Research on Rheumatic Diseases

Occasional Review Use of hyperbaric oxygen in rheumatic diseases: case report and critical analysis

DJ Wallace,1,2 S Silverman,2* J Goldstein3 and D Hughes4
1Department of Medicine, Cedars-Sinai Medical Centre, 2UCLA School of Medicine, Los Angeles. CA.  3The Chronic Fatigue Syndrome Institute, Anaheim, CA and 4The Hyperbaric Oxygen Institute. San Bernardino, CA, USA

Hyperbaric oxygen has been used in patients with rheumatic disease for many years without reports of untoward or unusual complications for a variety of non-rheumatic indications. Recent evidence that hyperbaric oxygen inhibits the actions of certain cytokines, acts as an immune modulator and may help cognitive dysfunction has resulted in a re-examination of its potential role in rheumatic diseases. A case report of a lupus/scleroderma crossover patient is presented whose cognitive dysfunction improved after hyperbaric oxygen therapy. The history of hyperbaric oxygen and its physiology are related, along with a focused review of its effects on the immune and central nervous systems. Areas which might warrant further consideration by rheumatologists are outlined, as well as areas of concern.

Keywords:  hyperbaric oxygen: scleroderma: rheumatic diseases

Introduction 
Hyperbaric oxygen therapy is defined as the subjecting of patients to pure oxygen breathing at ambient temperatures which arc greater than normal atmospheric pressure. Although concepts of hyperbaric oxygen therapy were first employed in 1662, its modern use other than for decompres­sion dates from 1956 when hyperbaric oxygen was used to perform cardiac surgery in Holland.' Mechanically, the most common applications of hyperbaric oxygen are to dissolve air or gas emboli and treat divers with 'bends' or decompression sickness.

New insights into the biochemical and immune interactions of hyperbaric oxygen have increased interest in its potential applications over the past decade. The United States Medicare system has approved hyperbaric oxygen for 14 different indications ranging from acute carbon monoxide intoxication, gas gangrene and osteoradionecrosis to acute peripheral arteriolar insufficiency. Over the past 20 years, patients with a variety of conditions, especially multiple sclerosis, have reported cognitive improvements after undergoing hyperbaric oxygen. One lupus/scleroderma crossover patient whose case is reported here, underwent hyperbaric oxygen therapy specifically for cognitive impairment and experienced subjective and objective improve­ment. Her case is presented and our concepts of hyperbaric oxygen and the immune and central nervous systems are reviewed.

Case report 
A 53-year oldCaucasian woman flight attendant who was in her usual state of health until 1979 when she underwent thyroidectomy and inadvertent parathyroidectomy for Graves' disease. In February 1980 her Heyer-Schulte saline breast implants (placed in 1977 for cosmetic purposes) were replaced with Cox-Uphoff silicone prostheses. She was well until 1986 when she presented to UCLA Medical Center with subcutaneous edema, Raynaud's phenomenon, sclerodactyly, inflammatory arthritis and erythematous rashes. A work-up demonstrated an ANA of 1:40(speckled), elevated sedimentation rates (averaging in the high 30s), and persistently decreased IgA levels. She was diagnosed as having a lupus/scleroderma crossover, al­though the possibility of eosinophilic fasciitis was con­sidered. (It was ultimately ascertained that she occasionally took L-tryptophan to sleep after long flights.) No disease modifying therapy was given; supportive diuresis and nonsteroidal anti-inflammatory agents were prescribed. Over the following 7 years, her ANA rose to 1:1280 (homogeneous), a positive IgG anticardiolipin antibody was found, and her course was complicated by pericarditis and supraventricular tachyarrhythymias. The latter two items were felt to be suggestive of cardiac scleroderma: anti RNP was negative and her inflammatory arthritis subsided, sclerodactyly worsened and brawny subcutaneous edema persisted. By 1990, she was no longer able to work and went on disability. In 1991 she was explanted with subjective improvement in her musculoskeletal pains. Although she had intermittent myofascial tender points in her upper back and neck area, the ACR criteria for fibromyalgia were never fulfilled. Sinus surgery performed in 1993 incidentally revealed silicone granulomas in her sinuses. The patient began complaining of cognitive dysfunction and extreme fatigue by 1990 which did not improve with explantation. An MRI scan of the brain in 1993 showed left parieto occipital deep white matter perivascular changes. Her medications at the time included thyroid, estrogen/proges­terone hormonal replacement and vitamin D. On 7 January 1994 a SPECT scan demonstrated evidence for moderate and extensive temporal, parietal, frontal (more than two standard deviations below normal) and mild occipital and cerebellar (1.5 standard deviations below normal) hypoperfusion. She underwent 15 treatments over 3 weeks of hyperbaric oxygen with 1.5 atmospheres for 30 mm at a free-standing facility without complication in February 1994. Immediately afterwards, her cognitive abilities sub­jectively improved. She .applied for reinstatement with her airline and took a 3-week in-flight retraining course, graduating at the top of her class. Nine months later, on 11 October the SPECT scan was repeated at the same facility. The original abnormalities were still present, but an overall 3-6% improvement of tracer distribution was evident. In the left occipital lobe and left and right superior parietal lobes, approximately 12% improvements were noted. At that time her ANA was 1:1280 (homogeneous), Westergren sedimentation rate 5 mm/h, and she was a senior flight attendant on the Los Angeles-Hong Kong route for her airline, making three round trips a month.

Discussion. 
Several of our patients with lupus have undergone hyper­baric oxygen for osteomyelitis over the years without problems, and a few reported a slight decrease in their lupus activity and improved ability to think clearly. The case presented is the first where dramatic cognitive improvements were purported, although detailed cogni­tive-related objective testing other than SPECT scanning was not performed before and after treatment She pre­sented with an unusual and perhaps unique combination of features that could be consistent with silicone adjuvant arthropathy, eosinophilic myalgic syndrome, Graves' disease, systemic lupus erythematosus and scleroderma. Al­though it is possible that the timing of her cognitive improvements and hyperbaric oxygen were coincidental, it is our belief that this case warrants further examination of the potential use of hyperbaric oxygen in rheumatic diseases.
 
What is hyperbaric oxygen therapy and how is it adrninistered?2-4
At one atmosphere, patients with a normal hemoglobin (15 g/dl) can theoretically transport about 20 ml of oxygent 100 ml of blood (95% as oxyhemoglobin and 5% in solution), but this actually decreases by two thirds after passing through the capillaries. The ability of a gas to dissolve into liquid is dictated by its index of solubility, partial pressure and temperature (Henry's General Gas Law). With hyperbaric oxygen, enough molecular oxygen can be dissolved into a patient's blood stream to satisfy all metabolic requirements. For example, breathing 100% oxygen at 1, 2 or 3 atmospheres results in 2,4 and 6 ml of oxygen in solution per 100 ml of blood, respectively. Patients are usually treated with 1.2-3.0 times atmospheric pressure for 30-90 min which is equivalent to the pressure that a diver is exposed to at a depth of between 5 and 20 metres underwater.

The cost of hyperbaric oxygen ranges from $200 to $500 per treatment and a course of therapy ranges from 15 to 40 treatments ($3,000-$20,000). Hyperbaric oxygen can be administered in a variety of pressure chambers: large multiplace units where six or more patients are treated at the same time; smaller one or two place chambers which are also pressurized with air and patients breathe oxygen through aviation-type masks, or hoods; and smaller single place chambers which are pressurized with oxygen and no mask system is needed.

What are the physiologic actions of hyperbaric oxygen therapy? 
Increased oxygen tension has profound effects on the body's metabolism and cellular milieu. By preserving ATP in cell membranes it decreases edema and is particularly useful in burn patients. Hyperbaric oxygen promoted capillary angiogenesis, decreases leukocyte adhesion and platelet aggrega­tion to capillary walls after trauma, increases the ability of white blood cells to engage in microbial killing, increases tissue levels of superoxide dismutase and increases collagen and fibroblast formation.5,6 Hyperbaric oxygen decreases blood flow to tissues while increasing their oxygen tension. Clinically, it has been used to promote wound healing, especially to ischemic areas. Other physiologic effects include a 10-20% reduction in cardiac output due to slowing the heart rate.7

How does hyperbaric oxygen affect the immune system?
Healthy volunteers given hyperbaric oxygen have a sig­nificant increase in CD8 levels and decrease in CD4 levels. This is associated with a rise in the number of HLA-DR antigen bearing cells, with a transient increase in monocytes.8 These changes are observable for a little over 24 h.

CD3 levels, B cell and natural killer cell values do not change. Similar findings have been found in normal mice in two separate studies.9-10 Interestingly, the administration of hyperbaric oxygen to NZB or MRL/lpr mice suppressed immunoglobulin production by spleen cells.9 Long-term hyperbaric oxygen delayed the development of proteinuria. facial erythema and lymphadenopathy in MRL/lpr mice. Inamoto et al showed that hyperbaric oxygen has im­munosuppressive properties modulated by decreasing interleukin 1 and prostaglandin E2 production, but interleukin 6 production was not altered.11

How does hyperbaric oxygen affect the central nervous system?
Studies of hyperbaric oxygen on the central nervous system show that at tensions of 1.2-1.5 atmospheres absolute (ATA), it decreases blood flow by 1-20% (mean of various studies is about 10%).2 Other physiologic changes occur. These include greater permeability of the blood-brain barrier to medications and increased oxygen tensions to tissues that far outweigh the net effects of mild vasocon­striction. The deformability of erythrocytes is increased resulting in improved oxygen transportation in the microvasculature circulation and lactate removal.12 Hyperbaric oxygen stimulates the metabolism of nerve cells deprived of oxygen. As early as the 1960s, Meijne reported cognitive improvements in patients to performing mathematical calculations and demonstrated increased typewriter skills after hyperbaric oxygen.13 An area of controversy among hyperbaricists concerns the possibility that once 1.5 ATA is exceeded, anaerobic metabolism is favored and thus cognitive skills do not improve as well as they would at lower pressures. Di Sabato et al14performed a controlled study (with sham hyperbaric controls) on patients with cluster headaches. The dramatic improvements were attributed to vasoconstriction, decreased edema, increased serotonin synthesis and decreased cerebral hypoxia. Additionally, in the central nervous system hyperbaric oxygen decreases adrenaline and monoamine oxidase levels as well as promoting axonal regeneration.15

Hyperbaric oxygen for multiple sclerosis and other autoimmune diseases
As hyperbaric oxygen decreases demyelination from perivascular edema, over 6000 patients with multiple sclerosis have undergone this therapy in the past 10 years. A published trial by The New England Journal of Medicine suggesting improvement with hyperbaric oxygen in 40 patients in 1983 stimulated considerable interest.16 However, it was evident that even though hyperbaric oxygen increased helper T lymphocyte levels, patients liked the treatment and reported subjective improvements (especially in sense of well-being, cognition and bladder function), four separate placebo-controlled double-blind trials failed to demonstrate any objective benefits of using the Kurtzke Disability Status Scale or any other parameters.17-20 This was also confirmed in a 22 institution multicenter registry of 312 patients followed for 2 years.21

Occasionally patients with other rheumatic syndromes and associated complications have been held to respond to hyperbaric oxygen. Aseptic necrosis complicating systemic lupus, for example, appears to be worthy of greater scrutiny. 22 Abstracts and presentations at seminars and meetings on hyperbaric oxygen claim benefits for pneumatosis cystoides intestinalis in scleroderma, livedo reticularis with vasculitis and Raynaud's phenomenon. Articles have appeared advocating hyperbaric oxygen for Crohn's disease and cyclophosphamide-associated hemorrhagic cystitis.23,24

How safe is hyperbaric oxygen?
Hyperbaric oxygen is generally quite safe, but serious complications can occur.25 Absolute contraindications to hyperbaric oxygen include pregnancy, underlying malig­nancy, untreated pneumothorax, concomitant therapy with doxorubicin, cis-platinum or disulfiram. Special considerations need to be taken into account if the patient has upper respiratory tract infections or chronic sinusitis (which make clearing the ears and sinuses problematic), low seizure thresholds (with high fevers or epilepsy), emphysema with CO2 retention (which suppresses breath­ing), and congenital spherocytosis (hemolysis can result). The most common complication of hyperbaric oxygen is barotrauma to the ears and sinuses caused by pressure changes, which has been reported in about 5%. Occurring in 0.1-5% of patients are hypersensitivity reactions, confinement anxiety, central nervous system oxygen tox­icity, pulmonary oxygen toxicity and temporary changes in eyesight. To minimize risks, patients are advised to have an ear, nose and throat examination by the treating physician before therapy, not to drink alcohol or take any medication for 4 h prior to treatment, and to wear cotton clothing.

Is there a potential role for hyperbaric oxygen in rheumatic diseases?
Very little is known about the influence of hyperbaric oxygen on the immune system. Animal models of autoimmune disease and normal mice are conducive to hyperbaric oxygen studies. Hyperbaric oxygen might be useful in combination with other therapeutic modalities. Further study is needed in these areas before proceeding to human trials. Nevertheless, anecdotal testimonials that hyperbaric oxygen helps people think more clearly should be taken seriously and ultimately subjected to a prospective trial.
Systemic lupus erythematosus (SLE) is an autoimmune disorder that afflicts several hundred thousand Americans. Nearly half manifest similar cognitive deficits that do not respond to Corticosteroids.26 In the past few years, the development of single photon emission computerized tomography (SPECT) has shown hypoperfusion abnormalities bitemporally and bifrontally in patients with SLE and,  incidentally,  with  fibromyalgia/chronic fatigue syndromes.27-29

Hyperbaric oxygen is a well characterized, old technology whose immunomodulatory properties and effects on cognition have never been adequately studied. Although relatively expensive, this reasonably safe procedure might have potential heretofore unrealized applications to patients with rheumatic disease.

References
1  Meijne NG. The history of hyperbaric oxygen. In: NG Meine (ed.) Hyperbaric Oxygen and its Clinical Value. Springfield. IL: C Thomas.1970: 3-10.
2  Fischer D et al. Handbook of Hyperbaric Oxygen Therapy. Geneva: Springer Verlag. 1989.
3 Bakker DJ. Hyperbaric oxygen therapy: past. present and future indications. Adv Exp Med Biol  1992: 317: 95-105.
4  NHLBI Workshop Summary. Hyperbaric oxygen therapy. Am Rev Respir Dis 1991:144:1414-1421.
5  Kindwall EP. Hyperbaric oxygen: more indications than many doctors realise. Br Med J 1993;    307: 515-516 (editorial).
6   Kaelin CM et al Theeffects of hyperbaric oxygen on free flaps in rats. Arch Surg 1990; 125:    607-609.
7   Committee Report on Hyperbaric Oxygen Therapy. Publication no. 3OCR (HBO) 1989.    revised edition. Undersea and Hyperbaric Medical Society, Bethesda. MD. USA.
8   Bittennan N et al Effect of a single expoxure oxygen on blood mononuclear cells in human subjects. Undersea Hyper Med 1993: 20:194-204.
9   Saito K et al Suppressive effect of hyperbaric oxygen on immune responses of normal and autoimmune mice. Clin Exp Immun 1991:86: 322-327.
10  Gadd MA er al. Effect of hyperbaric oxygen on murine neutrophil and T lymphocyte  functions. Crit Care Med 1991 18: 974-979.
11  Inamoto Y et al Effect of hyperbaric oxygen on macrophage function in mice. Biochem Biophys Res Commun 1991; 179: 886-891.
12  Neubauer RA. Gottlieb SF. Miala A Jr. Identification of hypometabolic areas in the brain using brain imaging and hyperbaric oxygen. Clin Nuc Med 1992: 17: 477-481.
13  Meijic NG. The influence of high nitrogen tensions on workers in compressed air. In: NG Meijne (ed.) Hyperbaric Oxygen and its Clinical Value. Springfield IL: C Thomas. 1970: 84-93.
14  Di Sabato et al. Hyperbaric oxygen therapy in cluster headache. Pain,1993; 52: 243-245.
15  Fischer D et al. Hyperbaric oxygen in disorders of the nervous system.In: Fischer D (ed) Handbook of Hyperbaric Oxygen Therapy. Geneva: Springer 1989:135-149.
16  Fisher BH. Marx M, Reich T. Hyperbaric oxygen treatment of multiple sclerosis: a randomized and placebo controlled double-blind Study. N EngI J Med 1983;308: 181-186.
17  Wiles CM et al. Hyperbaric oxygen in multiple sclerosis: a double blind trial. Br Med J 1986; 292: 367-371.
18  Barnes MP et al. Hyperbaric oxygen an:l multiple sclerosis: short-term results of a placebo-controlled. double-blind trial. Lancet 1985: 1:297-300.
19  Wood J et al. A double-blind trial of hyperbaric oxygen in the treatment of multiple sclerosis. Med J Aust 1985; 143: 238-240.
20  Harpur GD et al Hyperbaric oxygen therapy in chronic stable multiple sclerosis: double-blind study. Neurology 1986: 36: 988-991.
21  Kindwall EP et al Treatment of multiple sclerosis with hyperbaric oxygen. Results of a national registry. Arch Neur 1991: 48:195-199.
22  Marx RE, Johnson RP Studies in the radiobiology of Osteor­adionecrosis and their clinical significance. Oral Surg Oral Med Oral Pathol 1987; 64: 379-390.
23  Brady CE, Cooley BI,Davis JC. Healing of Severe perianal and cutaneous Crohn'sdisease with hyperbaric oxygen. Gastrenterology1989;97: 756-760
24  Hader JE et al. Hyperbaric oxygen treatment for experimental cyclophosphamide-induced hemorrhagic cystitis. J UroI 1993: 149:1617-1621.
25  KK Jain (ed). Textbook of Hyperbaric Medicine. Lewiston, NY: Hogart & Huber, 1992.
26  Wallace DJ, Metzger et al. Systemic lupus and the nervous system. In Wallace DJ, Han BH (eds), Dubois’ Lupus Erythematosus, 4th end. Philadelphia, PA: Lea & Febiger. 1993; 370-385.
27  Rubbert A et al. Single photon emission computed tomography analysis of cerebral blood flow in the evaluation of central nervous system involvement in patients with systemic lupus erythematosus.Arthritis Rheum 1993; 36:1253-1262.
28  Ichise M et al. Assessment of regional cerebral perfusion by 99mTchMPAO SPECT in chronic fatigue syndrome. Nuc Med Comm 1992:13: 767-772.
29  Goldstein JA et al. The assessment of vascular abnormalities in late life chronic fatigue syndrome by brain SPECT: comparison with late life major depressive disorder. J Chr Fatigue Syndrome  1995:1: 55-79.

For those interested in receiving HBOT that may have difficulty with financing the treatments, we have people that can give advice on fund-raising. The previous case studies are only a glimpse of the hundreds of people which have received HBOT at the Richmond Hyperbaric Center for a variety of conditions with favorable outcomes. Please contact us for more information on a particular condition which may benefit from hyperbaric oxygen therapy.

The Richmond Hyperbaric Health Center has engaged in scientific research projects including a pilot study on the treatment of RSD/CRPS. We would like to pursue future research studies as well and are open to any inquiries about the use of  HBOT  for researching various conditions.