The Stroke Oxygen Supplementation Study Chief Investigator: Prof. Christine Roffe Trial Manager: Dr Sarah Pountain North Staffordshire Combined Healthcare Trust Funded by National Institute For Research: Research for Patient Benefit

Hypoxia ABG [kPa] Saturation [%] Normal  Mild hypoxia  Moderate hypoxia  Severe hypoxia  Life threatening 

Oxygen saturation in acute stroke patients Roffe et al, Stroke 2003;34:

Unexpected nocturnal hypoxia in acute 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:

68 year old male with left hemiparesis and pneumonia. Post-stroke hypoxia is usually caused by complications Airway Obstruction Aspiration Pneumonia Pulmonary emboli Fluid overload Sleep apnoea SpO 2 (%)

Adverse effects of hypoxia after stroke 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 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:

Adverse effects nocturnal hypoxia after stroke Silva,Cerebrovasc Dis 2001;11(suppl 4):70, Sandberg, JAGS 2001;49:  10 desaturations/h >10 desaturations/h Increased level of disability Good, Stroke 1996;27:

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:

When to start oxygen? Views of British Stroke Physicians Arora et al, Br J Cardiol 2005;12:

n=105 Mean age 74.0 years (SD 9.6 years) Mean oxygen saturation 96.3% (SD 1.6%) Stroke Oxygen pilot Study in progress, baseline demographic data, Age (years) Oxygen Saturation (%) Oxygen saturation on arrival in hospital

Should we give oxygen to prevent hypoxia?

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:

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:

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)

Potential adverse effects of oxygen Masking of an important warning sign of underlying pathology Formation of toxic free radicals Stress imposed by the mask or cannula Drying of mucous membranes Hospital acquired infection through the plastic tubing Immobilization of the patient Unintended effects on staff attitude to the patient Respiratory depression in patients with severe COPD

Oxygen for Stroke Oxygen is increasingly given to acute stroke patients No uniform guidelines for the prescription of oxygen to acute stroke patients Variation amongst clinicians of when oxygen supplementation should be given

SOS Study A multi-centre, randomised, open, blinded- endpoint study Routine oxygen treatment for 72 h after a stroke

Aims of SOS Study Main Hypothesis Fixed dose oxygen treatment during the first 3 days after an acute stroke improves outcome. Secondary hypothesis Restricting oxygen supplementation to night time only is more effective than continuous supplementation.

PROTOCOL The Stroke Oxygen Supplementation Study

Eligibility for the study Inclusion criteria – Adult patients with acute stroke – No definite indications or definite contraindications for O 2 treatment – Within 24 hours of admission Exclusion criteria – Potential indications for O 2 treatment O 2 saturation on air <90% dyspnoea Medical indications for oxygen (PE, severe pneumonia, acute asthma) Patients on long term oxygen for chronic lung disease – If the stroke is not the main clinical problem – Serious life threatening illness

Types of consent for SOS Study Patient written consent Relative/carer or legal representative consent Independent Physician consent Patient confirmation of consent (after recovery)

Baseline and Randomisation Randomisation form – Baseline O 2 saturation & demographics – Date & time of event – Glasgow Coma Scale – NIHSS – Predictors of outcome Log on or phone to randomise – – Tel: Assigned to a treatment group

Treatment Groups No routine O 2 O 2 per nasal cannulae for 3 nights: – 3 L/min if O 2 saturation at baseline is ≤ 93% – 2 L/min if O 2 saturation at baseline is > 93% Continuous oxygen per nasal cannulae for 72 hours – 3 L/min if O 2 saturation at baseline is ≤ 93% – 2 L/min if O 2 saturation at baseline is > 93%

1 week post recruitment Local, trained, research team member 7 days ± 1 day after enrolment – Confirm diagnosis – Document death – NIHSS – Compliance with the intervention – Complications Data entered online

3, 6 & 12 month post recruitment Centrally by SOS team Questionnaire sent to patient – Deaths – Discharge status – Modified Rankin Score – Barthel ADL score – Nottingham EADL score – EuroQuol score – Memory – Sleep – Speech

Outcome Measures No. of patients with neurological deterioration Mortality Highest/lowest oxygen saturation during the first 72hr Modified Rankin score Quality of life Level of disability

Study Documentation

SOS Study File 1.SOS Study Contact Details 2.Study Documentation 3.Investigator Site Personnel & Signed Agreements 4.Regulatory/Ethics Committee 5.Subject Documentation 6.Safety Reporting 7.Data Collection 8.Study Monitoring & Reports 9.Correspondence

1. SOS Study Contact Details SOS Study Manager Dr Sarah Pountain Tel: SOS Chief Investigator Dr Christine Roffe Tel: Stroke Research Office, North Staffordshire Combined Healthcare NHS Trust, Holly Lodge, 62 Queens Road, Hartshill, Stoke-on-Trent, ST4 7LH. Tel: HOUR RANDOMISATION EMERGENCY CONTACT DETAILS M obile No (main) (back-up)

2. Study Documents Version updates – PI, announced on website On site headed note paper - consent forms, patient information sheets and the GP letter File Notes Equipment Validation Patient Document Tracking Log SOPs

3. Investigator Site Personnel Delegation Log Training Log CVs & Job Description Financial Information CTA

4. Regulatory/Ethics Committee MHRA Approval Oxygen Data Sheet Ethics Application & Approval R & D Approval Safety updates Reports End of trial notification Correspondence to/from ethics/MHRA

5. Subject Documentation Screening Log Subject Enrolment/Identification Log Signed consent forms

6. Safety Reporting Adverse Events – report on R&D-RF-SOS-001 (from website) fax and to Sponsor within 14 days SAEs & SUSARs – notify study centre immediately, complete SAE form and fax to Study centre AND sponsor within 24 hours of becoming aware of the event. Reporting of Safety Measures - notify study centre immediately – complete form R&D-RF-SOS-002 (from website) fax or to study centre AND sponsor, within 24 hours.

7. Data Collection Completing the CRF Consent – types of, obtaining, consent procedure dialogue Information sheets and consent forms Randomising patient’s into SOS study How to randomise using the web based system Completing the week 1 follow up Inputting the week 1 follow up Long term follow up Notification of death Completed notification of death forms

Click on New Randomisation Confirm your site Select clinician Identifying details - patient surname, forename, sex, DOB, Unit no. Eligibility – time since admission, time since stroke, expected to die within 1 year from non-stroke related illness, indications for O2, contraindications for O2 Patient details – date of stroke, time of stroke, O2 given in the ambulance (if yes how much), O2 given on arrival (if yes how much)

Medical History – COAD, other chronic lung problem, heart failure, IHD, AF GCS NIHSS Prognostic factors - live alone?, independent in daily living, lift affect arm, walk unaided, O2 sat. at randomisation Consent Confirm all details Check randomisation options

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1 Week follow up data input Log into database from Click on patient forms Select relevant patient

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Notification of death In the event of death can you please complete the notification of death form for your records and complete the form on line. To access the form online log onto the SOS website ( Click on “Click here to randomise or enter data”. Enter user name and password, select live as data type. Select Patient forms to enter data. Select the patient and click on View Details. Select Notification of Death from the left hand side of the screen and click on View form. Enter details, click on save. Click on Exit. Exit website, will automatically log out when website closed down.

8. Study Monitoring & Reports Final Study Reports Interim Reports Publications/Abstracts Safety Updates and Reports Initiation Visit Report Visit Log Close out Letter

9. Correspondence General Correspondence SOS Newsletter Minutes of Meetings

Study Contacts SOS Study Manager Dr Sarah Pountain Tel: SOS Chief Investigator Dr Christine Roffe Tel: Stroke Research Office, North Staffordshire Combined Healthcare NHS Trust, Holly Lodge, 62 Queens Road, Hartshill, Stoke-on-Trent ST4 7LH

Trial Management Committee Dr Christine Roffe Prof. Peter Jones Prof. Peter Crome Prof. Richard Gray Mr Peter & Mrs Linda Handy (Strokes R Us) Trial Steering Committee Prof. Richard Lindley Prof. Martin Dennis Prof. Lalit Kalra Prof. Sian Prothero Jane Daniels Mrs Peta Bell Data Monitoring & Safety Committee Prof. S Jackson Prof. T Robinson Dr Martyn Lewis International Advisory Committee Prof. Richard Lindley Patient Representatives Peter & Linda Handy Mrs Peta Bell Sponsor North Staffordshire Combined Healthcare NHS Trust