The Stroke Oxygen Supplementation PILOT Study C. Roffe, K.Ali, A. Warusevitane, S. Sills, S. Pountain, P Jones, R Gray, P. Crome North Staffordshire Combined Healthcare Trust University Hospital of North Staffordshire Brighton and Sussex University Hospital University Hospital Birmingham Keele University The North Staffordshire Medical Institute

Background Incidence of hypoxia 63% in the first 2 days Sulter et al, J Neurol Sci 2000;179:65-9.

Oxygen saturation within the first 72 hours of acute stroke Roffe et al, Stroke 2003;34:

Adverse effects of hypoxia after stroke I Early deterioration Silva et al, Cerebrovasc Dis 2001;11(suppl 4): consecutive patients with acute stroke Oxygen saturation <90 doubles risk of early deterioration.

Adverse effects of hypoxia after stroke II Increased mortality N=153 assessed from arrival and during transfers till ward admission Hypoxia defined as SpO2 10% of assessment phase Oxygen saturation lowest during transfers Hypoxic pts are more likely to have a history of chest problems Hypoxia doubles mortality, but no longer significant if corrected for stroke severity No effect on long-term disability Rowat et al. Cerebrovasc Dis 2006;21:

Unexpected nocturnal hypoxia in stroke patients Time spent with an oxygen saturation <90% at night 52% more than 5 minutes 23% more than 30 minutes 15% more than 1 hour Roffe et al, Stroke 2003;34:

Experimental Evidence 100% oxygen increases oxygen delivery to the ischaemic brain in mice Infarct size at 2 days reduced by 45% Shin, H. K. et al. Brain : % O2 reduced neurological deficit and infarct size in rats Liu et al J Cereb Blood Flow Metab. 2006;26:

Ronning and Guldvog, Stroke 1999;30: Routine oxygen supplementation Oxygen No oxygen Oxygen No oxygen All strokes Mild strokes SSS>40 (top) Severe strokes SSS  (bottom)

Selective high dose (45L/min) short burst oxygen supplementation Methods— acute stroke <12 h and perfusion-diffusion "mismatch" on MRI RCT of high-flow oxygen via mask for 8 hours (n=9) vs room air (n=7) Results— Oxygen tended to improve stroke scale scores at 4 h and 1 week, and significantly at 24 h, but there was no significant difference at 3 months. MRI lesion volumes were significantly reduced at 4 hours, but not subsequent time points. Cerebral blood volume and blood flow within ischemic regions improved More petechial hemorrhages (50% w oxygen vs 17% w room air) Singhal et al. Stroke. 2005;36:

National and international Stroke Guidelines UK National Clinical Guidelines for Stroke Arterial oxygen concentration should be maintained within normal limits 2004 Give Oxygen to maintain oxygen saturation at or above 95% 2008 European Stroke Initiative Recommendations for Stroke Management 2-4L/min when indicated in 2003 Oxygen if saturation<92% in 2007 American Stroke Association Guidelines Oxygen if saturation <95% in 2003 and 2005 Oxygen if saturation </=92% in 2007 National Clinical Guidelines for Stroke. RCP 2004, 2008, NICE 2008, EUSI 2004, ESO 2007; ASA, Stroke. 2003;34(4): , 2005;36:916-23, 2007;38:

Stroke Oxygen PILOT Study Routine oxygen supplementation during the first three days after an acute stroke Prospective randomized open study

SOS PILOT Study – patient recruitment

Recruitment Control group Oxygen group Total Randomized Excluded after randomization Not a stroke () Withdrawal of consent () 5 (4) (1) 7 (6) (1) 12 (10) (2) Included

Baseline Results Control N=139 Oxygen N=148 Age (mean)72 sd 1273 sd 12 Sex (n ( % male))71 (51%)65 (44%) GCS (mean)15 sd 1 COPD12 (9%)14 (9%) LVF18 (13%)16 (11%) IHD37 (27%)35 (24%) AF19 (14%)34 (23%) TIA3 (2%)4 (3%) TAC24 (17%)24 (16%) PAC45 (32%)47 (32%) POC6 (4%) LAC58 (42%)58 (39%)

Baseline Results Cont… Control (no O 2 ) N=139 Treatment (O 2 ) N=148 Time admission to recruitment (hh:mm, mean) 12:07 sd 7:1512:49 sd 7:13 Respiratory Rate at presentation (mean)18 sd 3 Oxygen at presentation (mean)97 sd 2% Oxygen at randomisation (mean)96 sd 2%

Effect of oxygen supplementation on oxygen saturation (mean, sd)Control N=126 Oxygen N=139 Mean nocturnal SpO 2 94% (2)96% (2)*** 4% Oxygen desaturation index3 (14)2 (6)* Lowest SpO 2 88% (5)89%(6)** Time with SpO 2 >98 (minutes) a 71 (444)147 (166)*** Time with SpO 2 <95 (minutes) a 224 (158)121 (141)*** Time with SpO 2 <90 (minutes) a 16 (42)8 (23) SpO 2 : oxygen saturation a Time corrected to a standard 8 hour night *p<0.05, **p<0.01, ***p<0.01

Neurological Outcome at 1 week Control N=139 Oxygen N=148 NIHSS at randomisation (mean)7 sd 6 NIHSS difference baseline to week 1 (mean) -2 sd 5-3 sd 3*** NIHSS: National Institute for Health Stroke Scale; ***p<0.001

Other results at 1 week Control N=139 Oxygen N=148 Highest temperature (mean, sd)37 (1) Highest heart rate (mean, sd)92 (19)92 (16) Highest systolic (mean, sd)166 (28)167 (29) Highest diastolic (mean, sd)92 (15)93 (19) Antibiotics given (N)22 (16%)27 (18%) O 2 given outside of protocol (N)16 (12%)12 (8%) Sedatives given (N)9 (6%)

Completeness of follow –up at 6 months Control n=139 Oxygen n=148 Total n=287 Outcome known Questionnaire returned Death before 6 mo follow-up 134 (96%) 113 (81%) 21 (15%) 144 (97%) 118 (80%) 26 (17%) 278 (97%) Outcome not known5 (4%)4 (3%)9 (3%)

How was the questionnaire completed? Control Group Oxygen Group Total By the participant alone36 (38%)41 (50%)77 (44%) By the participant with help from others21 (22%)18 (22%)39 (22%) By someone else37 (39%)23 (28%)60 (34%) No of participants answering this question

Outcomes at 6 months (mean, sd)Control n=113 Oxygen n=118 P- value Disability (mRS including deaths, scores 0-6) 3.0 (2.0)3.1 (2.0)0.6 Basic activities of daily living (Barthel index 0-100) 95 (10)90 (10)0.4 Extended Activities of daily living (Nottingham EADL) 46 (19)47 (20)0.8 Quality of Life (EuroQuol) 59 (25)61 (25)0.7 mRS modified Rankin Scale;

Conclusion 1 This pilot study demonstrates 1.That routine oxygen supplementation effectively increased oxygen saturation when given in a non- intensive clinical environment 2.That oxygen supplementation was well tolerated without observable adverse effects 3.That the outcomes are feasible and deliver over 95% returns at 1 week (clinical) and 6 months (questionnaire)

Conclusion 2 This pilot study was not powered to look at neurological or functional outcomes or to do subgroup analyses Results so far are that routine oxygen supplementation Led to a small but statistically significant improvement in neurological outcome at 1 week Had no significant effect on mortality and functional outcome at 6 months A larger study is required to determine whether routine oxygen supplementation is effective in reducing neurological deficit and improving functional outcome