Directed Immuno Nutrition by L-arginine for Critically Ill Patients

Critically Ill Clinical Trial

— Immunolarg  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01038622
• Other study ID #: P090203
• Status: Completed
• Phase: Phase 4
• First received: December 22, 2009
• Last updated: September 17, 2013
• Start date: November 2009
• Est. completion date: January 2011

Study information

• Verified date: December 2009
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: January 2011
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Critical Illness
• Critically Ill

Intervention

Drug:
• L-arginine
5-day L-arginine treatment
• placebo
5-day placebo treatment

Locations

Country	Name	City	State
France	Medical Intensive Care Unit, Pompidou Hospital	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (1)

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Expression of HLA-DR in the L-arginine group as compared to the placebo group		on day 3	No
Secondary	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	No
Secondary	Nosocomial infections		in the first 15 days	No
Secondary	Safety issue: organ failure score (SOFA score) on day 3 and 7; issue from ICU		on day 3 and 7	Yes