The HEAT Trial – Acetaminophen in ICU Patients with Fever

19 Oct
October 19, 2015

The HEAT Trial 1Background: Acetaminophen (paracetamol) is commonly used to lower the temperature of patients with fever suspected to be causeed 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.

The HEAT Trial

What Study are we Discussing?

Young P et al. Acetaminophen for fever in critically ill patients with suspected infection. NEJM 2015. PMID: 26436473

What They Did:

  • Prospective, Parallel-Group, Blinded Randomized Controlled Trial
  • Randomly assigned 700 ICU patients aged 16 years of age or older with fever (≥38°C) and known or suspected infection in 1:1 ratio to receive 1g IV acetaminophen vs placebo (5% dextrose in water) every 6hrs until:
    • ICU discharge
    • Resolution of fever
    • Cessation of Antimicrobial Therapy
    • Death
  • Patients Excluded: See table S1 (BELOW)

Exclusion Criteria
AST or ALT >5x the upper limit of normal, or bilirubin > 2x the upper limit of normal, or any other contraindication to 4g acetaminophen per day
A requirement for ongoing use of non-steroidal anti-inflammatory drugs (in excess of low dose 300mg/day aspirin)
Admission to ICU following a cardiac arrest which is currently being treated with therapeutic hypothermia or where a need for therapeutic hypothermia is anticipated
Evidence of acute brain injury during the current hospital admission (defined as any acute traumatic brain injury, subarachnoid hemorrhage, acute ischeaemic stroke, acute intracerebral hemorrhage, or acute intracranial infection
Hyperthermic syndromes including heat stroke; current biochemical evidence of thyrotoxicosis (thyroid function tests are not required before recruitment into the trial unless clinically indicated); malignant hyperthermia, neuroleptic malignant syndrome, or other drug-induced hyperthermia
Limitation of therapy order or aggressive treatment is deemed unsuitable
Moribund; death is perceived to be imminent (within 24 hours)
Rhabdomyolysis deemed by the treating clinician to be clinically significant
Transferred from another ICU where they spent >12hrs and fulfilled all inclusion criteria while there
Pregnancy
Previously enrolled or previously eligible for enrollment during the current ICU admission but not enrolled in the study (i.e. patients who were not enrolled within 12hrs of onset of fever in association with satisfying other eligibility criteria may not be enrolled at a later point in the ICU admission)

Outcomes:

  • 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”)
  • Secondary:
    • 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

Results:

  • 700 patients (10 withdrew consent and not included in analysis) in 23 adult medical-surgical ICUS in Australia and New Zealand
    • Acetaminophen Arm: 346 patients
    • Placebo Arm: 344 patients
  • Number of ICU-free days to day 28
    • Acetaminophen Group: 23 days
    • Placebo Group: 22 days
    • Not Statistically Significant p = 0.07
  • Mortality by day 90
    • Acetaminophen Group: 55/345 patients (15.9%)
    • Placebo Group: 57/344 patients (16.6%)
    • RR 0.96 (95% CI 0.66 – 1.39; p = 0.84)

Strengths:

  • 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

Limitations:

  • 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

Discussion:

  • Acetaminophen was associated with shorter ICU stay than placebo in survivors and longer ICU stay among non-survivors, but there was no statistically significant difference between groups with respect to 28d mortality, 90d mortality, or survival time to day 90

Author Conclusion: Early administration of acetaminophen to treat fever due to probably infection did not affect the number of ICU-free days.

Clinical Take Home Point: 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.

References:

  1. Young, P et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. NEJM 2015; [epub ahead of print]

For More Thoughts on This Topic Checkout:

Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)

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Anand Swaminathan

Clinical Assistant Professor of Emergency Medicine at Bellvue/NYU
REBEL EM Associate Editor and Author
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