The Stroke Oxygen Supplementation PILOT Study

C. Roffe, K.Ali, A. Warusevitane, S. Sills, S. Pountain, P Jones, R Gray, P. CromeNorth Staffordshire Combined Healthcare Trust

University Hospital of North StaffordshireBrighton and Sussex University Hospital

University Hospital BirminghamKeele 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

Acute StrokeN=100

ControlsN=85

Age (years) 74 sd 8 72 sd 8

Awake SpO2 (mean) 94.5 sd 1.7 %*** 95.8 sd 1.7 %

Mean nocturnal SpO2 93.5sd 1.9 %** 94.3 sd 1.9 %

Lowest nocturnal SpO2 82.5 sd 6.4 %* 84.6 sd 7.8 %

Results are given as means, *p<0.05, **p<0.01, ***p<0.001

Roffe et al, Stroke 2003;34:2641-2645.

Adverse effects of hypoxia after stroke I

Early deterioration

Silva et al, Cerebrovasc Dis 2001;11(suppl 4):70

381 consecutive patients with acute strokeOxygen 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<90 for >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;21:166-172.

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;34:2641-2645

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 2007 130:1631-1642

• 95% O2 reduced neurological deficit and infarct size in rats

Liu et al J Cereb Blood Flow Metab. 2006;26:1274-84.

Ronning and Guldvog, Stroke 1999;30:2033-37.

Routine oxygen supplementation

Oxygen

No oxygen

No oxygen

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;36:797-802.

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 GuidelinesOxygen 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):1056-83, 2005;36:916-23, 2007;38:1655-1711.

Stroke Oxygen PILOT Study

Routine oxygen supplementation during the first three days after an acute stroke

Prospective randomized open study

Inclusion criteria Acute stroke

Less than 24 hours after hospital admission No definite indications for oxygen treatment

No definite contraindications for oxygen treatment No other serious medical condition limiting life expectancy

Consent or assent

Baseline assessment

No routine oxygen

Oxygen is not given routinely, but may be prescribed if definite clinical indications develop

Continuous humidified oxygen per nasal cannula for 72 h

3l/min if oxygen saturation at baseline is 94% 2/min if oxygen saturation at baseline in 94%

Randomise

Week 1 Neurological examination, complications

Night 2 Pulse oximetry

Month 6 Questionnaire functional outcome, quality of life

SOS Pilot Study Patient Accrual

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SOS PILOT Study – patient recruitment

Recruitment

Control group

Oxygen group

Total

Randomized 144

155 299

Excluded after randomization Not a stroke () Withdrawal of consent ()

5(4)(1)

7(6)(1)

12(10)(2)

Included 139 148 287

Baseline ResultsControl N=139

Oxygen N=148

Age (mean) 72 sd 12 73 sd 12

Sex (n ( % male)) 71 (51%) 65 (44%)

GCS (mean) 15 sd 1 15 sd 1

COPD 12 (9%) 14 (9%)

LVF 18 (13%) 16 (11%)

IHD 37 (27%) 35 (24%)

AF 19 (14%) 34 (23%)

TIA 3 (2%) 4 (3%)

TAC 24 (17%) 24 (16%)

PAC 45 (32%) 47 (32%)

POC 6 (4%) 6 (4%)

LAC 58 (42%) 58 (39%)

Baseline Results Cont…

Control (no O2) N=139

Treatment (O2) N=148

Time admission to recruitment (hh:mm, mean)

12:07 sd 7:15 12:49 sd 7:13

Respiratory Rate at presentation (mean) 18 sd 3 18 sd 3

Oxygen at presentation (mean) 97 sd 2% 97 sd 2%

Oxygen at randomisation (mean) 96 sd 2% 96 sd 2%

Effect of oxygen supplementation on oxygen saturation

(mean, sd) Control N=126

OxygenN=139

Mean nocturnal SpO2 94% (2) 96% (2)***

4% Oxygen desaturation index 3 (14) 2 (6)*

Lowest SpO2 88% (5) 89%(6)**

Time with SpO2>98 (minutes)a 71 (444) 147 (166)***

Time with SpO2<95 (minutes)a 224 (158) 121 (141)***

Time with SpO2<90 (minutes)a 16 (42) 8 (23)

SpO2: oxygen saturation a Time corrected to a standard 8 hour night *p<0.05, **p<0.01, ***p<0.01

Neurological Outcomeat 1 week

Control N=139

Oxygen N=148

NIHSS at randomisation (mean) 7 sd 6 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) 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%)O2 given outside of protocol (N) 16 (12%) 12 (8%)

Sedatives given (N) 9 (6%) 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 known 5 (4%) 4 (3%) 9 (3%)

How was the questionnaire completed?

Control Group

OxygenGroup

Total

By the participant alone 36 (38%) 41 (50%) 77 (44%)

By the participant with help from others 21 (22%) 18 (22%) 39 (22%)

By someone else 37 (39%) 23 (28%) 60 (34%)

No of participants answering this question 94 82 176

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 1This 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 2This 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