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N Engl J Med. 2015 Dec 3;373(23):2215-24. doi: 10.1056/NEJMoa1508375. Epub 2015 Oct 5.

Acetaminophen for Fever in Critically Ill Patients with Suspected Infection.

Collaborators (158)

Young P, Saxena M, Bellomo R, Freebairn R, Hammond N, van Haren F, Holliday M, Henderson S, McArthur C, McGuinness S, Mackle D, Myburgh J, Weatherall M, Webb S, Beasley R, Lipman J, Anderson B, Bailey M, Cowdrey K, Gilder E, McCarthy L, McGuinness S, Parke R, Benefield K, Chen Y, McArthur C, McConnochie R, Newby L, Bellomo R, Eastwood G, Peck L, Young H, Edmunds N, van Haren F, Harney A, Milburn K, Nourse M, Rai S, Rodgers H, Bowie D, Davidson N, Gibson A, Henderson S, Hitchings L, Knight D, Mehrtens J, Minto E, Morgan M, Morris A, Noble S, Shaw G, Townend K, Bailey M, France D, Hutchison R, Chadwick L, Freebairn R, Chapman C, Stapleton A, Thompson T, Hogan C, Kazemi A, Pelayo E, Rust L, Song R, Tai J, Tilsley A, Williams T, Bhonagiri D, Micallef S, Ranggappa R, Sanghavi R, King B, Price R, Tollafield S, Bell J, Hacking D, Holland U, Lawrey Y, Burgess O, Duke G, Ghosh A, Park M, Barge D, Harley N, Jordan A, MacIsaac C, Sriram S, Bass F, Bird S, Bradford C, Finfer S, Flower O, Hammond N, O'Connor A, Yarad E, Buhr H, Coakley J, Gattas D, Hutch D, Inskip D, Miller J, Saxena M, Faraone E, Santamaria J, Smith R, Tobin A, Knowles S, Nair P, Reynolds C, Durning J, Forrest A, Frengley R, La Pine M, Andrews L, Barry B, Dinsdale D, Hicks P, Hunt A, Hurford S, Mackle D, Ongley J, Poynter C, Psirides A, Sturland S, Tang-Hickey J, Ure B, Young P, Bates S, French C, McGain F, Tippett A, Towns M, Geng W, Johnson B, Sterba M, Young P, Baker T, Holliday M, Beasley R, Braithwaite I, Fabian D, Hurford S, Mackle D, Pilcher J, Pritchard A, Read J, Stretch M, Tan E, Saxena M, Hammond N, Correa M, Glass P, Gould A, Hanna D, Myburgh J, Micallef S, Rajbhandari D.

Author information

From the Intensive Care Unit, Wellington Regional Hospital (P.Y., D.M.), Medical Research Institute of New Zealand (P.Y., R.F., M.H., S.H., D.M., C.M., S.M., R. Beasley), and Wellington School of Medicine, University of Otago (M.W.), Wellington, Intensive Care Unit, Hawke's Bay Hospital, Hastings (R.F.), Intensive Care Unit, Christchurch Hospital, Christchurch (S.H.), and the Department of Critical Care Medicine (C.M.) and Cardiothoracic and Vascular Intensive Care Unit (S.M.), Auckland City Hospital, Auckland - all in New Zealand; and the Critical Care and Trauma Division, George Institute for Global Health, Sydney (M.S., N.H., J.M.), Intensive Care Unit, St. George Hospital, Kogarah (M.S., J.M.), Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, St. Leonards (N.H.), and Faculty of Medicine, St. George Clinical School, University of New South Wales, Kensington (J.M.), NSW, Intensive Care Unit, Austin Hospital (R. Bellomo), the Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University (R. Bellomo), and Faculty of Medicine, University of Melbourne (R. Bellomo), Melbourne, VIC, the Intensive Care Unit, Canberra Hospital, Canberra, ACT (F.H.), and the Intensive Care Unit, Royal Perth Hospital, Perth (S.W.), and the School of Medicine and Pharmacology, University of Western Australia, Crawley (S.W.), WA - all in Australia.



Acetaminophen is a common therapy for fever in patients in the intensive care unit (ICU) who have probable infection, but its effects are unknown.


We randomly assigned 700 ICU patients with fever (body temperature, ≥38°C) and known or suspected infection to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from the need for intensive care) from randomization to day 28.


The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges-Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P=0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P=0.84).


Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. (Funded by the Health Research Council of New Zealand and others; HEAT Australian New Zealand Clinical Trials Registry number, ACTRN12612000513819.).

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