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. Our 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). We 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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Condition	Intervention	Phase
Critical Illness	Drug: Glutamine dipeptide	Phase III

Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcomes: Hospital mortality; % of patients who do not develop nosocomial infections after entry
Secondary Outcomes: Immune cell function; Blood cytoprotective molecules (glutamine, heat shock protein, glutathione); Presence of bacterial products flagellin and LPS in blood
Expected Total Enrollment:  132

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, our 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 P.I.’s 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). We 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. We 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 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 IgM, IgA and IgG immunoglobulins; and c) improves key indices of innate/adaptive immune cell function.

Ages Eligible for Study:  18 Years   -   80 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria: 1) A signed informed consent; 2) Age between 18 and 80 years; 3) Weight < 150 kg; 4) Patient currently requires SICU care and is between 2 to 4 days following CABG, cardiac valve, vascular (non-neurosurgical), or colonic surgery; 5) Subject is deemed to require central venous PN for approximately 7 subsequent days by the investigative team and the attending physician after entry; 6) Venous access available for administration of the study PN; 7) No evidence of acute, uncontrolled infection on the day of entry or history of clinical sepsis within the 24 hrs prior to entry; 8) No current evidence of active malignancy, significant hepatic dysfunction (total bilirubin > 4.0 mg/dl or more than a 5-fold elevation in serum transaminase concentrations), significant renal dysfunction (evolving acute renal failure or requirement for dialysis therapy), or concomitant burn or trauma injury; 9) no history of seizures or a pre-existing seizure disorder; 10) Primary physician(s) willing to allow investigative team to primarily manage study PN and enteral feedings during the current hospitalization.

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Exclusion Criteria: 1) Patient, family or primary physician requests withdrawal from study; 2) Inability to initiate the study PN between 2-4 days postoperatively; 3) Inability or unwillingness to participate in certain study procedures at entry (e.g. GCRC visits, blood draws);

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Please refer to this study by ClinicalTrials.gov identifier  NCT00248638

Thomas R. Ziegler, MD      404-727-7351    tzieg01@emory.edu

Colorado
      University of Colorado Health Sciences Center, Denver,  Colorado,  80262,  United States
Georgia
      Emory University, Atlanta,  Georgia,  30322,  United States
Rhode Island
      The Miriam Hospital/Brown University, Providence,  Rhode Island,  02906,  United States
Tennessee
      Vanderbilt University, Nashville,  Tennessee,  37212-2713,  United States

Study chairs or principal investigators

Thomas R Ziegler, MD,  Principal Investigator,  Emory University   

Study ID Numbers:  DK69322
Last Updated:  December 8, 2005
Record first received:  November 3, 2005
ClinicalTrials.gov Identifier:  NCT00248638
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2006-01-10