Even fewer trials have specifically addressed the role of antipyretic therapy in septic patients. A large multicenter prospective observational study assessed the effects of acetaminophen, NSAIDs, and physical cooling on 28-day mortality in critically ill patients.18 Among the 606 patients with sepsis, multivariate analysis demonstrated that fever control with either NSAIDs or acetaminophen was an independent risk factor for death. Physical cooling was neither protective nor harmful. Bernard et al19 performed a multicenter randomized controlled trial to examine the effects of IV ibuprofen in critically ill patients with severe sepsis. Body temperature, heart rate, minute ventilation, oxygen consumption, and lactate levels were all significantly decreased in the ibuprofen group compared with the placebo group after 48 h. However, degree of organ failure and 30-day mortality were unchanged. When the subset of patients who met the criteria for septic shock was analyzed separately, differences in mortality remained insignificant. All patients randomized to the treatment group were treated with ibuprofen regardless of the presence or absence of fever, so the direct effect of ibuprofen on fever in septic patients is difficult to ascertain. However, it is important to note that although the physiologic goals of fever control were met in the patients treated with ibuprofen (decreased temperature, heart rate, minute ventilation, and oxygen consumption), this had no effect on clinically significant outcomes.