Paracetamol (Acetaminophen) in stroke trial: results of a randomized, double blind clinical trial

Background: Body temperatures over 37.5°C are found in about a third of patients within the day after stroke onset and have been associated with increased case fatality and poor functional outcome. This relation is probably limited to the first 12 to 24 hours from stroke onset. In patients with acute ischaemic stroke, paracetamol in a daily dose of 6g reduces body temperature by about 0.3°C within 4 hours from start of treatment. The aim of the Paracetamol (Acetaminophen) In Stroke trial (PAIS; ISCRTN74418480) was to assess whether early treatment with paracetamol improves functional outcome in patients with acute stroke by reducing body temperature and preventing fever.

Methods: Patients with ischaemic stroke or intracerebral haemorrhage and a body temperature between 36°C and 39°C were randomly assigned to treatment with paracetamol (6g daily for three days) or placebo within 12 hours from symptom onset. The planned size of the trial was 2500 patients. The primary effect estimate was the odds ratio for improvement beyond expectation on the modified Rankin scale at 3 months, according to the sliding dichotomy approach. Analyses were adjusted for potentially confounding factors.

Results: The trial was terminated prematurely after inclusion of 1400 patients because of slow recruitment and lack of funding. There was a tendency for more patients in the paracetamol group (260/697; 37%) to improve beyond expectation than in the placebo group (232/703; 33%) (adjusted OR 1.20; 95% CI: 0.96 to 1.50). In a post-hoc analysis of patients with a baseline body temperature between 37.0°C and 39.0°C, treatment with paracetamol was associated with improved outcome (adjusted OR 1.43; 95% CI: 1.02 to 1.97). Treatment with paracetamol was associated with a 0.26°C (95% CI, 0.18 to 0.31) reduction in mean body temperature at 24 hours from the start of treatment as compared with placebo. No relation was found between baseline body temperature and improvement (adjusted OR 0.95; 95% CI: 0.79 to 1.14). Increased body temperature at 24 hours from the start of treatment was associated with a lower likelihood of improvement.

Conclusion: These results do not provide sufficient evidence to support routine use of high-dose paracetamol in patients with acute stroke. Paracetamol may have a beneficial effect on functional outcome in patients admitted with a body temperature between 37.0°C and 39.0°C. This finding needs confirmation in an independent study.