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

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.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock; Multiple Organ Failure
• Intervention / Treatment: Biological: Whole blood samples

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.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Julien DEMISELLE, MD; Phone Number: +33 2 41 35 58 65; Email: Julien.Demiselle@chu-angers.fr
• Study Contact Backup: Name: Pierre ASFAR, MD PhD; Phone Number: +33 2 41 35 58 65; Email: PiAsfar@chu-angers.fr

Study Locations

• France
  • Maine Et Loire
    • Angers, Maine Et Loire, France, 49933
      • Recruiting
      • CHU
      • Contact: ASFAR Pierre, MD-PhD; Phone Number: 00332355865; Email: PiAsfar@chu-angers.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• 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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Septic shock admitted in Angers' ICU; Patients aged more than 18, admitted in University Hospital of Angers, who meet the full criteria of septic shock	Biological: Whole blood samples; Whole blood samples at admission, from day one to three after admission

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Angers
• Investigators: Principal Investigator: Julien DEMISELLE, MD, University Hospital of Angers

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2020
• Primary Completion (Estimated): July 9, 2024
• Study Completion (Estimated): August 9, 2024

Study Registration Dates

• First Submitted: February 21, 2020
• First Submitted That Met QC Criteria: February 27, 2020
• First Posted (Actual): February 28, 2020

Study Record Updates

• Last Update Posted (Actual): September 25, 2023
• Last Update Submitted That Met QC Criteria: September 21, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: mitochondrial dysfunction
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Multiple Organ Failure
• Other Study ID Numbers: 49RC19_0189

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No