Acetaminophen for Fever in Critically ill Patients with Suspected Infection

Janet Kairu, Mercer University College of Pharmacy

According to four observational studies on fever management in various critical care settings, fever is one of the cardinal signs of infection and infectious diseases remain a major cause of morbidity and mortality.  In this studies, the presence of fever was associated with either an increased risks of death or no difference in mortality risk compared to a normal temperature.  Despite this, it is unclear whether fever itself is truly the enemy or whether, in fact, the febrile response represents an important means to help the body fight infection. [1]

Two recently published meta-analyses found no evidence that antipyretic therapy was either beneficial or harmful in non-neurologically injured Intensive Care Unit (ICU) patients.  In both meta-analyses, the authors noted that existing studies lacked adequate statistical power to detect clinically important differences and recommended that large randomized controlled trials were urgently needed. [2][3]

Title: Acetaminophen for Fever in Critically Ill Patients with Suspected Infection [4]
Design Blinded, randomized controlled trial; N = 700
Objective To determine the effects of acetaminophen therapy for patients in the intensive care unit (ICU) who have probable infection
Study Groups Eligible patients were randomly assigned, in a 1:1 ratio, to receive either an infusion containing 1 g of intravenous acetaminophen (n = 352) or an infusion of 5% dextrose in water, every 6 hours (n = 348).
Methods Patients with fever (body temperature, ≥38°C) and known or suspected infection were randomly assigned to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death.
Duration February 2013 to July 2014
Primary Outcome Measure ICU-free days (days alive and free from the need for intensive care) from randomization to day 28
Baseline Characteristics
Characteristic Acetaminophen

(n = 347)


(n = 344)

Age (y) 59.1 +/- 16.9 57.9 +/- 17.4
Male sex 224 (64.6) 225 (65.4)
Weight (kg) 86.5 +/- 26.0 85.4 +/-24.8
Inotropic or vasopressor support 174 (50.1) 181 (52.6)
Renal-replacement therapy 12 (3.5) 12 (3.5)
Receiving aspirin 53 (15.3) 54 (15.7)
Outcome Acetaminophen

(n = 346)


(n = 344)

Absolute difference   (95% CI) p value
ICU free days median 23 (13-25) 22 (12-25) 0 (0-1) 0.07
Adverse Events Common Adverse Events: None reported
Serious Adverse Events: Elevates body temperature associated with death in one patient assigned to placebo
Percentage that Discontinued due to Adverse Events: A total of 28 of 347 patients (8.1%) assigned to acetaminophen and in 34 of 344 patients (9.9%) assigned to placebo (odds ratio, 0.89; 95% CI, 0.69 to 1.16; p=0.40) discontinued due to liver dysfunction.
Study Author Conclusions Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. There was no significant between-group difference in 28-day mortality, 90-day mortality, or survival time to day 90.

The findings did suggest that acetaminophen had a modest clinical effect as an antipyretic in ICU patients with fever and probable infection but did not reduce ICU-free days.

The author’s mention that the administration of acetaminophen to treat fever was administered for a relatively short period of time, thus, the results do not preclude the possibility that a more prolonged course of acetaminophen may have a greater influence on patient-centered outcomes.  Further studies are required to evaluate this possibility.


  1. Young PJ, Saxena M. Fever management in intensive care patients with infections.Critical Care. 2014;18(2):206. doi:10.1186/cc13773.
  1. Jefferies S, Weatherall M, Young P, Eyers S, Perrin KG, Beasley CR:The effect of antipyretic medications on mortality in critically ill patients with infection: a systematic review and meta-analysis. Crit Care Resus 2011, 13(1):25-131
  1. Niven DJ, Stelfox HT, Laupland KB. Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis. J Crit Care. 2013;28(3):303-10.
  1. Young P, Saxena M, Bellomo R, et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med. 2015;

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