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

October 19, 2023 updated by: Centre Hospitalier Intercommunal Creteil

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Estimated)

820

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Amiens, France
      • Angers, France
      • Argenteuil, France
      • Belfort, France
      • Cholet, France
      • Créteil, France
      • Créteil, France
        • Active, not recruiting
        • Hopital Henri Mondor
      • Dijon, France
        • Active, not recruiting
        • CHD Dijon
      • Grenoble, France
        • Active, not recruiting
        • CHU Grenoble
      • Jossigny, France
        • Recruiting
        • GH Est Francilien
        • Contact:
      • La Roche sur Yon, France
      • Le Kremlin-Bicêtre, France
        • Active, not recruiting
        • CHU Kremlin Bicêtre
      • Le Mans, France
      • Libourne, France
        • Active, not recruiting
        • Ch Libourne
      • Lyon, France
      • Marseille, France
        • Active, not recruiting
        • Hôpital Timone
      • Mulhouse, France
      • Nantes, France
      • Nice, France
      • Nice, France
        • Active, not recruiting
        • CHU Archet 1
      • Paris, France
        • Recruiting
        • Hopital Lariboisière - Réanimation Médicale
        • Contact:
      • Paris, France
      • Poitiers, France
      • Reims, France
        • Active, not recruiting
        • CHU Reims
      • Rouen, France
        • Active, not recruiting
        • CHU Charles Nicolle
      • Suresnes, France
      • Tarbes, France
      • Vannes, France
        • Active, not recruiting
        • CHBA Vannes-Auray
      • Versailles, France

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Up to Day 7
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
Day 28
Number of renal replacement therapy free days
Time Frame: Day 28
Number of free days will be assessed as proposed by YEHYA et al.
Day 28
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
Day 28
Mortality
Time Frame: Day 28
All causes mortality
Day 28
Number of patients with shivering
Time Frame: Day 2
Shivering will be monitored according to a specific scale
Day 2
Number of patients with seizure
Time Frame: Day 3
Seizure will be clinically documented or reveal by EEG
Day 3
Number of patients with at least 1 episode of cardiac arrhythmia
Time Frame: Day 3
Patient with new episode of supraventricular or ventricular arrhythmia
Day 3
Secondary acquired nosocomial infections
Time Frame: Day 28
Only the first episode will be taken into account
Day 28
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
Up to Day 3
Number of patients with hypothermia
Time Frame: Day 3
Number of patients with body temperature lower than 36°C
Day 3
Acute kidney injury in patients free of RRT at inclusion
Time Frame: Up to Day7
Maximal stage of AKI according to the KDIGO definition
Up to Day7

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier Intercommunal Creteil

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2022

Primary Completion (Estimated)

December 1, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

July 28, 2020

First Submitted That Met QC Criteria

July 28, 2020

First Posted (Actual)

July 31, 2020

Study Record Updates

Last Update Posted (Actual)

October 23, 2023

Last Update Submitted That Met QC Criteria

October 19, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SEPSISCOOL II

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Strictly anonymized data will be available upon justified request from the coordinating investigator and the study sponsor

IPD Sharing Time Frame

After publication upon justified request from the coordinating investigator and the study sponsor

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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