(Stroke. 1999;30:2033-2037.)
© 1999 American Heart Association, Inc.
Original Contributions |
From the Foundation for Health Services Research, Central Hospital of Akershus, Nordbyhagen, Norway.
Correspondence and reprint requests to Ole Morten Rønning, Foundation for Health Services Research, HELTEF, Central Hospital of Akershus, 1474 Nordbyhagen, Norway. E-mail bguldvog{at}sia.pilot.akershus-f.kommune.no
| Abstract |
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MethodsSubjects admitted to the Central Hospital of Akershus, Norway, with stroke onset <24 hours before admittance were allocated to 2 groups by a quasi-randomized design using birth numbers. All patients with acute stroke admitted to hospital within 24 hours after a stroke were included and enrolled. Patients were allocated to a group that received supplemental oxygen treatment (100% atmospheres, 3 L/min) for 24 hours (n=292) or to the control group, which did not receive additional oxygen. Main outcome measures were 1-year survival, neurological impairment (Scandinavian Stroke Scale), and disability (Barthel Index) 7 months after stroke.
ResultsOne-year survival was 69% in the oxygen group and 73%
in the control group (OR 0.82; 95% CI 0.57 to 1.19;
P=0.30). Impairment scores and disability scores were
comparable 7 months after stroke. Among patients with Scandinavian
Stroke Scale (SSS) scores of
40, 82% in the oxygen group and 91% in
the control group survived (OR 0.45; 95% CI 0.23 to 0.90;
P=0.023). For patients with SSS scores of <40, 53% in
the oxygen group and 48% in the control group survived (OR 1.26; 95%
CI 0.76 to 2.09; P=0.54).
ConclusionsSupplemental oxygen should not routinely be given to nonhypoxic stroke victims with minor or moderate strokes. Further research is needed to give conclusive advice concerning oxygen supplementation for patients with severe strokes.
Key Words: oxygen stroke management stroke outcome
| Introduction |
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Early mobilization is paramount in treatment of stroke patients,14 15 and thus it is important to reduce the number of procedures that prevent such mobilization. We hypothesized that supplemental oxygen was not effective to increase survival among stroke patients, nor to reduce impairment or disability. In particular, we hypothesized that patients with less-severe strokes would not benefit from supplemental oxygen, because ventilation among these patients is rarely impaired.
The study was performed to compare supplemental oxygen with no such treatment in patients with acute stroke of various severity, assessing the effect on survival, impairment, and disability.
| Subjects and Methods |
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27, 29, 31) were allocated to the
control group and patients with even digits to the treatment group.
Stroke patients in the treatment group received 100% oxygen at
atmospheric pressure at a rate of 3 liters per minute through a nasal
catheter for 24 hours after they entered the hospital. Separate parts
of the stroke study, evaluating the effect of a stroke unit and a
hospital-based rehabilitation unit with respect to survival and
disability, are described elsewhere.17 18
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The study was analyzed on an intention-to-treat basis. No patients were excluded from the study because they withdrew or because of pulmonary diseases or other conditions that could interfere with oxygen treatment. We chose to use intention-to treat-analysis because we were aware of the theoretical possibility that quasi-randomization based on birth digits could violate the requirement of a proper randomized study that all patients should have the same chance of receiving each treatment. Therefore, the protocol did not allow the admitting clinician to exclude patients with acute stroke from the study for any reason. If a patient was hypoxic or suffered from serious chronic obstructive lung disease, the physician responsible for the patient was instructed to give supplemental oxygen or not, as he found necessary, independent of the treatment to which the patient was allocated. Hence, we avoided introduction any systematic bias in this study. Informed consent regarding participation in this study was obtained from each patient or the next of kin. The experimental protocol was approved by the regional ethics committee. The research protocol contained ethical considerations stating that documentation of a benefit of oxygen therapy was lacking for stroke patients without respiratory insufficiency and that experiment was justified on this basis. A physician who was engaged in the investigation was involved when informed consent was obtained. Both the patients and the physician responsible for treatment could at any time withdraw the patient from the study or adjust the treatment. All of the patients (or the next of kin) who were asked accepted inclusion of the patient in the study.
Information on death was collected until March 1, 1997, through the National Register, an official register containing name, date of birth, address, and date of death. This register is continually updated. Impairment was assessed by Scandinavian Stroke Scale (SSS)19 score on admission and after 7 months. Disability was assessed by Barthel Index (BI)20 the first day after admittance and after 7 months. The initial assessment on admission was performed by the practitioner on duty, who also carried out the inclusion, assignment, and initiation of treatment. One of the investigators (O.M.R.) evaluated impairment and disability after 7 months (±1 month), without knowledge of the date of birth (and hence the treatment group) before the scoring. It has been recommended21 that outcome after stroke should be measured at 6 months because most significant recovery will be completed by that time.
We performed a subgroup analysis on patients with SSS
40 on
admission, in corroboration with our hypothesis that patients with
particularly moderate or minor strokes did not benefit from
supplemental oxygen. This analysis was prespecified, but we
chose 40 as the SSS score cutoff point after the start of the
study.
Thirty-three patients in the treatment group did not receive supplemental oxygen as prescribed. They were either not given such treatment or they received the treatment for <24 hours. Sixty-six patients in the control group were given oxygen treatment, but most of these patients were treated for considerably <24 hours. Eight of these patients had severe strokes and clinically impaired respiration and hence were offered supplemental oxygen.
Statistical Analysis
The associations between the normally distributed continuous
variables and treatment group were examined by using the unpaired
t test. The
2 test was
used to investigate the association between the categorical
variables and the treatment group. Survival curves were plotted
with the Kaplan-Meier method. The log-rank test was used for
calculations of survival. Neurological and functional scores were
analyzed by the Mann-Whitney test. The study had 75% power in
tracing a 10% difference in mortality between the groups, given a 5%
significance level. The study was approved by the Regional Medical
Ethics Committee (approval No. S-93231) and by a local reference group
in the hospital.
| Results |
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Table 3
shows the outcomes separately for
stroke patients with SSS <40 and SSS
40. One-year survival was
higher in the control group than the treatment group for these patients
(P=0.023), but the groups did not differ in other outcomes.
If patients with hemorrhagic stroke were excluded from the
analysis, survival was still in favor of the control group (12
of 129 and 25 of 122, respectively; P=0.030). For patients
with severe stroke, there was a tendency for higher 1-year survival
among the patients who received oxygen supplementation (53%) than
among the control patients (48%), but the difference was not
statistically significant (P=0.60).
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Figure 2
shows survival curves for the 2
treatment groups with all patients included; Figure 3
shows survival curves for
patients with mild or moderate strokes and patients with severe
strokes, by treatment group.
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| Discussion |
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How could oxygen possibly contribute to worsening the prognosis for patients with moderate or minor strokes? We do not know the cause of these findings, even though there are some reports of a possible harmful effect of oxygen therapy.
One small controlled study did not show any effect of hyperbaric oxygenation after stroke whereas another study found that such treatment might worsen outcome.22 23 Controlled clinical studies of the effect of breathing an oxygen-enriched atmosphere has not been performed. One study of gerbils12 supports the hypothesis of damaging effects of oxygen supplementation. Several factors could contribute to this result. Free radicals of oxygen or reactive oxygen species and xanthine oxidase occur during reperfusion following ischemia.3 4 5 24 Mitochondrial respiration is impaired after ischemia,25 and an increase in molecular oxygen could theoretically result in an increase in reactive oxygen species, which could further result in tissue injury.26 In addition, oxygen supplementation by nasal catheter theoretically could reduce the opportunity of early mobilization in the treatment group, but we did not find differences in onset of mobilization between the groups.
Why could supplemental oxygen be of less harm among the patients with severe strokes? Some patients with severe strokes may have impaired respiration that is clinically undetectable and obviously could have benefited from supplemental oxygen. Further, such patients may have insufficient reperfusion of ischemic areas of the brain to allow a harmful effect of oxygen treatment, while the stroke patients who are less disabled on admission are those who have reperfusion of these areas. One possible damaging effect of supplemental oxygen could be dependent on this reperfusion, because reoxygenation of ischemic brain is a prerequisite for oxygen products that may participate in a postischemic neuronal damage. Because this is the first study of its kind, we recommend that the results be interpreted with caution. However, we have reason to believe that the possible damaging effect of supplemental oxygen may be even more pronounced than shown in our study, because some patients (n=33; 11%) allocated to the treatment group did not receive such treatment for a full 24 hours. In addition, some patients in the control group (n=66; 26%) were offered oxygen by paramedics before arrival at the hospital and/or in the emergency room.
Could our study be biased? The number of patients with odd and even birth numbers in the month admitted, and hence the number in the treatment group (n=292) and control group (n=258), were different. This difference in the occurrence of odd and even birth numbers among stroke patients admitted to hospital must have happened by chance. All patients who complied with the criteria were enrolled in the study, no referring doctor in the area knew about the randomization methods of the study, and the professional guidelines used by the primary health care and paramedics recommended that all patients with acute stroke should immediately be admitted to the hospital. Although we acknowledge the theoretical possibilities of bias with allocation based on the date of birth, we maintain that the allocation method in this case practically equals full randomization.
Through further investigation we intend to analyze the causes of death in the 2 groups, but a complete list of causes of death is not yet available. We do not know the duration or the threshold of the possible deleterious effect of breathing 100% oxygen through a nasal catheter. We recommend that further studies be performed to assess the effects of supplemental oxygen on patients with severe strokes. We believe, however, that our study probably gives sufficient documentation to recommend that supplemental oxygen should not be given routinely to patients with mild and moderate strokes.
Received May 31, 1999; revision received June 28, 1999; accepted June 28, 1999.
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