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Stroke. 2003;34:e153-e155
Published online before print August 21, 2003, doi: 10.1161/01.STR.0000087115.91721.6E
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(Stroke. 2003;34:e153-a.)
© 2003 American Heart Association, Inc.

Letters to the Editor

Hyperbaric Oxygen Therapy

G.B. Hart, MD M.B. Strauss, MD

Department of Baromedicine, Memorial Medical Center, Long Beach, California

To the Editor:

We applaud the authors’ efforts in attempting to use randomized controlled trials to study the effects of hyperbaric oxygen (HBO) in acute ischemic strokes. Although we agree that the pressure at which the patients were treated (2.5 atm absolute [ATA]) is appropriate, we feel that several of their other methodologies and interpretations require comments.

First: The time interval from onset of symptoms to the first HBO treatment is critical. The "golden period" from blockage of a vessel of the brain by thrombus or embolus with onset of neurological dysfunction is 3 hours.1 This is defined as the first reperfusion period. The second reperfusion period occurs from 3 to 5 hours2 after the occlusion. Successful outcomes in the treatment of cerebral gas embolism with HBO during the second reperfusion have been observed.3 Hence, any study using HBO has to consider these 2 reperfusion times.

Second: The complication of cerebral edema associated with the treatment of arterial gas embolism has been observed4,5 even with immediate HBO treatment. We have reported evidence of a post-HBO exposure vasodilatation occurring in otherwise healthy volunteers.6 We do not feel these observations are a cause of morbidity.

Third: The minimum of a 1-hour HBO exposure at 2 ATA is required to saturate the mixed venous hemoglobin return to the right atrium in normal resting males.7 An additional 30 minutes is needed to saturate the other tissues of the body. Treatment duration less than this would not be expected to give optimal results.

Fourth: For optimal results with acute ischemia of the brain, repetitive HBO treatments are recommended.3,8 Adequate treatment pressures, durations, and repetitions improve outcomes.9

An earlier controlled study, which also showed no benefit from HBO, has some of the same criticisms as this study: for example, treatment durations were 40 minutes and treatment pressures were only 1.5 ATA.10

In view of our experience we recommend the following management for all thrombotic/embolic cerebrovascular episodes within 6 hours of onset of symptoms. This management has been used in >80 patients treated in a monoplace chamber compressed in and breathing HBO without using air breaks—improvement percentages using the Rankin scoring system equaled the NIH tPA study.11

I. HBO and thrombolytic routine (thrombolysis is to be used within the first 3 hours from symptom onset) prior to CT scan. Note: The combinations of thrombolysis and HBO have been reported as safe and with benefits in myocardial infarction.12

II. HBO at 3 ATA for 30 minutes then 2.0 to 2.5 ATA for 60 minutes (with time needed for compression and decompression, total exposure to elevated oxygen pressure approaches 2 hours). (A) Methyldopa 250 mg IV every 6 hours if normotensive and 500 to 1000 mg if hypertensive prior or during first HBO treatment. (B) One-hour air break on the surface. A CT scan is obtained immediately following the first HBO treatment. Additional HBO treatments are based on the following permutations: (1) If CT scan reveals intracranial hemorrhage (ICH): (a) resume HBO if neurological improvement has occurred with first treatment, or (b) stop HBO if neurologically unchanged or deterioration is observed. (2) If CT scan reveals no ICH, continue HBO.

III. HBO 1.5 ATA x 3 hours—may use air breaks at 30-minute intervals.

IV. Eight hours air break with indicated supportive and diagnostic care.

V. Then HBO at 2.0 to 2.5 ATA for 90-minute duration without air breaks twice a day if improvement continues for 7 to 10 days.

References

  1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.
  2. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S, for the Atlantis Study: Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. JAMA. 1999; 282: 2019–2026.
  3. Blanc P, Boussuges A, Henriette K, Sainty JM, Deleflie M. Iatrogenic cerebral air embolism: importance of an early hyperbaric oxygenation. Intensive Care Med. 2002; 28: 559–563.
  4. Pearson RR, Goad RF. Delayed cerebral edema complicating cerebral arterial gas embolism: case histories. Undersea Biomed Res. 1982; 9: 283–296.
  5. Leitch DR, Greenbaum LJ Jr, Hallenbeck JM. Cerebral arterial air embolism, IV: failure to recover with treatment and secondary deterioration. Undersea Biomed Res. 1984; 11: 265–274.
  6. Hart GB, Wells CH, Guest MM, Goodpasture JE, Sanders W. Inert gas diffusion and hyperoxia. In: Smith G, ed. Proceedings of the Sixth International Congress on Hyperbaric Medicine. Aberdeen University Press; 1979:130–139.
  7. Wells CH, Goodpasture JE, Horrigan DJ, Hart GB. Tissue gas measurements during hyperbaric oxygen exposure. In: Smith G, ed. Proceedings of the Sixth International Congress on Hyperbaric Medicine. Aberdeen University Press; 1979:118–124.
  8. Rivera JC. Decompression sickness among divers: an analysis of 935 cases. Mil Med. 1964; 129: 314–334.
  9. Rogatsky GG, Shifrin EG, Mayevsky A. Optimal dosing as a necessary condition for the efficacy of hyperbaric oxygen therapy in acute ischemic stroke: a critical review. Neurol Res. 2003; 25: 95–98.
  10. Nighoghossian N, Trouillas P, Adeleine P, Salord F. Hyperbaric oxygen in the treatment of acute ischemic stroke: a double-blind pilot study. Stroke. 1995; 26: 1369–1372.
  11. Boer KM, Boer RC Jr, Strauss MB, Jimenez A, Minkiewitz KM. Hyperbaric oxygen therapy for acute ischemic stroke. Undersea Hyperb Med. 1998; 5 (suppl): 13. Abstract.
  12. Shandling AH, Ellestad MH, Hart GB, Crump R, Marlow D, Van Natta B, Messenge JC, Strauss MB, Stravitsky Y. Hyperbaric oxygen and thrombolysis in myocardial infarction: the "Hot MI" pilot study. Am Heart J. 1997; 134: 544–550.

Response

Daniel E. Rusyniak, MD for the Hot Stroke Study Group

Departments of Emergency Medicine, Pharmacology & Toxicology & Neurology, Indiana University School of Medicine, Indianapolis, Indiana

Dr Jain criticizes this study primarily for its choice of dive pressure at 2.5 ATA. A number of case reports and case series in which HBO has been used in stroke have been published using a variety of pressures ranging from 1.5 to 3.0 ATA with the majority of them suggesting benefit of treatment. Despite these case reports, only 2 randomized trials had been completed prior to our study. Both of these studies used pressures of 1.5 ATA. Their decision seems to be based partially on a study in 1977 by Holbach et al.1 This study looked at carbohydrate metabolism in 30 patients with traumatic brain injuries and completed strokes (only 7 were strokes and none acute) that underwent hyperbaric oxygen treatment in an unrandomized and unblinded fashion at either 1.5 or 2.0 ATA. By measuring arterial venous (AV) oxygen differences along with AV differences in glucose, lactate, and pyruvate, the authors suggested that at 2 ATA there was increased cerebral anaerobic glycolysis, but at 1.5 ATA glucose metabolism was balanced and oxygen utilization increased. Unfortunately this study does not give any demographics on the patients in the 2 groups and their own data seem to suggest that after the treatment, those patients who underwent treatment at 2.0 ATA had better oxygen utilization. The authors also point out that clinically the patients in the 2.0-ATA group had no adverse events or outcomes. Despite these data, numerous studies in animals have suggested that HBO therapy has benefits that may not occur until pressures are >2.0 ATA.

In animal studies, hyperbaric oxygen treatment at 3 ATA significantly prevented carbon monoxide–induced brain lipid peroxidation, whereas treatments with 1 or 2 ATA oxygen showed no benefit.2 Studies in both humans and rats have shown that the activation of leukocytes through beta-2 integrin receptors can be inhibited by hyperbaric oxygen at pressures greater than 2 atm, but not at pressures less than or equal to 2 ATA.3,4 HBO has also been shown to downregulate ICAM-1 expression in ischemic cells and that this effect was completely attenuated only at pressures of 2.5 ATA.5 Similarly, HBO therapy at atmospheres of 2.8 ATA has been shown to maintain the integrity of the blood brain barrier after brain ischemia in rabbits.6,7 Numerous animal studies of ischemic stroke have shown HBO therapy at pressures ranging from 1.5 to 3.0 ATA to be beneficial. Another criticism was our inclusion of patients after 6 hours from stroke onset. We chose 24 hours as our inclusion time based on data that have shown viability of the penumbra for up to 24 hours after ischemia.8 Since it is impossible clinically to determine which patients’ strokes are completed and those in which there is a viable penumbra, we chose to initially include all patients within 24 hours. The clinical cases and studies to which Dr Jain refers in his letter dove patients primarily after the 6-hour time window and in some studies even months and years after the stroke. Lastly, Dr Jain’s comment that we have closed the door to further trials on HBO in stroke is likely a misinterpretation of our final statement. We state that "we will not pursue the use of our protocol in a larger clinical trial." This, however, does not mean that further studies should not be done using different protocols. Our commitment to this area is demonstrated in our current work with a clinical trial utilizing a pressure at 1.5 ATA.

We agree with the comments of Dr Zhang and colleagues in regard to the outcome interpretation of our study and appreciate their significant contributions to this area of research. Our decision to use a sham treatment at 1.14 ATA was based on our desire to blind the study as much as possible. Our chambers are pressurized with 100% O2 and to simulate the pressure changes on the ear in the sham group the equivalent of approximately 4 feet of sea water was needed, or 1.14 ATA. Other set-ups with our system would likely have decreased our ability to blind the patients. Zhang and colleagues correctly point out that our sham group had impressive results and may even reflect a benefit of the sham group compared the treatment group. Although the study by Ronning et al9 showed no benefit on 1-year survival in stroke patients given supplemental O2 for 24 hours compared with placebo, the possibility that higher concentrations of oxygen, for shorter durations, may have benefit is conceivable. In response to whether we have information on tissue perfusion status or stroke subtypes, we did not perform any testing on either of these issues. With regard to immediate response, we did follow up at NIHSS scores at 24 hours on each patient. In those treated within 12 hours of stroke onset 14% in the HBO compared with 33% in sham group and 20% versus 30% in those between 12 and 24 hours had clinical improvement as defined as complete resolution of symptoms or decrease of >=4 points on the NIHSS.

In response to Drs Hart and Strauss’s question of the duration of treatment, we chose 60 minutes based on prior animal studies showing a sustained benefit from treatments of <=60 minutes.10,11 Although multiple dives for brain ischemia have been suggested, there have been no controlled trials in humans showing benefit of 1 versus multiple dives, whereas numerous animal studies have shown sustained benefit from a single dive.10,11 Prior randomized trials of HBO for stroke in humans employed multiple dives as part of their protocols.12,13 As mentioned in our article, both of these studies suffered significant protocol violations secondary to the number of dives employed.

It is the conclusion of these authors that the question of the benefit of HBO in acute ischemic stroke is still unanswered and that further studies will be needed to determine if lower pressures and possibly greater number of dives results in improved clinical outcomes.

References

  1. Holbach KH, Caroli A, Wassmann H. Cerebral energy metabolism in patients with brain lesions of normo- and hyperbaric oxygen pressures. J Neurol. 1977; 217: 17–30.
  2. Thom SR. Antagonism of carbon monoxide-mediated brain lipid peroxidation by hyperbaric oxygen. Toxicol Appl Pharmacol. 1990; 105: 340–344.
  3. Thom SR, Mendiguren I, Hardy K, et al. Inhibition of human neutrophil beta2-integrin-dependent adherence by hyperbaric O2. Am J Physiol. 1997; 272 (3 Pt 1): C770–777.
  4. Thom SR. Functional inhibition of leukocyte B2 integrins by hyperbaric oxygen in carbon monoxide-mediated brain injury in rats. Toxicol Appl Pharmacol. 1993; 123: 248–256.
  5. Buras JA, Stahl GL, Svoboda KK, Reenstra WR. Hyperbaric oxygen downregulates ICAM-1 expression induced by hypoxia and hypoglycemia: the role of NOS. Am J Physiol Cell Physiol. 2000; 278: C292–C302.
  6. Mink RB, Dutka AJ. Hyperbaric oxygen after global cerebral ischemia in rabbits reduces brain vascular permeability and blood flow. Stroke. 1995; 26: 2307–2312.
  7. Mink RB, Dutka AJ. Hyperbaric oxygen after global cerebral ischemia in rabbits does not promote brain lipid peroxidation. Crit Care Med. 1995; 23: 1398–1404.
  8. Read SJ, Hirano T, Abbott DF, et al. The fate of hypoxic tissue on 18F-fluoromisonidazole positron emission tomography after ischemic stroke. Ann Neurol. 2000; 48: 228–235.
  9. Ronning OM, Guldvog B. Should stroke victims routinely receive supplemental oxygen? A quasi-randomized controlled trial. Stroke. 1999; 30: 2033–2037.
  10. Corkill G, Van Housen K, Hein L, Reitan J. Videodensitometric estimation of the protective effect of hyperbaric oxygen in the ischemic gerbil brain. Surg Neurol. 1985; 24: 206–210.
  11. Weinstein PR, Anderson GG, Telles DA. Results of hyperbaric oxygen therapy during temporary middle cerebral artery occlusion in unanesthetized cats. Neurosurgery. 1987; 20: 518–524.
  12. Nighoghossian N, Trouillas P, Adeleine P, Salord F. Hyperbaric oxygen in the treatment of acute ischemic stroke: a double-blind pilot study. Stroke. 1995; 26: 1369–1372.
  13. Anderson DC, Bottini AG, Jagiella WM, et al. A pilot study of hyperbaric oxygen in the treatment of human stroke. Stroke. 1991; 22: 1137–1142.




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