Respiratory involvement of SARS-CoV2 leads to acute respiratory distress syndrome (ARDS) and significant immunosuppression (lymphopenia) exposing patients to long ventilation duration and late mortality linked to the acquisition of nosocomial infections. Lymphopenia characteristic of severe forms of ARDS secondary to SARS-CoV2 infection may be linked to expansion of MDSCs and arginine depletion of lymphocytes. Severe forms of COVID-19 pneumonitis are marked by persistent ARDS with acquisition of nosocomial infections as well as by prolonged lymphocytic dysfunction associated with the emergence of MDSC. It has been found in intensive care patients hypoargininaemia, associated with the persistence of organ dysfunction (evaluated by the SOFA score), the occurrence of nosocomial infections and mortality. Also, it has been demonstrated that in these patients, the enteral administration of ARG was not deleterious and increased the synthesis of ornithine, suggesting a preferential use of ARG by the arginase route, without significant increase in argininaemia nor effect on immune functions. L-citrulline (CIT), an endogenous precursor of ARG, is an interesting alternative to increase the availability of ARG. Recent data demonstrate that the administration of CIT in intensive care is not deleterious and that it very significantly reduces mortality in an animal model of sepsis, corrects hypoargininemia, with convincing data on immunological parameters such as lymphopenia, which is associated with mortality, organ dysfunction and the occurrence of nosocomial infections. The availability of ARG directly impacts the mitochondrial metabolism of T lymphocytes and their function. The hypothesis is therefore that CIT supplementation is more effective than the administration of ARG to correct hypoargininaemia, decrease lymphocyte dysfunction, correct immunosuppression and organ dysfunction in septic patients admitted to intensive care. The main objective is to show that, in patients hospitalized in intensive care for ARDS secondary to COVID-19 pneumonia, the group of patients receiving L-citrulline for 7 days, compared to the group receiving placebo, has a score of organ failure decreased on D7 (evaluated by the SOFA score) or by the last known SOFA score if the patient has died or been resuscitated.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
33
Administration of citrulline enterally for 7 days.
Administration of placebo (water) enterally for 7 days
Rennes University Hospital
Rennes, Britanny, France
SOFA
SOFA score for organ failures on D8 or last known SOFA score if the patient has died or been resuscitated
Time frame: Day 8
Number and phenotype of lymphocytes
Number and phenotype of lymphocytes on days 1, 8 and 14
Time frame: Days 1, 8 and 14
HLA-DR
Monocytic expression HLA-DR (Flow cytometry) on days 1, 8 and 14
Time frame: Days 1, 8 and 14
Number of Myeloid-derived suppressor cells
Number of Myeloid-derived suppressor cells (Flow cytometry) on days 1, 8 and 14
Time frame: Days 1, 8 and 14
Plasma cytokines / chemokines
Plasma cytokines / chemokines (IL-6, IL-8, IL-10, IL-7, CXCL10, G-CSF, TNF-alpha, IFN-β) at days 1, 8 and 14
Time frame: Days 1, 8 and 14
Repertoire T
Diversity of the repertoire T at days 1, 3, 8, 10 and 14
Time frame: Days 1, 3, 8, 10 and 14
Lymphocyte T exhaustion
T lymphocyte exhaustion: measurement of lymphocyte apoptosis and lymphocyte proliferation on days 1, 8 and 14
Time frame: Days 1, 8 and 14
Mitochondrial activity
Measurement of mitochondrial activity (measurement of the number of mitochondria and their membrane potential, measurement of the expression of Beclin1) on days 1, 8 and 14
Time frame: Days 1, 8 and 14
Plasma amino acids
Plasma amino acids (arginine and its metabolites (ornithine, glutamate, glutamine, citrulline, proline) and tryptophan / kynurenine) on days 1, 8 and 14
Time frame: Days 1, 8 and 14
SOFA
SOFA score of organ failures on days 3, 7, 10 and 14
Time frame: Days 3, 7, 10 and 14
Duration of hospitalization in intensive care
Duration of hospitalization in intensive care (days), up to day 28 maximum
Time frame: Day 28
Duration of hospital stay in hospital
Duration of hospital stay in hospital (days), up to day 28 maximum
Time frame: Day 28
Duration of mechanical ventilation
Duration of mechanical ventilation (days), up to day 28 maximum
Time frame: Day 28
Mortality in intensive care on day 28
Mortality in intensive care on day 28
Time frame: Day 28
Hospital mortality on day 28
Hospital mortality on day 28
Time frame: Day 28
Measurement of the presence of SARS-CoV2
Measurement of the presence of SARS-CoV2 in the tracheal aspiration by PCR on days 1, 8 and 14
Time frame: Days 1, 8 and 14
Nosocomial infections
Incidence of nosocomial infections during the intensive care unit (maximum D28). The diagnosis of nosocomial infections will be made according to the definitions of nosocomial infections of the CDC. An independent committee of experts will validate or not the infections
Time frame: D28
Number of days of exposure to each antibiotic per 1000 days of hospitalization
Number of days of exposure to each antibiotic per 1000 days of hospitalization (maximum day 28).
Time frame: Day 28
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