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: [email protected]: 0300 123 0891
• SOS Chief InvestigatorDr Christine RoffeE-mail: [email protected]: 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: [email protected]: 0300 123 0891
• SOS Chief InvestigatorDr Christine RoffeE-mail: [email protected]: 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