Sepsis - to Reduce Mortality in the Intensive Care Unit, Septic Shock
Conditions
Keywords
lactate, CO2 gap, resuscitation strategie, sepsis, hemodynamic therapy
Brief summary
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.
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.
Interventions
PROCEDURECO2gap-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).
Sponsors
University Hospital, Clermont-Ferrand
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Data will be collected and entered into the electronic web-based case report form by trial or clinical trained personal blinded to the allocation group. Statistical analyses will be performed with the statistician blinded to the allocation group.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary end point is all-cause mortality at 28 days after randomization | Every day until Day 28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key secondary endpoints | Every day until Day 28 | Duration of septic shock (i.e., vasopressor use) up to Day 28 |
| Secondary Efficacy Endpoints | Every day until Day 28 | Vasopressor-free and inotrope-free days up to Day 28 |
| Secondary Safety Endpoints | Every day until Day 28 | 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 |
Countries
France
Contacts
CONTACTLise Laclautre
Outcome results
None listed