1. HAIST HAIST The Hypothermia for Acute Ischaemic Stroke Trial Malcolm Macleod PhD FRCPE Senior Lecturer, Clinical Neurosciences, University of Edinburgh Clinical Lead, South East Scotland Stroke Research Network Treasurer, European Stroke Research Network for Hypothermia

2. HAIST Why hypothermia? Objectives of pilot study –Cooling –Brain temperature measurement –Anti shivering strategy –Biomarkers

3. HAIST Why hypothermia? Effective following cardiac arrest Effective in neonatal hypoxic ischaemic brain injury Possibly effective in traumatic brain injury Highly effective in animal studies

4. HAIST Variables to be considered

5. HAIST Delay to initiation Speed of induction Depth Duration Stability at target temperature Speed of rewarming

6. HAIST Delay to initiation Speed of induction Depth Duration Stability at target temperature Speed of rewarming

7. HAIST What we know about potential benefit Depth of hypothermia

8. HAIST What we know about potential benefit Delay to treatment

9. HAIST What we know about potential benefit Duration of hypothermia

10. HAIST What we know about potential harm Not much in stroke patients, but –Likely to be related to depth and duration of cooling –Likely to include infections; GI bleeding; coagulopathy –Likely to vary with patient specific factors (age, comorbidity, …)

11. HAIST What this means for a clinical trial program Benefit is likely to increase with depth, shorter delay to and longer duration of cooling; and a large RCT will be required to demonstrate benefit. Harm is likely to increase with depth and duration of cooling Thresholds for harm will be apparent with smaller groups of patients than required to show benefit

12. HAIST Cooling Patients with acute ischaemic stroke admitted within 3 hours of onset in whom cooling can be initiated within 4.5 hours Initiated with 20ml/kg ice cold saline Maintained with Arctic Sun All get MRI 2-3hrs after initiation of cooling – means latest recruitment approx. 2-3pm

13. HAIST Hypothermia in Acute Ischaemic Stroke Trial – Edinburgh (HAIST-E) Pilot dose escalation study Safety, tolerability, feasibility –2:1 treatment : control –Block 1: 35°C for 12 hours –Block 2: 35°C for 24 hours –Block 3: 33°C for 12 hours –Block 4: 33°C for 24 hours Imaging and biomarker components HAIST

14. Temperature measurement Oesophageal probe – disconnect for scan Tympanic – intermittent, infra red Bladder probe – disconnect for scan Rectal probe – fluoroptic, use until after scan, drive temperature during scan

15. HAIST Brain temperature measurement How do we know that cooling the body cools the brain Which is the best surrogate of brain temperature measurement

16. HAIST MR Spectroscopy NAA peak T = 37°C + 100(CS NAA – 2.035)

17. HAIST Temperature measurement

18. HAIST Anti-shivering strategy Pethidine –0.5mg/kg bolus –0.25 mg/kg/hr –Adjusted according to shivering score with Bolus of 10-25mg Increase infusion by 5mg/hr Gloves and socks NG tube

19. HAIST Biomarkers DNA, RNA or Protein Peripheral blood markers of brain injury –Change in cell number –Change in cell surface expression Serve as markers of –the extent of brain injury, –likely outcome, –likely response to treatment Measured at baseline; 6hr; 24hr; 48hr

20. HAIST Summary Small-ish number of patients Patients themselves are potentially moe difficult than e.g. head injury –Co-morbidities –Imaging Could transform stroke care