Efficacy and Mechanisms of GLN Dipeptide in the SICU

Summary

Relative glutamine (GLN) deficiency may contribute to morbidity and mortality in surgical intensive care unit (SICU) patients. During critical illness, GLN utilization by the immune system, gut mucosa and other tissues exceeds endogenous production and plasma GLN concentrations decrease, which may contribute to cellular dysfunction and increase nosocomial infection risk and mortality. Conventional GLN-free parenteral nutrition (PN) has a limited impact on SICU outcomes and does not repair the GLN deficit. Recent pilot data show that GLN dipeptide-supplemented PN decreases nosocomial infections and improves clinical outcomes in SICU patients. The process of benefit is poorly understood, but animal and human data suggest that GLN treatment correlates with a) up-regulation of cytoprotective molecules in blood and tissues \[e.g, GSH, specific heat shock proteins (HSPs) and GLN\]; and b) improved epithelial barrier defenses and immune cell number and function. Properties of L-GLN limit provision in solution, but the GLN dipeptide alanyl-GLN (AG) confers stability and solubility in PN (AG-PN). Investigators propose a multicenter, double-blind, randomized, controlled phase III trial based on our pilot data to test the hypothesis that AG-PN improves clinical outcomes in SICU patients requiring PN after cardiac, vascular or colonic operations. Subjects will receive either standard GLN-free PN or isocaloric, isonitrogenous, AG-PN until enteral feeds are established. Specific Aim 1 is to determine whether AG-PN decreases hospital mortality, nosocomial infection and other important indices of morbidity. Specific Aim 2 is to obtain novel, mechanistically relevant observational data in the Aim 1 subjects on whether AG-PN a) increases serial blood levels of GSH, HSP-70 and -27, and GLN; b) decreases the presence in serum of the bacterial products flagellin and LPS and the adaptive immune response to these mediators; and c) improves key indices of innate/adaptive immunity. This study is designed to delineate the clinical benefit of a major new nutrition support strategy in high-risk SICU patients.

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Conditions

• Critical Illness

Interventions

DRUG

Glutamine dipeptide with 15% Clinisol

Subjects randomized to AG-PN will receive PN containing 0.5 g/kg/day of L alanyl L GLN (AG) dipeptide (Dipeptiven 20%; Fresenius-Kabi) and 1.0 g/kg/day of 15% Clinisol (Baxter Inc., Deerfield, IL) AA solution (total = 1.5 g/kg/day, with AG replacing 1/3 of Clinisol AA). The amount of GLN dipeptide administered each day will be determined by daily PN volume intake data.

DRUG

15% Clinisol

Subjects randomized to STD-PN will receive 1.5 g/kg/day of 15% Clinisol. The amount of Clinisol administered each day will be determined by daily PN volume intake data.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  collaborator NIH

• Emory University

  lead OTHER

Principal Investigators

• Thomas R Ziegler, MD · Emory University

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

90 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2006-09-30

Primary Completion

2012-12-31

Completion

2012-12-31

Countries

• United States

Study Locations