HEAT: Acetaminophen for Fever
Acetaminophen for Fever in Critically Ill Patients with Suspected Infection.
Young P, Saxena M, Bellomo R, et al.; HEAT Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group.
N Engl J Med. 2015 Dec 3;373(23):2215-24. [Full text]
The thermoregulatory center in the hypothalamus maintains thermal homoeostasis. Fever is caused by a disturbance in that thermal homeostasis induced by pyrogens as a response to inflammation and infection [1].
Fever is part of the inflammatory response and can inhibit bacteria and viral reproduction in some circumstances, and inhibit resistance to infection in others [2]. Fever is associated with improve vascular tone and decrease oxygen consumption [3] but also seizures, organ failure, and brain damage.
Hyperthermia differs from fever as it is an increase of the body’s core temperature independent of the thermoregulatory center.
Could fever be both beneficial and detrimental? It has been hypothesized that it might have evolved as a mechanism “for accelerating recovery of individuals from localized or mild to moderately severe systemic infections in the interest of continued propagation of the species and for hastening the elimination of fulminantly infected individuals who pose a threat of epidemic disease” [1]. In fact, prior studies, with conflicting benefit and harm, would seem to support this hypothesis.
The permissive HypErthermia through Avoidance of AceTaminophen in Known or Suspected Infection in the Intensive Care Unit (HEAT) trial group attempted to address this uncertainty by conducting a multicenter, blinded, randomized, controlled trial with the hypothesis that IV acetaminophen to treat fever would worsen outcomes.
Patient population and Design
Patients ≥16 years with a temperature ≥38°C within 12 hours of enrollment, who were receiving antimicrobial therapy for a known or suspected infection were eligible. Patients were excluded with acute brain disorders or if acetaminophen use was contraindicated by liver dysfunction.
Eligible patients were randomly assigned to either 1 g of IV acetaminophen or 5% dextrose in water, every 6 hours. The study medications were packaged in indistinguishable 100-ml glass bottles. Patients continued the study drug until 28 days or until one of the following: discharge from the ICU, resolution of fever, cessation of antimicrobial therapy, death, or contraindication developed to the study drug. Rescue physical cooling was permitted if the body temperature rose to ≥39.5°C . Open-label acetaminophen was permitted after study course was completed.
Outcomes
The primary outcome measure was ICU-free days, a composite combining mortality and ICU length of stay, up to 28 days. Key secondary outcomes include all-cause mortality at 28 and 90 days; ICU and hospital length of stay; and hospital-free days, and days free from inotropes or vasopressors.
Results
From February 2013 through July 2014 from 23 adult medical–surgical ICUs in Australia and New Zealand 346 were assigned to receive acetaminophen and 344 placebo. The study groups had similar characteristics at baseline. The median number of doses was 8 (IQ range 5-14) in the acetaminophen group and 9 (IQ 6-15) for placebo.
Open-label acetaminophen (after the study period) was somewhat common in each group, administered 30% (104 of 347) of the acetaminophen group and 29.4% (101 of 344) placebo (OR 1.01; 95% CI 0.86-1.19; P=0.86). The study drug was more frequently discontinued because of sustained resolution of fever in the acetaminophen group, 22.8% (79 of 347), compared to palcebo, 16.9% (58 of 344), but the difference did not reach statistical significance (OR 1.45; 95% CI, 0.99-2.12; P=0.05).
There was no significant difference in the number of ICU-free days to day 28 between the acetaminophen group and the placebo group: 23 days vs. 22 days (absolute difference 0 days; 96.2% CI 0-1; P=0.07).
There mortality at day 28 or at day 90 was similar between the acetaminophen and placebo groups, When looking at the survivors subgroup, acetaminophen was associated with a shorter median ICU length of stay than placebo (3.5 vs. 4.3 days, P=0.01) but a longer median ICU length of stay among non-survivors (10.4 vs. 4.0 days, P<0.001).
Liver dysfunction led to a similar frequency of discontinuation, 8.1% vs. 9.9% (OR 0.89; 95% CI 0.69-1.16; P=0.40).
Discussion
The study found that early administration of IV acetaminophen for treatment of fever in adult ICU patients with probable infection did not affect the number of ICU-free days compared to a placebo. Secondary outcomes like mortality at 28 and 90 days were similar, as were the rates of adverse events like liver dysfunction.
What could explain the observation that non-survivors had longer ICU and hospital length of stay with acetaminophen compared to placebo? Besides the teleologic explanation, it may be that controlling fever effects how treating clinicians perceive the patient’s illness severity and/or prognosis, or both.
There were some factors that could have made a true difference difficult to observe. Only a relatively few study doses were administered (median 8 vs. 9) and open label acetaminophen use occurred in nearly 1/3 of patients in each group.
Since the current study, a large meta-analysis looking at multiple cooling methods (anti-pyretics and physical cooling) in varied populations (critically ill and non critically ill) found no difference in the risk of death, adverse events, or even quality of life [3]. The present study and the totality of the evidence is a reminder that treating the underlying disease remains key, while symptom management like fever control remains in the realm of supportive care.
| F: Follow up | 28 then 90 days |
| R: Randomization | Yes, block randomization, stratified by center |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes |
| S: Source (funding) | Health Research Council of New Zealand and others; |
- Holgersson J, Ceric A, Sethi N, Nielsen N, Jakobsen JC. Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses. BMJ. 2022 Jul 12;378:e069620. doi: 10.1136/bmj-2021-069620. PMID: 35820685; PMCID: PMC9274300.
- Mackowiak PA. Fever: blessing or curse? A unifying hypothesis. Ann Intern Med. 1994 Jun 15;120(12):1037-40.
- Schortgen F, Clabault K, Katsahian S, et al.; Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012 May 15;185(10):1088-95.
