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

Key Points

Question  Does routine prophylactic low-dose oxygen supplementation after acute stroke improve functional outcome?

Findings  In this randomized clinical trial, 8003 patients with acute stroke were randomized within 24 hours of admission to 3 days of continuous oxygen, nocturnal oxygen, or control. After 3 months, there was no significant difference in death and disability for the combined oxygen groups compared with control (odds ratio, 0.97) or for the continuous oxygen group compared with the nocturnal oxygen group (odds ratio, 1.03).

Meaning  Routine low-dose oxygen did not improve outcomes in nonhypoxic patients after acute stroke.

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

Hypoxia is common during the first days after an acute stroke¹ and associated with higher rates of neurological deterioration,² death and institutionalization,³ and greater mortality.⁴ While cells in the ischemic penumbra are only viable for a few hours, brain cells beyond the ischemic core and penumbra remain at risk of delayed cell death for several days owing to vasogenic edema, inflammation, and programmed cell death, particularly if metabolic disturbances are compounded by hypoxia.^5-7 Continuous monitoring is associated with better outcomes,⁸ but even in intensively monitored patients, hypoxia is not always identified and treated. Adverse outcomes were observed to be increased when only some desaturations of less than 90% were treated with oxygen and reduced when all were treated.³

Quiz Ref IDSupplemental oxygen could improve outcomes by preventing hypoxia and secondary brain damage but could also have adverse effects.⁹ These include vasoconstriction and pulmonary toxicity with high concentrations,⁹ respiratory tract infection due to contamination of the nasal tubes, the tubing acting as an impediment to mobilization, stress, and the direct effects of oxygen on vascular tone and blood pressure.¹⁰ Three small trials of short-term (≤12 hours) high-flow (10 to 45 L/min) therapeutic oxygen, aimed at generating supraphysiological blood oxygen levels, have not shown improved outcomes.^11-13 A larger trial (n = 550) using low-dose supplemental oxygen (3 L/min for 24 hours) also showed no benefit,¹⁴ but early neurological recovery was improved in a study giving low-dose oxygen over 72 hours.¹⁵

The primary aim of the Stroke Oxygen Study (SO₂S) was to determine whether low-dose oxygen therapy during the first 3 days after an acute stroke improves outcome compared with usual care (oxygen only when needed). Because oxygen may restrict mobility and interfere with daytime activities, the secondary hypothesis was that oxygen given at night only, when hypoxia is most likely, is more effective than continuous oxygen supplementation.

This was a multicenter randomized clinical trial of oxygen supplementation with single-blind outcome assessment. The protocol and statistical analysis plan (Supplement 1 and Supplement 2),^16,17 and data collection forms¹⁸ are published. Fully informed written or witnessed oral consent was given by the participants or, if they did not have capacity to consent, by a legal representative. The protocol was approved by the North Staffordshire Research Ethics Committee (06/Q2604/109).

Quiz Ref IDAdults (aged ≥18 years) with a clinical diagnosis of acute stroke within 24 hours of hospital admission (136 participating centers in the United Kingdom), who had no clinical indications for or contraindications to oxygen treatment or any concomitant condition likely to limit life expectancy to less than 12 months were eligible (see eAppendix in Supplement 3 for definition of acute stroke).

Participants were allocated 1:1:1 via central web-based minimized randomization¹⁹ to (1) continuous oxygen supplementation; (2) nocturnal oxygen supplementation only; or (3) no routine oxygen (control). The factors for which imbalances were minimized were the Six Simple Variables prognostic index for independent survival at 6 months²⁰ (cutoffs: ≤0.1, >0.1 to ≤0.35, >0.35 to ≤0.70, >0.70), oxygen treatment before randomization (yes, no, unknown), baseline oxygen saturation on air (<95%, ≥95%), and time since stroke onset (cutoffs: ≤3, >3 to ≤6, >6 to ≤12, >12 to ≤24, >24 hours). Stroke onset was defined as the last time well for wake-up strokes. No blocking was used. Oxygen was administered per nasal tubes either continuously (day and night) during the first 72 hours after randomization or overnight (21:00 hours to 07:00 hours) for 3 nights. Oxygen was given at a flow rate of 3 L/min if baseline saturation was 93% or below or at a flow rate of 2 L/min if baseline saturation was greater than 93%. In the control group, no routine oxygen supplementation was given.

Vital signs were observed at least 4 times per day, with any abnormal findings treated independently of trial allocation. Patients requiring oxygen in the control group, patients in the nocturnal oxygen group during the day, or patients needing changes in oxygen dosage for clinical reasons were given the appropriate concentration of oxygen irrespective of treatment group. In addition, for 4144 patients recruited in the latter half of the study, spot checks of treatment adherence were undertaken at midnight and 6 am.

Outcomes were assessed at 1 week by a member of the local research team and at 90 days via postal questionnaire. Telephone interviews were conducted with nonresponders or to clarify unclear or missing answers. Quiz Ref IDThe primary outcome was the modified Rankin Scale (mRS) ²¹ score (disability range, 0 [no symptoms] to 6 [death]; minimum clinically important difference 1 point) assessed at 90 days. Secondary outcomes were number of participants with neurological improvement (≥4-point decrease on the National Institutes of Health Stroke Scale [NIHSS])^22,23 between randomization and day 7, the highest and lowest oxygen saturations within the first 72 hours, and mortality at 1 week. Further secondary outcomes at 90 days were mortality, number of participants alive and independent (mRS ≤2), number of participants living at home, Barthel Index activities of daily living (ADL) score,²⁴ quality of life (EuroQol [EQ5D-3L]) score,²⁵ and Nottingham Extended Activities of Daily Living score.²⁶ For the NIHSS and Barthel Index, deaths were recorded as the worst outcome on the scale.²⁷ Participants, their physicians, and local research staff who recorded the 1-week outcomes were not blind to the study interventions. Ninety-day assessments were undertaken by the SO₂S study office, which was blind to treatment allocation.

The initial recruitment target was 6000 participants, which was estimated to provide 90% power to detect small (0.2 mRS-point [eg, a 1-point improvement among 1 in 5 participants]) differences between oxygen (continuous and night-only groups combined) and no oxygen at a P value of less than or equal to .01 and 90% power at a P value of less than or equal to .05 to detect small differences between continuous oxygen and nocturnal-only oxygen. The study size was subsequently revised to 8000 participants, using ordinal methods,^16,17 without knowledge of interim results, to increase the number of patients with severe stroke and thereby provide greater power to investigate any differential effectiveness of oxygen vs control within subgroups (defined by severity).

The trial was designed to answer 2 key questions: whether oxygen supplementation improves outcome (mRS at 90 days) and whether giving oxygen at night is more effective than giving it continuously. The main comparisons, therefore, were of the 2 combined oxygen groups (continuous and nocturnal only) vs control, and of continuous oxygen vs nocturnal-only oxygen. The statistical analysis plan describes the analysis methods in detail (Supplement 1 and Supplement 2).¹⁷

The mRS was analyzed by ordinal logistic regression, which yields a common odds ratio (OR) for a move from one level to the next better (lower) level with an OR more than 1.00 indicating an improvement. For this and other outcome variables, a primary unadjusted analysis and a secondary covariate-adjusted analysis were performed. Adjusted analyses incorporated the following covariates: age, sex, baseline NIHSS score, baseline oxygen saturation, and the Six Simple Variables prognostic index for 6-month independence (or for analysis of mortality, the Six Simple Variables prognostic index for 30-day survival). Sensitivity analysis for the mRS used multiple imputation of missing values (using a chained equations method with 20 imputed data sets). Additional imputations were performed to allow for the possibility that data were missing not at random and were either better or worse than expected; missing values were thereby replaced by either very good (ie, lowest) or very poor (ie, highest) scores on the mRS as appropriate (eTable 3 in Supplement 3). Subgroups, for the mRS only, were analyzed by an interaction term and were predefined in the statistical analysis plan.¹⁷

For continuous outcomes, means and standard deviations or medians and interquartile ranges (IQRs) are reported, as appropriate. Unadjusted analyses used unrelated t tests, with the mean difference between treatments and corresponding CIs reported. The adjusted analysis used analysis of covariance, with the covariates specified earlier included in the analysis. For dichotomous outcomes, percentages were compared across the treatment comparisons using a χ² test (unadjusted analyses). Adjusted analyses of dichotomous outcomes used binary logistic regression, with the covariates listed earlier; ORs and CIs are reported.

All analyses were by intention to treat, ie, according to the treatment group to which participants were allocated, irrespective of treatment actually received. Statistical significance was set at a P value of less than or equal to .05 with 95% CIs for the primary outcome and at a P value of less than or equal to .01 with 99% CIs for secondary outcomes. All reported P values are 2-sided. The main analysis was performed in SAS software for Windows, version 9.4 (SAS Institute Inc), and IBM SPSS for Windows, version 22 was used for sensitivity analyses.

Interim analyses of safety and effectiveness were reviewed annually by an independent data monitoring and safety committee. No α-spending adjustments were made.

A total of 8003 participants from 136 collaborating centers in the United Kingdom were randomized and followed up between April 24, 2008, and January 27, 2015, (Figure 1). Baseline demographic and clinical characteristics, including stroke severity and oxygen saturation at randomization, were well-balanced in the 3 groups (Table 1). The mean (SD) age of participants was 72 (13) years, 4398 (55%) were men, and 7332 (92%) could undertake activities of daily living independently before the stroke. The mean (SD) NIHSS score was 7 (6) and the median score was 5 (IQR, 3 to 9). Prior to randomization, oxygen had been given to 1601 (20%) participants either in the ambulance or in the hospital. Patients were enrolled at a median of 20:43 hours (IQR, 11:59 to 25:32 hours) after symptom onset. The mean (SD) oxygen saturation at randomization was 96.6% (1.7%). All participants had a clinical diagnosis of stroke at the time of enrollment. The final diagnosis at 7 days was ischemic stroke in most cases (n = 6555; 82%), 588 (7%) had a primary intracerebral hemorrhage, and 294 (4%) were strokes without computed tomography diagnosis. There were 168 (2%) participants who were given a final diagnosis of transient ischemic attack, and 292 (4%) were found to have other nonstroke diagnoses with missing data in 106 (1%).

Informed consent was provided by 6991 (87%) participants, and 1012 (13%) had consent given by a relative, caregiver, or an independent legal representative (eTable 1 in Supplement 3). Of the participants who were unable to personally provide consent and were included by a representative, 6 (0.1%) refused consent at the 1-week reassessment and 22 (2%) refused at the 90-day assessment and were withdrawn.

Adherence was similar in the continuous oxygen group (2158 [81%]) and the nocturnal oxygen group (2225 [83%]), all of whom were prescribed the full course of treatment (eTable 2 in Supplement 3). Use of oxygen was discontinued prematurely among 433 (16%) participants in the continuous oxygen group and 361 (14%) in the nocturnal oxygen group. The most common reason for early discontinuation of oxygen was discharge from the hospital. In the control group, trial oxygen was recorded as being given to 33 (1.2%) participants, with no recording of whether oxygen was given among 406 (15%).

Oxygen treatment resulted in a significant increase of 0.8% in the highest oxygen saturation and 0.9% in the lowest oxygen saturation during the 72 hours of the intervention period in the continuous oxygen group compared with controls, and of 0.5% in the highest oxygen saturation and 0.4% in the lowest oxygen saturation during the 72 hours of the intervention period in the nocturnal oxygen group compared with controls (P < .001 for all comparisons; Table 2). Significantly more participants in the combined oxygen groups (n = 463 [9%]) required oxygen for clinical reasons during the intervention period than in the control group (n = 176 [7%]) (P < .001). Similarly, more participants in the continuous oxygen group (n = 254 [10%]) required oxygen than in the nocturnal oxygen group (n = 209 [8%]); P = .03.

Quiz Ref IDThe primary analysis demonstrated that oxygen supplementation did not significantly improve functional outcome at 90 days (Figure 2). The unadjusted OR for a better outcome (lower mRS) 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 nocturnal oxygen. Secondary analyses adjusted for age, sex, baseline NIHSS score, baseline oxygen saturation, and the Six Simple Variables prognostic index yielded very similar results for the combined oxygen group vs control (OR, 0.97 [95% CI, 0.89 to 1.06]; P = .54) and for continuous oxygen vs nocturnal oxygen (OR, 1.01 [95% CI, 0.92 to 1.12]; P = .81). With similar numbers of missing responses in the 3 groups (continuous oxygen, n = 101; nocturnal oxygen, n = 106; and control, n = 119), findings were much the same in sensitivity analyses using multiple imputation or analyzing only participants who adherered to protocol (eTable 3 in Supplement 3).

Subgroup analysis (Figure 3) found no indication that treatment effectiveness differed in any of the predefined subgroups, even those in whom most benefit might be expected such as patients with more severe stroke or those for whom oxygen supplementation was started early after stroke onset.

Analyses of secondary outcomes also showed no benefit from oxygen (Table 2). Neurological impairment at 1 week improved from baseline to the same degree in all 3 groups with median NIHSS scores of 2 (IQR, 1 to 6) by 1 week. Oxygen treatment did not increase the number of participants who were alive and independent or back in their home, the ability to perform basic (Barthel Index) or extended (Nottingham Extended Activities of Daily Living) activities of daily living, or quality of life (EuroQol-5D-3L) at 90 days. The results remained unchanged after adjustment for baseline prognostic factors (eTable 4 in Supplement 3). Mortality (Figure 4) was similar in the oxygen (both groups combined) and control groups (hazard ratio [HR], 0.97 [99% CI, 0.78 to 1.21]; P = .75), and for continuous oxygen vs nocturnal oxygen (HR, 1.15 [99% CI, 0.90 to 1.48]; P = .15).

There was no evidence of increased stress levels (higher heart rates, higher blood pressure, and need for sedation) in the oxygen-treated group than in the control group or evidence that oxygen treatment was associated with more infections, with little difference in the highest temperature or the need for antibiotics (Table 2).

The number of serious adverse events by 90 days was similar in the combined oxygen and control groups, but lower in the nocturnal oxygen group when compared with the continuous oxygen group (Table 2; eTable 5 in Supplement 3). No oxygen-related adverse events (respiratory depression, drying of mucous membranes) were reported.

In this clinical trial of patients with acute stroke, routine prophylactic low-dose oxygen supplementation did not improve outcome among patients who were not hypoxic at baseline, whether oxygen was given continuously for 72 hours or at night only. This applied to the primary 90-day functional outcome and to all other tested outcomes, including early neurological recovery, mortality, disability, independence in basic and extended activities of daily living, and quality of life. The results remained unchanged in analyses adjusted for baseline prognostic factors and in sensitivity analyses using multiple imputation or analyzing adherers only. Quiz Ref IDSubgroup analyses did not identify any characteristics that would make a patient more likely to benefit from oxygen treatment (includes enrollment between 3 to 6 hours after stroke onset, patients with a lower baseline oxygen saturation, severe strokes, a reduced level of consciousness, and a history of heart failure or lung disease [ie, characteristics for which benefit from oxygen was most anticipated]). Because of the large overall size of this trial, these patient subgroups were each sufficiently large for the lack of observed benefit to be likely real and not a false negative.

In contrast to the much smaller SOS Pilot study,¹⁵ this trial showed no evidence of better early neurological recovery with oxygen. Subgroup analysis of an earlier study of low-dose oxygen supplementation in acute stroke¹⁴ suggested that oxygen might adversely affect outcome in patients with mild strokes, possibly through formation of toxic free radicals. A more recent study of short-burst high-flow oxygen (45 L/min) was terminated early (after enrollment of 85 patients) because of excess mortality in the actively treated group.¹³ Hyperoxia was independently associated with mortality in a large retrospective cohort study of ventilated patients with stroke.²⁸ Although suggestive of potential harm, these findings could be due to confounding factors.

As a large pragmatic trial, this study included unselected patients with a clinical diagnosis of acute stroke without radiological confirmation. The sample therefore included ischemic and hemorrhagic strokes and participants who were later found to have mimics or transient ischemic attacks.

More than half of all acute stroke services in the United Kingdom participated, and wide inclusion criteria allowed enrollment of a representative sample of patients with ischemic and hemorrhagic stroke across the whole range of severity. Stroke severity was similar to that of the UK stroke population as a whole, with a median NIHSS of 5 in this trial and 4 in the UK Sentinel Stroke National Audit Programme, which includes every stroke patient admitted to UK hospitals.²⁹ The median NIHSS of 127 950 patients with acute ischemic stroke in the US Get with the Guidelines Register³⁰ was 5, as in this trial. A median NIHSS of 5 at baseline was also recorded in a large Dutch study of antibiotic prophylaxis after stroke, with similarly wide inclusion criteria.³¹

This study has several limitations. Minor benefits from oxygen treatment might have been masked by poor adherence. However, this seems unlikely given the high statistical power to detect even small improvements. Moreover, sensitivity analyses did not show better outcomes in the adherers-only group (eTable 3 in Supplement 3). Furthermore, this trial found significant increases in the oxygen saturations in the treated groups compared with the control group. Patients with acute stroke are often restless and confused. Ensuring full adherence would ideally require a 1 to 1 nurse-to-patient ratio. However, this is not possible outside an intensive care setting. The main outcome was assessed by postal questionnaire and supported by telephone interviews with nonresponders. This method has been used successfully in large pragmatic trials^32,33 but has been replaced by remote multiple-rater video-recorded interviews or in-person interview and examination by an allocation-blinded rater using formal structured assessments in several more recent studies.³⁴ Low-dose oxygen supplementation may not be sufficient to prevent severe desaturations; both the SOS Pilot¹⁵ and this trial found no significant difference in severe desaturations between the treatment and control groups. A small (N = 46) nonrandomized study comparing high-flow oxygen treatment via mask with low-flow supplementation via nasal cannula showed a trend toward lower mortality with high flow that was not statistically significant. However, evidence from randomized trials of high-flow oxygen treatment in acute stroke^11-13 does not show that higher doses of oxygen are associated with better outcomes. Early administration of high-dose oxygen might help maintain the viability of the ischemic penumbra and allow a broader time window for neuroprotection or thrombolysis. This question was not addressed in this trial of prophylactic oxygen, but will be tested in the PROOF trial.³⁵

The median time from stroke onset to randomization in this trial was 20 hours, 43 minutes. However, 101 participants were enrolled early (within 3 hours of symptom onset). Subgroup analysis (Figure 3) showed a similar lack of effect for oxygen in the small subset of patients enrolled early as in those enrolled later but was underpowered. Larger trials in the early time window would be needed to definitely exclude a benefit.

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.

Corresponding Author: Christine Roffe, MD, Institute for Science and Technology in Medicine, Keele University, Guy Hilton Research Centre, Thornburrow Drive, Stoke-on-Trent, Staffordshire ST4 7QB, United Kingdom (christine.roffe@uhnm.nhs.uk).

Accepted for Publication: August 12, 2017.

Correction: This article was corrected on November 14, 2017, for an incorrect SI conversion factor in Table 1, several incorrect 99% CIs in Table 2, an incorrect P value in Figure 3, and for minor typographical errors.

Author Contributions: Drs Roffe and Bishop had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Roffe, Gray.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Roffe, Sim, Ives, Ferdinand, Gray.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Sim, Bishop, Ives, Gray.

Obtained funding: Roffe, Gray.

Administrative, technical, or material support: Roffe, Nevatte, Sim.

Supervision: Roffe, Ives, Gray.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Roffe reports receipt of a grant from the Research for Patient Benefit Programme and the Health Technology Assessment Programme of the National Institute for Health Research (NIHR), receipt of lecture and travel fees from Air Liqude, and independent membership on the data safety and monitoring committee of the PROOF trial. No other disclosures were reported.

Funder/Support: This project was funded by the NIHR Health Technology Assessment Programme (project number 09/104/21) and the Research for Patient Benefit Programme.

Role of the Funder/Sponsor: The NIHR had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment, NIHR, the National Health Service (NHS), or the Department of Health. The Stroke Oxygen Study (SO₂S) was sponsored by North Staffordshire Combined Healthcare NHS Trust.

SO₂S Collaborators: Writing Committee: Christine Roffe, Tracy Nevatte, Julius Sim, Jon Bishop, Philip Ferdinand, Natalie Ives, and Richard Gray. Statistical Analysis: Jon Bishop, Julius Sim, Natalie Ives. Trial Management Group: Christine Roffe (Chair), Tracy Nevatte, Julius Sim, Richard Gray, Natalie Ives, Jon Bishop, Sarah Pountain, Peter and Linda Handy. Trial Steering Committee: Martin Dennis (Chair), Lalit Kalra, Sian Maslin-Prothero, Jane Daniels, Peta Bell, Richard Lindley. Data Safety and Monitoring Committee: Stephen Jackson (Chair), Thompson Robinson, Martyn Lewis. Trial Coordinating Center: Alison Buttery, Clare Gething, Joy Dale, Wendy Lawton, Chris Buckley, Eddie Skelson, Nicola Mellor, Kathryn McCarron, Jean Leverett, Emily Linehan, Stephanie Edwards, Terri Oliver, Loretto Thompson, Sian Edwards, Clare Lees and Jackie Richards. Study Team at Birmingham Clinical Trials Unit: Andrew Howman, Robert Hills, Nick Hilken, Samir Mehta and Chakanaka Sidile. Literature Searches: Frank Lally, Philip Ferdinand, Girish Muddegowda. Editorial Assistance: Frank Lally, David Roffe, Steve Alcock.
Participating Centers and SO₂S Collaborative Group Members (asterisks indicate principal investigator[s]; numeric values indicate the number of participants enrolled): Royal Stoke University Hospital, Stoke-on-Trent: K Finney, S Gomm, J Lucas, H Maguire, C Roffe* (478); St George’s Hospital, London: I Jones, L Montague, B Moynihan*, J O’Reilly, C Watchurst (288); The Royal Liverpool University Hospital, Liverpool: P Cox, G Fletcher, A Ledger, S Loharuka*, P Lopez, A Manoj* (257); Royal Bournemouth General Hospital, Bournemouth: O David, D Jenkinson*, J Kwan, E Rogers, E Wood (240); Kings College Hospital, London: A Davis, L Kalra*, E Khoromana, R Lewis, H Trainer (231); Leeds General Infirmary, Leeds: M Kambafwile, L Makawa, E Veraque, P Wanklyn*, D Waugh (204); Salford Royal Hospital, Salford: E Campbell, J Hardicre, V O’Loughlin, C Smith*, T Whittle (192); Southend Hospital, Southend: P Guyler*, P Harman, A Kumar Kundu, D Sinha, S Tysoe (188); Countess of Chester Hospital, Chester: S Booth, K Chatterjee*, H Eccleson, C Kelly, S Leason (176); The Royal Victoria Infirmary, Newcastle upon Tyne: A Barkat, J Davis, A Dixit*, M Fawcett, V Hogg (168); Royal Sussex County Hospital, Brighton: K Ali*, J Breeds, J Gaylard, J Knight, G Spurling (164); Musgrove Park Hospital, Taunton: S Brown, L Caudwell, L Dunningham, J Foot, M Hussain* (156); Bristol Royal Infirmary, Bristol: J Chambers, P Murphy*, M Osborn, A Steele (151); Royal Preston Hospital, Preston: S Duberley, C Gilmour, B Gregary, S Punekar*, S Raj (148); University Hospital Aintree, Liverpool: J Atherton, R Durairaj*, T Fluskey, Z Mellor, V Sutton (148); Birmingham Heartlands Hospital, Birmingham: P Carr, J McCormack, D Sandler*, C Stretton, K Warren (143); Pennine Acute Hospital, Rochdale: L Harrison, L Johnson, R Namushi*, N Saravanan, N Thomas (133); Queen’s Hospital, Burton: J Birch, R Damant, B Mukherjee* (131); University Hospital Coventry, Walsgrave: L Aldridge, P Kanti Ray*, S Nyabadza, C Randall, H Wright (129); Wansbeck Hospital, Northumberland: C Ashbrook-Raby, A Barkat, R Lakey, C Price*, G Storey (124); Royal Devon and Exeter Hospital, Wonford: L Barron, A Bowring, H Eastwood, M James*, S Keenan (113); Royal United Hospital, Bath: J Avis, D Button, D Hope, B Madigan, L Shaw* (113); Royal Cornwall Hospital, Treliske: K Adie, G Courtauld, F Harrington, C Schofield (112); Queen Elizabeth the Queen Mother Hospital, Margate: G Gunathilagan*, S Jones, G Thomas (105); York Hospital, York: J Coyle*, N Dyer, S Howard, M Keeling, S Williamson (105); University Hospital of North Durham, Durham: E Brown, S Bruce, B Esisi*, R Hayman, E Roberts (99); Derriford Hospital, Plymouth: C Bailey, B Hyams, A Mohd Nor*, N Persad (96); Selly Oak Hospital (Acute), Birmingham: J Hurley, E Linehan, J McCormack, J Savanhu, D Sims* (92); Whiston Hospital, Prescot: R Browne, S Dealing, V Gowda* (89); Torbay District General Hospital, Torbay: C Bailey, P Fitzell, C Hilaire, D Kelly*, S Szabo (88); Charing Cross Hospital, London: E Beranova, J Pushpa-Rajah, T Sachs, P Sharma*, V Tilley (87); Leighton Hospital, Crewe: N Gautam, C Maity*, R Miller, C Mustill, M Salehin*, A Walker (87); Kent & Canterbury Hospital, Canterbury: H Baht, I Burger*, L Cowie, T Irani, A Thomson (84); New Cross Hospital, Wolverhampton: P Bourke, K Fotherby*, D Morgan, K Preece (84); Northwick Park Hospital, Harrow: L Burgess, D Cohen*, M Mpelembue (83); Barnsley District General Hospital, Barnsley: M Albazzaz*, R Bassi, C Dennis, K Hawley, S Johnson-Holland (82); Blackpool Victoria Hospital, Blackpool: H Goddard, J Howard, C Jeffs, J Mcilmoyle*, A Strain (82); North Tyneside General Hospital, North Shields: J Dickson, K Mitchelson, C Price*, V Riddell, A Smith (79); Eastbourne District General Hospital, Eastbourne: C Athulathmudali*, E Barbon (76); Warrington Hospital, Warrington: K Bunworth, L Connell, G Delaney-Sagar, K Mahawish*, O Otaiku*, H Whittle (75); Princess Royal Hospital, Haywards Heath: R Campbell*, A Nyarko (71); City Hospitals, Sunderland: S Crawford, C Gray*, D Gulliver, R Lakey, N Majmudar*, S Rutter (69); William Harvey Hospital, Ashford: L Cowie, D Hargroves*, T Webb (69); Stepping Hill Hospital, Stockport: A Brown, H Cochrane, S Krishnamoorthy*, J McConniffe (66); The James Cook University Hospital, Middlesborough: D Broughton*, K Chapman, L Dixon, A Surendran (66); Northampton General Hospital (Acute), Northampton: M Blake*, F Faola, A Kannan, P Lai, B Vincent (59); Leicester General Hospital, Leicester: M Dickens, D Eveson, S Khan, R Marsh, A Mistri*,(57); Rotherham District General Hospital, Rotherham: J Harris, J Howe, K McNulty, J Okwera* (56); St Peter’s Hospital, Chertsey: R Nari*, E Young (56); Macclesfield District General Hospital, Macclesfield: A Barry, B Menezes, M Sein*, H Rooney, L Wilkinson (55); Manor Hospital, Walsall: S Hurdowar, K Javaid*, K Preece (54); Bradford Royal Infirmary, Bradford: R Bellfield, B Hairsine, L Johnston, C Patterson*, S Williamson (53); Luton & Dunstable Hospital, Luton: F Justin, S Sethuraman*, L Tate (50); Royal Blackburn Hospital, Blackburn: A Bell, M Goorah, N Goorah*, A Sangster (50); University College Hospital, London: N Bhupathiraju, L Latter, P Rayson, R Simister*, R Uday Erande (50); Addenbrooke’s Hospital, Cambridge: N Butler, D Day, E Jumilla, J Mitchell, E Warburton* (48); Queen Alexandra Hospital, Portsmouth: T Dobson, C Edwards, J Hewitt*, L Hyatt, D Jarret* (47); North Devon District Hospital, Barnstaple: G Belcher, M Dent*, F Hammonds, J Hunt, C Vernon (45); Solihull Hospital, Solihull: A Carter, K Elfandi*, S Stafford (45); Pilgrim Hospital, Boston: A Hardwick, D Mangion*, S Marvova* (44); Norfolk & Norwich University Hospital, Norwich: J Jagger, P Myint*, G Ravenhill, N Shinh*, E Thomas, N Wyatt (41); Gloucestershire Royal Hospital, Gloucester: P Brown, F Davis, D Dutta*, J Turfrey, D Ward (40); Royal Surrey County Hospital, Guildford: O Balazikova, A Blight*, C Lawlor, K Pasco (39); Southport & Formby District General Hospital, Southport: M Marshall, P McDonald*, H Terrett (39); Bishop Auckland General Hospital, Bishop Auckland: E Brown, A Mehrzad* (35); Airedale General Hospital, Keighley: R Bellfield, P Garnett, B Hairsine, S Mawer*, M Smith*, S Williamson (34); Calderdale Royal Hospital, Halifax: C Button, J Greig, B Hairsine, A Nair, P Rana*, I Shakir* (34); Doncaster Royal Infirmary, Doncaster: P Anderton, D Chadha*, L Holford, D Walstow (34); East Surrey Hospital, Redhill Y Abousleiman*, S Collins, A Jolly, B Mearns* (34); Medway Maritime Hospital, Gillingham: P Akhurst, B Bourne, S Burrows, S Sanmuganathan*, S Thompson (34); Royal Derby Hospital, Derby: T England*, A Hedstrom, M Mangoyana, M Memon*, L Mills, K Muhiddin*, I Wynter (33); Wycombe General Hospital, High Wycombe: A Benford, M Burn*, A Misra, S Pascall (33); The Princess Royal Hospital, Telford: R Campbell*, N Motherwell (32); Harrogate District Hospital, Harrogate: S Appleby, S Brotheridge*, J Strover (30); Peterborough City Hospital, Peterborough: S D’Souza, P Owusu-Agyei*, S Subramonian, N Temple (30); West Cumberland Hospital, Whitehaven: R Jolly, O Orugun* (30); Colchester General Hospital, Colchester: M Keating, R Saksena*, A Wright (29); Royal Hampshire County Hospital, Winchester: D Ardern, C Eglinton, R Honney, N Smyth*, J Wilson (29); Dorset County Hospital, Dorchester: S Breakspear, L O’Shea, H Prosche*, S Sharpe (27); Frimley Park Hospital, Frimley: S Atkinson, B Clarke*, L Moore (27); Royal Hallamshire Hospital, Sheffield: S Duty, K Harkness, M Randall*, E Richards, K Stocks (27); Yeovil District Hospital, Yeovil: S Board, C Buckley, D Hayward, K Rashed*, R Rowland-Axe (25); Poole General Hospital, Poole: C Dickson, L Gleave, S Ragab* (24); Frenchay Hospital, Bristol: N Baldwin*, S Hierons, H Skuse, L Whelan (22); Princess Alexandra Hospital, Harlow: L Brown, M Burton, A Daniel, S Hameed*, S Mansoor* (22); West Suffolk Hospital, Bury St Edmunds: A Azim*, M Krasinska, J White (22); The Ulster Hospital, Dundonald: M Power*, B Wroath (21); Watford General Hospital, Watford: D Collas*, S Sundayi, E Walker (21); Southampton General Hospital, Southampton: M Brown, G Durward*, V Pressly, B Watkins, N Weir*, D Whittaker (20); Craigavon Area Hospital, Portadown: C Douglas, M McCormick*, M McParland (19); Royal Lancaster Infirmary, Lancaster: C Culmsee, P Kumar* (18); Basildon Hospital, Basildon: M Bondoc, B Hadebe, R Rangasami*, I Udeozor, U Umansankar* (17); Birmingham City Hospital, Sandwell: F Kinney, S Hurdowar, S Ispoglou*, S Kausar* (17); City Hospital, Nottingham: P Cox, A Ferguson, D Havard, F Shelton, A Shetty* (16); Antrim Area Hospital, Antrim: C Edwards, C McGoldrick, A Thompson, D Vahidassr* (15); Pinderfields General Hospital, Wakefield: G Bateman, P Datta*, A Needle (15); Royal Albert Edward Infirmary, Wigan: P Farren, S Herath* (15); Good Hope Hospital, Sutton Coldfield: I Memon*, S Montgomery (13); Hereford County Hospital, Hereford: S Black, S Holloman, C Jenkins*, F Price (13); South Tyneside District General Hospital, South Shields: M Duffy, J Graham, J Scott (13); Broomfield Hospital, Chelmsford: A Lyle, F Mcneela, K Swan, J Topliffe, V Umachandran* (12); Wythenshawe Hospital, Wythenshawe: B Charles, E Gamble*, S Mawn (11); Warwick Hospital, Warwick: M Dean, B Thanvi* (10); Ipswich Hospital, Ipswich: M Chowdhury*, J Ngeh, S Stoddart (9); Kettering General Hospital, Kettering: K Ayes*, J Kessell (9); Nevill Hall Hospital, Abergavenny: B Richard*, E Scott (9); Princess Royal University Hospital, Orpington: L Ajayo, E Khoromana, E Parvathaneni, B Piechowski-Jozwiak*, L Sztriha* (9); Scarborough General Hospital, Scarborough: L Brown, K Deighton, E Elnour, J Paterson*, E Temlett (9); Hull Royal Infirmary, Hull: A Abdul-Hamid*, J Cook, K Mitchelson (8); King’s Mill Hospital, Sutton-in-Ashfield: M Cooper*, I Wynter (8); The Royal London Hospital, London: P Gompertz*, O Redjep, J Richards, R Uday Erande (8); Trafford General Hospital, Manchester: S Anwar*, A Ingram, S McGovern, S Musgrave*, L Tew (8); Altnagelvin Area Hospital, Londonderry: J Corrigan*, C Diver-Hall, M Doherty, M McCarron* (7); Darent Valley Hosptial, Dartford: P Aghoram*, T Daniel, S Hussein, S Lord (7); Royal Berkshire Hospital, Reading: N Mannava, A van Wyk* (6); Arrowe Park Hospital, Wirral: J Barrett*, R Davies*, A Dodd, D Lowe*, P Weir (5); Basingstoke and North Hampshire Hospital, Basingstoke: D Dellafera, E Giallombardo* (5); Lincoln County Hospital, Lincoln: S Arif, R Brown, S Leach* (5); Hexham General Hospital, Hexham: C Price*, V Riddell (4); Manchester Royal Infirmary, Manchester: J Akyea-Mensah, J Simpson* (4); Salisbury District Hospital, Salisbury: T Black*, C Clarke, M Skelton (4); Croydon University Hospital, Croydon: J Coleman, E Lawrence* (3); Russells Hall Hospital, Dudley: A Banerjee*, A Boyal, A Gregory (3); Worthing Hospital, Worthing: S Ivatts*, M Metiu (3); Bedford Hospital, Bedford: A Elmarimi*,S Hunter (2); James Paget Hospital, Great Yarmouth: H Benton, M Girling, P Harrison*, H Nutt, S Mazhar Zaidi*, C Whitehouse (2); St Richard’s Hospital, Chichester: G Blackman, S Ivatts* (2); Erne Hospital, Fermanagh: M Doherty, J Kelly* (1); University Hospital Lewisham, Lewisham: M Patel* (1); Bronglais General Hospital, Aberystwyth: P Jones* (0); Hillingdon Hospital, Hillingdon: A Parry* (0); Kingston Hospital, Kingston upon Thames: L Choy* (0); Morriston Hospital, Morriston: M Wani* (0); North Middlesex Hospital, Enfield: T Adesina, A David, R Luder* (0); Staffordshire District General Hospital, Stafford: A Oke* (0); St Helier Hospital, Carshalton: V Jones*, P O’Mahony, C Orefo (0); Whipps Cross University Hospital, London: R Simister* (0).