Clinical trial NCT04288635: Impact of Metabolite Supplementation to Restore Mitochondrial Dysfunction During Septic Shock: a Preclinical Study
Official title: Impact of Metabolite Supplementation to Restore Mitochondrial Dysfunction During Septic Shock: a Preclinical Study: MEFDASE Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Septic Shock
Multiple Organ Failure
Keywords: mitochondrial dysfunction
Lead sponsor: University Hospital, Angers
Sponsor class: OTHER_GOV
First posted: 2020-02-28
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients aged 18 or more who meet the SEPSIS-3 criteria for septic shock : a 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 to the medical ICU of Angers University Hospital.

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in mitochondrial metabolism (mitochondrial membrane depolarization and respiration) with the supplementation of metabolite in the cell culture medium
timeFrame: Day 0 (whole blood after cells separation), Day 1-3 after cell culture
Secondary outcomes:
measure: Overall survival at 28 days
timeFrame: Day 28
measure: Change in organs failure
timeFrame: From Day 0 to Day 4
measure: Change and correlation between lactic acidosis, ketogenesis and mitochondrial function evolutions
timeFrame: From Day 1 to Day 3
measure: Need for renal replacement therapy during the ICU stay
timeFrame: From Day 1 to Day 28
measure: Need for vasopressors during the ICU stay
timeFrame: From Day 1 to Day 28
measure: Need for mechanical ventilation during the ICU stay
timeFrame: From Day 1 to Day 28
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU
state: Maine et Loire
Study officials:
affiliation: University Hospital of Angers
name: Julien DEMISELLE, MD
role: PRINCIPAL_INVESTIGATOR
References: