By Dean L. Winslow, MD, FACP, FIDSA
Dr. Winslow is Clinical Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine.
Dr. Winslow reports no financial relationships relevant to this field of study.
SYNOPSIS: Seven hundred ICU patients with fever and known or suspected infection were randomly assigned to receive acetaminophen 1 g IV or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. Early administration of acetaminophen did not affect number of ICU-free days.
SOURCE: Young P, et al. Acetaminophen for fever in critically ill patients with suspected infection. N Engl J Med 2015 Oct. 5; [Epub ahead of print].
Seven hundred adult intensive care unit (ICU) patients with fever (temperature ≥ 38°C) and known or suspected infection were randomized to receive either acetaminophen 1 g IV or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from need for ICU care) from randomization to day 28.
Baseline characteristics of the patients were similar between the groups. Common coexisting conditions included cancer (20-21%), chronic pulmonary disease (12-14%), diabetes (25-26%), and ischemic heart disease (15%). Virtually all patients met criteria for “sepsis,” 50-53% required vasopressors, and 57-60% required mechanical ventilation.
There was no difference between the acetaminophen and placebo groups in the primary outcome (23 ICU-free days in acetaminophen group vs. 22 days in the placebo group), nor in the secondary endpoints (hospital-free days, days free from mechanical ventilation, days free from inotropes/vasopressors, renal replacement therapy, or days free from ICU support). Similarly, there was no difference between the groups in death by day 28 (13.9 vs. 13.7%), and death by day 90 (15.9 vs. 16.6%) in the acetaminophen and placebo groups, respectively. Hospital length of stay among non-survivors was significantly longer (13.9 days vs. 7.7 days), as was ICU length of stay in non-survivors (10.4 days vs. 4.0 days) in acetaminophen-treated patients compared to placebo-treated patients. There was no difference between the groups in either hospital length of stay or ICU length of stay in survivors.
There were no discernible differences in adverse events between acetaminophen- and placebo-treated patients. Slightly more than 8% of acetaminophen-treated patients and 9.9% of placebo-treated patients experienced liver dysfunction leading to study drug discontinuation.
COMMENTARY
This is an interesting study, conducted in New Zealand, which demonstrates no discernible benefit from routine administration of acetaminophen in critically ill febrile patients with known or suspected sepsis. The use of acetaminophen in this setting also did not appear to result in any obvious harm. The observation that ICU and hospital lengths of stay were longer in acetaminophen-treated patients who eventually died is intriguing. This result is consistent with an earlier study, which showed that physical cooling to normothermia delayed death in mechanically ventilated patients with septic shock.1 Similarly, an older retrospective cohort study in ICU patients showed that acetaminophen-treated patients had a significantly longer time to death than did those who did not receive acetaminophen.2 This effect of acetaminophen delaying death without affecting mortality at day 28 or day 90 is intriguing and potentially generates many different hypotheses as to why this phenomenon is observed.
REFERENCES
- Schortgen F, et al. Fever control using external cooling in septic shock: A randomized controlled trial. Am J Resp Crit Care Med 2012;185:1088-1095.
- Suzuki S, et al. Paracetamol therapy and outcome of critically ill patients: A multicenter retrospective observational study. Crit Care 2015;19:162.
