haist haist the hypothermia for acute ischaemic stroke trial malcolm macleod phd frcpe senior...

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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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• Why hypothermia?• Objectives of pilot study

– Cooling– Brain temperature measurement– Anti shivering strategy– Biomarkers

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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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Variables to be considered

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• Delay to initiation• Speed of induction• Depth• Duration• Stability at target temperature• Speed of rewarming

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• Delay to initiation• Speed of induction• Depth• Duration• Stability at target temperature• Speed of rewarming

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What we know about potential benefitDepth of hypothermia

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What we know about potential benefitDelay to treatment

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What we know about potential benefit

Duration of hypothermia

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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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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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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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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

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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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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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MR Spectroscopy

NAA peak

T = 37°C + 100(CSNAA – 2.035)

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Temperature measurement

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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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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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Summary

• Small-ish number of patients• Patients themselves are potentially

moe difficult than e.g. head injury– Co-morbidities– Imaging

• Could transform stroke care