Effect of Routine Low-Dose Oxygen Supplementation on Death and Disability in Adults With Acute Stroke: The Stroke Oxygen Study Randomized Clinical Trial

Abstract

Importance: Hypoxia is common in the first few days after acute stroke, is frequently intermittent, and is often undetected. Oxygen supplementation could prevent hypoxia and secondary neurological deterioration and thus has the potential to improve recovery.

Objective: To assess whether routine prophylactic low-dose oxygen therapy was more effective than control oxygen administration in reducing death and disability at 90 days, and if so, whether oxygen given at night only, when hypoxia is most frequent, and oxygen administration is least likely to interfere with rehabilitation, was more effective than continuous supplementation.

Design, setting, and participants: In this single-blind randomized clinical trial, 8003 adults with acute stroke were enrolled from 136 participating centers in the United Kingdom within 24 hours of hospital admission if they had no clear indications for or contraindications to oxygen treatment (first patient enrolled April 24, 2008; last follow-up January 27, 2015).

Interventions: Participants were randomized 1:1:1 to continuous oxygen for 72 hours (n = 2668), nocturnal oxygen (21:00 to 07:00 hours) for 3 nights (n = 2667), or control (oxygen only if clinically indicated; n = 2668). Oxygen was given via nasal tubes at 3 L/min if baseline oxygen saturation was 93% or less and at 2 L/min if oxygen saturation was greater than 93%.

Main outcomes and measures: The primary outcome was reported using the modified Rankin Scale score (disability range, 0 [no symptoms] to 6 [death]; minimum clinically important difference, 1 point), assessed at 90 days by postal questionnaire (participant aware, assessor blinded). The modified Rankin Scale score was analyzed by ordinal logistic regression, which yields a common odds ratio (OR) for a change from one disability level to the next better (lower) level; OR greater than 1.00 indicates improvement.

Results: A total of 8003 patients (4398 (55%) men; mean [SD] age, 72 [13] years; median National Institutes of Health Stroke Scale score, 5; mean baseline oxygen saturation, 96.6%) were enrolled. The primary outcome was available for 7677 (96%) participants. The unadjusted OR for a better outcome (calculated via ordinal logistic regression) was 0.97 (95% CI, 0.89 to 1.05; P = .47) for oxygen vs control, and the OR was 1.03 (95% CI, 0.93 to 1.13; P = .61) for continuous vs nocturnal oxygen. No subgroup could be identified that benefited from oxygen. At least 1 serious adverse event occurred in 348 (13.0%) participants in the continuous oxygen group, 294 (11.0%) in the nocturnal group, and 322 (12.1%) in the control group. No significant harms were identified.

Conclusions and relevance: Among nonhypoxic patients with acute stroke, the prophylactic use of low-dose oxygen supplementation did not reduce death or disability at 3 months. These findings do not support low-dose oxygen in this setting.

Trial registration: ISRCTN Identifier: ISRCTN52416964.

Figure 1.. Flow of Participants Enrolled in the Continuous Oxygen, Nocturnal Oxygen, and Control Groups

^aThe number of patients screened for eligibility was not available. ^bSee eTable 2 in Supplement 3 for adherence data.

Figure 2.. Main Outcome Assessed by Modified Rankin Scale Score at 90-Day Follow-up

From the ordinal regression analysis, the unadjusted odds ratio for a better outcome (lower modified Rankin Scale [mRS] score) was 0.97 (95% CI, 0.89 to 1.05; P = .47) for combined oxygen vs control, and 1.03 (95% CI, 0.93 to 1.13; P = .61) for continuous oxygen vs nightly oxygen (mRS score range, 0 to 6 [0, no symptoms; 1, few symptoms but able to carry out all previous activities and duties; 2, unable to carry out all previous activities but able to look after own affairs without assistance; 3, needs some help with looking after own affairs but able to walk without assistance; 4, unable to walk without assistance and unable to attend to own bodily needs without assistance but does not need constant care and attention; 5, major symptoms such as bedridden and incontinent and needs constant attention day and night; 6, death]).

Figure 3.. Subgroup Analyses for an Improved Outcome Assessed by Modified Rankin Scale Score Comparing Oxygen vs Control at 90 Days

The x-axis depicts the common odds ratio (OR) for a better outcome over all 7 levels of the modified Rankin Scale score (mRS), derived from ordinal logistic regression. ORs greater than 1 indicate that a good outcome (low mRS) is more likely with oxygen than with control (reference category). The size of the markers reflects the total sample size in each subgroup, with larger markers indicating more precise estimates. The subgroup thresholds for oxygen concentration at randomization were revised from the prespecified thresholds because the analysis did not converge using the prespecified values. SSV indicates Six Simple Variables risk score; COPD, chronic obstructive pulmonary disease; GCS, Glasgow Coma Scale.

Figure 4.. Patient Mortality From 0 Through 90 Days

Cutoff for mortality differs from the 90-day mortality reported in Table 2 and Figure 2, in which responses were accepted up to 6 months if 3-month outcomes were not returned. Median duration of follow-up was 90 days (range, 0 to 90) in each treatment group.