(Stroke. 1995;26:1369-1372.)
© 1995 American Heart Association, Inc.
Articles |
Hyperbaric Oxygen in the Treatment of Acute Ischemic Stroke
A Double-blind Pilot Study
From the Department of Neurology, Cerebrovascular Disease and Ataxia Research Center (N.N., P.T.), and Department of Anesthesiology (F.S.), Neurological Hospital, and Laboratoire d'Informatique Médicale, UFR Alexis Carrel (P.A.), Lyon, France.
Correspondence to Dr N. Nighoghossian, Service de Neurologie du Pr Trouillas (Urgences Neurovasculaires et Centre de Recherches sur l'Ataxie), Hôpital Neurologique, 59 Bd Pinel, Lyon 69003, France.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Background and Purpose The effects of hyperbaric oxygen (HBO) therapy on humans are uncertain. Our study aims first to outline the practical aspects and the safety of HBO treatment and then to evaluate the effect of HBO on long-term disability.
Methods Patients who experienced middle cerebral artery occlusion and were seen within 24 hours of onset were randomized to receive either active (HBO) or sham (air) treatment. The HBO patients were exposed daily to 40 minutes at 1.5 atmospheres absolute for a total of 10 dives. We used the Orgogozo scale to establish a pretreatment functional level. Changes in the Orgogozo scale score at 6 months and 1 year after therapy were used to assess the therapeutic efficacy of HBO. In addition, we used the Rankin scale and our own 10-point scale to assess long term-disability at 6 months and 1 year. Two sample t tests and 95% confidence intervals were used to compare the mean differences between the two treatment groups. Student's two-tailed test was used to compare the differences between pretherapeutic and posttherapeutic scores at 6 months and 1 year in the two treatment groups.
Results Over the 3 years of study enrollment, 34 patients were randomized, 17 to hyperbaric treatment with air and 17 to hyperbaric treatment with 100% oxygen. There was no significant difference at inclusion between groups regarding age, time from stroke onset to randomization, and Orgogozo scale scores.
Neurological deterioration occurred during the first week in 4 patients in the sham group, 3 of whom died; this worsening was clearly related to the ischemic damage. Treatment was also discontinued for 3 patients in the HBO group who experienced myocardial infarction, a worsening related to the ischemic process, and claustrophobia. Therefore, 27 patients (13 in the sham group and 14 in the HBO group) completed a full course of therapy.
The mean score of the HBO group was significantly better on the Orgogozo scale at 1 year (P<.02). However, the difference at 1 year between pretherapeutic and posttherapeutic scores was not significantly different in the two groups (P<.16). Moreover, no statistically significant improvement was observed in the HBO group at 6 months and 1 year according to Rankin score (P<.78) and our own 10-point scale (P<.50).
Conclusions Although the small number of patients in each group precludes any conclusion regarding the potential deleterious effect of HBO, we did not observe the major side effects usually related to HBO. Accordingly, it can be assumed that hyperbaric oxygen might be safe. We hypothesize that HBO might improve outcome after stroke, as we detected an outcome trend favoring HBO therapy. A large randomized trial might be required to address the efficacy of this therapy.
Key Words: hyperbaric oxygenation • outcome • oxygen • stroke management
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Hyperbaric oxygen (HBO) might be of benefit in the treatment of ischemic stroke. An improved outcome has been demonstrated in experimental studies.1 2 3 4 Conversely, the effectiveness of HBO exposure in humans relies mainly on anecdotal or uncontrolled studies.5 6 7 8 Results from a recent double-blind trial9 that indicated an outcome trend favoring sham treatment raise the possibility that HBO might worsen outcome. We undertook a pilot double-blind study of HBO in the early treatment of stroke in humans to outline the practical aspects of HBO treatment and evaluate long-term disability.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Patients enrolled in the study had a neurological deficit highly suggestive of middle cerebral artery (MCA) occlusion and were between 20 and 75 years old. Radiological evidence on early or repeat CT scan of a recent ischemic stroke in the MCA territory was required. Inclusion into the trial was restricted to patients who presented within 24 hours of stroke onset. Patients who had a significant deficit (ie, a score of <80 on the 100-point quantitative scale of Orgogozo,10 in which 100 is normal) were enrolled. Informed consent was obtained from the patient or the next of kin. Patients were excluded if they had a history of stroke assessed by clinical and CT scan data; exhibited substantial improvement or resolution of the deficit within 1 hour after onset; were pregnant; experienced seizures at stroke onset; or had metabolic encephalopathy, significant pulmonary disease that contraindicated HBO exposure, congestive heart failure, or uncontrolled hypertension.
Patients were placed in a monoplace chamber. They were randomly assigned to receive either active (HBO) or sham (air) treatment. Pressure was raised at 0.2 atmospheres absolute (ATA) over 5 minutes in the sham group to mimic the HBO pressure effect. The patients were maintained at 1.5 ATA in the HBO group. Compression and decompression rates did not exceed 0.5 psi/min or those tolerated by the patients. A daily exposure of 40 minutes' duration was required in both groups. Protocol was completed when 10 dives were performed. Dives were directly supervised by a physician and a neurological intensive care unit nurse trained in the administration of hyperbaric gases. The patients' electrocardiograms and blood pressures were continuously monitored during each dive.
All patients received a standard therapy that combined low-dose heparin
sodium (10 000 IU divided into two doses) for prevention of deep-vein
thrombosis and supportive care (eg, nursing, rehabilitation, and speech
and occupational therapy). Three scales were applied to assess
neurological outcome at 6 months and 1 year. The Orgogozo
scale10 (a 100-point quantitative scale in which 100 is
normal), the Rankin disability scale,11 and our own
10-point scale (the Trouillas scale, described in Table 1
) were used for functional assessment. Special
attention was paid to recording side effects usually expected
with HBO treatment, such as difficulty clearing the ears, lung
atelectasis, and seizures. Patients who had neurological deterioration
associated with a comatose state at any time during the 10-dive course
were withdrawn from the dives. Etiologic workup included neck
ultrasonography, four-vessel angiography, electrocardiographic
monitoring, and echocardiography. Large-vessel
disease was suspected as the cause of infarction when there was a
stenosis of 50% or greater or an occlusion in the appropriate
large artery. Potential cardiac sources of embolism were considered
according to the results of cardiac monitoring and
echocardiographic data. Infarct distribution within the
MCA was defined with the Damasio template.12
|
Statistical Methods
The design of this study was the classic two-group randomized
experiment pretest-posttest design.13 Thus, the
pretherapeutic and posttherapeutic measures were analyzed by
the following methods: (1) comparison of the means of pretherapeutic
and posttherapeutic scores in the two groups by Student's two-tailed
test and (2) comparison of the differences of posttherapeutic scores
observed at 6 months and 1 year. These differences were calculated by
subtracting pretherapeutic scores from posttherapeutic scores. A
comparison of these differences was made between the two treatment
groups by Student's two-tailed test.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
From December 1988 to March 1992, 34 patients were randomized, 17 to treatment with medical air (sham group) and 17 to hyperbaric treatment with 100% oxygen. We did not observe any significant difference at inclusion between the groups regarding age, time from stroke onset to randomization, and Orgogozo scale scores. Demographic data, average time from onset of symptoms until the first dive, and Orgogozo scale score values for both groups are listed in Table 2
.
|
Dives were discontinued for 7 patients. The participation of 4 patients
was terminated before completion in the sham group due to a worsening
of neurological status that occurred in the first week (3 of the 4
died). This worsening was clearly shown on CT scan to be related to
ischemic damage. Additionally, dives were not completed in the
HBO group by 3 patients who experienced myocardial infarction,
worsening of neurological condition related to ischemic injury,
and claustrophobia. We did not observe any patient from either group in
a comatose state during therapy in the chamber. Therefore, only 27
patients completed a full course of therapy (13 control subjects versus
14 in the HBO group). Only 1 patient in the sham group had died at the
6-month follow-up. There was a significant difference between the two
groups at the 1-year follow-up according to the mean scores on the
Orgogozo (P<.02) and Trouillas (P<.03) scales,
whereas the Rankin scale score did not show any difference
(P<.11) (Table 3). Conversely, the
comparison of the pretherapeutic and posttherapeutic differences in the
two groups at 6 months and 1 year did not show any statistical
significance whatever the scale we used (Table 4).
|
|
Etiologic workup was used to assess the potential mechanism of stroke in 14 patients in the sham group and 12 in the HBO group; it remained unknown in 8 patients (3 in the sham and 5 in the HBO groups). An atherothrombotic mechanism was suspected in 8 patients (3 in the sham and 5 in the HBO groups), whereas a cardioembolic mechanism was suspected in 16 patients (8 in the sham and 8 in the HBO groups). An arterial dissection was found in 2 patients (1 in the sham and 1 in the HBO groups).
The distribution of infarction within the MCA area is presented
in Table 5.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In 1960, Boerema et al14 observed that HBO enabled hemoglobin to deliver sufficient oxygen to the tissues to sustain life and neurological function. Clinical improvement during exposure to HBO in patients with ischemic stroke has been reported by Ingvar and Lassen.5
Holbach et al15 attempted to elucidate the metabolic effect of HBO and suggested that exposure to 1.5 ATA for 35 to 40 minutes had a favorable effect on the glucose or energy metabolism of the brain as well as on the clinical course. Moreover, some cerebral blood flow studies16 17 have suggested that arterial oxygen content is a determining factor of blood flow velocity in the MCA. By enhancing tissue survival, HBO might also reduce the formation of edema, which otherwise further compromises local perfusion.18
Acute ischemic stroke treatment trials may have a narrow time window if potential beneficial effects are to be detected. The period of time that HBO can be utilized to delay the onset of symptomatic cerebral ischemia after arterial occlusion is limited by the onset of oxygen toxicity19 ; however, the threshold of oxygen concentration and the duration of exposure needed to produce deleterious effects of oxygen have yet to be determined. In addition, results of studies of stroke in humans suggest that the timing of the initial HBO exposure has yet to be determined, as an equally high response rate has been reported with exposure during the subacute and chronic phases.6 20 In our study, however, we included patients within 24 hours after stroke onset, sooner than in previous studies.
Patients having large-vessel stenosis or occlusion with residual blood flow insufficient to support cerebral function are likely to respond favorably to HBO.20 Accordingly, we focused our selection on patients who had a clinical picture consistent with large-vessel thrombosis, in contrast to previous studies in which a distinction was not made between large- and small-vessel thrombosis.
Despite the promising experimental and clinical data, the major criticism to most HBO studies has been the lack of controlled prospective analysis in the early postischemic period. Recently, Anderson et al9 administered HBO or air in a double-blind protocol to 39 patients with ischemic cerebral infarction. The study was not completed, as a trend favoring the air-treated patients was observed. Conversely, our study did not share the same conclusion, and this discrepancy raises some controversy. Although the small number of patients in each group precludes any conclusion regarding potential deleterious effects of HBO, we did not observe major side effects clearly related to HBO. (One patient experienced claustrophobia, which is a complication more likely attributed to the use of a monoplace chamber.)
A trend favoring HBO treatment was observed at 1 year according to the mean scores on the Orgogozo and Trouillas scales; however, we did not find a significant difference in outcome between groups according to the pretherapeutic and posttherapeutic differences after the 1-year follow-up. Given these considerations, we hypothesize that HBO might improve the outcome after stroke; a large randomized trial would be required to address the efficacy of this therapy.
|
Acknowledgments |
|---|
The authors gratefully acknowledge the assistance of Mrs D. Durand in performing the hyperbaric treatments and the willingness of the patients to tolerate the discomfort and uncertainty involved in testing this treatment.
Received September 21, 1994; revision received April 20, 1995; accepted April 26, 1995.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1. Smith G, Lawson DD, Renfrew S, Ledingham IM, Sharp GR. Preservation of cortical activity by breathing oxygen at two atmospheres of pressure during cerebral ischemia. Surg Gynecol Obstet. 1961;113:13-16.
2. Fuson RL, Moor JF, Smith WW, Brown IW. Hyperbaric oxygenation in experimental cerebal ischemia. Surg Forum. 1965;16:416-418. [Medline] [Order article via Infotrieve]
3. Moor GF, Fuson RL, Margolis G, Brown IW, Smith WW. Protective effect of hyperbaric oxygenation on the central nervous system during circulatory arrest. In: Brown IW, Cox BG, eds. Proceedings of the Third International Conference on Hyperbaric Medicine. Washington, DC: National Academy of Sciences; 1966:367-371.
4. Thomas AN, Hall AD, Blaisdell FW, Connolly JE. Survival after prolonged induced circulatory arrest, hyperbaric oxygenation, and hypothermia. In: Brown IW, Cox BG, eds. Proceedings of the Third International Conference on Hyperbaric Medicine. Washington, DC: National Academy of Sciences; 1966:382-390.
5. Ingvar HD, Lassen NA. Treatment of focal cerebral ischemia with hyperbaric oxygen. Acta Neurol Scand. 1965;41:92-95. [Medline] [Order article via Infotrieve]
6.
Hart GB, Thompson RE. The treatment of cerebral
ischemia with hyperbaric oxygen (OHB).
Stroke. 1971;2:247-250.
7. Kapp JP. Hyperbaric oxygen as an adjunct to acute revascularization of the brain. Surg Neurol. 1979;12:457-461. [Medline] [Order article via Infotrieve]
8.
Neubauer RA, End E. Hyperbaric
oxygenation as an adjunct therapy in strokes due to
thrombosis: a review of 122 patients. Stroke. 1980;11:297-300.
9.
Anderson DC, Bottini AG, Jagiella WM, Westphal B, Ford
S, Rockswold GL, Loewenson RB. A pilot study of hyperbaric
oxygen in the treatment of human stroke. Stroke. 1991;22:1137-1142.
10. Orgogozo JM, Capildeo R, Anagnostou CN, Juge O, Péré JJ, Dartigues JF, Steiner TJ, Yotis A, Rose FC. Mise au point d'un score neurologique pour l'évaluation clinique des infarctus sylviens. Presse Med. 1983;12:3039-3044.
11. Rankin J. Cerebral vascular accidents in patients over the age of 60, II: prognosis. Scott Med J. 1957;2:200-215. [Medline] [Order article via Infotrieve]
12.
Damasio H. A computed tomographic guide to the
identification of cerebral vascular territories. Arch
Neurol. 1983;40:138-142.
13. Huitema BE. The Analysis of Covariance and Alternatives. New York, NY: John Wiley & Sons Inc; 1980:127-128.
14. Boerema I, Meyne NG, Brummelkamp WK, Bouma S, Mensch MH, Kammermans F, Sternhanf M, Van Aaldern W. Life without blood: a study of influence of high atmospheric pressure and hypothermia on dilution of blood. Cardiovasc Surg. 1960;1:133-146.
15. 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. [Medline] [Order article via Infotrieve]
16.
Brown MM, Wade JPH, Marshall J. Fundamental
importance of arterial oxygen content in the determination
of cerebral blood flow in man. Brain. 1985;108:81-93.
17. Brown MM, Marshall J. Regulation of cerebral blood flow in response to change in blood viscosity. Lancet. 1985;16:604-609.
18. Sukoff MH, Hollin SA, Espinosa OE, Jacobson JH. The protective effect of hyperbaric oxygenation in experimental cerebral edema. J Neurosurg. 1968;29:236-241. [Medline] [Order article via Infotrieve]
19.
Mickel HS, Vaishnav YN, Kempski O, von Lubitz D, Weiss
JF, Feuerstein G. Breathing 100% oxygen after global
ischemia in Mongolian gerbils results in increased lipid
peroxidation and increased mortality. Stroke. 1987;18:426-430.
20.
Holbach KH, Hohelüchter KI, Wassmann HW.
Reversibility of chronic post-stroke state.
Stroke. 1976;7:296-300.
This article has been cited by other articles:
 |
|
 |
|
  L. Sun, H. H. Marti, and R. Veltkamp Hyperbaric Oxygen Reduces Tissue Hypoxia and Hypoxia-Inducible Factor-1{alpha} Expression in Focal Cerebral Ischemia Stroke, March 1, 2008; 39(3): 1000 - 1006. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists Stroke, May 1, 2007; 38(5): 1655 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bennett, J. Wasiak, C. French, P. Kranke, and A. Schnabel Response to Letter by Helms et al Stroke, April 1, 2007; 38(4): 1138 - 1139. [Full Text] [PDF]
|
|
|
|
|
|
A. K. Helms, H. T. Whelan, and M. T. Torbey Hyperbaric Oxygen Therapy of Acute Ischemic Stroke Stroke, April 1, 2007; 38(4): 1137 - 1137. [Full Text] [PDF]
|
|
|
|
 |
|
 K. P. Stoller Quantification of Neurocognitive Changes Before, During, and After Hyperbaric Oxygen Therapy in a Case of Fetal Alcohol Syndrome Pediatrics, October 1, 2005; 116(4): e586 - e591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Carson, M. McDonagh, B. Russman, and M. Helfand Hyperbaric oxygen therapy for stroke: a systematic review of the evidence Clinical Rehabilitation, August 1, 2005; 19(8): 819 - 833. [Abstract] [PDF]
|
|
|
|
|
|
A. B. Singhal, T. Benner, L. Roccatagliata, W. J. Koroshetz, P. W. Schaefer, E. H. Lo, F. S. Buonanno, R. G. Gonzalez, and A. G. Sorensen A Pilot Study of Normobaric Oxygen Therapy in Acute Ischemic Stroke Stroke, April 1, 2005; 36(4): 797 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.L. Gill and C.N.A. Bell Hyperbaric oxygen: its uses, mechanisms of action and outcomes QJM, July 1, 2004; 97(7): 385 - 395. [Full Text] [PDF]
|
|
|
|
|
|
J. H. Zhang, A. B. Singhal, and J. F. Toole Oxygen Therapy in Ischemic Stroke Stroke, September 1, 2003; 34 (9): e152 - e153. [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, R. J. Adams, T. Brott, G. J. del Zoppo, A. Furlan, L. B. Goldstein, R. L. Grubb, R. Higashida, C. Kidwell, T. G. Kwiatkowski, et al. Guidelines for the Early Management of Patients With Ischemic Stroke: A Scientific Statement From the Stroke Council of the American Stroke Association Stroke, April 1, 2003; 34(4): 1056 - 1083. [Full Text] [PDF]
|
|
|
|
|
|
D. E. Rusyniak, M. A. Kirk, J. D. May, L. W. Kao, E. J. Brizendine, J. L. Welch, W. H. Cordell, and R. J. Alonso Hyperbaric Oxygen Therapy in Acute Ischemic Stroke: Results of the Hyperbaric Oxygen in Acute Ischemic Stroke Trial Pilot Study Stroke, February 1, 2003; 34(2): 571 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Singhal, R. M. Dijkhuizen, B. R. Rosen, and E. H. Lo Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke Neurology, March 26, 2002; 58(6): 945 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Uchino, D. Billheimer, and S. C. Cramer Entry Criteria and Baseline Characteristics Predict Outcome in Acute Stroke Trials Stroke, April 1, 2001; 32(4): 909 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bhalla, C.D.A. Wolfe, and A.G. Rudd Management of acute physiological parameters after stroke QJM, March 1, 2001; 94(3): 167 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. M. Ronning and B. Guldvog Should Stroke Victims Routinely Receive Supplemental Oxygen? : A Quasi-Randomized Controlled Trial Stroke, October 1, 1999; 30(10): 2033 - 2037. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||