COOLing for Ischaemic Stroke Trial.

Background:

Cooling to 32 - 34°C improves outcome in patients with post-anoxic encephalopathy after cardiac arrest. Animal studies strongly suggest that cooling also improves outcome after ischaemic stroke. In these studies, cooling was efficacious at temperatures of 35°C or below, with lower temperatures associated with a greater benefit. In clinical practice however, each °C decrease in temperature may be tolerated less well by awake patients on a stroke unit. In contrast to endovascular cooling, surface cooling can probably be combined with concurrent thrombolysis. The feasibility of surface cooling to temperatures of 35°C or below in patients with acute ischaemic stroke has not been evaluated systematically in clinical studies.



Hypotheses:

1. Cooling to 34, 34.5 or 35°C by means of a surface cooling device, started within 4.5 hours after the onset of acute ischaemic stroke and maintained for 24 hours in awake patients on a stroke unit is safe.

2. In awake patients with ischaemic stroke, the feasibility of cooling decreases with each °C temperature reduction.



Aim:

To compare the feasibility and safety of surface cooling to 34, 34.5 and 35°C, started within 4.5 hours after the onset of acute ischaemic stroke and maintained for 24 hours, in awake patients on a stroke unit.



Methods:

This is a randomised, open, multi-centre, phase II clinical trial with masked outcome assessment, comparing three different surface cooling strategies with standard treatment in 48 awake adult patients with acute ischaemic stroke and a score on the NIH Stroke Scale > 6, admitted to a stroke unit. Intravenous or intra-arterial thrombolysis or thrombectomy are not exclusion criteria. Patients will be randomised to conventional treatment (n = 12) or to surface cooling to 34, 34.5, or 35°C maintained for 24 hours (n = 12 in each group). In all patients randomised to hypothermia, cooling will be started within 4.5 hours after the onset of symptoms by means of intravenous infusion of 20 ml/kg cooled normal saline (4°C) over 30 to 60 minutes, followed by surface cooling. Shivering and discomfort will be prevented and treated with intravenous pethidine and with oral buspirone. The primary outcome measure is feasibility, defined as the number of patients that has successfully completed the treatment strategy they had been assigned to. Secondary outcome measures include the time to target temperature, stability at target, complications, and the score on the modified Rankin scale at three months.



Sample size:

Based on an alpha of 0.05 and a power of 80%, we will need 12 patients per group to detect a difference in feasibility of 40%.



Study monitoring:

Unblinded outcome and safety data will be forwarded to an international data safety monitoring committee (DSMC) after final follow-up of the first 12, 24 and 36 patients, after which the DMSC will advise the steering committee with regard to the continuation of the study.



Expected results:

This study will provide adequate information on the feasibility and safety of different surface cooling strategies on a stroke unit. A validation study, in which the two most promising treatment strategies will be assessed again, is anticipated. The results of the present trial and those of the validation trial will inform the design of a conclusive phase III trial of surface cooling for acute ischaemic stroke. As cooling is probably more effective with lower temperatures, cooling to 34°C will be preferred if shown feasible and safe.

1. Cooling to 34, 34.5 or 35°C by means of a surface cooling device, started within 4.5 hours after the onset of acute ischaemic stroke and maintained for 24 hours in awake patients on a stroke unit is safe;

2. In awake patients with ischaemic stroke, the feasibility of cooling decreases with each °C temperature reduction.

Feasibility: 24 hours;

Complications: 3 months;

Modified Rankin scale: 3 months.

Patients will be randomised to conventional treatment (n = 12) or to surface cooling to 34, 34.5 or 35°C maintained for 24 hours (n = 12 in each group). In all patients randomised to hypothermia, cooling will be started within 4.5 hours after the onset of symptoms by means of intravenous infusion of 20 ml/kg cooled normal saline (4°C) over 30 to 60 minutes, followed by surface cooling. Shivering and discomfort will be prevented and treated with intravenous pethidine and with oral buspirone.