The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial

doi:10.1016/S1474-4422(09)70051-1

The Lancet Neurology

Volume 8, Issue 5, May 2009, Pages 434-440

https://doi.org/10.1016/S1474-4422(09)70051-1 Get rights and content

Summary

Background

High body temperature in the first 12–24 h after stroke onset is associated with poor functional outcome. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial aimed to assess whether early treatment with paracetamol improves functional outcome in patients with acute stroke by reducing body temperature and preventing fever.

Methods

In a multicentre, randomised, double-blind, placebo-controlled trial, patients with ischaemic stroke or intracerebral haemorrhage and body temperature between 36°C and 39°C were randomly assigned treatment with paracetamol (6 g daily) or placebo within 12 h from symptom onset. Treatment allocation was based on a computer-generated list of random numbers with varying block size. The primary outcome was improvement beyond expectation on the modified Rankin scale at 3 months, according to the sliding dichotomy approach. This trial is registered, number ISRCTN74418480.

Findings

Between March, 2003, and May, 2008, 1400 patients were randomly allocated treatment. 260 (37%) of 697 patients receiving paracetamol and 232 (33%) of 703 receiving placebo improved beyond expectation (adjusted odds ratio [OR] 1·20, 95% CI 0·96–1·50). In a post-hoc analysis of patients with baseline body temperature 37–39°C, treatment with paracetamol was associated with improved outcome (1·43, 1·02–1·97). There were 55 serious adverse events in the paracetamol group (8%) and 70 in the placebo group (10%).

Interpretation

These results do not support routine use of high-dose paracetamol in patients with acute stroke. Paracetamol might have a beneficial effect on functional outcome in patients admitted with a body temperature 37–39°C, but this post-hoc finding needs further study.

Funding

Netherlands Heart Foundation.

Introduction

Many patients admitted with stroke have fever or subfebrile body temperatures, which are associated with case fatality and poor functional outcome. About a third of patients have temperatures greater than 37·5°C within the first hours of stroke onset.1, 2, 3, 4 The odds of poor outcome were doubled for every degree increase in body temperature measured within 12 h of stroke onset.⁴ This association was independent of initial stroke severity, lesion volume, age, sex, and stroke type. The relation with clinical outcome is probably limited to body temperatures measured in the first 12–24 h of stroke onset.3, 4, 5

High body temperature might be a direct consequence of stroke or a result of accompanying infections. Studies in animals have suggested that high body temperature increases damage caused by cerebral ischaemia through increased metabolic demands, an increased release of neurotransmitters, increased free-radical production, breakdown of the blood–brain barrier, and increased proteolysis.⁶ Mitigation of even mild spontaneous hyperthermia conferred neuroprotection in animal models of stroke,⁶ and induced hypothermia reduced infarct volume and improved functional outcome.⁷ Therefore, reduction of body temperature and prevention of fever might be a promising approach in treatment to improve functional outcome after stroke.

Guidelines for the treatment of acute ischaemic stroke8, 9 or intracerebral haemorrhage¹⁰ recommend antipyretic drugs in patients with fever or body temperature above 37·5°C, and most European stroke specialists view the monitoring of body temperature as an essential component of care in stroke units.¹¹ However, no evidence from randomised trials has shown that strategies to prevent or treat high body temperature reduce case fatality and improve functional outcome after stroke.

Paracetamol (acetaminophen) is one of the most commonly used antipyretic drugs. Potent inhibition of prostaglandin production in the CNS presumably confers its antipyretic properties.¹² Paracetamol is usually well tolerated by patients with acute stroke and has almost no side-effects in doses up to 6 g per day.13, 14, 15 In patients with acute ischaemic stroke, paracetamol at a daily dose of 6 g reduces body temperature by about 0·3°C within 4 h from start of treatment.¹⁶

In the Paracetamol (Acetaminophen) In Stroke (PAIS) trial, we aimed to assess whether early treatment with paracetamol improves functional outcome in patients with acute stroke.

Section snippets

Patients

PAIS was a multicentre, randomised, double-blind, placebo-controlled, clinical trial in which patients were enrolled between March, 2003, and May, 2008. The study protocol has been published previously.¹⁷ In brief, patients were eligible for inclusion if they were 18 years or older, had a clinical diagnosis of ischaemic stroke or intracerebral haemorrhage, and were able to receive the study drug within 12 h of symptom onset. In patients who noticed symptoms after waking from sleep, the time

Results

In 29 participating centres in the Netherlands, 697 patients were randomly assigned to treatment with paracetamol and 703 to placebo. 21 patients assigned paracetamol (3%) and 34 assigned placebo (3%) discontinued treatment within the first 24 h, and about 30% of all patients did not complete the 3-day treatment period. Early discharge (41%) or death (20%) were the most common reasons for not completing the full treatment period. One patient was lost to follow-up (figure 1).

Baseline

Discussion

In the PAIS trial, more patients allocated paracetamol improved beyond expectation than did patients treated with placebo, although the difference was not statistically significant. Paracetamol did not affect secondary outcome measures or outcomes in predefined subgroups. However, in patients with a baseline body temperature of 37–39°C, treatment with paracetamol was associated with improved outcome.

Two phase II trials in patients with acute ischaemic stroke showed that high-dose paracetamol

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Fast track — ArticlesThe Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Lancet

Lancet

Fever in acute stroke worsens prognosis. A prospective study

Stroke

Stroke severity determines body temperature in acute stroke

Stroke

Timing for fever-related brain damage in acute ischemic stroke

Stroke

Combating hyperthermia in acute stroke: a significant clinical concern

Stroke

Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis

Brain

Circulation

Guidelines for management of ischaemic stroke and transient ischaemic attack 2008

Cerebrovasc Dis

Circulation

The main components of stroke unit care: results of a European expert survey

Cerebrovasc Dis

Paracetamol and phenacetin

Drugs

Effect of paracetamol (acetaminophen) on body temperature in acute ischemic stroke: a double-blind, randomized phase II clinical trial

Stroke

Prophylactic antipyretic treatment with acetaminophen in acute ischemic stroke: a pilot study

Neurology

Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial

Stroke

Fast track — Articles
The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial