The Stroke Oxygen Supplementation Study

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 Age (years) Acute Stroke N=100 74 sd 8 Controls N=85 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 Post-stroke hypoxia is usually caused by complications SpO2 (%) 100 90 80 68 year old male with left hemiparesis and pneumonia.

Airway Obstruction Aspiration Pneumonia Pulmonary emboli Fluid overload Sleep apnoea Adverse effects of hypoxia after stroke Early deterioration 381 consecutive patients with acute stroke Oxygen saturation <90 doubles risk of early deterioration. Silva et al, Cerebrovasc Dis 2001;11(suppl 4):70 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 Increased level of disability 10 desaturations/h >10 desaturations/h Good, Stroke 1996;27:252-259 Silva,Cerebrovasc Dis 2001;11(suppl 4):70, Sandberg, JAGS 2001;49:391-397. 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 % 90 %

0 20 40 60 80 100 120 140

Numerical code for respondents Arora et al, Br J Cardiol 2005;12:456-458. Oxygen Saturation (%) Oxygen saturation on arrival in hospital 102 100 98 96 94 92

90 88 40 50 60 70 80 90 100

Age (years) 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, 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. Routine oxygen supplementation No oxygen No oxygen Oxygen Oxygen Oxygen

All strokes No oxygen Mild strokes SSS>40 (top) Severe strokes SSS (bottom) Ronning and Guldvog, Stroke 1999;30:2033-37. 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, blindedendpoint 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. The Stroke Oxygen Supplementation Study PROTOCOL

Patient eligible for the study 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 to a few months or less Explain study Obtain informed consent or informed assent Document baseline oxygen saturation Complete randomisation form Log in to or phone number below to randomise the patient

Prescribe Either or 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 Oxygen per nasal cannula for 3 nights 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 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 1 week post recruitment Complete Assessment Form 1 3, 6 and 12 months post recruitment SOS team to send assessment forms 2, 3 and 4 to the patient 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 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. 2. 3. 4.

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

1. SOS Study Contact Details SOS Study Manager Dr Sarah Pountain E-mail: [email protected] Tel: 0300 123 0891 SOS Chief Investigator Dr Christine Roffe E-mail: [email protected] Tel: 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 RANDOMISATION EMERGENCY CONTACT DETAILS Mobile No 07740 372852 (main) 07734 068408 (back-up) 2. Study Documents

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 patients 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 nonstroke 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 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 ( 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 E-mail: [email protected] Tel: 0300 123 0891 SOS Chief Investigator

Dr Christine Roffe E-mail: [email protected] Tel: 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 Patient Representatives Prof. S Jackson Prof. T Robinson Dr Martyn Lewis

Sponsor North Staffordshire Combined Healthcare NHS Trust Peter & Linda Handy Mrs Peta Bell International Advisory Committee Prof. Richard Lindley

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