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

Official title

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

Overview

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

• 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 conditio

Primary outcome measures

• The primary end point is all-cause mortality at 28 days after randomization [Time frame: Every day until Day 28]

Secondary outcome measures (12)

• Key secondary endpoints [Time frame: Every day until Day 28]
• Key secondary endpoints [Time frame: Every day until Day 90]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 28]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 28]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 28]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 28]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 28]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 7]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 28]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 28]
• Secondary Efficacy Endpoints [Time frame: Every day until Day 28]
• Secondary Efficacy Endpoints [Time frame: At Day 90 after randomization]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 28 centers

• CHu Angers — Angers
• CH Aurillac — Aurillac
• CH de la Côte Basque — Bayonne
• CHU Bordeaux Hôpital Haut Lévèque — Bordeaux
• CHU Bordeaux Pellegrin Hospital — Bordeaux
• CHU Clermont-Ferrand Estaing — Clermont-Ferrand
• CHU Clermont-Ferrand Gabriel Montpied — Clermont-Ferrand
• CHU Dijon — Dijon
• … and 20 more centers

Publications

• Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA. 1993 Dec 22-29;270(24):2957-63. doi: 10.1001/jama.270.24.2957. PMID 8254858
• Levey AS, Becker C, Inker LA. Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review. JAMA. 2015 Feb 24;313(8):837-46. doi: 10.1001/jama.2015.0602. PMID 25710660
• Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10. doi: 10.1007/BF01709751. No abstract available. PMID 8844239
• Laterre PF, Berry SM, Blemings A, Carlsen JE, Francois B, Graves T, Jacobsen K, Lewis RJ, Opal SM, Perner A, Pickkers P, Russell JA, Windelov NA, Yealy DM, Asfar P, Bestle MH, Muller G, Bruel C, Brule N, Decruyenaere J, Dive AM, Dugernier T, Krell K, Lefrant JY, Megarbane B, Mercier E, Mira JP, Quenot JP, Rasmussen BS, Thorsen-Meyer HC, Vander Laenen M, Vang ML, Vignon P, Vinatier I, Wichmann S, W PMID 31577035
• STARRT-AKI Investigators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group; United Kingdom Critical Care Research Group; Canadian Nephrology Trials Network; Irish Critical Care Trials Group; Bagshaw SM, Wald R, Adhikari NKJ, Bellomo R, da Costa BR, Dreyfuss D, Du B, Gallagher MP, Gaudry S, Hoste EA, Lamontagne F, Joannidis M, Landoni G, L PMID 32668114
• Fergusson D, Aaron SD, Guyatt G, Hebert P. Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ. 2002 Sep 21;325(7365):652-4. doi: 10.1136/bmj.325.7365.652. No abstract available. PMID 12242181
• Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994 Jun 16;330(24):1717-22. doi: 10.1056/NEJM199406163302404. PMID 7993413
• Deis AS, Whiles BB, Brown AR, Satterwhite CL, Simpson SQ. Three-Hour Bundle Compliance and Outcomes in Patients With Undiagnosed Severe Sepsis. Chest. 2018 Jan;153(1):39-45. doi: 10.1016/j.chest.2017.09.031. Epub 2017 Oct 5. PMID 28987477

Identifiers

NCT: NCT07179276 · PHRC N 2020 FUTIER

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗