Fever Control Using External Cooling in Mechanically Ventilated Patients With Septic Shock
- Conditions
- Septic Shock
- Interventions
- Other: External Cooling
- Registration Number
- NCT04494074
- Lead Sponsor
- Centre Hospitalier Intercommunal Creteil
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 820
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Fever Control by external cooling External Cooling External cooling during 48 hours to obtain normothermia
- Primary Outcome Measures
Name Time Method Mortality Day 60 from randomization All causes mortality
- Secondary Outcome Measures
Name Time Method Number of ventilator free days Day 28 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
Number of vasopressor free days Day 28 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
Mortality Day 28 All causes mortality
Number of patients with shivering Day 2 Shivering will be monitored according to a specific scale
Number of patients with at least 1 episode of cardiac arrhythmia Day 3 Patient with new episode of supraventricular or ventricular arrhythmia
Secondary acquired nosocomial infections Day 28 Only the first episode will be taken into account
Number of patients with ARDS development among patients free of ARDS at inclusion Up to Day 3 Secondary acquired ARDS according to Berlin definition
Number of renal replacement therapy free days Day 28 Number of free days will be assessed as proposed by YEHYA et al.
Evolution of SOFA Score Up to Day 7 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 24Number of patients with seizure Day 3 Seizure will be clinically documented or reveal by EEG
Number of patients with hypothermia Day 3 Number of patients with body temperature lower than 36°C
Acute kidney injury in patients free of RRT at inclusion Up to Day7 Maximal stage of AKI according to the KDIGO definition
Trial Locations
- Locations (33)
CHU Amiens
🇫🇷Amiens, France
CHU Angers
🇫🇷Angers, France
CH Victor Dupouy
🇫🇷Argenteuil, France
Hôpital Nord Franche Comté
🇫🇷Belfort, France
CH Cholet
🇫🇷Cholet, France
Centre hospitalier intercommunal de Créteil
🇫🇷Créteil, France
Hôpital Henri Mondor
🇫🇷Créteil, France
CHD Dijon
🇫🇷Dijon, France
CHU Grenoble
🇫🇷Grenoble, France
GH Est Francilien
🇫🇷Jossigny, France
CHD Vendée
🇫🇷La Roche sur Yon, France
CHU Kremlin Bicetre
🇫🇷Le Kremlin-Bicêtre, France
CHU Le Mans
🇫🇷Le Mans, France
CH Lens
🇫🇷Lens, France
CH Libourne
🇫🇷Libourne, France
Hôpital Saint Joseph Saint Luc
🇫🇷Lyon, France
Hôpital de la Croix-Rousse
🇫🇷Lyon, France
Hôpital Timone
🇫🇷Marseille, France
CHR Metz Hôpital de Mercy
🇫🇷Metz, France
GRH Mulhouse
🇫🇷Mulhouse, France
CHU Hotel Dieu
🇫🇷Nantes, France
CHU Archet 1
🇫🇷Nice, France
Hôpital Pasteur
🇫🇷Nice, France
Hopital Lariboisière - Réanimation Médicale
🇫🇷Paris, France
Hôpital Lariboisière -Réanimation chirurgicale
🇫🇷Paris, France
CHU La Milétrie Poitiers
🇫🇷Poitiers, France
CHU Reims
🇫🇷Reims, France
CHU Charles Nicolle
🇫🇷Rouen, France
CHU Réunion Sud
🇫🇷Saint-Denis, France
Hôpital FOCH
🇫🇷Suresnes, France
CH BIGORRE SITE GESPE Tarbes
🇫🇷Tarbes, France
CHBA Vannes-Auray
🇫🇷Vannes, France
Centre Hospitalier Mignot
🇫🇷Versailles, France