haist haist the hypothermia for acute ischaemic stroke trial malcolm macleod phd frcpe senior...
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HAIST
HAISTThe Hypothermia for Acute Ischaemic Stroke Trial
Malcolm Macleod PhD FRCPE
Senior Lecturer, Clinical Neurosciences, University of EdinburghClinical Lead, South East Scotland Stroke Research NetworkTreasurer, European Stroke Research Network for Hypothermia
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HAIST
• Why hypothermia?• Objectives of pilot study
– Cooling– Brain temperature measurement– Anti shivering strategy– Biomarkers
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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
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HAIST
Variables to be considered
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HAIST
• Delay to initiation• Speed of induction• Depth• Duration• Stability at target temperature• Speed of rewarming
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HAIST
• Delay to initiation• Speed of induction• Depth• Duration• Stability at target temperature• Speed of rewarming
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HAIST
What we know about potential benefitDepth of hypothermia
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HAIST
What we know about potential benefitDelay to treatment
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HAIST
What we know about potential benefit
Duration of hypothermia
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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, …)
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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
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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
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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
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HAIST
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
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HAIST
Brain temperature measurement
• How do we know that cooling the body cools the brain
• Which is the best surrogate of brain temperature measurement
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HAIST
MR Spectroscopy
NAA peak
T = 37°C + 100(CSNAA – 2.035)
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HAIST
Temperature measurement
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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
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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
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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