Efficacy and Mechanisms of GLN Dipeptide in the SICU
Condition: Critical Illness
MeSH terms: Critical Illness
Intervention: Glutamine dipeptide with 15% Clinisol; 15% Clinisol
Intervention description: 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.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 150.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No

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.

      .
    

Eligibility criteria:

        Inclusion criteria: 1) A signed informed consent is in place on the patient's chart; 2) The
        patient is at least 18 but not more than 90 years of age at time of surgery; 3) The patient
        has a body mass index (BMI) < 40 kg/m2 prior to surgery; 4) The patient currently requires
        SICU care and is within 14 days postoperative from one of the following open
        (non-laparoscopic) surgical procedures: coronary artery bypass graft(CABG), cardiac valve,
        vascular (non-neurosurgical), or esophageal gastrointestinal resection of esophagus,
        stomach, small bowel, colon and/or rectum), or operation to identify the source of
        peritonitis when there is evidence of a bowel perforation (with or without bowel
        resection); 5) The patient will require central venous PN for 7+ subsequent days after
        entry on a clinical basis≠; 6) There is central venous access for administration of the
        study PN; and 7) The patient's primary physician(s) will allow the investigative team to
        manage the study PN and enteral feedings during the current hospitalization.

        Exclusion Criteria: 1) The patient is pregnant; 2) The patient has clinical sepsis [defined
        as unstable blood pressure despite pressor support AND mean arterial pressure (MAP) < 60 mm
        Hg on at least 3 consecutive readings within a 3-hour period during the 24 hours prior to
        study entry; 3) a) The patient has a current malignancy requiring surgery as the GLND
        qualifying operation OR b) the patient is currently receiving an active regimen of
        chemotherapy and/or radiotherapy to treat a previously diagnosed malignancy†; 4) The
        patient has a history of seizures or pre-existing seizure disorder; 5) The patient has a
        current encephalopathy*; 6) The patient has a known history of cirrhosis OR a serum total
        bilirubin level ≥ 10.0 mg/dL); 7) The patient has a history of chronic renal failure
        requiring dialysis, or has significant renal dysfunction (defined as serum creatinine > 2.5
        mg/dL and is not receiving continuous renal replacement therapy (CRRT) or the patient
        requires acute hemodialysis postoperatively; 8) The patient has a concomitant burn or
        trauma injury; 9) The patient has previously undergone an organ transplantation;10) the
        patient has a history of HIV/AIDS; 11) The patient has received any investigational drug
        within 60 days prior to study entry; 12) The patient has received enteral or parenteral
        enteral feedings enriched in arginine and/or glutamine within 30 days prior to study entry;
        and 13) The patient is unable or unwilling to participate in study procedures such as
        longitudinal blood draws and out patient follow-up visits, etc.

        *Encephalopathy for GLND can be diagnosed only in non-chemically sedated patients by the
        primary critical care physicians or neurologist consultants and is defined as either a
        comatose state OR severe abnormalities diagnosed by electroencephalogram (EEG), OR if all
        of the following criteria are met: a) patient goes to sleep but is arousable to verbal and
        painful stimuli; does not open eyes spontaneously (decreased level of consciousness); b)
        patient exhibits severe confusion or complete disorientation when aroused (disorientation);
        c) patient exhibits severe lethargy or bizarre behavior (behavioral dysfunction); and d)
        patient exhibits inability to cooperate, asterixis, ataxia, clonus, decortication,
        decerebration, seizures, or rigidity (severe neuromuscular dysfunction).

        † Patients with malignant metastasis and terminal untreatable carcinoma will be excluded as
        per the operational definition agreed upon by the Data Safety and Monitoring Board (DSMB).

        ≠ Please note that the patient should be in the SICU at the initial PN hang time.