Citrulline and Arginase Activity in Severe Sepsis and Septic Shock (CARS)

Activity and Expression of Plasma Arginase in Patients With Severe Sepsis or Septic Shock as Prognostic Value

Sepsis is an acute pathology defined as an inappropriate response of the host to infection, resulting in the onset of organ failure (Quick SOFA ≥2, or SOFA ≥2). Septic shock is a sepsis associated with an elevation of lactate ≥ 2 mmol / l and an arterial hypotension requiring vasoactive drugs. Several studies highlighted that sepsis is associated with a plasma L-arginine deficiency. This deficiency induces a lower availability of L-arginine for multiple metabolic pathways including those involved in the synthesis of nitric oxide (NO) in the vascular endothelium via NO synthase. NO is the main endogenous vasodilator mediator, a lower synthesis induces a vascular and endothelial dysfunction that can promote the occurrence of an organic dysfunction during sepsis. Decrease in available NO was confirmed in patients with sepsis and appears correlated with severity.

L-arginine deficiency can have multiple origins:

• L-arginine deficiency resulting from a decrease in endogenous production from citrulline synthesized by the enterocytes. Such enterocyte dysfunction has been confirmed in patients with sepsis and is characterized biologically by elevated plasma levels of I-FABP (intestinal fatty acid binding protein - enterocyte-specific protein, cytolysis marker) and lower than that of citrulline (hypocitrullinemia, marker of lower activity).
• L-arginine deficiency may also result from a catabolism increase via arginase activity increased. This ubiquitous enzyme, having 2 isoforms (Arg1 and Arg2), allows the synthesis of urea and ornithine from L-arginine. An increase in arginase activity would decrease the available reserves of L-arginine for NO synthesis.

The objectives of this work is to evaluate, in patients with severe sepsis or septic shock, the prognostic value of the plasma arginase activity and the plasma expression of 2 isoforms Arg1 and Arg2, their kinetics, and the link between activity / expression of arginase and enterocyte dysfunction.

Study Overview

• Status: Unknown
• Conditions: Sepsis; Septic Shock; Biomarkers; Infection; Intensive Care Units

• Study Type: Observational
• Enrollment (Anticipated): 118

Contacts and Locations

• Study Contact: Name: Gaël PITON, MD; Phone Number: +33 381668127; Email: gpiton@chu-besancon.fr
• Study Contact Backup: Name: Lucie VETTORETTI; Phone Number: +33 381218378; Email: lvettoretti@chu-besancon.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

patients admitted to the ICU for severe sepsis or septic shock

Description

Inclusion Criteria:

• 18 years old or older
• Patient admitted to ICU
• Diagnosis, suspected or confirmed, of severe sepsis or septic shock
• Expected ICU stay of at least 2 days
• Affiliation to a social security system or recipient of a such system
• Signed informed consent

Exclusion Criteria:

• Pregnancy
• Chronic intestinal pathology
• Chronic renal failure defined by creatinine clearance <50 ml / min / 1.73m2 (CKD-EPI)
• Severe hepatic insufficiency (Child-Pugh stage C score)
• Legal incapacity or limited legal capacity
• Subject unlikely to cooperate with the study and / or weak cooperation anticipated by the investigator
• Patient within the exclusion period of another study or planned by the "national file of volunteers"

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
prognostic value of plasma arginase activity and expression at ICU admission in patients with severe sepsis or septic shock	activity / expression of plasma arginase at ICU admission and 28-day mortality rate from admission to intensive care	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
activity / expression kinetic of plasma arginase	3 points kinetic : admission, day 3 and day 7	during the first 7 days of ICU admission
prognostic value of enterocyte damage	at ICU admission and 28-day mortality rate from admission to intensive care	28 days

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Besancon
• Investigators: Principal Investigator: Gaël PITON, MD, CHU de Besancon

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): February 10, 2019
• Primary Completion (ANTICIPATED): May 10, 2019
• Study Completion (ANTICIPATED): August 10, 2019

Study Registration Dates

• First Submitted: February 8, 2019
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (ACTUAL): February 12, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: ICU, sepsis, septic shok, arginase, citrulline
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock
• Other Study ID Numbers: P/2018/353

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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