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Acetaminophen for Fever in Critically Ill Patients with Suspected Infection: HEAT trial


Fever occurs after infection, tissue damage and release of pyrogenic cytokines and interleukins. It inhibits the growth of microorganisms.  It’s one of the natural defence mechanism and forms part of innate immunity. However, fever adds an additional physiological stress on critically ill patients. It causes vasodilatation, increases oxygen consumption and cardiac output and lactate production and may affect the overall mortality and morbidity in critically ill patients. Hence, controlling fever in such group of patients may be beneficial.

Sepsis-cool, a French trial, 200 patients with septic shock (with vasopressor), has shown to decrease vasopressor requirements and early mortality with fever control. However, it was under powered and had significant imbalance in baseline doses of vasopressors used


Paul Young, M.D., Manoj Saxena, M.D., Rinaldo Bellomo, M.D., Ross Freebairn, M.D., Naomi Hammond, R.N., M.P.H., Frank van Haren, M.D., Ph.D., Mark Holliday, B.Sc., Seton Henderson, M.D., Diane Mackle, M.N., Colin McArthur, M.D., Shay McGuinness, M.D., John Myburgh, M.D., Ph.D., Mark Weatherall, M.D., Steve Webb, M.D., Ph.D.,and Richard Beasley, M.D., D.Sc., for the HEAT Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group



Administration of acetaminophen to lower temperature in patients with fever and probable infection is a frequent intervention in the community and in hospitals. HEAT trial was designed to evaluate the effect of intravenous paracetamol to treat fever on outcomes.



Multi centre, Investigator-initiated, prospective, parallel-group, blinded, randomized, controlled trial.


Inclusion : Patients of 16 years of age or older with a temperature of 38°C or higher, within 12 hours before enrolment and who were receiving antimicrobial therapy for a known or suspected infection were eligible for inclusion.


Exclusion: Liver dysfunction, ALT, AST > 5x , Bilirubin > 2x, Contraindication to Acetaminophen 4 g/day, Patients with post cardiac arrest requiring hypothermia, Acute brain injury, Hyperthermic syndromes, Pregnancy, On NSAIDS (Aspirin >300mg/day)


Endpoint of intervention:   Until discharge from the ICU, resolution of fever as defined by a pre-specified algorithm or until 28 days after enrolment.


Others: Rescue physical cooling if T > 39.5°C or higher. Open-label acetaminophen was permitted after the course of study medication was completed.




Primary: ICU-free days at day 28.

Secondary: All-cause mortality at day 28 and day 90, ICU and hospital length of stay, days free from mechanical ventilation, inotropes or vasopressors, renal replacement therapy, and any support.

Physiological and Laboratory variables: Mean and maximum axillary temperature. The proportion of patients who stopped the study drug owing to the development of liver dysfunction; Mean serum C-reactive protein (CRP). The proportion of pts with CK > 5000 U on days 1, 3, 5, or 7. Highest serum creatinine level in the ICU 7 days after randomization.



Primary outcome:  

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 (absolute difference, 0 days; 96.2% CI, 0 to 1; P = 0.07)


Secondary outcome:

No significant differences between the acetaminophen group and the placebo group with respect to mortality at day 28 or at day 90, ICU length of stay (4.1 days [2.1 to 8.3] vs.  4.2 days [2.0 to 9.0]; Hospital length of stay (13.7 days [7.6 to 22.9] vs.  13.8 days [7.1 to 24.3]

However, with acetaminophen, there was shorter median ICU length of stay than placebo among survivors (3.5 days vs. 4.3 days, P = 0.01) and longer among non-survivors (10.4 vs .4.0, p<0.001)



Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days.



  • Reasonably adequately powered to assess the outcomes
  • No difference in adverse effects between two groups.



  • Effect on ICU stay can be regarded as Hypothesis generating
  • Median duration of study drug administration was short. (median number of doses 8 in the acetaminophen group vs. 9 in the placebo group). 
  • Frequent use of open-label acetaminophen in both groups after completion of the study drug course (30.0% of the patients in the acetaminophen group, 29.4% of patients in the placebo group)





Acetaminophen for critically ill patients for control of fever doesn’t add to survival or ICU free days. 







                                                                                                                                                                                                                    Harshel G Parikh

                                                                                                                                                                                                                    MD(Anesth), Advanced trainee CICM


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