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

Septic Shock Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04494074
• Other study ID #: SEPSISCOOL II
• Status: Recruiting
• Phase: N/A
• Start date: October 1, 2022
• Est. completion date: December 1, 2026

Study information

• Verified date: May 2024
• Source: Centre Hospitalier Intercommunal Creteil
• Contact: Frédérique SCHORTGEN, MD
• Phone: 01 57 02 34 11
• Email: Frederique.schortgen[@]chicreteil.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 820
• Est. completion date: December 1, 2026
• Est. primary completion date: December 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Septic Shock
• Shock, Septic

Intervention

Other:
• External Cooling
External Cooling

Locations

Country	Name	City	State
France	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 de la Croix-Rousse	Lyon
France	Hôpital Saint Joseph Saint Luc	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

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Intercommunal Creteil

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality	All causes mortality	Day 60 from randomization
Secondary	Evolution of SOFA Score	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
Secondary	Number of ventilator free days	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
Secondary	Number of renal replacement therapy free days	Number of free days will be assessed as proposed by YEHYA et al.	Day 28
Secondary	Number of vasopressor free days	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
Secondary	Mortality	All causes mortality	Day 28
Secondary	Number of patients with shivering	Shivering will be monitored according to a specific scale	Day 2
Secondary	Number of patients with seizure	Seizure will be clinically documented or reveal by EEG	Day 3
Secondary	Number of patients with hypothermia	Number of patients with body temperature lower than 36°C	Day 3
Secondary	Number of patients with at least 1 episode of cardiac arrhythmia	Patient with new episode of supraventricular or ventricular arrhythmia	Day 3
Secondary	Secondary acquired nosocomial infections	Only the first episode will be taken into account	Day 28
Secondary	Number of patients with ARDS development among patients free of ARDS at inclusion	Secondary acquired ARDS according to Berlin definition	Up to Day 3
Secondary	Acute kidney injury in patients free of RRT at inclusion	Maximal stage of AKI according to the KDIGO definition	Up to Day7