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

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ClinicalTrials.gov Identifier: NCT04494074
Recruitment Status : Recruiting
First Posted : July 31, 2020
Last Update Posted : February 24, 2023
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Intercommunal Creteil

Tracking Information
First Submitted Date  ICMJE July 28, 2020
First Posted Date  ICMJE July 31, 2020
Last Update Posted Date February 24, 2023
Actual Study Start Date  ICMJE October 1, 2022
Actual Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 28, 2020)		 Mortality [ Time Frame: Day 60 ]
All causes mortality
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 8, 2021)
  • Evolution of SOFA Score [ Time Frame: 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 24
  • Number of ventilator free days [ Time Frame: 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 renal replacement therapy free days [ Time Frame: Day 28 ]
    Number of free days will be assessed as proposed by YEHYA et al.
  • Number of vasopressor free days [ Time Frame: 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 [ Time Frame: Day 28 ]
    All causes mortality
  • Number of patients with shivering [ Time Frame: Day 2 ]
    Shivering will be monitored according to a specific scale
  • Number of patients with seizure [ Time Frame: Day 3 ]
    Seizure will be clinically documented or reveal by EEG
  • Number of patients with hypothermia [ Time Frame: Day 2 ]
    Number of patients with body temperature lower than 36°C
  • Number of patients with at least 1 episode of cardiac arrhythmia [ Time Frame: Day 3 ]
    Patient with new episode of supraventricular or ventricular arrhythmia
  • Secondary acquired nosocomial infections [ Time Frame: Day 28 ]
    Only the first episode will be taken into account
  • Number of patients with ARDS development among patients free of ARDS at inclusion [ Time Frame: Up to Day 3 ]
    Secondary acquired ARDS according to Berlin definition
  • Acute kidney injury [ Time Frame: Up to Day7 ]
    Maximal stage of AKI according to the KDIGO definition
Original Secondary Outcome Measures  ICMJE
 (submitted: July 28, 2020)
  • Evolution of SOFA Score [ Time Frame: Up to Day 7 ]
    Sofa score will be calculated at d1, d2, d3 and d7 and compared between the 2 arms
  • Number of ventilator free days [ Time Frame: Day 28 ]
    Number of free days will be assessed as proposed by YEHAY at al. Patients who died before d28 will be considered as having 0 free day
  • Number of renal replacement therapy free days [ Time Frame: Day 28 ]
    Number of free days will be assessed as proposed by YEHAY at al.
  • Number of vasopressor free days [ Time Frame: Day 28 ]
    Number of free days will be assessed as proposed by YEHAY at al. Shock resolution will be defined by vasopressor stop during at least 24h in the absence of care withdrawing
  • Mortality [ Time Frame: Day 2 ]
    All causes mortality
  • Number of patients with shivering [ Time Frame: Day 3 ]
    Shivering will be monitored according to a specific scale
  • Number of patients with seizure [ Time Frame: Day 2 ]
    Seizure will be clinically documented or reveal by EEG
  • Number of patients with hypothermia [ Time Frame: Day 3 ]
    Number of patients with body temperature lower than 36°C
  • Number of patients with at least 1 episode of cardiac arrhythmia [ Time Frame: Day 3 ]
    Patient with new episode of supraventricular or ventricular arrhythmia
  • Secondary acquired nosocomial infections [ Time Frame: Day 28 ]
    Only the first episode will be taken into account
  • Number of patients with ARDS development among patients free of ARDS at inclusion [ Time Frame: Up to Day 3 ]
    Secondary acquired ARDS according to Berlin definition
  • Acute kidney injury [ Time Frame: Up to Day7 ]
    Maximal stage of AKI according to the KDIGO definition
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Fever Control Using External Cooling in Mechanically Ventilated Patients With Septic Shock
Official Title  ICMJE Intérêt du Traitement de la fièvre Par Refroidissement Externe Pour la Survie Des Patients ventilés en Choc Septique
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Septic Shock
Intervention  ICMJE Other: External Cooling
External Cooling
Study Arms  ICMJE
  • Experimental: Fever Control by external cooling
    External cooling during 48 hours to obtain normothermia
    Intervention: Other: External Cooling
  • No Intervention: Fever respected, no cooling
    Fever respect without any antipyretic therapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 28, 2020)		 820
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2024
Actual Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Frédérique SCHORTGEN, MD 01 45 17 56 83 Frederique.schortgen@chicreteil.fr
Contact: Camille JUNG, MD 0157022268 camille.jung@chicreteil.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04494074
Other Study ID Numbers  ICMJE SEPSISCOOL II
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Centre Hospitalier Intercommunal Creteil
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Centre Hospitalier Intercommunal Creteil
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Centre Hospitalier Intercommunal Creteil
Verification Date February 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP