Efficacy and Mechanisms of GLN Dipeptide in the SICU
Condition: Critical Illness
MeSH terms: Critical Illness
Study type: Interventional
Phase: Phase 3

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.

      .
    

Detailed description: 
      Overview: Relative deficiency of glutamine (GLN) appears to contribute to morbidity and
      mortality in surgical intensive care unit (SICU) patients, but conventional nutrition support
      does not repair this deficit. GLN requirements increase during critical illness when
      utilization by the immune system, gut mucosa and other tissues exceeds endogenous production.
      GLN depletion under these conditions may contribute to hospital morbidity and mortality.
      Conventional parenteral nutrition (PN) does not contain GLN and thus does not prevent GLN
      depletion in catabolic patients. However, a pilot study and other reports strongly suggest
      that GLN-supplemented PN improves metabolic and clinical outcomes in critically ill patients.
      Underlying mechanisms for GLN action are poorly understood, but may involve systemic
      upregulation of the cytoprotective molecules glutathione (GSH), specific heat shock proteins
      (HSP) and GLN itself, improved gut barrier defenses, and improved innate and/or adaptive
      immune function. Properties of L-GLN limit provision in PN, but the dipeptide
      alanyl-glutamine (AG) confers stability and solubility in PN solutions. The pilot study
      demonstrated a marked decrease in nosocomial infection, improved indices of organ function,
      and a possible decrease in hospital mortality in SICU patients receiving AG-supplemented PN
      (AG-PN) versus standard, GLN-free PN (STD-PN). Investigators propose a multi-center,
      double-blind, controlled, Phase III trial, based on a pilot study, that will determine the
      effect of parenteral GLN on important clinical outcomes in patients requiring SICU care and
      PN after cardiac, vascular or colonic surgery. Investigators also propose to obtain needed
      hypothesis-generating, descriptive data from the Aim 1 study subjects to inform subsequent,
      truly mechanistic studies of GLN action in animal and human models of surgical critical
      illness. Study subjects will be randomized on an intent-to-treat basis to receive AG-PN or
      isonitrogenous, isocaloric STD-PN until enteral feeding is established.

      Hypotheses:

        1. SICU patients receiving PN supplemented with GLN dipeptide (AG-PN) will demonstrate
           improved clinical outcomes compared to patients receiving STD-PN.

        2. Administration of AG-PN in the Aim 1 study subjects: a) increases serial blood levels of
           specific cytoprotective molecules and improves systemic redox status; b) is associated
           with decreased serum positivity for the bacterial products flagellin and
           lipopolysaccharide ( LPS) and the adaptive immune response to these mediators; and c)
           improves key indices of innate/adaptive immunity.

      Specific Aims:

      Aim 1: To perform a Phase III randomized controlled trial (RCT) to determine whether AG-PN
      decreases hospital mortality, nosocomial infections, and other indices of hospital morbidity
      versus STD-PN in SICU patients. The study will test whether AG-PN: decreases hospital
      mortality and the incidence of nosocomial infection (primary endpoints) in SICU patients
      after cardiac, vascular or colonic surgery. We will also determine whether AG-PN decreases
      total hospital infections, bloodstream infections (BSI), infections due to Staphylococcus
      aureus or fungal species, the number of days patients require mechanical ventilation, the
      SICU and total hospital length of stay and the 6-month mortality rate (secondary endpoints).

      Aim 2: To determine in the Aim 1 study subjects whether AG-PN: a) increases systemic blood
      concentrations of the cytoprotective molecules GSH, HSP-70, HSP-27 and GLN and improves
      systemic GSH and cysteine redox status; b) is associated with decreased serum positivity for
      the bacterial products flagellin and LPS and titers of anti-flagellin and anti-LPS
      immunoglobulin M (IgM), immunoglobulin A (IgA) and immunoglobulin G (IgG); and c) improves
      key indices of innate/adaptive immune cell function.
    

Intervention name(s): Glutamine dipeptide with 15% Clinisol; 15% Clinisol
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Other intervention name(s): Alanyl-glutamine Dipeptide; Dipeptiven
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment