Why Hypothermia?
Stroke is the second cause of long-term disability across high-income countries, including those of the European Union (EU), and the second leading cause of death world-wide and in Europe, accounting for just over 508,000 deaths in the EU each year. Approximately two thirds of patients remain disabled or die following a stroke. As stroke incidence rates rise exponentially with age, the social and economic burden of stroke will increase further with the ageing societies.
Currently, the treatment options for stroke are very limited. Both early intravenous thrombolysis and aspirin improve outcome of patients with ischaemic stroke. However, only a small minority (generally below 10% in high-income countries) of patients with acute stroke receive thrombolysis, mainly because of a short time window to treatment. The benefit of aspirin is small, with 79 patients needed to be treated to prevent one poor outcome. Accordingly, there is ample need for efficacious, cost-effective therapies that can be implemented in a broad section of the health care systems, across all lower and higher income European Member States and on a global scale.
Moderate hypothermia – the lowering of body temperature below normal – has emerged as one of the most promising therapeutic interventions, because of a relative simple application and robust effectiveness in experimental stroke models, as well as in patients with cardiac arrest, hypoxic neonatal encephalopathy, and early series and small clinical trials of patients with acute stroke. Hypothermia can therefore be regarded one of the most promising future interventions for the treatment of acute ischaemic stroke. The importance of hypothermia research has been recognized recently also by the Second Consensus Conference on Stroke Management (Helsingborg, 2006). This meeting was organised by the International Stroke Society, endorsed by the European Stroke Council and International Stroke Society, and was co-sponsored by the WHO Regional Office for Europe.
At the same time, while there are considerable data from related diseases and experimental data from animal stroke studies - whether hypothermia will also improve outcome of patients with stroke remains to be tested in planned proof-of-concept and randomised clinical trials. There are several questions without answer at this stage, for example: (1) the optimal depth and duration of hypothermia; (2) the optimal route of cooling (local, surface, or endovascular); (3) the optimal shivering management strategy; and (4) any impact of anti-shivering strategies on the protective effect of hypothermia in animal models.
A number of groups across Europe are currently active in this area. Translational scientists are exploring both the time-dependence of the effect of hypothermia in animal studies and the impact of pethidine, a drug used to control shivering, on the protective effect of hypothermia. There are at least 7 early phase clinical trials in progress or planned, each with slightly different designs, based in Malmo/Copenhagen; Erlangen; Heidelberg; Mainz; Utrecht; Edinburgh, and Helsinki. In contrast, in the US the ICTuS clinical trial program is a centrally funded multicentre endeavour which has been making some progress, but is as yet inconclusive due to low patient numbers. In Japan and other parts of the World there are no large scale trials planned or ongoing.
Since 2007 the principal investigators of the small European studies started to communicate with each other and met at International Congresses. More recently they established a (as yet unfunded) collaborative group, the European Stroke Research Network for Hypothermia (EUROHYP).