Veno-arterial Carbon Dioxide Partial Pressure Difference (CO2gap) for Early Resuscitation of Septic Shock (CARBON)

Veno-arterial Carbon Dioxide Partial Pressure Difference (CO2gap) for Early Resuscitation of Septic Shock: A Multicenter Prospective Randomized Trial (CARBON)

Sepsis is a dysregulated host response to infection that leads to life-threatening organ dysfunction and represents a major healthcare problem. Septic shock is the most severe form, characterized by increased capillary permeability and vasodilation, resulting in hypotension and tissue hypoxia. Early identification and treatment of tissue hypoperfusion are pivotal components of initial resuscitation to limit progression to multiple organ dysfunction and death. The 2021 Surviving Sepsis Guidelines recommend guiding initial resuscitation by targeting decreases in serum lactate levels in patients with elevated lactate. However, although elevated lactate levels may reflect tissue hypoxia, serum lactate is not a direct marker of tissue perfusion. Hyperlactatemia may be attributable to mechanisms other than tissue hypoperfusion, such as accelerated aerobic glycolysis driven by excessive β-adrenergic stimulation or impaired clearance (e.g., in liver failure).

The venous-to-arterial carbon dioxide partial pressure difference (CO₂ gap), which is inversely related to cardiac output, has been shown to reflect the adequacy of venous blood flow to remove CO₂ from tissues. The CO₂ gap is closely linked to microcirculatory blood flow during the early resuscitation phase of septic shock and may effectively identify persistent tissue hypoperfusion in shock states. A persistently high CO₂ gap during early resuscitation has been associated with significantly higher 28-day mortality and increased Sequential Organ Failure Assessment (SOFA) scores. Moreover, the CO₂ gap has been shown to respond to changes in cardiac output during inotrope infusion in patients with low blood flow, suggesting that its assessment could be useful for therapeutic adjustments. Therefore, there are compelling arguments to evaluate the usefulness of the CO₂ gap in guiding early resuscitation in patients with septic shock.

The investigators postulated that CO₂ gap-guided early resuscitation may be more effective in improving outcomes than lactate-guided resuscitation.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock; Sepsis - to Reduce Mortality in the Intensive Care Unit
• Intervention / Treatment: Procedure: CO2gap-guided resuscitation strategy

Detailed Description

Main objective: The aim of the CARBON trial is to compare a veno-arterial CO2 difference-guided resuscitation strategy (CO2gap-guided strategy) with a lactate level-guided resuscitation on mortality in adults intensive care unit (ICU) patients fulfilling the SEPSIS-3 criteria consensus definition.

HYPOTHESIS: The investigators hypothesized that a CO2gap-guided resuscitation strategy during early septic shock would reduce mortality compared with a lactate level-guided resuscitation.

• Study Type: Interventional
• Enrollment (Estimated): 750
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lise Laclautre; Phone Number: 0473754963; Email: promo_interne_drci@chu-clermontferrand.fr

Study Locations

• France
  • Angers, France
    • Not yet recruiting
    • CHU Angers
    • Principal Investigator: Sigismond Lasocki
  • Aurillac, France
    • Not yet recruiting
    • CH Aurillac
    • Principal Investigator: Emanuele TURBIL
  • Bayonne, France
    • Recruiting
    • CH de la cote basque
    • Principal Investigator: Hadrien ROZE
  • Bordeaux, France
    • Recruiting
    • CHU Bordeaux Hôpital Haut Lévèque
    • Principal Investigator: Antoine DEWITTE
  • Bordeaux, France
    • Recruiting
    • CHU Bordeaux Pellegrin Hospital
    • Principal Investigator: Matthieu BIAIS
  • Clermont-Ferrand, France
    • Recruiting
    • CHU Clermont-Ferrand Estaing
    • Principal Investigator: Emmanuel FUTIER
    • Contact: Lise Laclautre; Phone Number: 0473754963; Email: promo_interne_drci@chu-clermontferrand.fr
  • Clermont-Ferrand, France
    • Recruiting
    • CHU Clermont-Ferrand Gabriel Montpied
    • Principal Investigator: Thomas GODET
    • Contact: Lise Laclautre; Phone Number: 0473754963; Email: promo_interne_drci@chu-clermontferrand.fr
  • Dijon, France
    • Recruiting
    • CHU Dijon
    • Principal Investigator: Grégoire GUINOT
  • Grenoble, France
    • Not yet recruiting
    • CHU Grenoble
    • Principal Investigator: Marie Christine HERAULT
  • Le Puy-en-Velay, France
    • Recruiting
    • CH Le puy en Velay
    • Principal Investigator: Rémi ESPENEL
  • Lyon, France
    • Not yet recruiting
    • HCL - Lyon Sud
    • Principal Investigator: Romain FORT
  • Lyon, France
    • Not yet recruiting
    • HCL Hôpital Edouard Herriot
    • Principal Investigator: Anne Claire LUKASZEWICZ
  • Marseille, France
    • Recruiting
    • AP HM Hôpital la Timone
    • Principal Investigator: Pierre SIMEONE
  • Montpellier, France
    • Recruiting
    • CHU Montpellier
    • Principal Investigator: Samir JABER
  • Moulins, France
    • Not yet recruiting
    • CH Moulins-Yzeure
    • Principal Investigator: Pierre-antoine PIOCHE
  • Nantes, France
    • Recruiting
    • CHU Nantes
    • Principal Investigator: Paul ROOZE
  • Nîmes, France
    • Not yet recruiting
    • CHU Nîmes
    • Principal Investigator: Claire Roger
  • Paris, France
    • Recruiting
    • APHP Bicêtre
    • Principal Investigator: Benjamin BERGIS
  • Paris, France
    • Recruiting
    • APHP Lariboisière
    • Principal Investigator: Maxime COUTROT
  • Paris, France
    • Recruiting
    • APHP Beaujon
    • Principal Investigator: Emmanuel WEISS
  • Paris, France
    • Recruiting
    • APHP La pitié Salpêtrière - Anesthésie et soin intensif
    • Principal Investigator: Fanny VARDON
  • Paris, France
    • Recruiting
    • CHU la pitié slapêtrière - Anesthésie Réanimation
    • Principal Investigator: Constantin Jean Michel
  • Poitiers, France
    • Recruiting
    • CHU Poitiers
    • Principal Investigator: Quentin SAINT GENIS
  • Rennes, France
    • Recruiting
    • CHU Rennes
    • Principal Investigator: Yoann LAUNEY
  • Strasbourg, France
    • Recruiting
    • CHRU Strasbourg - Service d'anesthésie-Réanimation médicale
    • Principal Investigator: Olivier COLLANGE
  • Strasbourg, France
    • Recruiting
    • CHU Strasbourg Service d'Anesthésie-Réanimation chirurgicale
    • Principal Investigator: Julien POTTERCHER
  • Toulouse, France
    • Recruiting
    • CHU Toulouse
    • Principal Investigator: Fanny VARDON
  • Vichy, France
    • Not yet recruiting
    • CH Vichy
    • Principal Investigator: Loic DOPEUX

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged 18 years or older AND
• Acutely admitted to a study ICU AND

• Primary diagnosis of septic shock according to the Sepsis-3 criteria and defined as:

  • A suspected or documented site of infection or positive blood culture AND
  • Acute increase of at least 2 points in the Sequential Organ Failure Assessment (SOFA) score consequent to the infection AND
  • Having a serum lactate level >2 mmol/l AND
  • Requirement of vasopressors (any dose of norepinephrine) to maintain mean arterial pressure (MAP) ≥65 mmHg despite adequate fluid resuscitation (at least 1L of IV fluid in the last 24 hours prior to screening)

Exclusion Criteria:

• Septic shock for more than 12 hours at the time of screening
• Primary cause of hypotension not due to sepsis (e.g., acute bleeding)
• Decision not to resuscitate (or to limit full care) or not to intubate taken before obtaining consent
• Death is deemed to be imminent or inevitable or patients with an underlying disease process with a life expectancy of less than 3 months
• Anticipated surgery during the first 24 hours after randomization
• Patient or their relatives' refusal to participate
• Patients participating in another RCT with interventions possibly compromising the primary outcome
• Prior enrollment in the CARBON trial
• Known to be pregnant.
• Legal protection (i.e., incompetence to provide consent and no guardian or incarceration)
• No affiliation with the French health care system

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CO2gap-guided resuscitation strategy; CO2gap-guided resuscitation strategy aimed at maintaining central venous-to-arterial CO2 partial pressure difference (CO2gap) lower than 6 mmHg, using a sequential approach through a dedicated hemodynamic algorithm. Arterial and central venous blood samples will be drawn simultaneously and reassessed at 2 to 4-hour intervals	Procedure: CO2gap-guided resuscitation strategy; For patients assigned to the interventional arm, adherence to the algorithm will complement clinical practices in the following areas: Blood sampling for venous blood gas analysis. Blood samples will be taken from an existing central venous catheter; central venous access is common clinical practice in critically ill patients.; The use of dobutamine and blood transfusions in patients showing signs of oxygen deficiency (both will be carried out in accordance with the intended use and conditions of current practice).
No Intervention: Lactate level-guided resuscitation strategy; Lactate level-guided resuscitation strategy aimed at normalizing or decreasing lactate levels by 20% at 2 to 4-hour intervals, as per the surviving sepsis campaign guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary end point is all-cause mortality at 28 days after randomization	Every day until Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Key secondary endpoints	Duration of septic shock (i.e., vasopressor use) up to Day 28	Every day until Day 28
Key secondary endpoints	All-cause mortality at Day 90	Every day until Day 90
Secondary Efficacy Endpoints	Renal replacement therapy-free days (excluding patients on renal replacement therapy at time of randomization) up to Day 28	Every day until Day 28
Secondary Efficacy Endpoints	Mechanical ventilation-free days up to Day 28	Every day until Day 28
Secondary Efficacy Endpoints	Duration of renal replacement therapy (excluding patients on renal replacement therapy at time of randomization) up to Day 28	Every day until Day 28
Secondary Efficacy Endpoints	Duration of mechanical ventilation up to Day 28	Every day until Day 28
Secondary Efficacy Endpoints	Incidence of new organ dysfunction (based on the SOFA score) up to Day 7	Every day until Day 7
Secondary Efficacy Endpoints	ICU-free days up to Day 28	Every day until Day 28
Secondary Efficacy Endpoints	ICU length of stay up to Day 28	Every day until Day 28
Secondary Efficacy Endpoints	Hospital length of stay up to Day 28	Every day until Day 28
Secondary Safety Endpoints	Incidence of adverse events with specific emphasis on the incidence of ischemic (e.g., myocardial, stroke, intestinal, limb ischemia) and arrhythmia (excluding sinus tachycardia or sinus arrhythmia) events reported as having a reasonable possibility of a causal relationship with the study procedures	Every day until Day 28
Secondary Efficacy Endpoints	Vasopressor-free and inotrope-free days up to Day 28	Every day until Day 28
Secondary Efficacy Endpoints	EuroQol 5 Dimensions, 5 Levels (EQ-5D-5L) :a measure of health-related quality of life at Day 90: The EQ-5D-5L score is analyzed using the utility value (global index score). In France, the score ranges from about -0.53 (health states considered worse than death) to 1.00 (full health). 0.00 corresponds to a health state equivalent to death.	At Day 90 after randomization

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand

Publications and helpful links

General Publications

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Helpful Links

• How Can We Use Tissue Carbon Dioxide Measurement as an Index of Perfusion? E. Futier, J.-L. Teboul, and B. Vallet

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2026
• Primary Completion (Estimated): November 30, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: September 11, 2025
• First Submitted That Met QC Criteria: September 11, 2025
• First Posted (Actual): September 17, 2025

Study Record Updates

• Last Update Posted (Actual): June 15, 2026
• Last Update Submitted That Met QC Criteria: June 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: sepsis; lactate; hemodynamic therapy; CO2 gap; resuscitation strategie
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Sepsis; Shock, Septic
• Other Study ID Numbers: PHRC N 2020 FUTIER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No