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

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

Sponsors

Lead Sponsor: Centre Hospitalier Intercommunal Creteil

Source 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.

Overall Status Not yet recruiting
Start Date December 1, 2020
Completion Date February 1, 2023
Primary Completion Date December 1, 2022
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
Mortality Day 60
Secondary Outcome
Measure Time Frame
Evolution of SOFA Score Up to Day 7
Number of ventilator free days Day 28
Number of renal replacement therapy free days Day 28
Number of vasopressor free days Day 28
Mortality Day 2
Number of patients with shivering Day 3
Number of patients with seizure Day 2
Number of patients with hypothermia Day 3
Number of patients with at least 1 episode of cardiac arrhythmia Day 3
Secondary acquired nosocomial infections Day 28
Number of patients with ARDS development among patients free of ARDS at inclusion Up to Day 3
Acute kidney injury Up to Day7
Enrollment 820
Condition
Intervention

Intervention Type: Other

Intervention Name: External Cooling

Description: External Cooling

Arm Group Label: Fever Control by external cooling

Eligibility

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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Contact

Last Name: Frédérique SCHORTGEN, MD

Phone: 01 45 17 56 83

Email: [email protected]

Verification Date

July 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Fever Control by external cooling

Type: Experimental

Description: External cooling during 48 hours to obtain normothermia

Label: Fever respected, no cooling

Type: No Intervention

Description: Fever respect without any antipyretic therapy

Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov