Fever Control Using External Cooling in Mechanically Ventilated Patients With Septic Shock

Sepsis is a common syndrome responsible for multiple organ failure. Septic shock, defined as sepsis with hyperlactatemia and cardiovascular failure requiring vasopressor infusion despite adequate fluid resuscitation has an extremely high mortality rate. Fever is a frequent disease process during sepsis. Fever increases oxygen consumption and can worsen imbalance between oxygen supply and oxygen requirements. Fever increases inflammation but reduces viral and bacterial growth. The beneficial effects of active fever control on inflammation have been mainly shown in a context of lung injury. Pneumonia represents the first cause of septic shock in developed countries.

In a pilot study (SEPSISCOOL I), we showed that fever treatment using external cooling significantly increased the resolution of shock, improved organ functions and decreased d-14 mortality. Although reduced, hospital mortality was not significantly different. This study was underpowered to allow conclusion on mortality. A more pronounced beneficial effect was observed among the most severely ill patients with elevated serum lactate level.

Fever treatment is commonly applied in septic patients but its impact on survival remains undetermined.

The main objective of the study is to compare two strategies of fever management in febrile (body temperature \> 38.3°C) septic shock patients requiring invasive mechanical ventilation and sedation. These patients will be randomly allocated in two arms:

1. Fever respect 2. Fever control by external cooling to obtain normothermia during 48 hours

A covariate-adaptive randomization will be used to ensure the comparability of the two groups at each stage of the study. We will use an adaptive multistage population-enrichment design with a pre-specified subgroup of patients with ARDS identified at randomization.

An independent Safety and Data Monitoring Committee will review data on serious adverse events. The decision of study stop for potential harmful effect of one strategy will be let at the entire responsibility of the committee.

One interim analysis will be performed by independent observers after enrolment of half of the population. The assumption that fever treatment is more effective in patients with ARDS will be confirmed or not. According to pre-defined rules based on the conditional power calculated in the two subgroups, the trial will be stopped for futility, continued as planned or continued by enrolling only patients with ARDS.

• Evolution of SOFA Score [Time frame: Up to Day 7]
• Number of ventilator free days [Time frame: Day 28]
• Number of renal replacement therapy free days [Time frame: Day 28]
• Number of vasopressor free days [Time frame: Day 28]
• Mortality [Time frame: Day 28]
• Number of patients with shivering [Time frame: Day 2]
• Number of patients with seizure [Time frame: Day 3]
• Number of patients with hypothermia [Time frame: Day 3]
• Number of patients with at least 1 episode of cardiac arrhythmia [Time frame: Day 3]
• Secondary acquired nosocomial infections [Time frame: Day 28]
• Number of patients with ARDS development among patients free of ARDS at inclusion [Time frame: Up to Day 3]
• Acute kidney injury in patients free of RRT at inclusion [Time frame: Up to Day7]