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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04494074
Recruitment Status : Recruiting
First Posted : July 31, 2020
Last Update Posted : November 3, 2022
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Septic Shock Other: External Cooling Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 820 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Intérêt du Traitement de la fièvre Par Refroidissement Externe Pour la Survie Des Patients ventilés en Choc Septique
Actual Study Start Date : October 1, 2022
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : December 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fever Shock

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



Primary Outcome Measures :
  1. Mortality [ Time Frame: Day 60 ]
    All causes mortality


Secondary Outcome Measures :
  1. 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


  2. 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

  3. Number of renal replacement therapy free days [ Time Frame: Day 28 ]
    Number of free days will be assessed as proposed by YEHYA et al.

  4. 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

  5. Mortality [ Time Frame: Day 28 ]
    All causes mortality

  6. Number of patients with shivering [ Time Frame: Day 2 ]
    Shivering will be monitored according to a specific scale

  7. Number of patients with seizure [ Time Frame: Day 3 ]
    Seizure will be clinically documented or reveal by EEG

  8. Number of patients with hypothermia [ Time Frame: Day 2 ]
    Number of patients with body temperature lower than 36°C

  9. Number of patients with at least 1 episode of cardiac arrhythmia [ Time Frame: Day 3 ]
    Patient with new episode of supraventricular or ventricular arrhythmia

  10. Secondary acquired nosocomial infections [ Time Frame: Day 28 ]
    Only the first episode will be taken into account

  11. 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

  12. Acute kidney injury [ Time Frame: Up to Day7 ]
    Maximal stage of AKI according to the KDIGO definition



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04494074


Contacts
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Contact: Frédérique SCHORTGEN, MD 01 45 17 56 83 Frederique.schortgen@chicreteil.fr
Contact: Camille JUNG, MD 0157022268 camille.jung@chicreteil.fr

Locations
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France
CHU Angers Not yet recruiting
Angers, France
Contact: ASFAR Pierre, MD         
Centre hospitalier intercommunal de Créteil Not yet recruiting
Créteil, France, 94000
Contact: SCHORTGEN Frédérique, MD         
CHD Dijon Not yet recruiting
Dijon, France
Contact: QUENOT Jean Pierre, MD         
CHD Vendée Not yet recruiting
La Roche sur Yon, France
Contact: LACHARADE Jean Claude, MD         
CHU Kremlin Bicetre Not yet recruiting
Le Kremlin-Bicêtre, France
Contact: ANGUEL Nadia, MD         
CHU Hotel Dieu Recruiting
Nantes, France
Contact: REIGNIER Jean, MD         
Hopital Lariboisière - Réanimation Médicale Not yet recruiting
Paris, France, 75010
Contact: DEYE Nicolas, MD         
Hôpital Lariboisière -Réanimation chirurgicale Not yet recruiting
Paris, France, 75010
Contact: CHOUSTERMAN Benjamin, MD         
Centre Hospitalier Mignot Recruiting
Versailles, France
Contact: LEGRIEL Stéphane, MD         
Sponsors and Collaborators
Centre Hospitalier Intercommunal Creteil
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Responsible Party: Centre Hospitalier Intercommunal Creteil
ClinicalTrials.gov Identifier: NCT04494074    
Other Study ID Numbers: SEPSISCOOL II
First Posted: July 31, 2020    Key Record Dates
Last Update Posted: November 3, 2022
Last Verified: November 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centre Hospitalier Intercommunal Creteil:
External cooling,
Fever
ARDS
Additional relevant MeSH terms:
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Shock, Septic
Shock
Pathologic Processes
Sepsis
Infections
Systemic Inflammatory Response Syndrome
Inflammation