By Elaine Chen, MD
Assistant Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Section of Palliative Medicine, Rush University Medical Center
Dr. Chen reports no financial relationships relevant to this field of study.
SYNOPSIS: Scheduled intravenous acetaminophen lowers temperature but does not affect ICU-free days, mortality, length of stay, or adverse events in patients with sepsis.
SOURCE: Young P, et al. Acetaminophen for fever in critically ill patients with suspected infection. N Engl J Med 2015;373:2215-2224.
Fevers are common in critically ill patients with suspected infection. Elevated temperatures can create additional physiologic stress on critically ill patients but can also enhance immune cell function, inhibit pathogen growth, and increase the activity of antimicrobial drugs. A study of external cooling of mechanically ventilated patients with septic shock showed decreased vasopressor requirements and decreased early mortality.1 Acetaminophen is commonly administered to lower the temperature of febrile, critically ill patients but has not been well studied for clinical benefit. Young et al hypothesized that the early administration of intravenous acetaminophen in febrile patients with probable infection would result in fewer ICU-free days compared to placebo.
The study was a prospective, blinded, parallel-group, randomized, controlled trial in Australia and New Zealand. Subjects included adults with a temperature > 38º C receiving antimicrobial therapy; patients with acute brain disorders and liver dysfunction were excluded. Patients were assigned to scheduled intravenous infusion of either 1 g of acetaminophen or placebo every 6 hours for 28 days or until cessation criteria were met. The primary outcome was ICU-free days from randomization to day 28. Secondary outcomes included all-cause mortality at days 28 and 90, survival time, ICU and hospital length of stay, hospital-free days, and ventilator-free days, among others. Researchers also collected physiologic and laboratory outcome variables.
An intention-to-treat population of 690 was obtained, with 346 subjects assigned to acetaminophen and 344 assigned to placebo. Median doses of study drug were 8 in the acetaminophen group and 9 in the placebo group. Most common reasons for discontinuation of study drug were discharge from ICU and resolution of fever. Physiologically, the group receiving acetaminophen had significantly lower daily peak and average body temperatures, and a significantly increased number had sustained resolution of fever. There were no statistically significant differences in ICU-free days at day 28 (primary outcome), mortality at 28 and 90 days, ICU length of stay, or hospital length of stay.
Acetaminophen was associated with a shorter median ICU length of stay than placebo among survivors but a longer median ICU length of stay among non-survivors. Both groups had similar rates of liver dysfunction. Overall, this study showed that the early administration of acetaminophen did not affect clinical outcomes. Acetaminophen lowered body temperature and did not cause significantly more adverse events. Similar to prior studies, acetaminophen works as an antipyretic, and cooling to normothermia may delay death.1-3
COMMENTARY
While outcomes in critically ill patients with infection continue to improve due to evidence-based changes in care, mortality due to sepsis remains high. Clinicians administer acetaminophen commonly to febrile patients without contraindications to lower temperature. First, a few questions. Does one order acetaminophen in this patient population? If so, what are the goals? Is it to decrease the temperature? This, as the study demonstrated, will happen. Is one hoping to decrease physiologic concerns, such as shivering and metabolic demand? This study does not address this. Does one think there would be morbidity or mortality benefit or simply symptomatic improvement?
In this study, researchers administered 4 g acetaminophen intravenously daily. This is in contrast to usual clinical practice of as-needed enteral acetaminophen with a dose limit of 3 g daily in patients with normal liver function. From this study, it seems higher-dose acetaminophen does not cause harm.
Researchers did not perform subjective assessments. If a drug causes no harm and no significant clinical benefit, use can be justified for improving patient comfort. In patients who are febrile but sedated, such sedation use ensures patient comfort. In awake patients, fevers can cause significant discomfort.
That acetaminophen administration may result in a longer ICU stay in non-survivors and shorter ICU stay in survivors has no clear clinical implication at this point. In non-survivors, for whom death seems to be delayed, is there any way to predict this group and avoid acetaminophen use in them? If hospital death is inevitable, then delaying death increases hospital costs and prolongs suffering of patients, family, and staff.
Is there a difference between medically mediated cooling and external cooling? In two prior studies, one using paracetamol administration and one using external cooling, there was a decrease in early mortality but overall mortality did not change, reflecting a delay of death similar to this study.1,4
Will this change my practice? Probably not. I will continue to use acetaminophen in highly febrile patients without hepatic dysfunction. If a patient is intubated and sedated, but febrile to 104º F, I will try to decrease the temperature, even though I only may be treating myself.
REFERENCES
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Schortgen F, et al. Fever control using external cooling in septic shock: A randomized controlled trial. Am J Respir Crit Care Med 2012;185:1088-1095.
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Greenberg RS, et al. Acetaminophen has limited antipyretic activity in critically ill patients. J Crit Care 2010;25:363.e1-363.e7.
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Dippel DWJ, et al. Timing of the effect of acetaminophen on body temperature in patients with acute ischemic stroke. Neurology 2003;61:677-679.
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Suzuki S, et al. Paracetamol therapy and outcome of critically ill patients: A multicenter retrospective observational study. Crit Care 2015;19:162-171.
