The impact of fever and its management in different medical and surgical populations of critically ill patients has not been explained to date. The current study aims to assess the safety and efficacy of treatment of critically ill patients with a permissive versus aggressive fever treatment strategy.

The impact of fever and its management in different medical and surgical populations of critically ill patients has not been explained to date. Clinical trials in critically ill surgical patients have demonstrated null or potentially harmful effects of treatment of moderate degrees of fever. However, the pathophysiological effects of fever treatment are not well defined according to different patient populations, and clinical trial results are questionably generalized to medical ICU patients. This may relate to different mechanisms of fever in these populations and merits further investigation. There is also very little known about the exact timing of expression of the diverse pro and anti-inflammatory mediators involved in inducing, maintaining and eventually abrogating the fever response. Treating on the sole basis of an elevated temperature may lead to detrimental effects if the anti-inflammatory cascade naturally regulating this response is active, demonstrating the importance of understanding the normal pattern of regulation of these diverse mediators. The current study aims to assess the safety and efficacy of treatment of critically ill patients with a permissive versus aggressive fever treatment strategy. In addition, the effect of anti-pyretic therapy on markers of inflammation in neurologically intact critically ill adults will be evaluated.

The study population will be neurologically intact febrile adults (≥18 years) admitted to the Peter Lougheed Center (PLC) or Foothills Medical Center (FMC) ICU over a 12-month period in Calgary, Alberta, Canada. Consenting patients that fulfill enrolment criteria will be randomly allocated to either the permissive or aggressive treatment group (see Interventions section for details). Randomization will be concealed using the consecutively numbered sealed opaque envelope technique. Samples of blood will be collected from study patients at enrolment and subsequently at 12, 24 and 48 hours for assessment of inflammatory mediators.

Markers of feasibility will include the rate of enrolment, adherence of patients to assigned treatment regimen/protocol violation, acceptance of the protocol by staff, and facility and maintenance of random allocation technique. Markers of safety will include potential adverse events such as 28-day survival, nosocomial infection rate, and evidence of myocardial ischemia, or hepatocellular inflammation during the febrile episode.

Inclusion Criteria:

• Age ≥18 years old
• Fever (two consecutive measurements ≥ 38.3°C at least 2 hours apart or a single temperature measurement ≥ 39.5°C)
• Admitted to ICU with an expected length of stay at least 48 hours related to critical illness
• Attending physician approval

Exclusion Criteria:

• Admission to ICU for support for specific procedure (e.g. endoscopy, acute dialysis, bronchoscopy)
• Acute brain injury due to any etiology
• Acute myocardial ischemia
• Documented hepatitis with elevated alanine aminotransferase (ALT) more than twice the upper limit of normal, or chronic hepatic failure (defined by evidence of cirrhosis on available imaging or known varices, ascites, hepatic encephalopathy, hepatorenal syndrome, and/or hepatocellular carcinoma)
• Hyperthermia syndromes (malignant hyperthermia, heat stroke, neuroleptic malignant syndrome, serotonin syndrome, or endocrine causes including thyrotoxicosis, pheochromocytoma, and adrenal crisis)
• Refractory shock with lactic acidosis >4 mmol/L (at the time of screening for study enrollment) despite supportive therapy or need for paralytic treatment to reduce metabolic demand
• Requirement for use of anti-pyretic agents (acetaminophen or NSAIDs) for indications other than treatment of fever
• Receipt of anti-pyretic pharmacotherapy within 6-hours of expected study enrollment (650mg acetaminophen, 800mg ibuprofen, or 325mg acetylsalicylic acid)
• Contraindications to esophageal temperature monitoring
• Pregnancy (all women of child-bearing potential need to have a pregnancy test performed prior to enrollment)
• Time from onset of fever in the ICU to consideration for study enrollment is > 12 hours