Impact of Metabolite Supplementation to Restore Mitochondrial Dysfunction During Septic Shock: a Preclinical Study

Impact of Metabolite Supplementation to Restore Mitochondrial Dysfunction During Septic Shock: a Preclinical Study: MEFDASE Study

Septic shock is defined as a subset of sepsis with severe metabolism alterations, leading to organ failure. Septic shock is associated with a high mortality, around 40% according to the SEPSIS 3 definition.

Metabolic alterations are responsible for lactic acidosis, and results in mitochondrial dysfunction.

This study aims at evaluate the impact of exogenous metabolites on restoring mitochondrial function in septic shock patients with lactate acidosis.

Mitochondrial metabolism (quantitative analysis, mitochondrial function) in intact Peripheral Blood Mononuclear Cells (PBMC) will be isolate and analyse from patients at the early phase of septic shock (admission), at day 2 and 4. Participant's medical history will be recorded: renal and liver metabolism, severity scores and outcomes and the need for supportive care in the intensive care unit (ICU) until 28 days after admission.

Furthermore, the investigators will evaluate wether selected metabolites added to the cell culture medium may improve mitochondrial metabolism.

In this prospective study, the investigators will include patients admitted to the medical ICU of Angers University Hospital and meeting the SEPSIS-3 criteria for the definition of septic shock (Sequential Organ Failure Assessment (SOFA) score > 2, hyperlactatemia > 2 mmol/L and sepsis).

Blood samples will be collected during the usual care of initial resuscitation and analyzed in the laboratory INSERM (Institut national de la santé et de la recherche médicale) U1232 (University Hospital of Angers).

Mitochondrial metabolism will be analyzed in freshly isolated PBMC and after culture for 1-3 days, with or without the addition of selected metabolites to the cell culture medium.

The evolution of ketogenesis, mitochondrial function, acidobasic status will be assessed across the time (blood samples at day 2 and 4).

Survival, renal and liver metabolism, severity scores and outcomes and the need for supportive care in the intensive care unit (ICU) until 28 days after admission will be recorded.

Inclusion Criteria:

• All patients aged 18 or more
• Patients with criteria for septic shock according to SEPSIS 3 definition (presumed sepsis, with persisting hypotension requiring vasopressors to maintain mean arterial pressure > 65 mmHg and having a serum lactate > 2 mmol/L despite adequate fluid expansion).
• Admitted in the ICU of Angers University Hospital

Exclusion Criteria:

• Minor patients (aged less 18)
• Patient subject to legal protection measures
• Refusal of the patient or his family
• Preexisting mitochondrial disease
• Patient with aplasia
• Pregnant or parturient women