Seventy-five patients were randomized and included in the study between October 2000 and October 2001. Almost half of the patients started treatment within 12 hours after onset of symptoms. Prognostic factors, and other factors that could be related to increased body temperature were evenly distributed amongst the three treatment groups (Table ). However, patients in the acetaminophen group had a lacunar stroke less often, they had a higher score on the NIHSS and were drowsy more often, and the mean body temperature at the start of treatment was higher than in the placebo group (0.3°C).
Demographics, stroke risk factors and clinical characteristics of the study population.
All but one patient were on treatment after 24 hours. Twenty-six patients did not complete the full five-day-treatment schedule (Figure ). Of the 7 patients in the placebo group who stopped, 4 were discharged within 5 days, 2 withdrew their consent, and 1 patient forgot to take the last 3 doses on day 5. In the ibuprofen group, 6 patients were discharged within 5 days, 2 withdrew consent, and 2 developed a hemorrhagic gastritis. Finally, in the acetaminophen group, one patient, a woman with a severe middle cerebral artery infarction did not complete the first 24 hours of treatment, and died from herniation after hemorrhagic transformation of the infarct. One other patient on acetaminophen died from progressive stroke within the first five days. Four patients were discharged early, one patient had a high serum creatinine, one had slightly elevated transaminases at baseline, which made the local investigator decide to stop the study treatment and finally, one patient withdrew consent. Patients who died within the study period or who had stopped taking their medication, could still be considered as having completed the 28-day outcome assessment.
At 24 hours, the mean rectal body temperatures in the three groups did not differ significantly (Table ). However, compared with placebo, treatment with acetaminophen resulted in a 0.3°C (95% CI: 0.0 to 0.6°C) larger reduction in body temperature in the first 24 hours. This effect occurred early and was stable (Figure ). In the first 24 hours, ibuprofen had no significant effect on body temperature as compared with placebo. The difference in reduction in body temperature at 24 hours after start of treatment between ibuprofen and acetaminophen was 0.2°C (95% CI: -.2°C to 0.6°C).
Effect of treatment on body temperature (in °C) and outcome. Effects on area under the curve measurements were adjusted for body temperature at start of treatment.
Figure 2 Time course of change in tympanic body temperature compared to start of treatment during the first 24 hours of treatment, in the three treatment groups. Discrepancies with Table are caused by rounding and by the use of tympanic measurements. (more ...)
Body temperature measurements at five days from the start of treatment were available in 52 of the 75 patients. In the 21 patients who died, withdrew consent, or were discharged within 5 days from randomization, no further temperatures could be taken, and in 2 other patients who had discontinued study treatment, temperature measurements were inadvertently stopped. After the first day, mean body temperatures tended to be lower in both groups who were on active treatment (Figure ). After 5 days, ibuprofen treatment resulted in 0.5°C lower body temperatures, and acetaminophen treatment led to 0.2°C lower body temperatures than placebo treatment, but these differences were not statistically significant (Table ). In addition, only about half of the patients were still on treatment on day 5.
The comparison between the areas under the temperature curve was hampered by differences in temperature at start of treatment. After adjustment for differences in baseline temperature, the areas for acetaminophen and ibuprofen were significantly smaller than for placebo. Finally, no significant differences in functional outcome were observed between the three regimens (Table ).
During the treatment period, 1 patients died from herniation and 1 from a a progressive stroke, both were on acetaminophen. One patient (on acetaminophen) developed pneumonia, and two patients (both on ibuprofen) had gastric retention and signs of hemorrhagic gastritis. Liver function disturbances occurred in 3 patients who were on placebo, in 6 patients who used ibuprofen, and in 6 patients who used acetaminophen, resulting in a relative risk of 1.9 (95% CI: 0.5 to 6.7) of acetaminophen compared to the placebo group. According to the local investigators, the liver function disturbances and the gastic disturbances were possibly related to the study treatment.