Acetaminophen for fever in critically ill patients with suspected infection

This article looked at the administration of acetaminophen for 700 Intensive Care Unit patients exhibiting fever along with other symptoms. A placebo or acetaminophen was given and the effectiveness of the acetaminophen was measure by the number of ICU-free days. They were given 1 gram of acetaminophen or placebo every 6 hours by IV until fever reduction or ICU discharge occurred. The results of the study concluded that the administration of acetaminophen did not affect the number of ICU-free days. While acetaminophen does have a modest clinical effect it did not reduce the number of ICU-free days to a significant amount.

What interested me about this article in particular was the chosen dose and frequency of the drug. The patients were given a gram of the medication every 6 hours, which could total 4 grams per day. This dose happens to be at the maximum daily-recommended dose for acetaminophen. Even though acetaminophen has such a wide therapeutic index, I would expect many of the patients to experience liver toxicity given that they were receiving 4 grams per day. It turns out that 8.1% of the participants had to discontinue the study due to liver toxicity. Do you think acetaminophen should really be used in the care of critically ill patients for fever reduction if 8.1% of those in this study had to discontinue? With such a wide therapeutic window, as discussed in Principles of Drug Action, is this really worth it considering there was not a significant impact on ICU-free days compared to the placebo group? Are there any alternatives for fever reduction in these situations?

Young P, Saxena M, Bellomo R et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med. 2015; 373: 2215-24.

http://www.nejm.org.pitt.idm.oclc.org/doi/full/10.1056/NEJMoa1508375#t=articleDiscussion

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