group of HBO-treated rabbits. However, these experiments did not include an antibiotic treatment group, or antibiotic and HBO treatment group. In 1978, Mader et al11 compared the effect of fuur treatment programs on established OM in the long bone of a rabbit. Their treatment groups were: no treatment, HBO alone, antibiotic alone, and HBO and antibiotic in combination. They found significant dift"erences in outcome between the control animals and all treatment groups; however, there was no difference between any one of the three treatment groups. They concluded that HBO did not appear to be synergistic or additive with cephalothin (the antibiotic used) in the treatment of OM.
Several large series of patients with refractory OM, treated with HBO in combination with surgery and antibiotics, have been reported. a.u.-.111.rr These uncontrolled trials show success rates of 63 percent to &5 percent. However, important criticisms should be made of these trials. In one study the duration of previous infection ranged from one week to 20 years. 11 OM ofone weeks duration can hardly be described as chronic. rr The studies are, without exception, lacking in control groups, the intention being that each patient should act as his/her own "historic control." It is impossible to know if the surgical and medical aspects of the combined HBO treatment program are identical to those employed befure HBO was commenced. One study stated, " ... the absence of medical records prevented precise documentation of the adequacy of previous treatment." That being so, the ability of a patient to stand as his or her own historic control is in doubt. Moreover, the use ofhistoric controls are notoriously unreliable. In conclusion, the current evidence fur the efficacy of HBO as an adjuvant in the treatment of refractory OM is drawn from animal studies where HBO-treated groups ofanimals are compared with those given no treatment, and uncontrolled human case studies. As such, it would seem that the claim that HBO is "rational, scientific and proven therapy fur chronic refractory OM" is, at best, premature and probably unfuunded. •
Selected Mycotic Infections The use of HBO in any mycotic infection has never been adequately documented. In fact, with the availability of current antifungal agents, the use of HBO must be considered particularly unscientific. ·
Cyanide Poisoning This is a rare furm of poisoning, and the death rate is estimated at between 80 to 400 cases per 10 million population.• Presumably, HBO could compete with CN· binding to cytochrome 88a·30 Animal studies do not indicate efficacy. 31 The case reports from human cases are equally unimpressive. •:1.1 There is an excellent non-toxic therapeutic agent, hydroxycobalamine, :w and it is diflicult to escape the conclusion that the use of HBO as a furm of therapy in the case of CN· poisoning stems from the Sir Edmund Hillary dictum (who climbed Mt. Everest because "the mountain was there"): "the HBO chamber is there."
Brain Edema with and without Head '.lrauma Rationales fur the use of HBO include reductions in intracranial pressure because of cerebral vasoconstriction and enhanced brain oxygen supply. The lack of good experimental evidence ofbenefit and the problems ofoxygen toxicity have made the use of this method almost, but not entirely, obsolete. 311 A prospective, randomized trial of 30 patients eliminated from consideration the least sick patients and the most sick patients. This left eight controls and seven HBO-treated patients to be analyzed. There was no significant dift"erence in survival in the two groups. These results would seem to be unpromising and at variance with the conclusions drawn by the investigators: Based on the experience in the literature cited previously and on our own Initial aperlence, we hope in the future to convincingly demonstrate that the treatment ofsevere bnin-injured patients with HBO will result in an overall bene&cial response in tenns of longterm functional recovery and decreased mortality rates. 311
Thermal Burns Only one hyperbaric chamber consistently uses HBO fur burns, and has treated over a thousand patients. The rational fur its use is based on enhancement of leukocyte bacteriocidal activity and enhancement ofwound healing. There have been no controlled clinical trials and one is left to wonder how patient or family permission was obtained to treat these patients.
Anemia from Exceptional Blood Lou This treatment is suggested fur the most part when blood transfusions are not acceptable fur religious reasons. The theory is that enough oxygen can be physically dissolved in the plasma to supply metabolic needs. Obviously, the efficacy has not been put to any type of critical scrutiny.
Enhancement of Wound Healing The rationale is that HBO increases the bacteriocidal activity of leukocytes and improves oxygen supply to poorly vascularized tissue. Increasing tissue Po1 may enhance collagen synthesis by fibroblasts. No acceptable clinical trials are available.
Radiation Necrosis This area of disease may become the gas gangrene of the 1980s. Progressive proliferative endoarteritis may result from
high doses of ionizing radiation. The primary tissues involved include bone (osteoradionecrosis) and soft tissues. Dating back to 1973, clinical observations suggested that HBO treatCHEST I 92 I 8 I DECEMBER, 1887
1077
ment was valuable iOr partially ischemic, hypoxic bone and soft tissue lesions. 37 The putative mechanisms iOr improvement included the ability of HBO to stimulate fibroblastic proliferation and enhance collagen synthesis and capillary angiogenesis. 38 The major iOrm iOr treatment bas been osteoradionecrosis involving the head. One randomi7.ed prospective clinical trial has been reported. The issue was whether HBO could prevent the development of osteoradionecrosis of the mandible after tooth removal in a high-risk patient population. In the group of patients receiving HBO, there were signi&cantly fewer tooth socket wounds that tailed to heal as compared to a group ofpatients receiving penicillin without HBO. 38 No controls using 100 percent oxygen at ambient pressures were studied. The clinical trial studied a highly speciali7.ed and circumscribed problem: the rate ofresolution of tooth socket healing after radiation. The number of such patients in the general population must be very small. For example, in one major center over a 15-year period, a total of 101 patients were treated. 40 The extrapolation of these favorable results to the general problem of radiation necrosis is neither medically nor scientifically justified. In fact, therapeutic and prophylactic attempts to deal with radiation necrosis in other areas, in an uncontrolled study fraught with polypharmacy, did not provide striking evidence of efficacy. The sites which were treated included the chest wall, the pelvis and lumbar area, the spinal cord, the brain, and the larynx. 41 'Ibis scanty data base is now being extrapolated to consider the use of prophylactic HBO in all or most patients receiving high doses of therapeutic radiation. The patient population iOr such treatment would be very large. What proportion of these patients would develop clinically signi&cant radiation necrosis is unknown. Whether HBO would be effective prophylactically is also not established. Tu implement such a proposal without a prior controlled, prospective randomi7.ed clinical trial would be to repeat the errors of the past. It is useful to describe two examples of more or less discredited indications iOr the use of HBO. Senility
The possibility of improving cognitive function in the senile by HBO bas been a pragmatic indication iOr widespread use of HBO iOr a number of years. 'Ibis approach was provided a scientific rationale and some experimental support by studies reported in the late 1960s. 4 The scientific rationale was that HBO increases oxygen supply to a brain with a deficient cerebral circulation. The experimental studies consisted of comparing several tests of cognitive function in 13 aged subjects with chronic brain syndrome subjected to hyperbaric 100 percent oxygen with five similar subjects subjected to 2.5 atmospheres of 10 percent oxygen. Thirty treatments of90 minutes each were provided iOr 30 days and three tests of cognitive function were applied beiOre and 24 hours after the last treatment administered by an examiner who was blinded as to which breathing mixture bad been used in which subject. It was reported that there was a remarkable and signi&cant improvement in the test scores of treated patients compared to those who breathed an ambient-ail'-like gas mixture.
1078
Several aspects of these studies warrant comment. The majority of the patients almost certainly did not have cerebral arteriosclerosis as the basis of their chronic brain state. An accurate diagnosis of the majority of patients was almost certainly Alzheimer's disease, a fact which was not appreciated in 1969." Thus, assuming that the treatment worked, it was not because cerebral vascular insufficiency was being temporarily alleviated twice a day iOr 180 minutes. Thus, at most, the treatment "worked" iOr the wrong reasons. The putative benefit of the treatments continued iOr 24 hours after the HBO treatment bad ceased. 'Ibis would require that the cause ofany benefitwas a mechanism unknown then and currently unknown. The sensitivity and speci&city and depth of resolution of the three psychologic tests administered to test the ~ tiveness of HBO treatment are essentially unknown. It is probable that the tests were inadequate to test cognition accurately and quantitatively. Rather than stimulating an adequate clinical trial embracing an adequate number of patients with accurately diagnosed cognitive disorders, the results stimulated mass use of HBO treatment in the senile (aged). Masses ofsenior citi7.ens were lined up to have their senility treated. The complications resulting from HBO in this group of patients are essentially undescribed. By 1983 the practice bad largely faded from use as a iOrm of treatment of senility in the US, although iOur patients with Alzheimer$ disease were treated in 1985. 1 No results are available. It is probable that the gradual abandonment of HBO treatment iOr senility was related to lack of effectiveness. It is, of course, barely possible that some subgroup of patients was benefitted by the treatment to account iOr the results of the early clinical trial. H so, then a potentially beneficial iOrm of treatment bas been abandoned because of inadequate scientific validation. . The point is that the existing lack of scientific rigor not only leads to the use ofineffective treatment, but could also lead to premature abandonment of effective iOrms of treatment. Thus, the use of HBO in the treatment of Alzheimer$ disease remains an unsettled issue. While it is our opinion that an adequate clinical trial will fiUl to show benefit, the use of HBO remains a iOrmal scientifically and medically unsettled issue. Multiple Scleroris (MS)
The suggestion that HBO might be useful in the treatment of MS originally rose in 1970 in Czechoslovakia.• Animal studies were reported which suggested that HBO ameliorated experimental allergic encephalomyelitis in guinea
pigs." 'Ibis was iOllowed by a series of uncontrolled clinical trials suggesting partial to complete remission in human subjects with MS treated with HB0. 44 The major impetus to its widespread use stemmed from the results of a small "controlled" trial reporting benefit and published in a prestigious medical journal. 'Ibis study noted objective improvement in 12of17 patients treated with HBO and in one of 20 patients treated with placebo (p<0.001). Improvement was transient in seven of the patients treated with oxygen and long lasting in &ve patients. The authors themselves recognjzed the inadequacy
"°
of this study; however, the peer reviewers did not. 45 This report was greeted with enthusiasm and, fullowing publication, numerous patients with MS in the US and UK were placed on HBO therapy. In 1983, over 1,300 patients with MS were treated, and in 1984, over 1,100 patients were treated in the US alone. 1 The initial clinical trial stimulated a series of randomized, prospective, controlled clinical trials. At least nine have been published between 1985 and 1986. None has shown efficacy. - Simply stated, there is overwhelming scientific evidence that HBO does not work. But that is not the end of the story. There has been a spate of letters to the editors of various medical journals by protagonists. An organization called the Association fur Research into MS (not to be confused with the Multiple Sclerosis Society) was (is) soliciting money in order to establish hyperbaric chambers. The truly convinced remain convinced, and it will be some time befure HBO use in MS suffers the same fate as oil of evening primrose and snake venom in the treatment of MS. At least in the US, enthusiasm fur this furm of treatment appears to be abating.
How
MANY PATIENTS
ARE TREATED
WITH
HBO?
The magnitude of usage from 1977 to 1985 may be judged from the fullowing figures. A total of 36,937 patients were reported being treated. 1 Of these, 17,885 (49 percent) were treated fur indications fur which there is substantial current enthusiasm and 18,912 (51 percent) were treated fur indications of various degrees of dubiousness. RISKS OF
HBO
With few exceptions, the potential risks of HBO treatment have not received substantial emphasis. In qualitative terms, a number of risks have been described and these are summarized in Table 3. Briefly stated, these risks arise from high barometric pressures during the process of compression; from responses to high oxygen tensions such as brain and lung injury; from gas embolism arising during the process of decompression; from chamber accidents arising from fire (several deaths, including a patient and attendants during a fire in Germany); and from several furms of toxicity, the mechanisms of which are unknown, including myopia and increases in refractive error lasting fur weeks to months, anxiety, nausea and vomiting. Contraindications to the use of HBO are said to include pneumothorax, severe obstructive pulmonary disease, pulmonary blebs and bullae, optic neuritis, acute viral infections and inability to equali7.e middle ear pressures. 114 The precise quantitative extent of the risks associated with HBO will require appropriate clinical trials. Some estimate can be derived from the literature. In an early series of 445 patients, minor complications related to barotrauma occurred in about 30 percent of the patients, convulsions occurred in 2 percent, and psychologic symptoms occurred in about 20 percent. 1111 In a series of 88 patients, there were eight grand mal seizures and in one patient the convulsions persisted and the patient died. ia In another series of87 patients, barotrauma occurred in 28 percent of the patients; anxiety was noted in 43 percent. Dyspnea and chest pain occurred in 18 percent of the pa-
tients, neurologic symptoms occurred in 10 percent, and 5 percent had grand mal fits. 17 In a series of 109 patients treated over a 15-year period, major complications included 2 percent with convulsions; one of these patients suffered a stroke and one an acute myocardial infarction. Minor complications resulting from barotrauma occurred in about 2 percent of the patients. 40 Tu the extent that these data are representative, severe CNS manifestations occur in 1 to 2 percent of treated patients, symptomatic barotrauma in perhaps 15-20 percent of patients, and optic symptoms in perhaps 20 percent of patients. Death attributed to HBO (aside from deaths resulting from fire) is very rare. In summary, then, HBO is not as safe or benign as might be inferred from past and present descriptions of the procedure. ECONOMICS
As A DRIVING PRESSURE
Evidence is abundant that increased use of HBO is closely coupled to a desire fur increased profits. This is not a new development When HBO was thought to be a useful furm of treatment fur multiple sclerosis, the number of private (fur profit) HBO units in the UK increased. As aptly stated by Bates,
There is, of coune, the inevitable fact that the provision of these chambers represents a significant investment in personal eJIOrt, time and money which it will be so hard to accept has been fruitless.•
Current classifications ofthe validity ofthe use of HBO fur various conditions suggest that so-called category 1 diseases are covered by third-party carriers-other categories are not sr The importance of clinical trials is asserted to be based on obtaining evidence which will increase insurance payments fur HBO: Third party insurers who pay fur major medical treatment today have
Table 3-Knmon .Riab tfHBO Therapg Barotrauma from increased barometric pressure (Compression manifestation) ears
sinuses middle ear hemorrhage deafness Oxygen toxicity
brain
convulsions and sequelae other CNS manifestation lung pulmonary edema, hemorrhage, respiratory fi.ilure pulmonary oxygen toxicity Decompression sickness pneumothoru nitrogen emboli-CNS, joints, etc. Fire huard patients medical attendants
Mechanism unknown myopia
fatigue headaches vomiting claustrophobia
CHEST I 92 I 8 I DECEMBER, 1987
1079
to be convinced of scientific validity and we don't always have documented proof[ofHBO efficacy]. We need well-controlled animal work and prospective clinical studies to document who and fur what disorders this therapy should be used. 58
Just how much money has been expended by patients on HBO? Assuming that an average course of treatment is two months and that the treatment cost is $1,0
The medical literature involving HBO contains more than 12 references during the past 15 years commenting on the desirability of adequate and appropriate clinical trials of one disease or another. Despite these sentiments, little has been done. There are a number of problems. One is the sheer magnitude of the various disorders fur which HBO is used. A second problem is that, by dint of training, experts in HBO are not trained or experienced in the organization and implementation of appropriate clinical trials. A third problem is that clinical trials, to paraphrase the immortal words of Willie Sutton, is "not where the money is." A need for appropriate clinical trials can be derived by analyzing the system of classification suggested by the Hyperbaric Medicine Society fur summarizing the status of various indictions fur HBO. 81 Category 1: conditions fur which HBO treatment is known to be effective (and is third-party reimbursable). 1080
Given the lack of acceptable data showing efficacy fur most of these conditions, the word "known" is a substantial oveJ'o statement. At best, most conditions in this category represent a consensus opinion by workers using HBO based on pragmatic and uncritical considerations. Category 2: conditions fur which HBO treatment is unproved clinically or experimentally and is not reimbursable. This category raises even more sharp issues than category 1. If the treatment is experimental, is infurmed consent obtained from the patient or his surrogate to permit the use of the patient in an experiment? (Parenthetically, not to obtain infurmed consent in most legal jurisdictions represents a furm of malpractice.) Are patients required to pay fur experiments perfurmed on them? If so, what is the justification? Are such studies on patients really scientific experiments? What are the hypotheses which are tested? What controls are used? What quality control measures are used to ensure high standards and unifurmity of data collection? What mechanisms are used fur critical evaluation of the data and interpretation of the data? Or is HBO treatment usually a pragmatic, uncritical, unstructured effort? WHAT MIGHT BE DONE
A starting point might be to select one or two conditions fur appropriate clinical trials; fur example, the treatment of CO poisoning and the prophylaxis of radiation necrosis might be suitable areas. While these trials are being conducted, a voluntary or mandated moratorium on the random use of HBO could be suggested or enfurced. A national conference on the application of risk-benefit analysis to HBO, sponsored by the Hyperbaric Medical Committee of the Undersea Medical Society, might be useful. Physicians referring patients fur HBO therapy should be aware of the major uncertainties. SUMMARY
The application of HBO to the therapy of various human diseases developed over a 300 year period. Like most of medicine, the basis of these applications was and continues to be pragmatic in nature, and involves uncritical and untested judgments. The possibility of risks bas been undeJ'o stated and possible benefits have been overstated. Individual physicians offering HBO and organized groups, such as the Undersea Medical Society, advocating its use may well be highly motivated, well meaning, and sincerely convinced that HBO is an important therapeutic approach. It may be that, buried among the host of indications, will be some disorders fur which HBO is uniquely and highly effective. Ifso, the present nonsystem fur evaluating responses to HBO will require modification, so that these potentially valuable additions to therapeutics are not lost. Because of its almost global application to a wide variety of diseases, HBO therapy lends itself easily to medical adventurism (therapy in search of a disease) and economic exploitation. If there is some patient benefit to come from the experience of the last 300 years, changes in approach, initiated by· baromedical devotees or by medicine generally, or resulting from pressures outside of medicine, will be required. Hyperbarlc Oa: A~
In Sellrd1 al Dile-. (Gabb, Robin)
REFERENCES
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13 Thompson RA. Carbon monoxide poisoning: 'li'eatment with hyperbaric oxygen. Arimnia Med 1984; 41:21-22 14 Ackerman WE ill. Hyperbaric oxygen therapy as treatment fur carbon monoxide poisoning. J Kentucky Med Assoc 1985; 83: 401-03 15 Myers RAM, Snyder SK, Emhoff TA. Suhacute sequelae of carbon monoxide poisoning. Ann Emerg Med 1985; 14:1163-67 16 Brummellcamp WH, Boermea I, Hoogendijk I. 'li'eatment of clostridial infections with hyperbaric oxygen drenching. Lancet 1963; 1:235-38 17 Ellis ME, Mandal BK. Hyperbaric oxygen treatment: Ten years experience of a regional infectious diseases unit. J Infect Dis 1983; 6:17-28 18 Darke SC, King AM, Slack WK. Gas gangrene and related infection: Classification, clinical features and etiology, management and mortality. A report of 88 cases. Br J Surg 1977; 64: 104-12 19 Slack WK, Thomas DA, Perrins D. Hyperbaric oxygenation in chronic osteomyelitis. Lancet 1965; 2:1093-04 20 Hamblen DL. Hyperbaric oxygenation: Its effect on experimental staphylocoocal osteomyelitis in rats. J Bone Joint Surg 1968; 50A:ll29 21 1iiplett RC, Bronham GB, Gillmore JD, Lorber M. Experimental mandibular osteomyelitis: Therapeutic trials with hyperbaric oxygen. J Oral Muillofac Surg 1982; 40:640-46 22 Mader J1; Guckian JC, Glass DL, Reinarz JA. Therapy with hyperbaric oxygen fur experimental osteomyelitis due to Staphylocoocal aureus in rabbits. J Infect Dis 1978; 138:312-18 23 Depenbusch FL, Thompson RE, Hart GB. Use of hyperbaric oxygen in the treatment of refractory osteomyelitis: A preliminary report. J 'Ii'auma 1972; 12:807-12 24 Bingham EL, Hart GB. Hyperbaric oxygen treatment of refractory osteomyelitis. Postgrad Med 1977; 61:70-3 25 Morrey BF, Dunn JD, Heimbach RD, Davis JD. Hyperbaric oxygen and chronic osteomyelitis. Clin Orthopaedics and Rel Res 1979; 144:121-27
26 Eltorai I, Hart GB, Strauss MB. Osteomyelitis in the injured spinal cord: A review and a preliminary report on the use of hyperbaric oxygen therapy. Paraplegia 1984; 22:16-24 27 Davis JC, Heckman JD, DeLee JC, Busbvld FJ. Chronic nonhematogenous osteomyelitis treated with adjuvant hyperbaric oxygen. J Bone Joint Surg 1986; 68:1210-17 28 Anonymous. Medicine under glass: Hyperbaric therapy gets a new lease on life. Colorado Med 1984; 81:167-70 29 Chen KK, Rose CL. Nitrite and thiosulf8te in cyanide poisoning. JAMA 1952; 149:113-19 30 Graham DL, Laman D, Theodore J, Robin ED. Acute cyanide poisoning complicated by lactic acidosis and pulmonary edema. Arch Intern Med 1977; 137:1051 31 Way JL, End E, Sheehy MH. Effects ofoxygen on cyanide intoxication rv. Hyperbaric oxygen. Tuxicol Appl Pharmacol 1972; 22:415-21 32 Bismuth C, Cantineau JP, Pontal P. Priorite de I'oxygenation dans l'intoxication cyanhydrique. J Toxicol Med 1984; 4:107-21 33 Litovitz TL, Larkin RF, Myers RAM. Cyanide poisoning treated with hyperbaric oxygen. Am J Emerg Med 1983; 1:94-101 34 Cottrell JE, Casthal P, Brodie JD. Prevention of nitroprussideinduced cyanide toxicity with hydroxocobalamine. N Engl J Med 1978; 298:809-11 35 Dearden NM. Management of raised intracranial pressure after severe head injury. Br J Hosp Med 1986; 36:94-103 36 Rockswold CL, Ford SE. Preliminary results of a prospective randomi7.ed trial fur treatment of severely brain-injured patients with hyperbaric oxygen. Minnesota Med 1985; 68:533-35 37 Green'WOOd Tw, Gilchrist AC. Hyperbaric oxygen and -wound healing in postirradiation head and neck surgery. Br J Surg 1973; 60:394-97
38 Hunt TIC, Pai MK. The effect ofvarying ambient oxygen tensions on -wound metabolism and collagen synthesis. Surg Gynecol Obstet 1972; 135:561-67 39 Marx RE, Johnson RP, Kline SN. Prevention of osteoradionecrosis: A randomi7.ed prospective clinical trial of hyperbaric oxygen versus penicillin. JADA 1985; 111:49-54 40 Giebfried JW, Lawson W. Biller HF. Complications ofhyperbaric oxygen in the treatment of head and neck disease. Otolaryngol Head Neck Surg 1986; 94:508-12 41 Farmer JC Jr; Shelton DL, Bennedest PD, Angellilo JD, Hudson WR. 'li'eatment of radiation-induced tissue injury by hyperbaric oxygen. Ann Otol Rhinol Laryngol 1978; 87:707-15 42 Roth M, Tomlinson BE, Blessed G, Correlations between scores fur dementia and counts of senila plaques in cerebral grey matter of elderly subjects. Nature 1966; 209:109-10 43 Boschetty V. Cernoch J. Aplikase kysliuku m pretlalru nekterych. Neurologickych Anemocneni 1970; 53:298-302 44 Neubauer RA. Exposure of multiple sclerosis patients to hype... baric oxygen at 1.5--2 ATA: A preliminary report. J Fla Med Assoc 1980; 67:498-504 45 Fisher BH, Marks M, Reich T. Hyperbaric-oxygen treatment of multiple sclerosis: A randomi7.ed, placebo controlled double blind study. N Engl J Med 1983; 108:181-86 46 Barnes MP, Cartlidge NEF, Bates D, French JM, Shaw DA. Hyperbaric oxygen and multiple sclerosis: Short-term results ofa placebo-controlled, double-blind trial. Lancet 1985; 1:297-300 47 Neiman J, Nilsson B~ Barr PO, Perrins DJD. Hyperbaricoxygen in chronic progressive multiple sclerosis: Visual evoked potentials and clinical effects. JNeurol Neurosurg Psychiatry 1985; 48: 497-500 48 Wiles CM, Clarke CRA, Irwin HP, Edgar EF, Swan AV. Hype.,. baric oxygen in multiple sclerosis: A double blind trial. Br Med J 1986; 292:367-71 49 Harpur GD, Suke R, Bass BH, Martin MJ, Bull SB, Reese L, et al. Hyperbaric oxygen therapy in chronic stable multiple sclerosis: Double-blind study. Neurology 1986; 36:988-91 CHEST I 92 I 6 I DECEMBER. 1967
1081
50 Erwin CW, Massey EW, Brendle AC, Shelton DL, Bennett PB. Hyperbaric oxygen inHuences on the visual evoked potentials in multiple sclerosis patients. Neurology 1985; 35(Suppl 1):104 51 Murthy KN, Maurice PB, Wilmeth JB. Double-blind randomized study of hyperbaric oxygen 9HBOO versus placebo in multiple sclerosis (MS). Ibid 52 Massey EW, Shelton DL, Pact V, Greenberg J, Erwin W. Saltzman H, et al. Hyperbaric oxygen in multiple sclerosis: Doubleblind crossover study of 18 patients. Ibid 53 Siddharthan R, Sheremata WA, Defurtuna S, Suant A, Sheldon J. Multiple Sclerosis (MS): Correlation of magnetic resonance imaging with cerebrospinal fluid findings. Ibid 54 Davis JC, Dunn JM, Heimbach RD. Indications fur hyperbaric oxygen therapy. Texas Med 1980; 76:44-7 55 Slack WK, Gillian C, Harison HER, Cockerill G, O'Connor R. Analysis of complications of hyperbaric oxygen therapy in 455
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56 57
58 59 60 61
patients treated in single-person hyperbaric oxygen chambers. In: Proceedings of the Fourth International Congress on Hyperbaric Medicine. Wada J, Iwa 'I; eds. Baltimore: Williams and Wilkins 1970; 305-09 Bates D. Hyperbaric oxygen in multiple sclerosis: Discussion paper. J R Soc Med 1986; 79:535-37 Myers RAM, Schnitzer BM. Hyperbaric oxygen use update 1984. Postgraduate Med 1984; 76:83-95 Heimback RD. Quoted in Medical News. JAMA 1981; 246:1058 Marx RE. Letter to the editor. J Oral Maxillofiic Surg 1984; 42: 141-42 Califano JA Jr. Americas health care revolution. New York: Random House, 1986:104-05 Hyperbaric Committee of the Undersea Medical Society, revised classification, 1983
Hyperbaric <>t: A Therapy In Sean:h of D1seaaes (Gabb, Robin)