The Stroke Oxygen Supplementation Study Chief Investigator: Prof. Christine Roffe Trial Manager: Dr Sarah Pountain North Staffordshire Combined Healthcare.

The Stroke Oxygen Supplementation Study

Chief Investigator: Prof. Christine RoffeTrial Manager: Dr Sarah Pountain

North Staffordshire Combined Healthcare Trust

www.so2s.co.uk

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

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.

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;34:2641-2645

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 (%

)100

80

90

Adverse effects of hypoxia after stroke

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

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.

Adverse effects nocturnal hypoxia after stroke

Silva,Cerebrovasc Dis 2001;11(suppl 4):70, Sandberg, JAGS 2001;49:391-397.

10 desaturations/h

>10 desaturations/h

Increased level of disability

Good, Stroke 1996;27:252-259

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.

When to start oxygen?Views of British Stroke Physicians

0 20 40 60 80 100 120 140

Numerical code for respondents

90%

94%

98%

100

96

92%

Saturation (%)

Arora et al, Br J Cardiol 2005;12:456-458.

88

90

92

94

96

98

100

102

40 50 60 70 80 90 100

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)

Oxy

gen

Satu

ratio

n (%

)

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 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.

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.

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)

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 hypothesisRestricting oxygen supplementation to night time only is more effective than continuous supplementation.

PROTOCOL

The Stroke Oxygen Supplementation Study

Patient eligible for the studyAcute stroke

Less than 24 hours after hospital admissionNo definite indications for oxygen treatment

No definite contraindications for oxygen treatmentNo other serious medical condition limiting life expectancy to a few months or less

Explain study Obtain informed consent or informed assent

Document baseline oxygen saturationComplete randomisation form

Log in to www.so2s.co.uk or phone number below to randomise the patient

No routine oxygen

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

clinical indications develop

Advise ward staff to monitor BP, HR, T, oxygen saturation at least

6 hourly

PrescribeEither or

1 week post recruitmentComplete Assessment Form 1

3, 6 and 12 months post recruitmentSOS team to send assessment forms 2, 3 and 4 to the patient

Oxygen per nasal cannulafor 3 nights

3l/min if oxygen saturation at baseline is 93%

2L/min if oxygen saturation at baseline in > 93%

Advise ward staff to monitor BP, HR, T, oxygen saturation

at least 6 hourly

Continuous oxygen per nasal cannula for 72 h

3l/min if oxygen saturation at baseline is 93%

2L/min if oxygen saturation at baseline in > 93%

Advise ward staff to monitor BP, HR, T, oxygen saturation

at least 6 hourly

Patient eligible for the studyAcute stroke

Less than 24 hours after hospital admissionNo definite indications for oxygen treatment

No definite contraindications for oxygen treatmentNo other serious medical condition limiting life expectancy to a few months or less

Explain study Obtain informed consent or informed assent

Document baseline oxygen saturationComplete randomisation form

Log in to www.so2s.co.uk or phone number below to randomise the patient

No routine oxygen

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

clinical indications develop

Advise ward staff to monitor BP, HR, T, oxygen saturation at least

6 hourly

PrescribeEither or

1 week post recruitmentComplete Assessment Form 1

3, 6 and 12 months post recruitmentSOS team to send assessment forms 2, 3 and 4 to the patient

Oxygen per nasal cannulafor 3 nights

3l/min if oxygen saturation at baseline is 93%

2L/min if oxygen saturation at baseline in > 93%

Advise ward staff to monitor BP, HR, T, oxygen saturation

at least 6 hourly

Continuous oxygen per nasal cannula for 72 h

3l/min if oxygen saturation at baseline is 93%

2L/min if oxygen saturation at baseline in > 93%

Advise ward staff to monitor BP, HR, T, oxygen saturation

at least 6 hourly

Eligibility for the study• Inclusion criteria

– Adult patients with acute stroke– No definite indications or definite contraindications for O2

treatment– Within 24 hours of admission

• Exclusion criteria– Potential indications for O2 treatment

• O2 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 O2 saturation & demographics– Date & time of event– Glasgow Coma Scale– NIHSS – Predictors of outcome

• Log on or phone to randomise– www.so2s.co.uk – Tel: 0300 123 0891

• Assigned to a treatment group

Treatment Groups

• No routine O2

• O2 per nasal cannulae for 3 nights:– 3 L/min if O2 saturation at baseline is ≤ 93%

– 2 L/min if O2 saturation at baseline is > 93%

• Continuous oxygen per nasal cannulae for 72 hours– 3 L/min if O2 saturation at baseline is ≤ 93%

– 2 L/min if O2 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 Details2. Study Documentation3. Investigator Site Personnel & Signed Agreements4. Regulatory/Ethics Committee5. Subject Documentation6. Safety Reporting 7. Data Collection8. Study Monitoring & Reports9. Correspondence

1. SOS Study Contact Details• SOS Study Manager

Dr Sarah PountainE-mail: sarah.pountain@northstaffs.nhs.ukTel: 0300 123 0891

• SOS Chief InvestigatorDr Christine RoffeE-mail: christine.roffe@northstaffs.nhs.ukTel: 0300 123 1465

Stroke Research Office, North Staffordshire Combined Healthcare NHS Trust, Holly Lodge, 62 Queens Road, Hartshill, Stoke-on-Trent, ST4 7LH.Tel: 0300 123 0891

• 24 HOUR RANDOMISATIONhttp://www.so2s.co.uk

• EMERGENCY CONTACT DETAILSMobile No 07740 372852 (main) 07734 068408 (back-up)

2. Study Documents

• http://www.so2s.co.uk• Version updates – e-mail 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 e-mail 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 e-mail 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

Go back

1 Week follow up data input

• Log into database from http://www.so2s.co.uk

• Click on patient forms• Select relevant patient

Go back

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

(http://www.so2s.co.uk). • 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 ManagerDr Sarah PountainE-mail: sarah.pountain@northstaffs.nhs.ukTel: 0300 123 0891

• SOS Chief InvestigatorDr Christine RoffeE-mail: christine.roffe@northstaffs.nhs.ukTel: 0300 123 1465

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