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

Study Overview
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Brief Summary
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The best strategy for managing fever in patients with septic shock remains unknown. In a pilot study, the investigators showed that fever control at normothermia allowed a better control of shock and evolution of organ failures. In this second trial the investigators will conduct a multicentre, open-label, randomized controlled, superiority trial in which two strategies will be compared: Respect of fever Fever control at normothermia using external cooling The primary end point will be d-60 mortality.

Detailed Description
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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: Fever respect 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.

Official Title
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Intérêt du Traitement de la fièvre Par Refroidissement Externe Pour la Survie Des Patients ventilés en Choc Septique

Conditions
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Septic Shock

Intervention / Treatment
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* Other: External Cooling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented or suspected infection either communautary or hospital acquired Septic shock defined by the need for vasopressor and lactate>2 mmol/l despite adequate fluid resuscitation (sepsis-3 definition) Patients under invasive mechanical ventilation Body core temperature>38.3°C Intravenous sedation or opioids Ongoing antimicrobial treatment and/or intervention for infection source control Attending physician confirms clinical equipoise without substantial risk if the patient participates in the trial Informed consent of next of kin/other designated person before inclusion or procedure for inclusion in emergency situation Exclusion Criteria: Cardiac arrest within previous 7 days Acute brain injury within previous 7 days Extensive burns or epidermal necrolysis <18 years old Body core temperature >41°C Under legal guardianship No affiliation with the French health-care system Pregnancy Participation in another interventional study with mortality as the primary endpoint An investigator's decision not to resuscitate Patient already recruited in the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fever Control by external cooling<br>External cooling during 48 hours to obtain normothermia | Other: External Cooling<br>* External Cooling<br>|
| No Intervention: Fever respected, no cooling<br>Fever respect without any antipyretic therapy | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | All causes mortality | Day 60 from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of SOFA Score | Sequential Organ Failure Assessment (SOFA) score will be calculated at d1, d2, d3 and d7 and compared between the 2 arms. Higer the score higher the severity of organ dysfunctions. Min 0 Max 24 | Up to Day 7 | 
| Number of ventilator free days | Number of free days will be assessed as proposed by YEHYA et al. Patients who died before d28 will be considered as having 0 free day | Day 28 | 
| Number of renal replacement therapy free days | Number of free days will be assessed as proposed by YEHYA et al. | Day 28 | 
| Number of vasopressor free days | Number of free days will be assessed as proposed by YEHYA et al. Shock resolution will be defined by vasopressor stop during at least 24h in the absence of care withdrawing | Day 28 | 
| Mortality | All causes mortality | Day 28 | 
| Number of patients with shivering | Shivering will be monitored according to a specific scale | Day 2 | 
| Number of patients with seizure | Seizure will be clinically documented or reveal by EEG | Day 3 | 
| Number of patients with hypothermia | Number of patients with body temperature lower than 36°C | Day 3 | 
| Number of patients with at least 1 episode of cardiac arrhythmia | Patient with new episode of supraventricular or ventricular arrhythmia | Day 3 | 
| Secondary acquired nosocomial infections | Only the first episode will be taken into account | Day 28 | 
| Number of patients with ARDS development among patients free of ARDS at inclusion | Secondary acquired ARDS according to Berlin definition | Up to Day 3 | 
| Acute kidney injury in patients free of RRT at inclusion | Maximal stage of AKI according to the KDIGO definition | Up to Day7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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External cooling,, Fever, ARDS