Clinical trial NCT04494074: Fever Control Using External Cooling in Mechanically Ventilated Patients With Septic Shock
Official title: Intérêt du Traitement de la fièvre Par Refroidissement Externe Pour la Survie Des Patients ventilés en Choc Septique
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Septic Shock
Keywords: External cooling,
Fever
ARDS
Lead sponsor: Centre Hospitalier Intercommunal Creteil
Sponsor class: OTHER
First posted: 2020-07-31
Enrollment: 820
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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:

1. Respect of fever
2. Fever control at normothermia using external cooling The primary end point will be d-60 mortality.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Mortality
timeFrame: Day 60 from randomization
Secondary outcomes:
measure: Evolution of SOFA Score
timeFrame: Up to Day 7
measure: Number of ventilator free days
timeFrame: Day 28
measure: Number of renal replacement therapy free days
timeFrame: Day 28
measure: Number of vasopressor free days
timeFrame: Day 28
measure: Mortality
timeFrame: Day 28
measure: Number of patients with shivering
timeFrame: Day 2
measure: Number of patients with seizure
timeFrame: Day 3
measure: Number of patients with hypothermia
timeFrame: Day 3
measure: Number of patients with at least 1 episode of cardiac arrhythmia
timeFrame: Day 3
measure: Secondary acquired nosocomial infections
timeFrame: Day 28
measure: Number of patients with ARDS development among patients free of ARDS at inclusion
timeFrame: Up to Day 3
measure: Acute kidney injury in patients free of RRT at inclusion
timeFrame: Up to Day7
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Angers
country: France
facility: CHU Angers
city: Argenteuil
country: France
facility: CH Victor Dupouy
city: Belfort
country: France
facility: Hôpital Nord Franche Comté
city: Cholet
country: France
facility: CH Cholet
city: Créteil
country: France
facility: Centre hospitalier intercommunal de Créteil
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: CHD Dijon
city: Grenoble
country: France
facility: CHU Grenoble
city: Jossigny
country: France
facility: GH Est Francilien
city: La Roche sur Yon
country: France
facility: CHD Vendée
city: Le Kremlin-Bicêtre
country: France
facility: CHU Kremlin Bicetre
city: Le Mans
country: France
facility: CHU Le Mans
city: Lens
country: France
facility: CH Lens
city: Libourne
country: France
facility: CH Libourne
city: Lyon
country: France
facility: Hôpital Saint Joseph Saint Luc
city: Lyon
country: France
facility: Hôpital de la Croix-Rousse
city: Marseille
country: France
facility: Hôpital Timone
city: Metz
country: France
facility: CHR Metz Hôpital de Mercy
city: Mulhouse
country: France
facility: GRH Mulhouse
city: Nantes
country: France
facility: CHU Hotel Dieu
city: Nice
country: France
facility: CHU Archet 1
city: Nice
country: France
facility: Hôpital Pasteur
city: Paris
country: France
facility: Hopital Lariboisière - Réanimation Médicale
city: Paris
country: France
facility: Hôpital Lariboisière -Réanimation chirurgicale
city: Poitiers
country: France
facility: CHU La Milétrie Poitiers
city: Reims
country: France
facility: CHU Reims
city: Rouen
country: France
facility: CHU Charles Nicolle
city: Saint-Denis
country: France
facility: CHU Réunion Sud
city: Suresnes
country: France
facility: Hôpital FOCH
city: Tarbes
country: France
facility: CH BIGORRE SITE GESPE Tarbes
city: Vannes
country: France
facility: CHBA Vannes-Auray
city: Versailles
country: France
facility: Centre Hospitalier Mignot
Study officials:
References: