Several studies have demonstrated a strong relationship between an increased body temperature in the first hours after stroke and poor functional outcome [3
]. To date, it is still unclear whether this relationship is causal. Some authors suggest that increased body temperatures after stroke are just an epiphenomenon of extensive cerebral damage and, thereby, of poor outcome. In a recent study of 725 consecutive patients admitted within 6 hours from the onset of acute ischemic stroke, no relation was found between initial body temperature and outcome [27
]. The authors used a rather insensitive method of statistical analysis (Spearman correlation and comparison of median modified Rankin scale scores with a nonparametric test). All patients with a body temperature of 37.0°C were treated with acetaminophen. Consequently, the results of this study should be interpreted with care.
In the Copenhagen Stroke study, the relationship between body temperature and outcome remained present after adjustment for initial stroke severity [5
]. Furthermore, early body temperature measurements (within the first 6 hours) seemed to be more strongly related to outcome than later measurements [24
]. This suggests that the relationship with poor outcome is not confounded by the occurrence of secondary infections, such as pneumonia or urinary tract infection, because these usually appear later in the course of the disease. Arguments for a causal relationship stem from the observation that the effect of body temperature on outcome is independent of the size of the brain lesion and from the beneficial effect of temperature-lowering treatment on infarct volume in animal models. Animal studies have demonstrated that higher body temperatures may worsen ischemic damage through an increase of blood-brain-barrier permeability and increased metabolic demands, resulting in acidosis and higher levels of deleterious excitatory amino-acids [28
]. In a recent meta-analysis of controlled animal studies on the effect of hypo- and hyperthermia in focal cerebral ischemia, Miyazawa showed that hyperthermia increases infarct volume whereas hypothermia reduces infarct volume [29
]. These reproducible observations from observational clinical studies and animal experiments strongly suggest that hypothermia may be a potent neuroprotective intervention, but this has never been studied in adequately powered clinical trials.
Randomized clinical trials of hypothermia in brain injury and hypoxic brain damage have provided conflicting results. In patients with coma after closed head injury, treatment with hypothermia, with body temperature reaching 33°C within eight hours after injury, was not effective in improving outcome [30
]. In patients who had been successfully resuscitated after cardiac arrest, hypothermia with body temperatures between 32°C and 34°C increased the chances of favorable outcome and reduced mortality [31
]. Perhaps the lack of effect in traumatic brain injury can be explained by the abundant presence of direct, i.e. non-ischemic damage.
Other methods of body temperature reduction
The feasibility of different methods of reducing body temperature in patients with acute stroke has been studied in several pilot studies.
A case-control study was conducted in 74 patients (17 cases, 56 controls) to assess the feasibility and safety of reducing body temperature to approximately 35.5°C with cooling blankets in combination with pethidine to prevent shivering [33
Another study on the feasibility of several methods of lowering body temperature was conducted in eight patients. Two patients were treated with 1 gram acetaminophen at 4-hour intervals. Two patients were cooled with cooling blankets, in two patients sponging with 70% alcohol was applied, and 2 patients served as a control group and were only monitored. Target temperature reductions of 1°C were reached within 6 hours [34
A study in 50 patients with a severe middle cerebral artery infarct demonstrated that body temperature can be reduced to 32 to 33°C, with the use of cooling blankets, alcohol and ice bags, under complete anesthesia [35
]. The procedure had many side effects; the most frequent complications were thrombocytopenia (70%), bradycardia (62%), and pneumonia (48%).
The many complications that occurred in the study of Schwab can be explained by the fact that these patients all had severe middle cerebral artery infarcts. In the remaining studies safety concerns were less prominent.
The COOL-AID study was a randomized controlled study of endovascular cooling to 33°C compared to standard medical treatment in 40 patients with acute ischemic stroke. Shivering was suppressed by warming blankets and sedatives [36
Most studies showed that cooling using the different methods was feasible, although it was more labor intense in the more invasive methods that induced larger body temperature decreases. However, in the COOL-AID study the feasibility was poor: 5 of the 18 treated patients did not reach the target temperature.
Mild reductions in body temperature – around 1°C – can be reached with external cooling blankets and general measures, within six hours, or more rapidly with an endovascular temperature management system. This approach requires mild sedation or morfine to reduce shivering, may be uncomfortable to patients, and is labor intensive. More aggressive approaches require anesthesia, and may induce increased risk of pulmonary- and other complications. This suggests that there is a need for a simple, medical intervention that may reduce body temperature to a lesser extent, but is cheap and safe.
Observational studies have shown an association between an increased body temperature and a poor outcome. Several national and international guidelines suggest that raised body temperature in stroke patients should be treated [13
]. However, the efficacy of temperature-lowering treatment to improve functional outcome has not yet been demonstrated in randomized trials [37
]. This dilemma is the rationale for PAIS.
PAIS: a simple trial
PAIS is a large, randomized, multi-center clinical trial. To keep the threshold for including patients low, the study design has been kept simple. The amount of data to be gathered is therefore limited; it consists of two one-page forms, one to be filled out at inclusion and one to be filled out at discharge. The local investigator will keep a log of randomized patients. The 3-month follow-up will be conducted by telephone from the central trial office. New centers are welcome to join the trial.