Citation: JAMA, The Journal of the American Medical Association, April 25, 1990 v263 n16 p2216(5)

Title: Hyperbaric oxygen therapy.
Authors: Grim, Pamela S.; Gottlieb, Lawrence J.; Boddie, Allyn; Batson, Eric
 

Subjects: Hyperbaric oxygenation Evaluation
Oxygen therapy Complications
Hyperbaric oxygenation Complications
Reference #: A8988013
 

Abstract: Hyperbaric oxygen (HBO) therapy involves intermittent inhalation of pure oxygen under a pressure greater than one atmosphere. During the 1960s, HBO was proposed as a treatment for cancer, heart attack, senility, and other conditions, but research studies did not obtain reproducible results. The skepticism engendered among medical personnel by these failures extended to HBO's use for treating clinical conditions that it had been shown to help. A review of these conditions is provided. HBO acts both mechanically, due to its pressure component, and physiologically, due to its oxygen component. HBO therapy has been effective in treating decompression sickness (the illness resulting from too-rapid changes in pressure by divers or aviators), and air embolism (introduction of air into the circulatory system, often unintentionally by medical personnel) by mechanically reducing the size of gas bubbles, and increasing oxygen levels in the blood. Oxygen is essential for proper function of certain cells of the immune system and, in certain injuries, such as burns and crush injuries, HBO treatment can increase the supply of oxygen to tissues otherwise deprived of it. Complications of HBO treatment include trauma to or rupture of cavities, neurotoxicity resulting from exposure to 100 percent oxygen for long periods, and other sequelae. HBO therapy is indicated for decompression sickness, air embolism, carbon monoxide poisoning, acute traumatic ischemia (crush injuries that deprive tissues of oxygen), and bacterial invasion of a necrotic wound (in which tissue has died). HBO may also stimulate regrowth of blood vessels in damaged tissue adjacent to areas treated by radiation therapy and may promote bone formation in cases of osteomyelitis (bone infection) that have not responded to other treatments. This therapy also shows promise for treating a variety of 'problem wounds', but randomized, prospective studies are lacking. Overall, HBO therapy is safe and effective for certain conditions, and well-formulated clinical trials could help extend its use to others. (Consumer Summary produced by Reliance Medical Information, Inc.)

Full Text COPYRIGHT American Medical Association 1990

Hyperbaric Oxygen Therapy Hyperbaric oxygen therapy involves intermittent inhalation of 100% oxygen under a pressure greater than 1 atm. Despite over a century of use in medical settings, hyperbaric oxygen remains a controversial therapy. The last 20 years have seen a clarification of the mechanism of action of hyperbaric therapy and a greater understanding of its potential benefit. However, despite the substantial evidence that hyperbaric oxygen may have a therapeutic effect in certain carefully defined disease states, many practitioners remain unaware of these findings or are concerned about using hyperbaric therapy because of the controversy it has engendered. This review examines the indications currently considered appropriate for hyperbaric oxygen and briefly evaluates animal and clinical data substantiating these indications. Areas in which the mechanism of action of hyperbaric oxygen is still not well understood, as well as possible new areas of applications, are discussed.

Hyperbaric oxygen (HBO) therapy involves intermittent inhalation of 100% oxygen under a pressure greater than 1 atm. [1] Both therapeutic and toxic effects result from two features of treatment: mechanical effects of increased pressure and physiologic effects of hyperoxia.

Hyperbaric oxygen therapy has long been accepted as a primary treatment for decompression sickness [2]; however, other proposed indications have been controversial. During the 1960s there was widespread enthusiasm for hyperbaric treatment of myocardial infarction, stroke, senility, and cancer. Enthusiasm waned after results of clinical trials (and direct experience) showed little benefit for these diseases.

The overzealous claims about the effectiveness of HBO therapy have left a legacy of skepticism among physicians. [3] However, animal studies, clinical trials, and greater clinical experience over the last two decades have produced a set of indications for which HBO therapy appears beneficial. These clinical conditions are substantially different from those in the 1960s. However, there has been no recent interdisciplinary review of HBO therapy delineating these current indications, despite their broad applications. Thus, while substantial evidence supports use of HBO therapy in certain carefully defined settings, many patients who might benefit go untreated because of their physician's unfamiliarity with recent research and overall uncertainty about the legitimacy of HBO as therapy.

We discuss the mechanism of action of HBO therapy and the commonly accepted clinical indications (Table 1) as delineated by the Undersea and Hyperbaric Medical Society, [1] the professional association of physicians administering HBO therapy, and we briefly review the data supporting current indications.

MECHANISMS OF ACTION

Pressure
 

In disease such as air embolism and decompression sickness, the therapeutic effect of HBO therapy is achieved through the mechanical reduction in bubble size brought on by an increase in ambient pressure. A 5 atm a bubble is reduced to 20% of its original volume and 60% of its original diameter.

Increasing pressure in HBO therapy is often expressed in multiples of atmospheric pressure absolute (ATA); 1 ATA equals 1 kg/c[m.sup.2] or 735.5 mm Hg. Most HBO treatments are performed at 2 to 3 ATA. In air embolism and decompression sickness, where pressure is crucial to therapeutic effect, treatments frequently start at 6 ATA.

This additional pressure, when associated with inspiration of high levels of oxygen, substantially increases the level of oxygen dissolved into blood plasma. This state of serum hyperoxia is the second beneficial effect of hyperbaric oxygen therapy.

Hyperoxia: Life Without Blood
 

At sea level in room air, hemoglobin is approximately 97% saturated with oxygen (19.5 vol% oxygen, of which approximately 5.8 vol% is extracted by tissue). The amount of oxygen dissolved into plasma is 0.32 vol%. An increase in P[O.sub.2] has a negligible impact on total hemoglobin oxygen content; however, it does result in an increase in the amount of oxygen dissolve directly into plasma. With 100% inspired oxygen the amount of plasma oxygen increases to 2.09 vol%. At 3 ATA plasma contains 6.8 vol% oxygen, a level equivalent to the average tissue requirements for oxygen. Thus, HBO treatment could and has sustained life without hemoglobin. [4]

The immune system, wound healing, and vascular tone are all affected by oxygen supply. Oxygen alone has little direct antimicrobial effect, even for most anaerobes [5]; it is, however, a crucial factor in immune function. Neutrophils require molecular oxygen as a substrate for microbial killing. The oxidative burst seen in neutrophils after phagocytosis of bacteria involves a 10-to 15-fold increase in oxygen consumption. [6] Here oxygen serves as a substrate in the formation of free radicals, which directly or indirectly initiate phagocytic killing. [7] This endogenous antimicrobial system virtually ceases functioning under conditions of hypoxia. A tissue [PO.sub.2] of at least 30 mm Hg of oxygen is considered necessary for normal oxidative function to occur. [8]

Oxygen partial pressures below this are often seen in damaged and infected tissues. Increasing the oxygen level in this tissue can allow restoration of white blood cell function and return of adequate antimicrobial action. [9] The cardiovascular effects of hyperbaric oxygen include a generalized vasoconstriction and a small reduction in cardiac output. [10] This ultimately may decrease the overall blood supply to a region, but the increase in serum oxygen content results in an overall gain in delivered oxygen. In conditions such as burns, cerebral edema, and crush injuries, this vasoconstriction may be beneficial, reducing edema and tissue swelling while maintaining tissue oxygenation. [11]

COMPLICATIONS

Usual complications of HBO therapy are listed in Table 2. They are a result of either barometric pressure changes or oxygen toxicity. The most common complications involve cavity trauma due to change in pressure. [12] Any air-filled cavity that cannot equilibrate with ambient pressure, such as the middle ear when the eustachian tube is blocked, is subject to deformity and barotrauma during pressure changes in HBO therapy.

Pneumothorax is a rare complication of HBO treatment, usually occurring only in patients with severe lung disease. Air embolism, presumably resulting from a small tear in the pulmonary vasculature, is another rare complication. [13] One hundred percent oxygen under high pressure is neurotoxic and can lower the seizure threshold and affect central nervous system control of respiration. However, neurotoxicity is rare with the low-pressure, short-duration treatments used clinically in HBO therapy. In one series the incidence was reported as 1.3 seizures per 10 000 treatments. [14]

Pulmonary oxygen toxic reactions can occur with 100% inspired oxygen at less than 1 ATA with prolonged exposure. Almost all patients will show pulmonary toxicity after 6 continuous hours of inspired oxygen at 2 ATA. [15] No clinical HBO protocol requires this length of continuous exposure to 100% oxygen. However, HBO treatments may contribute to the pulmonary oxygen toxicity seen in critically ill patients who receive high concentrations of inspired oxygen between hyperbaric treatments.

Although a concern in premature newborns, retrolental fibroplasia has not been noted in infants, children, or adults undergoing HBO therapy. [16] Development of cataracts has been reported in patients receiving more than 150 HBO treatments. [17]

Hyperbaric oxygen

Hyperbaric oxygen can be administered in either a multiplace or a monoplace chamber. Multiplace Chamber. Multiplace chambers are large tanks accommodating 2 to 14 people (Fig 1). They are usually built to achieve pressures up to 6 atm and have a chamber lock-entry system that allows personnel to pass through without altering the pressure of the inner chamber. Patients can be directly cared for by medical staff within the chamber. The chamber is filled with compressed air; patients breathe 100% oxygen through a face mask, head hood, or endotracheal tube. Although fire hazards restrict the use of certain electronic equipment, some monitors and ventilators with solid-state circuitry can be used within the chamber, allowing intensive care of critically ill patients. [18] The multiplace chamber's ability to maintain pressures of 6 atm or more, makes it the chamber of choice for decompression sickness and air embolism. Monoplace Chamber

Monoplace chambers (Fig 2) are far less costly than their larger counterparts and have allowed hospitals to institute HBO programs without prohibitive capital outlays. Most chambers are sized to allow a single patient to lie supine under a transparent acrylic dome or viewing port. The internal environment of a monoplace chamber is maintained at 100% oxygen; thus, the patient does not wear a mask. This high concentration of oxygen precludes the use of any electronic equipment in the chamber. However, specially adapted ventilators and monitoring systems do allow treatment of critically ill patients.

CLINICAL INDICATIONS

Acute Conditions

Decompression Sickness.—Although occasionally seen in aviators, decompression sickness is generally a disease of divers. During a dive, the diver is exposed to pressures greater than 1 atm, and tissue uptake of nitrogen increases according to the principles of Henry's law. With ascent, a pressure gradient develops, and nitrogen leaves the tissue, dissolving into the blood and passing to the lungs, where it is exhaled. With rapid ascent a steep pressure gradient develops and intravascular nitrogen gas bubbles form. [19] These can be detected in asymptomatic divers. [20]

With greater pressure gradients, the nitrogen bubbles become large enough and prevalent enough to mechanically deform tissue and obstruct blood vessels. The gas-fluid interface also interacts with blood cells, platelets, and proteins, causing disruption of the intravascular coagulation system. [21] Decompression sickness results. Divers can experience decompression sickness as pain only, usually as a "deep and dull ache" in the extremities. More serious cases can present as paraplegia or cardiovascular collapse due to embolization of bubbles into the cardiac or central nervous system.

Hyperbaric oxygen therapy mechanically decreases the size of the bubbles, oxygenates ischemic tissue, and reduces the nitrogen gradient. Any patient with decompression sickness should be transferred immediately to the nearest HBO facility with the capacity to decompress to 3 to 6 ATA, as this has been shown in numerous series to be the most reliable and effective treatment. [22,23] The Duke University Divers Alert Network maintains a 24-hour emergency consultation telephone number, (919) 684-8111, and can identify the closest available HBO facility.

Air Embolism.—Air embolism can be a complication of uncontrolled ascent in diving but more frequently is seen medically in iatrogenic misadventures. Bubbles can embolize to the cerebral or cardiac circulation, producing either severe neurologic symptoms or sudden death. Hyperbaric oxygen therapy has been part of successful treatment of air embolism due to cardiovascular procedures, [24,25] lung biopsies, [26] hemodialysis, [27] and central line placement. [28] Presumably, HBO therapy decreases the volume of the embolism and oxygenates local tissues. Treatment involves immediate descent to 6 ATA for 15 to 30 minutes on air, followed by decompression to 2.8 ATA, where the patient receives prolonged oxygen treatment.

Carbon Monoxide Poisoning.—Carbon monoxide poisoning accounts for half of all fatal poisonings in the United States. Multiple series have shown that patients with carbon monoxide poisoning improve markedly following treatment with HBO. [29-31] However, both the mechanism of carbon monoxide toxicity and the therapeutic effect of HBO are poorly understood. Carbon monoxide toxicity was long thought to be due to anoxia alone; [32] however, there is evidence that the pathophysiologic effects occur with carbon monoxide binding to the cytochrome-oxidase system, causing anoxia at the mitochondrial level. [33] In either case, HBO therapy is the most rapid way of displacing carbon monoxide bound to hemoglobin and cytochromes. The serum half-life of carboxyhemoglobin is decreased from 5 hours 20 minutes with room air to 80 minutes with 100% oxygen and 23 minutes with 100% oxygen at 3 ATA. [34] In treating patients with carbon monoxide poisoning, it is important to remember that serum carboxyhemoglobin levels do not reflect tissue levels of carboxyhemoglobin and, therefore, may not correlate with the degree of toxicity. Accompanying signs and symptoms are as important to guiding therapy as the serum carboxyhemoglobin level. [35] Although HBO therapy remains the preferred treatment for significant exposure (Table 3), only a few controlled human studies with inconclusive results have compared HBO with 100% oxygen at 1 atm. [36,37] Clostridial Myonecrosis.—Clostridial myonecrosis occurs when a hypoxic environment within a necrotic wound allows clostridial spores to convert to vegetative organisms. These organisms produce exotoxins that destroy red blood cells, cause tissue necrosis, and abolish local host defenses. The most important exotoxin is alpha toxin. A tissue [PO.sub.2] of 250 mm Hg inhibits the production of alpha toxin by Clostridium. [38]

Hyperbaric oxygen is commonly used as an adjunct therapy in clostridial infections. In vivo studies have demonstrated decreased mortality rates and diminished tissue loss in infected mice. [39,40] In a study by DeMello et al, [41] using a dog model of clinical Clostridium infection, 100% of infected control dogs and dogs randomized to either HBO therapy or surgery died. Fifty percent of the dogs that received antibiotics survived, 70% of the dogs that received antibiotics and underwent surgery survived, and 95% of the dogs that received antibiotics and HBO therapy and underwent surgery survived.

Multiple series have evaluated the effect of HBO therapy on clostridial infections in humans. [42,43] Surgeons experienced with its use emphasize that early HBO treatment reduces systemic toxic reactions so that patients in shock seem more stable and better able to tolerate surgery, and there is clearer demarcation of viable and nonviable tissue. There have, however, been no randomized, controlled studies.

Hyperbaric oxygen therapy has been recommended for treatment of necrotizing fasciitis, since anaerobic bacteria play a role in the disease. [44,45] The diversity of clinical states in retrospective studies and the paucity of experimental data make it difficult to demonstrate the effect of HBO therapy on nonclostridial soft-tissue infection. Although necrotizing fasciitis is an accepted indication for HBO, the benefit HBO therapy may provide is still poorly understood, and surgery remains the cornerstone of therapy. [46] Acute Traumatic Ischemia.—Acute crush injury to an extremity may cause severe edema and ischemia in tissue and capillary beds not relieved by restoration of arterial perfusion. Hyperbaric oxygen therapy may aid salvage during the acute stages of revascularization by reducing edema via vasoconstriction and increasing oxygen delivery via plasma flow. [47] Investigators have used HBO therapy successfully as an adjunct to surgery in crush injuries. [48,49] Additional evidence has demonstrated that HBO therapy may also serve as an adjunct therapy in the compartment syndrome. [50]

Chronic Conditions

Irradiated Tissue.—Radiation therapy, in addition to its therapeutic effects, can damage normal adjacent tissue. The initial pathologic process is a progressive obliterative endarteritis, resulting in areas of tissue hypoxia and eventual cell death. [51] Large areas of hypocellular, hypovascular, and hypoxic tissue are created that are devoid of functioning fibroblasts and osteoblasts. [52] Hyperbaric oxygen therapy appears to assist in salvaging such tissue by stimulating angioneogenesis in marginally viable tissue. [53] Marx and Johnson [54] emphasize that, in reconstructive surgery involving recently irradiated tissue, presurgical HBO treatment can help promote a well-vascularized wound bed that will enhance reconstruction and graft take. Using a specific HBO protocol of presurgical and postsurgical treatments, they demonstrated a satisfactory surgical outcome in 92% of their patients and a complication rate of 9%.

In osteoradionecrosis, tissue destruction progresses to breakdown of overlying tissues and symptomatic destruction of bone. Prior to the introduction of HBO therapy, only 5% to 30% of patients who developed osteoradionecrosis could expect remission with conservative therapy. [55] In a protocol developed by Marx, [56] a series of 58 patients received an initial series of HBO treatments, followed by debridement and further HBO treatment, as dictated by their clinical course. All 58 patients studied had resolution of symptoms of osteoradionecrosis, with good results on long-term follow up. These impressive results have been corroborated by others. [57,58] Successful results have also been demonstrated for radiation-induced cystitis [59] and other radiation-damaged soft tissue. [60] Hyperbaric oxygen therapy is beneficial for patients at risk for the development of osteoradionecrosis, such as irradiated patients requiring tooth extraction. In a randomized trial comparing HBO and penicillin therapy in 74 previously irradiated patients, 30% of the patients who received penicillin developed osteoradionecrosis, while 5.4% of the patients who received HBO developed osteoradionecrosis. [61] Similar results have been reported elsewhere. [62]

Refractory Osteomyelitis.—Hyperbaric oxygen is currently being used as an adjunctive therapy with debridement and antibiotics in osteomyelitis that has remained refractory to standard therapy. Animal studies have demonstrated that HBO therapy used in experimental models of osteomyelitis has increased osseous repair [63] and promoted callus formation, [64] possibly by promoting osteoclast activity. [65] Human studies involve series of patients in whom standard treatment regimens have failed. Multiple clinical series demonstrate substantial success with HBO therapy in these patients. [66-68] However, to date there have been no randomized trials.

Problem Wounds.—The rationale for HBO therapy in problem wounds is to intermittently increase the tissue oxygen tension to optimize fibroblast proliferation [69] and white blood cell killing capacity [70] during periods of hyperoxia and to stimulate angioneogenesis during periods of relative hypoxia. [71] Series have been published showing improved healing with HBO therapy in problem wounds refractory to standard therapy. [72,73] Patients in whom increased oxygenation of wounds can be demonstrated following HBO therapy are the most likely to benefit. However, unlike osteoradionecrosis, where a well-defined clinical problem has been shown to improve with a carefully designed protocol incorporating HBO therapy, treatment of problem wounds remains an ill-defined field, and HBO data often consist of small series without standardized patient populations or treatment schedules.

Hyperbaric oxygen therapy cannot substitute for surgical revascularization in advanced arterial insufficiency and cannot reverse inadequate microvascular circulation. [74] Hyperbaric oxygen therapy may serve as an adjunct in the treatment of certain problem wounds, but it cannot replace meticulous local care based on sound physiologic principles.

Special Considerations

Certain animal data indicate that HBO therapy may improve the outcome of moderate and severe burns. [75] Few centers use HBO as standard therapy, but recent publications of patient series have demonstrated good response. [76-78] Broad-based justification of the use of HBO in burns, however, will depend on favorable results of randomized clinical trials.

SUMMARY

Hyperbaric oxygen therapy is a safe and effective primary therapy when administered for decompression sickness and air embolism. The role of HBO as an adjunctive therapy in the treatment and prevention of osteoradionecrosis has been impressively documented. Its contribution to the treatment of clostridial myonecrosis has been substantiated by both animal models and clinical experience. The role of HBO therapy in recovery from carbon monoxide poisoning, while probably significant, is poorly understood and awaits clarification of the mechanism of action of both carbon monoxide poisoning and the beneficial effects of oxygen therapy.

Hyperbaric oxygen therapy is clearly of value for carefully defined indications. Successful extension of its use in other situations will be predicated on in vitro and in vivo experimental evidence and appropriate well-controlled clinical trials.

References

[1.] Hyperbaric Oxygen Therapy: A Committee Report. Bethesda, Md: Undersea and Hyperbaric Medical Society; 1986.
[2.] Francis TJ, Dutka AJ, Hallenbeck JM. Pathophysiology of decompression sickness. In: Bove AA, Davis JC, eds. Diving Medicine. Philadelphia, Pa: WB Saunders Co; 1990:170-187.
[3.] Gabb G, Robin ED. Hyperbaric oxygen: a therapy in search of diseases. Chest. 1987;92:1074-1082.
[4.] Boerema I, Meyne NG, Brummelkamp WK, et al. Life without blood: a study of the influence of high atmospheric pressure and hypothermia on dilution of blood. J Cardiovasc Surg. 1960;1:133-146.
[5.] Tally FP, Stewart PR, Sutter VL, Rosenblatt JE. Oxygen tolerance of fresh clinical anaerobic bacteria. J Clin Microbiol. 1975;1:161-164.
[6.] Badwey JA, Karnovsky ML. Active oxygen species and the functions of phagocytic leukocytes. Ann Rev Biochem. 1980;49:695-726.
[7.] Forman HJ, Thomas MJ. Oxidant production and bactericidal activity of phagocytes. Ann Rev Physiol. 1986;48:669-680.
[8.] Hohn DC, MacKay RD, Halliday B, Hunt TK. The effect of [O.sub.2] tension on the microbicidal function of leukocytes in wounds and in vitro. Surg Forum. 1976;27:18-20.
[9.] Knighton DR, Halliday B, Hunt TK. Oxygen as an antibiotic: the effect of inspired oxygen on infection. Arch Surg. 1984;119:199-204.
[10.] Risber J, Tyssebotn I. Hyperbaric exposure to a 5 ATA He-[N.sub.2]-[O.sub.2] atmosphere affects the cardiac function and organ blood flow distribution in awake trained rats. Undersea Biomed Res. 1986;13:77-90.
[11.] Nylander G, Lewis D, Nordstrom H, Larsson J. Reduction of postischemic edema with hyperbaric oxygen. Plast Reconstr Surg. 1985;76:596-601.
[12.] Bassett BE, Bennett PB. Introduction to the physical and physiological bases of hyperbaric therapy. In: Davis JC, Hunt TK, eds. Hyperbaric Oxygen Therapy. Bethesda, Md: Undersea and Hyperbaric Medical Society; 1977:11-24.
[13.] Bond GF. Arterial gas embolism. In: Davis JC, Hunt, TK, eds. Hyperbaric Oxygen Therapy. Bethesda, Md: Undersea and Hyperbaric Medical Society; 1977:141-152.
[14.] Davis JC, Dunn JM, Heimbach RD. Hyperbaric medicine: patient selection, treatment procedures, and side effects. Davis JC, Hunt TK, eds. Problem Wounds: The Role of Oxygen. New York, NY: Elsevier Science Publishing Co Inc; 1988;225-235.
[15.] Clark JM, Lambertson CJ. Pulmonary oxygen toxicity: a review. Pharmacol Rev. 1971;23:37-133.
[16.] Nichols CW, Lambertsen CJ. Effects of high oxygen pressures on the eye. N Engl J Med. 1969;291:25-30.
[17.] Palmquist BM, Phillipson B, Barr PO. Nuclear cataract and myopia during hyperbaric oxygen therapy. Br J Ophthalmol. 1984;68:113-117.
[18.] Kindwall EP, Goldman RW, eds. Hyperbaric Medical Procedures. Milwaukee, Wis: Saint Lukes Medical Center; 1988.
[19.] Lynch PR, Brigham M, Tuma R, Wiedeman MP. Origin and time course of gas bubbles following rapid decompression in the hamster. Undersea Biomed Res. 1985;12:105-114.
[20.] Whitecraft DD, Karas S. Air embolism and decompression sickness in scuba divers. JACEP. 1976;5:355-361.
[21.] Tanoue K, Mano Y, Kuroiwa K, Suzuki H, Shibayama M, Yamazaki H. Consumption of platelets in decompression sickness of rabbits. J Appl Physiol. 1987;62:1772-1779.
[22.] Kizer KW. Delayed treatment of dysbarism: a retrospective review of 50 cases. JAMA. 1982;247:2555-2558.
[23.] Green RD, Leitch DR. Twenty years of treating decompression sickness. Aviat Space Environ Med. 1987;58:362-366.
[24.] Thomatis L, Nemiroff M, Riahi M, et al. Massive arterial air embolism due to rupture of pulsatile assist device: successful treatment in the hyperbaric chamber. Ann Thorac Surg. 1981;32:604-608.
[25.] Peirce EC II. Specific therapy for arterial air embolism. Ann Thorac Surg. 1980;29:300-303.
[26.] Cianci P, Posin JP, Shimshak RR, Singzon J. Air embolism complicating percutaneous thin needle biopsy of lung. Chest. 1987;92:749-750.
[27.] Baskin FE, Wozniak RL. Hyperbaric oxygenation in the treatment of hemodialysis associated air embolism. N Engl J Med. 1975;293:184-185.
[28.] Murphy BP, Hartford FJ, Cramer FS. Cerebral air embolism resulting from invasive medical procedures: treatment with hyperbaric oxygen. Ann Surg. 1985;201:242-245.
[29.] Myers RAM, Snyder SK, Linberg S, Cowley RA. Value of hyperbaric oxygen in suspected carbon monoxide poisoning. JAMA. 1981;246:2478-2480.
[30.] Norkool DM, Kirkpatrick JN. Treatment of acute carbon monoxide poisoning with hyperbaric oxygen: a review of 115 cases. Ann Emerg Med. 1985;14:1168-1171.
[31.] Goldbaum LR, Ramirez RG, Absalom KB. What is the mechanism of carbon monoxide toxicity? Aviat Space Environ Med. 1975;46:1289-1291.
[32.] Jackson DL, Menges H. Accidental carbon monoxide poisoning. JAMA. 1980;243:772-774.
[33.] Kindwall EP. Carbon monoxide poisoning treated with hyperbaric oxygen. Respir Ther. 1975;5:29-33.
[34.] Peterson JE, Stewart RD. Absorption and elimination of carbon monoxide by inactive young men. Arch Environ Health. 1970;21:165-175.
[35.] Kindwall EP. Carbon monoxide and cyanide poisoning. In: Davis JC, Hunt TK, eds. Problem Wounds: The Role of Oxygen. New York, NY: Elsevier Science Publishing Co Inc; 1988:177-190.
[36.] Raphael JC, Elkharrat D, Jars-Guincestre MC, et al. Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet. 1989;2:414-419.
[37.] Goulon M, Barois A, Rapin M, Nouailhat F, Grosbuis S, Labrousse J. Carbon monoxide poisoning and acute anoxia. J Hyperbar Med. 1986;1:23-41.
[38.] Van Unnik AJM. Inhibition of toxin production in Clostridium perfringens in vitro by hyperbaric oxygen. Antonie von Leeuwenhoek. 1965;31:181-186.
[39.] Holland JA, Hill GB, Wolfe WG, Osterhout S, Saltzman HA, Brown IW. Experimental and clinical experience with hyperbaric oxygen in the treatment of clostridial myonecrosis. Surgery. 1975;77:75-85.
[40.] Hill GB, Osterhout S. Experimental effects of hyperbaric oxygen on selected clostridial species, II: in vivo studies in mice. J Infect Dis. 1972;125:26-35.
[41.] DeMello FJ, Haglin JJ, Hitchcock CR. Comparative study of experimental Clostridium perfringens infection in dogs treated with antibiotic, surgery, and hyperbaric oxygen. Surgery. 1973;73:936-941.
[42.] Gibson A, Davis FM. Hyperbaric oxygen therapy in the management of Clostridium perfringens infections. N Z Med J. 1986;99:617-620.
[43.] Hart GB, Lamb RC, Strauss MB. Gas gangrene, II: a 15-year experience with hyperbaric oxygen. J Trauma. 1983;23:995-1000.
[44.] Schreiner A, Tonjum S, Digranes A. Hyperbaric oxygen therapy in Bacteroides infections. Acta Chir Scand. 1974;140:73-76.
[45.] Bakker DJ. Necrotizing soft tissue infections. J Hyperbar Med. 1987;2:161-169.
[46.] Miller JD. The importance of early diagnosis and surgical treatment of necrotizing faciitis. Surg Gynecol Obstet. 1983;157:197-200.
[47.] Davis JC, Heckman JD. Compromised soft tissue wounds. In: Davis JC, Hunt TK, eds. Problem Wounds: The Role of Oxygen. New York, NY: Elsevier Science Publishing Co Inc; 1988:125-142.
[48.] Loder RE. Hyperbaric oxygen therapy in acute trauma. Ann R Coll Surg Engl. 1979;61:472-473.
[49.] Monies-Chass I, Hashmonai M, Hoerer D, Kaufman T, Steiner E, Schramek A. Hyperbaric oxygen treatment as an adjuvant to reconstructive vascular surgery in trauma. Injury. 1977;8:274-277.
[50.] Strauss MB, Hargens AR, Gershuni DH, et al. Reduction of skeletal muscle necrosis using intermittent hyperbaric oxygen in a model compartment syndrome. J Bone Joint Surg Am. 1983;65:656-662.
[51.] Ewing J. Radiation osteitis. Acta Radiol. 1926;6:399-412.
[52.] Marx RE. Osteoradionecrosis: s new concept of its pathophysiology. J Oral Maxillofac Surg. 1983;41:283-288.
[53.] Hunt TK, Dai MP. The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet. 1972;135:561-567.
[54.] Marx RE, Johnson RP. Problem wounds in oral and maxillofacial surgery: the role of hyperbaric oxygen. In: Davis JC, Hunt TK, eds. Problem Wounds: The Role of Oxygen. New York, NY: Elsevier Science Publishing Co Inc; 1988;65-124.
[55.] Obwegesser HB, Sailer HF. Experience with intra-oral resection and immediate reconstruction in cases of radio-osteomyelitis of the mandible. J Maxillofac Surg. 1978;6:257-261.
[56.] Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg. 1983;41:351-357.
[57.] Farmer JC Jr, Sheldon DL, Angelillo JD, Bennett PD, Hudson WR. Treatment of radiation-induced tissue injury by hyperbaric oxygen. Ann Otol Rhinol Laryngol. 1978;87:707-715.
[58.] Davis JC, Dunn JM, Gates GA, Heimbach RD. Hyperbaric oxygen: a new adjunct in the management of radiation necrosis. Arch Otolaryngol Head Neck Surg. 1979;105:58-61.
[59.] Weiss JP, Boland FP, Mori H, et al. Treatment of radiation-induced cystitis with hyperbaric oxygen. J Urol. 1985;134:352-354.
[60.] Ferguson BJ, Hudson WR, Farmer JC Jr. Hyperbaric oxygen for laryngeal radionecrosis. Ann Otol Rhinol Laryngol. 1987;96:1-6.
[61.] Marx RE, Johnson RP, Kline SN. Prevention of osteoradionecrosis: a randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J Am Dent Assoc. 1985;111:49-54.
[62.] Kraut RA. Prophylactic hyperbaric oxygen to avoid osteoradionecrosis when extractions follow radiation necrosis. Arch Otolaryngol Head Neck Surg. 1985;7:17-20.
[63.] Triplett RG, Branham GB, Gillmore JD, Lorber M. Experimental mandibular osteomyelitis: therapeutic trials with hyperbaric oxygen. J Oral Maxillofac Surg. 1982;40:640-646.
[64.] Niinikoski J, Penttinen R, Kulonen E. Effect of hyperbaric oxygen on fracture healing in the rat: a biochemical study. Calcif Tissue Res. 1970;4(suppl):115-116.
[65.] Mader JT, Brown GL, Guskian JC. A mechanism for the amelioration by hyperbaric oxygen of experimental Staphylococcus osteomyelitis in rabbits. J Infect Dis. 1980;142:915-922.
[66.] Davis JC, Heckman JD, DeLee JC, Buckwold FJ. Chronic nonhematogenous osteomyelitis treated with adjuvant hyperbaric oxygen. J Bone Joint Surg Am. 1986;66:1210-1217.
[67.] Strauss MB. Refractory osteomyelitis. J Hyperbar Med. 1987;2:146-159.
[68.] Herman DS. Hyperbaric oxygen therapy and its role in the treatment of chronic osteomylelitis: a preliminary report involving refractory osteomyelitis in the foot. J Foot Surg. 1985;24:293-300.
[69.] Silver IA. Local and systemic factors which affect the proliferation of fibroblasts. In: Kulonen E, Pikkarainen J, eds. The Biology of Fibroblast. Orlando, Fla: Academic Press Inc;1973:507-520.
[70.] Hohn DC, Ponce B, Burton RW, Hunt TK. Antimicrobial systems of the surgical wound, I: a comparison of oxidative metabolism and microbicidal capacity of phagocytes from wounds and from periferal blood. Am J Surg. 1977;133:597-600.
[71.] Kighton D, Silver I, Hunt TK. Regulation of wound healing angiogenesis: effect of oxygen gradients and inspired oxygen concentration. Surgery. 1981;90:262-270.
[72.] Wyrick WJ, Mader JT, Butler E, Hulet WH. Hyperbaric oxygen in treatment of pyoderma gangrenosum. Arch Dermatol. 1978;114:1232-1233.
[73.] Bass BH. The treatment of varicose leg ulcers by hyperbaric oxygen. Postgrad Med. 1970;46:407-408.
[74.] Davis JC, Buckley CJ, Barr PO. Compromised soft tissue wounds: correction of wound hypoxia. In: Davis JC, Hunt TK, eds. Problem Wounds: The Role of Oxygen. New York, NY: Elsevier Science Publishing Co Inc; 1988:143-152.
[75.] Korn HN, Wheeler ES, Miller T. Effect of hyperbaric oxygen on second-degree burn wound healing. Arch Surg. 1977;112:732-737.
[76.] Cianci P, Lueders H, Lee H, et al. Adjunctive hyperbaric oxygen reduces the need for surgery in 40-80% burns. J Hyperbar Med. 1988;3:97-101.
[77.] Wiseman DH, Grossman AR. Hyperbaric oxygen in the treatment of burns. Crit Care Clin. 1985;1:129-145.
[78.] Niu AKC, Yang C, Lee HC, Chen SH, Chang LP. Burns treated with adjunctive hyperbaric oxygen therapy: a comparative study in humans. J Hyperbar Med. 1987;2:75-85.