ICITRU : Randomized Trial of Immunonutrition With L-citrulline in Patients Hospitalized in Intensive Care for Sepsis or Septic Shock
ICITRU : Randomized Trial of Immunonutrition With L-citrulline in Patients Hospitalized in Intensive Care for Sepsis or Septic Shock
Immunonutrition in intensive care has not yet demonstrated a beneficial effect on organ
 failure, the acquisition of nosocomial infections, or mortality. It did not correct for
 acquired immunosuppression in intensive care patients. Despite numerous methodological
 problems (use of several pharmaconutrients, very heterogeneous set of patients) and the
 absence of clinical data, deleterious effects have been attributed to immunonutrition in
 intensive care, in particular in septic patients and patients in intensive care . Arginine
 (ARG) is a semi-essential amino acid involved in many immunological mechanisms. It is
 synthesized in sufficient quantity under normal conditions but quickly becomes insufficient
 under catabolic conditions such as in severe sepsis. Arginine is not only the precursor of
 nitrogen monoxide (NO) but also an essential substrate for numerous enzymatic reactions which
 participate in the maintenance of immune homeostasis, in particular T lymphocyte function.
 Depletion of the cellular medium in arginine will induce an abnormality in the metabolism of
 immune cells responsible for a dysfunction of these cells (lymphopenia linked to early
 apoptosis) and thus expose patients to organ failure and nosocomial infections.

 It has been found that hypoargininemia in intensive care patients is associated with the
 persistence of organ dysfunction (SOFA score), the occurrence of nosocomial infections and
 mortality. Also, it has been demonstrated that in these patients, enteral administration of
 ARG was not deleterious and increased ornithine synthesis, suggesting a preferential use of
 ARG via the arginases route, without significant increase in argininaemia or effect on immune
 functions. L-citrulline (CIT), an endogenous precursor of ARG, constitutes an interesting
 alternative for increasing the availability of ARG. Sponsor 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. Our
 hypothesis is therefore that CIT supplementation is more effective than administration of ARG
 in correcting hypoargininemia, reducing lymphocyte dysfunction, correcting immunosuppression
 and organ dysfunction in septic patients admitted to intensive care.
Strategy :

 Enteral administration of citrulline for 5 days versus iso-nitrogenous placebo. Amino acid
 assay and immunological parameters (monocytic expression of HLA-DR, MDSCs, cytokines /
 chemokines, lymphocyte number and phenotype, apoptosis and lymphocyte proliferation and
 mitochondrial function and T lymphocyte repertoire) will only be carried out on patients
 included in Rennes (60 patients).
Inclusion Criteria:

 -  Septic patients in accordance with the definition of sepsis and septic shock published
 in 2016 (JAMA) and whose use is recommended by the European Society of Intensive Care
 Medicine;

 -  Initial aggression dated less than 4 days before admission to intensive care
 (selection of "community" patients). The onset of aggression will be defined by the
 onset of clinical signs of infection;

 -  Patients hospitalized for less than 48 hours before admission to intensive care
 (selection of patients without malnutrition and immunosuppression acquired in
 hospital) *;

 -  Patients under invasive mechanical ventilation with a foreseeable ventilation
 duration> 2 days **;

 -  Exclusive enteral nutrition;

 -  Affiliation to a social security scheme;

 -  Consent signed by the patient, relative or legal representative or inclusion under
 emergency procedure

 Non Inclusion Criteria:

 -  Pregnancy in progress;

 -  Morbid obesity (BMI> 40);

 -  State of immunosuppression defined by at least one of these criteria: continuous
 administration of steroids at any dose for more than one month before hospitalization,
 steroids at high doses (> 0.5 mg / kg / day of methylprednisolone or equivalent),
 radiotherapy or chemotherapy in the previous year, proven humoral or cellular
 deficiency;

 -  Contraindication to enteral nutrition (SRLF 2016 recommendations: "Enteral nutrition
 should probably not be used upstream of a high flow digestive fistula in cases of
 intestinal obstruction, ischemia of the small intestine or digestive hemorrhage.
 active (Strong agreement) ");

 -  Participation in intervention research on a drug, or intervention research that could
 impact the immune system

 Exclusion Criteria:

 - Institution of immunosuppressive therapy such as chemotherapy, cyclophosphamide, high
 dose corticosteroid therapy (> 0.5 mg / kg / day).