Directed Immuno Nutrition by L-arginine for Critically Ill Patients (Immunolarg)

Randomized Directed Immuno Nutrition by L-arginine for Critically Ill Patients

The main objective of this proof-of-concept study is to demonstrate that the only administration of L-arginine, based on a suspected deficit monitored by nasal nitric oxide measurement, can improve immune functions in critically ill patients at high risk of nosocomial infection.

Study Overview

• Status: Completed
• Conditions: Critically Ill
• Intervention / Treatment: Drug: L-arginine; Drug: placebo

Detailed Description

Background : A meta-analysis has demonstrated the beneficial effect of immuno nutrition in surgical patients, leading to half reduction of incidence of nosocomial infections (HEYLAND DK, JAMA ; 2001). This beneficial effect seems to be related to L-arginine content of formula. In medical intensive care, such an improvement has not been shown, in spite of similar impairment of immune response, which could be due to a more heterogenous population. Our hypothesis is that this beneficial effect could be observed in selected patients of medical intensive care units. L-arginine is a semi-essential amino acid that is the precursor of nitric oxide (NO) synthesis. NO is involved in immune response regulation and has antimicrobial properties, notably into airways where it can be measured in exhaled gas. A decrease in exhaled and nasal NO has been demonstrated in critically ill patients, which may suggest an impairment of its production.

Objectives : The aim of this study is to evaluate the immune effects of enteral L-arginine administration in non surgical critically ill patients. These patients will be selected based on the decrease in nasal NO: directed immuno nutrition. The main objective is to demonstrate that L-arginine administration, as compared to placebo administration, increases nasal NO and enhances immune functions (increase in HLA-DR expression on monocytes, modification of circulating Myeloid-Derived Suppressor Cells (MDSC), decrease in IL-6, IL-17 plasmatic concentrations): stimulation of immune response. The secondary objective is to demonstrate the safety of L-arginine administration on organ failure and on the incidence of nosocomial infections.

This is a monocentric therapeutic trial, randomized and double blind: standard enteral nutrition plus L-arginine (200 mg/kg/d for 5 days from the admission in ICU) versus standard enteral nutrition plus placebo.

Methods-Patients: Non surgical patients admitted in a single medical intensive care unit, under mechanical ventilation for an expected duration > 2 days, with decreased concentrations of nasal NO (< 60 ppb), without severe sepsis or septic shock, will be enrolled. On admission (before treatment), the severity will be evaluated (SAPS II and SOFA score) together with an assessment of plasmatic L-arginine, cytokines (IL-6, IL-17), MDSC, and expression of HLA-DR by monocytes. The same evaluation will be repeated on day 4 (during treatment) and on day 7 (after treatment). The enrolment of 50 patients is statistically enough to demonstrate an increased expression of HLA-DR in the L-arginine group as compared to the placebo group on day 4.

Expected results and perspectives: The aim of this study is to demonstrate the validity of the concept of directed immune stimulation by the sole L-arginine in medical intensive care unit, the patients being selected based on their decrease in exhaled and nasal NO concentrations. This pathophysiological study is the necessary first step before conducting a large clinical trial aimed at demonstrating a reduction of nosocomial infection incidence by L-arginine.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Medical Intensive Care Unit, Pompidou Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria :

• age > 18 years
• medical patient (absence of recent surgery or trauma)
• initial aggression < 5 days
• mechanically ventilated with expected duration of mechanical ventilation > 2 days
• enteral nutrition
• absence of previous immunosuppression
• nasal NO on day 1 of ICU stay < 60 ppb

Exclusion criteria :

• severe sepsis
• septic shock
• condition associated with a decreased nasal NO concentration (cystic fibrosis, nasal polyposis, primary ciliary dyskinesia
• pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: L-arginine; 5-day L-arginine treatment (200 mg/kg)	Drug: L-arginine; 5-day L-arginine treatment
Placebo Comparator: placebo; 5-day placebo treatment	Drug: placebo; 5-day placebo treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Expression of HLA-DR in the L-arginine group as compared to the placebo group	on day 3

Secondary Outcome Measures

Outcome Measure	Time Frame
HLA-DR on day 7, IL-10 and IL-17 on day 3 and 7, MDSC on day 3 and 7	on day 3 and on day 7
Nosocomial infections	in the first 15 days
Safety issue: organ failure score (SOFA score) on day 3 and 7; issue from ICU	on day 3 and 7

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Jean Marc TADIE, MD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Marik PE, Zaloga GP. Immunonutrition in critically ill patients: a systematic review and analysis of the literature. Intensive Care Med. 2008 Nov;34(11):1980-90. doi: 10.1007/s00134-008-1213-6. Epub 2008 Jul 15.
• Tadie JM, Cynober L, Peigne V, Caumont-Prim A, Neveux N, Gey A, Guerot E, Diehl JL, Fagon JY, Tartour E, Delclaux C. Arginine administration to critically ill patients with a low nitric oxide fraction in the airways: a pilot study. Intensive Care Med. 2013 Sep;39(9):1663-5. doi: 10.1007/s00134-013-2984-y. Epub 2013 Jun 19. No abstract available.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: December 22, 2009
• First Submitted That Met QC Criteria: December 23, 2009
• First Posted (Estimate): December 24, 2009

Study Record Updates

• Last Update Posted (Estimate): September 18, 2013
• Last Update Submitted That Met QC Criteria: September 17, 2013
• Last Verified: December 1, 2009

More Information

Terms related to this study

• Keywords: L-arginine; HLA-DR expression; Immune function; Critically ill; Nosocomial infection; Nasal NO; Medical ICU patients
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: P090203