Directed Immuno Nutrition by L-arginine for Critically Ill Patients

NCT ID: NCT01038622

Last Updated: 2013-09-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-30
• Study Completion Date: 2011-01-31

Brief Summary

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.

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.

Conditions

Critically Ill

Keywords

L-arginine; Nasal NO; Nosocomial infection; Immune function; HLA-DR expression; Critically ill; Medical ICU patients

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

L-arginine

5-day L-arginine treatment (200 mg/kg)

Group Type: ACTIVE_COMPARATOR

L-arginine

Intervention Type: DRUG

5-day L-arginine treatment

placebo

5-day placebo treatment

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

5-day placebo treatment

Interventions

L-arginine

5-day L-arginine treatment

Intervention Type: DRUG

placebo

5-day placebo treatment

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jean Marc TADIE, MD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Medical Intensive Care Unit, Pompidou Hospital

Paris, , France

Countries

France

References

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.

Reference Type: RESULT

PMID: 18626628 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23778831 (View on PubMed)

Other Identifiers

P090203

Identifier Type: -

Identifier Source: org_study_id