This review was cross-posted on REBEL EM.

Acetaminophen (paracetamol) is commonly used to lower the temperature of patients with fever suspected to be cause d by an infection in both homes across the world and the hospital. There are, however, opposing theories to the utility of decreasing fever in these situations. One side argues that fever places “additional physiological stress on patients,” who are already ill (Young 2015). Removing this source of increased metabolic demand would allow the body to allocate additional resources to fighting infection, respiratory function etc. On the other hand, fever may “enhance immune-cell function” and inhibit further growth and spread of an infecting pathogen (Young 2015). From a simple evolutionary standpoint, fever, which entails a significant cost likely evolved and persists because it benefits the host. To date we don’t have high-level evidence that acetaminophen treatment of fever due to probable infection is beneficial, ineffective, or harmful.

Clinical Question

Does the use of acetaminophen in an ICU population with fever from suspected infection decrease ICU utilization rates?


Patients > 16 years of age with a temperature > 38oC who are admitted to the ICU and are receiving antimicrobial therapy for a known or suspected infection.


1 gm IV acetaminophen Q6 until either ICU discharge, resolution of fever, cessation of antimicrobial therapy or death




Primary: ICU-free days (days alive and free from the need for intensive care) from randomization to day 28 (if the patient died during the study, they were counted as 0 “ICU-free days”)
• All-cause mortality at day 28 and 90
• Survival time (Number of days alive) from randomization until day 90
• ICU and hospital length of stay
• Hospital-free days, Days free from mechanical ventilation
• Days free from inotropes or vasopressors
• Days free from renal replacement therapy
• Days in the ICU that were free from support


Multi-center (23 ICUs), prospective, Parallel-Group, Blinded Randomized Controlled Trial


Liver failure, requirement for ongoing use of NSAIDs (except ASA), therapeutic hypothermia initiated or anticipated, acute brain injury, hyperthermic syndromes (i.e. heat stroke, malignant hyperthermia, neuroleptic malignant syndrome etc.), imminent death within 24 hours, rhabdomyolysis, transferred from another ICU (where they spent > 12 hours), pregnancy. A full list is available in Table S1 online.

Primary Results

Critical Findings

  • 700 patients (10 withdrew consent and not included in analysis) in 23 adult medical-surgical ICUS in Australia and New Zealand
  • ICU-free Days (primary outcome): 23 days (acetaminophen) vs 22 days (placebo) CI 0-1 p = 0.07
  • Death at 90 days: 15.9% (acetaminophen) vs 16.6% (placebo); RR = 0.96 CI: 0.66 – 1.39 p = 0.84


  • Study asks an important question with an important outcome
  • Only large, multicenter study of its kind
  • Randomization and blinding well performed
  • Excellent follow up (98.6%)
  • All analyses conducted prior to unmasking the study-group assignments


  • Protocol violations were high in both the acetaminophen (30%) and placebo (28%) groups
  • Open-label acetaminophen was administered to 30% of patients in both arms
  • Acetaminophen use before randomization or after ICU discharge was not recorded
  • 33% of patients received acetaminophen after the course of the study drug had been completed
  • It is unclear if these results can be extrapolated to the use of oral acetaminophen
  • Median duration of the study drug was short

Author's Conclusions

“Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU free days.”

Our Conclusions

In ICU patients, regular administration of acetaminophen to treat fever did not show a significant benefit to patients.

Bottom Line

Fever need not always be treated in patients with suspected infectious causes. It appears reasonable to give acetaminophen to patients in whom the fever is causing distress but it is similarly reasonable to withhold it in patients who are not distressed.

Read More

Intensive Care Network: Paul Young on SPLIT, HEAT and Platform Trials

The Bottom Line: HEAT Trial – Acetaminophen for Fever in critically Ill Patients with Suspected Infection

HEFT EM Cast: Fever, Friend or Foe?

FOAMCast: Core Content Journal Club