SGEM#146: The HEAT is On – IV Acetaminophen for Fever in the ICU

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Date: February 2nd, 2016

Guest Skeptic: Dr. Justin Morgenstern. Justin is an emergency physician and the director of simulation education at Markham Stouffville Hospital in Ontario. He loves skepticism and medical education, especially when it is free and open access. He is the author of the #FOAMed blog First10EM.com and is an associate editor of Emergency Medicine Cases.

Case: A 64-year-old woman presents to the emergency department with fever, urinary symptoms, and altered mental status. You diagnose her with sepsis with a probable urinary source. You rapidly provide empiric antibiotics and initiate fluid resuscitation. You are ready to send her up to the ICU for monitoring when your nurse asks, “shouldn’t we give her some acetaminophen for her fever?”

Background: If you work in emergency medicine, you are aware of the continuous debate about fever. Is it harmful? Is it helpful? Should it be treated? We did a great episode (SGEM#95) on pediatric fever with Dr. Anthony Crocco from SketchyEBM.

Dr. Anthony Crocco

When it comes to children, the American Academy of Pediatrics says: “…fever, in and of itself, is not known to endanger a generally healthy child. In contrast, fever may actually be of benefit; thus, the real goal of antipyretic therapy is not simply to normalize body temperature but to improve the overall comfort and well-being of the child.”

Dr. Crocco also did a great RANThony on the whole fever fear topic a few years ago. However, we are not talking pediatric fever today but rather adult ICU patients with fevers.

There are two opposing schools of thought about the value of fever in infection. One side argues that fever causes an increased metabolic stress than might be detrimental to already sick patients. The other side points out that fever is a natural immune response designed to fight infection. So eliminating this natural line of defence could make sick patients even sicker. Unfortunately, there has been little high quality evidence to answer this question – until now.

Clinical Question: Does regular administration of intravenous acetaminophen in febrile ICU patients being treated for a known or suspected infection impact the number of ICU-free days?

Reference: Young P et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. NEJM 2015

Population: ICU patients 16 years or older with a temperature of 38°C or higher and being treated for a known or suspected infection.
- Exclusion criteria: Acute brain disorders; liver dysfunction; post cardiac arrest where current or anticipated temperature control was required; rhabdomyolysis; pregnancy; previous enrolment.
Intervention: Acetaminophen 1 gram intravenous every six hours
Comparison: Placebo (5% dextrose in water) intravenous every six hours
Outcome:
- Primary outcome: ICU free days at day 28 (death counted as zero ICU free days)
- Secondary outcomes: All cause mortality at 28 and 90 days, number of days alive, ICU and hospital length of stay, hospital free days, number of days free from inotropes or vasopressors, mechanical ventilation, and renal replacement therapy. Physiological and laboratory-related outcomes.

Author’s Conclusions: “Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days.”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the ED. No. These were ICU patients.
The patients were adequately randomized. Yes. The patients were randomized in a 1:1 ratio in blocks of 6 using an encrypted, web based randomization system
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. Yes. They performed an intention to treat analysis. Although a handful of patients in each group received the wrong treatment pack, they were still analyzed in the group to which they were randomized.
The study patients were recruited consecutively (i.e. no selection bias). No – 1053 patients (out of a total of 3601) were eligible for the study, but were not enrolled. The reason these patients were missed is not stated.
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes. They lost 10 patients who withdrew consent, but otherwise they had full follow up data on all patients.
All patient-important outcomes were considered. Yes
The treatment effect was large enough and precise enough to be clinically significant. No. There was no statistically significant difference between the two groups.

Key Results: They enrolled 700 patients of which 690 were available for assessment. The mean age was in the late 50’s, two-thirds of the patients were male and the peak temperature was in the high 38C.

About half had a pulmonary source of infection, about half needed inotropic or vasopressor support and about half had invasive ventilation.

Primary Outcome: No statistical difference in ICU free days to day 28

23d (IQR 13-25) in the acetaminophen group vs. 22d in the placebo group (IQR 12-25)
Hodges–Lehmann estimate of absolute difference, 0 days (96.2% CI 0 to 1; P=0.07)

Secondary Outcomes: No statistical differences
- All cause mortality at 28 days: 13.9% with acetaminophen vs. 13.7% with placebo
- All cause mortality at 90 days: 15.9% with acetaminophen vs. 16.9% with placebo (relative risk, 0.96; 95% CI, 0.66 to 1.39; P = 0.84)
- ICU length of stay: 4.1 days with acetaminophen vs. 4.2 days with placebo
- Hospital length of stay: 13.7 days with acetaminophen vs. 13.8 days with placebo

However, in a pre-specified subgroup analysis, acetaminophen was associated with a shorter ICU length of stay among survivors, but with a longer ICU length of stay among non-survivors.

Non-survivors: 10.4 (IQR 4.1 – 16.9) vs. 4.0 (1.7 – 9.4); P<0.001
Survivors: 3.5 (IQR 1.9 – 6.9) vs. 4.3 (2.1 – 8.9); P< 0.01

There was a statistically but not clinically significant different in the mean daily peak body temperature (38.4±1.0°C vs.38.6±0.8°C; absolute difference, −0.25°C, 95% CI −0.38 to −0.11; P<0.001) and mean daily average body temperature (37.0±0.6°C vs. 37.3±0.6°C; absolute difference, −0.28°C (95% CI −0.37 to −0.19; P<0.001)

It is great to have some data in the adult population on whether or not treating a fever is beneficial. Knowing the pediatric literature we were not surprised with the primary result demonstrating no statistical difference with acetaminophen.

They did a number of things very well that strengthened the study. In particular they published their statistical analysis plan and crunched the numbers before un-blinding the study-group assignments.

Dr. Justin Morgenstern

There were a few issues to discuss:

Consecutive Patients: They excluded over 1,000 patients or almost 1/3 of the eligible population. We could not find in the article or the supplemental material why these patients were not randomized into the study. This could have led to selection bias and had an unknown impact on the results.
Pre-Enrollment Exposure: They did not track how many patients had acetaminophen prior to ICU admission. Two-thirds of these admissions came from the emergency department or the ward. How many of them had acetaminophen or another antipyretic prior to being transferred? How would this affect the results? We do not know.
Protocol Violators: Almost one out of every five patients in the treatment and the control group had protocol violations. The most common reasons were about 10% of patients missing a dose and 10% receiving an extra dose in both arms of the study. All the protocol violations were listed in Table S6 of the supplemental material. With so many violations it makes it harder to interpret the data.
Length of Use: The median number of doses of the study drug was only eight in the acetaminophen group and nine in the placebo group. The two most common reasons for discontinuing the study in both groups were discharge from the ICU (46% vs. 47%) or the fever had resolved (23% vs. 17%). Although I think unlikely, it is possible that the lack of difference seen was the result of not being on the acetaminophen long enough.
Open Label Post-Trial: While we do not know anything about acetaminophen use prior to randomization in the ICU we do know about what happened after the study concluded. Open label acetaminophen was used after the study drug was stopped in 30% of both arms. The affect of this on the primary outcome or any of the secondary outcomes is not known and again, makes it more difficult to interpret the data.

Comment on author’s conclusion compared to SGEM Conclusion: We would agree with the authors’ conclusion that intravenous acetaminophen to treat fever in ICU patients thought to be due to an infection did not affect the number of ICU-free days.

SGEM Bottom Line: The routine use of IV acetaminophen for the treatment of fever in ICU patients thought to be due to infection cannot be recommended at this time.

Case Resolution: You explain to your patient and nursing colleague that although acetaminophen does eliminate fever, it does not seem to change any other clinically important outcomes. You offer to provide acetaminophen if fever is causing your patient any discomfort, but otherwise suggest it is not required.

Clinically Application: There does not appear to be any benefit to providing routine acetaminophen to febrile ICU patients. However, it remains reasonable to provide acetaminophen to any patient for whom fever is causing distress or for pain control.

What do I tell my patient? Like many patients, you may have heard that fever requires treatment. Fever doesn’t seem to be harmful, and it may even be helping you fight off your infection. The best study we have so far shows that treating fever with acetaminophen does not improve your health, and therefore I don’t think it is required. However, if your fever causes you any discomfort, we can give you acetaminophen to make you feel better.

Keener Kontest: Last weeks’ winner was Jason Epstein a PGY3 from Michigan State University/Sparrow Emergency Medicine Residency. Jason knew the famous scientist’s whose eyes’ were removed when he died in 1955 and remain to this day in a safe deposit box in New York City is Albert Einstein.

Listen to the podcast for this weeks’ keener question. If you think you know the answer then send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed Resources:

REBEL EM: The HEAT Trial – Acetaminophen in ICU Patients with Fever
CORE EM: The HEAT Trial – Acetaminophen in Critical Illness
The Bottom Line: HEAT Trial: Acetaminophen for Fever in Critically Ill Patients with Suspected Infection
HEFT EM Cast: Fever, Friend or Foe?
Intensive Care Network: Fever in critical illness: Can the critically ill take the HEAT?