Septic ShockNCT04494074
Fever Control Using External Cooling in Mechanically Ventilated Patients With Septic Shock
A study testing External Cooling in people with Septic Shock, run by Centre Hospitalier Intercommunal Creteil at 33 sites in France.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Septic Shock
- What is being tested?
- External Cooling
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 820 participants
- Where
- 33 sitesFrance
- Study dates
- 1 Oct 2022to 1 Dec 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
33 sites in 1 country. Contact the study team or a site near you to ask about taking part.
33 sites in 1 country
France33 sites, 28 recruiting
- Recruiting
CHU Amiens
Amiens
Julien MAIZEL, MD, Maizel.Julien@chu-amiens.fr
- Recruiting
CHU Angers
Angers
ASFAR Pierre, MD, PiAsfar@chu-angers.fr
- Recruiting
CH Victor Dupouy
Argenteuil
Gaetan PLANTEFEVE, MD, gaetan.plantefeve@ch-argenteuil.fr
- Recruiting
Hôpital Nord Franche Comté
Belfort
Julio BADIE, MD, Julio.BADIE@hnfc.fr
- Recruiting
CH Cholet
Cholet
Julien DUPEYRAT, MD, julien.dupeyrat@ch-cholet.fr
- Recruiting
Centre hospitalier intercommunal de Créteil
Créteil
SCHORTGEN Frédérique, MD, Frederique.schortgen@chicreteil.fr
- Active, not recruiting
Hôpital Henri Mondor
Créteil
- Recruiting
CHD Dijon
Dijon
QUENOT Jean Pierre, MD, jean-pierre.quenot@chu-dijon.fr
- Recruiting
CHU Grenoble
Grenoble
Guillaume DUMAS, MD, GDumasgalant@chu-grenoble.fr
- Recruiting
GH Est Francilien
Jossigny
Ly Van Phach VONG, MD, lvpvong@ghef.fr
- Recruiting
CHD Vendée
La Roche-sur-Yon
TOUSSAINT Aurélie, MD, aurelie.toussaint@chd-vendee.fr
- Active, not recruiting
CHU Kremlin Bicetre
Le Kremlin-Bicêtre
- Recruiting
CHU Le Mans
Le Mans
Christophe GUITTON, MD, cguitton@ch-lemans.fr
- Not yet recruiting
CH Lens
Lens, 62300
Camille POUTREAU, MD
- Recruiting
CH Libourne
Libourne
Caroline JANNIERE NARTEY, MD, caroline.janniere-nartey@ch-libourne.fr
- Not yet recruiting
Hôpital Saint Joseph Saint Luc
Lyon, 69001
Emmanuel VIVIER, MD, evivier@saintjosephsaintluc.fr
- Recruiting
Hôpital de la Croix-Rousse
Lyon
Jean Christophe RICHARD, MD, j-christophe.richard@chu-lyon.fr
- Active, not recruiting
Hôpital Timone
Marseille
- Not yet recruiting
CHR Metz Hôpital de Mercy
Metz
Guillaume LOUIS, MD, guillaume.louis@chr-metz-thionville.fr
- Recruiting
GRH Mulhouse
Mulhouse
Anne Florence DUREAU, anne-florence.dureau@ghrmsa.fr
- Recruiting
CHU Hotel Dieu
Nantes
LASCARROU Jean Baptiste, MD, jeanbaptiste.lascarrou@chu-nantes.fr
- Active, not recruiting
CHU Archet 1
Nice
- Recruiting
Hôpital Pasteur
Nice
Alexandre ROBERT, MD, robert.a@chu-nice.fr
- Recruiting
Hopital Lariboisière - Réanimation Médicale
Paris
DEYE Nicolas, MD, nicolas.deye@aphp.fr
- Recruiting
Hôpital Lariboisière -Réanimation chirurgicale
Paris
CHOUSTERMAN Benjamin, MD, benjamin.chousterman@aphp.fr
- Recruiting
CHU La Milétrie Poitiers
Poitiers
Remi COUDROY, MD, Remi.coudroy@chu-poitiers.fr
- Active, not recruiting
CHU Reims
Reims
- Recruiting
CHU Charles Nicolle
Rouen
Dorothée CARPENTIER, MD, dorothee.carpentier@chu-rouen.fr
- Recruiting
CHU Réunion Sud
Saint-Denis
Simon OLIVIER, MD, olivier.simon@chu-reunion.fr
- Recruiting
Hôpital FOCH
Suresnes
Jérome DEVAQUET, MD, j.devaquet@hopital-foch.org
- Recruiting
CH BIGORRE SITE GESPE Tarbes
Tarbes
Philippe PETUA, MD, ppetua@ch-tarbes-vic.fr
- Recruiting
CHBA Vannes-Auray
Vannes
Agathe Delbove, MD, agathe.delbove@ch-bretagne-atlantique.fr
- Recruiting
Centre Hospitalier Mignot
Versailles
LEGRIEL Stéphane, MD, slegriel@ght78sud.fr
About this study
Official title: 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:
- Respect of fever
- Fever control at normothermia using external cooling The primary end point will be d-60 mortality.
Read the 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:
- Fever respect
- 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.
- Conditions
- Septic Shock
- Being tested
- External Cooling
- Keywords
- External cooling,, Fever, ARDS
- Medical subject headings
- Shock, Septic, Fever
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
External CoolingOther
External Cooling
| Study group | Role | What they receive |
|---|---|---|
| Fever Control by external cooling | Experimental | External cooling during 48 hours to obtain normothermia Receives: Other: External Cooling |
| Fever respected, no cooling | No intervention | Fever respect without any antipyretic therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
All causes mortality
Measured: Day 60 from randomization
Secondary outcomes (12)
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
Measured: Up to Day 7
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
Measured: Day 28
Number of renal replacement therapy free days
Number of free days will be assessed as proposed by YEHYA et al.
Measured: Day 28
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
Measured: Day 28
Mortality
All causes mortality
Measured: Day 28
Number of patients with shivering
Shivering will be monitored according to a specific scale
Measured: Day 2
Number of patients with seizure
Seizure will be clinically documented or reveal by EEG
Measured: Day 3
Number of patients with hypothermia
Number of patients with body temperature lower than 36°C
Measured: Day 3
Number of patients with at least 1 episode of cardiac arrhythmia
Patient with new episode of supraventricular or ventricular arrhythmia
Measured: Day 3
Secondary acquired nosocomial infections
Only the first episode will be taken into account
Measured: Day 28
Number of patients with ARDS development among patients free of ARDS at inclusion
Secondary acquired ARDS according to Berlin definition
Measured: Up to Day 3
Acute kidney injury in patients free of RRT at inclusion
Maximal stage of AKI according to the KDIGO definition
Measured: Up to Day7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jul 2020
- Study start1 Oct 2022
- Primary completion1 Dec 2028 (estimated)
- Study completion1 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Septic ShockStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 820 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre Hospitalier Intercommunal Creteil
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04494074
- Sponsor's protocol ID
- SEPSISCOOL II
- Status last verified
- Sep 2026
- First submitted
- 28 Jul 2020
- Last updated
- 21 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Strictly anonymized data will be available upon justified request from the coordinating investigator and the study sponsor
Publications
Guenegou-Arnoux A, Murris J, Bechet S, Jung C, Auchabie J, Dupeyrat J, Anguel N, Asfar P, Badie J, Carpentier D, Chousterman B, Bourenne J, Delbove A, Devaquet J, Deye N, Dumas G, Dureau AF, Lascarrou JB, Legriel S, Guitton C, Janniere-Nartey C, Quenot JP, Lacherade JC, Maizel J, Mekontso Dessap A, Mourvillier B, Petua P, Plantefeve G, Richard JC, Robert A, Saccheri C, Vong LVP, Katsahian S, Schortgen F; REVA Network. Protocol for fever control using external cooling in mechanically ventilated patients with septic shock: SEPSISCOOL II randomised controlled trial. BMJ Open. 2024 Jan 29;14(1):e069430. doi: 10.1136/bmjopen-2022-069430.
PubMed 38286691
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intérêt du Traitement de la fièvre Par Refroidissement Externe Pour la Survie Des Patients ventilés en Choc Septique
- ClinicalTrials.gov ID
- NCT04494074
- Acronym / sponsor ID
- SEPSISCOOL II
- Conditions
- Septic Shock
- Keywords
- External cooling,, Fever, ARDS
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 820 participants (estimated)
- Lead sponsor
- Centre Hospitalier Intercommunal CreteilUniversity, hospital or other
- Study start
- 1 Oct 2022 (actual)
- Primary completion
- 1 Dec 2028 (estimated)
- Study completion
- 1 Dec 2028 (estimated)
- First posted
- 31 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Respect of fever
- 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:
- Fever respect
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Fever Control by external cooling | Experimental | Other: External CoolingExternal cooling during 48 hours to obtain normothermia |
| Fever respected, no cooling | No intervention | –Fever respect without any antipyretic therapy |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| External CoolingExternal Cooling | Other | Fever Control by external cooling |
Primary outcome
Mortality
Time frame: Day 60 from randomization
All causes mortality
12 secondary outcomes
Evolution of SOFA Score
Time frame: Up to Day 7
Number of ventilator free days
Time frame: Day 28
Number of renal replacement therapy free days
Time frame: Day 28
Number of vasopressor free days
Time frame: Day 28
Mortality
Time frame: Day 28
Number of patients with shivering
Time frame: Day 2
Number of patients with seizure
Time frame: Day 3
Number of patients with hypothermia
Time frame: Day 3
Number of patients with at least 1 episode of cardiac arrhythmia
Time frame: Day 3
Secondary acquired nosocomial infections
Time frame: Day 28
Number of patients with ARDS development among patients free of ARDS at inclusion
Time frame: Up to Day 3
Acute kidney injury in patients free of RRT at inclusion
Time frame: Up to Day7
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2026.
- Derived from this study: PubMed 38286691Guenegou-Arnoux A, Murris J, Bechet S, Jung C, Auchabie J, Dupeyrat J, Anguel N, Asfar P, Badie J, Carpentier D, Chousterman B, Bourenne J, Delbove A, Devaquet J, Deye N, Dumas G, Dureau AF, Lascarrou JB, Legriel S, Guitton C, Janniere-Nartey C, Quenot JP, Lacherade JC, Maizel J, Mekontso Dessap A, Mourvillier B, Petua P, Plantefeve G, Richard JC, Robert A, Saccheri C, Vong LVP, Katsahian S, Schortgen F; REVA Network. Protocol for fever control using external cooling in mechanically ventilated patients with septic shock: SEPSISCOOL II randomised controlled trial. BMJ Open. 2024 Jan 29;14(1):e069430. doi: 10.1136/bmjopen-2022-069430.
- Individual participant dataSharing planned: Yes. Strictly anonymized data will be available upon justified request from the coordinating investigator and the study sponsor
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
33 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing External Cooling in people with Septic Shock, run by Centre Hospitalier Intercommunal Creteil at 33 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 33 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Frédérique SCHORTGEN, MD (01 57 02 34 11, Frederique.schortgen@chicreteil.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: Day 60 from randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04494074, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2026.