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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Septic Shock, Multiple Organ Failure

Intervention / Treatment
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* Biological: Whole blood samples


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Septic shock admitted in Angers' ICU<br>Patients aged more than 18, admitted in University Hospital of Angers, who meet the full criteria of septic shock | Biological: Whole blood samples<br>* Whole blood samples at admission, from day one to three after admission<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mitochondrial metabolism (mitochondrial membrane depolarization and respiration) with the supplementation of metabolite in the cell culture medium | Using Fluorescence-activated cell sorting system to assess the membrane depolarization of the mitochondria and Oroboros system for mitochondrial respiration | Day 0 (whole blood after cells separation), Day 1-3 after cell culture | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival at 28 days | Survival of patients after ICU admission | Day 28 | 
| Change in organs failure | Using the Sequential Organ Failure Assessment Score | From Day 0 to Day 4 | 
| Change and correlation between lactic acidosis, ketogenesis and mitochondrial function evolutions | biochemical analysis of blood samples, assessment of mitochondrial metabolism (quantitative and qualitative analysis). | From Day 1 to Day 3 | 
| Need for renal replacement therapy during the ICU stay | Need for renal replacement therapy and its duration | From Day 1 to Day 28 | 
| Need for vasopressors during the ICU stay | Need for vasopressors during the ICU stay and its duration | From Day 1 to Day 28 | 
| Need for mechanical ventilation during the ICU stay | Need for mechanical ventilation during the ICU stay and its duration | From Day 1 to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mitochondrial dysfunction