Critical Illness
Conditions
Brief 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.
Interventions
DRUGGlutamine 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.
DRUG15% 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
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hospital Mortality Rate | Current Hospitalization (Up to 6 Months) | Number of participants who died during hospitalization. |
| Percentage of Patients Who do Not Develop Hospital Infections | Current Hospitalization (Up to 6 Months) | Subjects remaining infection-free during the hospitalization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Glutathione Level | Baseline, Day 3, Day 7, Day 14, Day 21, Day 28 | Glutathione (GSH) levels will be measured in µM (micro moles) from baseline to day 28. Higher levels indicate a higher GSH presence. |
| Mean Heat Shock Proteins Level, HSP70 | Baseline, Day 3, Day 7, Day 14, Day 21, Day 28 | Levels of the heat shock protein,HSP70, will be measured in ng/mL from baseline to day 28. Higher levels indicate a higher protein presence. |
| Mean Heat Shock Proteins Level, HSP27 | Baseline, Day 3, Day 7, Day 14, Day 21, Day 28 | Levels of the heat shock protein, HSP27, will be measured in pg/mL from baseline to day 28. Higher levels indicate a higher protein presence. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Glutamine Dipeptide Glutamine dipeptide supplemented nutrition to be given to participants. | 75 |
| Standard Participants given standard nutrition without glutamine dipeptide | 75 |
| Total | 150 |
Baseline characteristics
| Characteristic | Standard | Glutamine Dipeptide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 32 Participants | 57 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants | 43 Participants | 93 Participants |
| Age, Continuous | 60.4 years STANDARD_DEVIATION 13 | 60.2 years STANDARD_DEVIATION 13.6 | 60.3 years STANDARD_DEVIATION 13.2 |
| Region of Enrollment United States | 75 participants | 75 participants | 150 participants |
| Sex: Female, Male Female | 30 Participants | 40 Participants | 70 Participants |
| Sex: Female, Male Male | 45 Participants | 35 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 75 | 13 / 75 |
| other Total, other adverse events | 22 / 75 | 12 / 75 |
| serious Total, serious adverse events | 39 / 75 | 40 / 75 |
Outcome results
Primary
Hospital Mortality Rate
Number of participants who died during hospitalization.
Time frame: Current Hospitalization (Up to 6 Months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glutamine Dipeptide | Hospital Mortality Rate | 11 participants |
| Standard | Hospital Mortality Rate | 13 participants |
Primary
Percentage of Patients Who do Not Develop Hospital Infections
Subjects remaining infection-free during the hospitalization.
Time frame: Current Hospitalization (Up to 6 Months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glutamine Dipeptide | Percentage of Patients Who do Not Develop Hospital Infections | 56 percentage of participants |
| Standard | Percentage of Patients Who do Not Develop Hospital Infections | 69 percentage of participants |
Secondary
Mean Glutathione Level
Glutathione (GSH) levels will be measured in µM (micro moles) from baseline to day 28. Higher levels indicate a higher GSH presence.
Time frame: Baseline, Day 3, Day 7, Day 14, Day 21, Day 28
Population: The number of participants currently hospitalized are included in each time point analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glutamine Dipeptide | Mean Glutathione Level | Baseline | 1.850 µM | Standard Deviation 0.195 |
| Glutamine Dipeptide | Mean Glutathione Level | Day 3 | 1.524 µM | Standard Deviation 0.156 |
| Glutamine Dipeptide | Mean Glutathione Level | Day 7 | 5.056 µM | Standard Deviation 3.619 |
| Glutamine Dipeptide | Mean Glutathione Level | Day 14 | 1.312 µM | Standard Deviation 0.22 |
| Glutamine Dipeptide | Mean Glutathione Level | Day 21 | 1.286 µM | Standard Deviation 0.266 |
| Glutamine Dipeptide | Mean Glutathione Level | Day 28 | 1.279 µM | Standard Deviation 0.232 |
| Standard | Mean Glutathione Level | Day 21 | 1.597 µM | Standard Deviation 0.297 |
| Standard | Mean Glutathione Level | Baseline | 1.880 µM | Standard Deviation 0.182 |
| Standard | Mean Glutathione Level | Day 14 | 1.327 µM | Standard Deviation 0.306 |
| Standard | Mean Glutathione Level | Day 3 | 1.374 µM | Standard Deviation 0.162 |
| Standard | Mean Glutathione Level | Day 28 | 1.430 µM | Standard Deviation 0.301 |
| Standard | Mean Glutathione Level | Day 7 | 1.473 µM | Standard Deviation 0.202 |
Secondary
Mean Heat Shock Proteins Level, HSP27
Levels of the heat shock protein, HSP27, will be measured in pg/mL from baseline to day 28. Higher levels indicate a higher protein presence.
Time frame: Baseline, Day 3, Day 7, Day 14, Day 21, Day 28
Population: The number of participants currently hospitalized are included in each time point analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP27 | Baseline | 1171.1 pg/mL | Standard Deviation 70.9 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP27 | Day 3 | 1189.3 pg/mL | Standard Deviation 68.9 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP27 | Day 7 | 1222.4 pg/mL | Standard Deviation 82 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP27 | Day 14 | 1161.0 pg/mL | Standard Deviation 98.7 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP27 | Day 21 | 1314.3 pg/mL | Standard Deviation 119.7 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP27 | Day 28 | 1177.5 pg/mL | Standard Deviation 137.8 |
| Standard | Mean Heat Shock Proteins Level, HSP27 | Day 21 | 1250.9 pg/mL | Standard Deviation 163.2 |
| Standard | Mean Heat Shock Proteins Level, HSP27 | Baseline | 1134.3 pg/mL | Standard Deviation 76 |
| Standard | Mean Heat Shock Proteins Level, HSP27 | Day 14 | 1253.4 pg/mL | Standard Deviation 107.1 |
| Standard | Mean Heat Shock Proteins Level, HSP27 | Day 3 | 1140.0 pg/mL | Standard Deviation 71.1 |
| Standard | Mean Heat Shock Proteins Level, HSP27 | Day 28 | 880.9 pg/mL | Standard Deviation 144.9 |
| Standard | Mean Heat Shock Proteins Level, HSP27 | Day 7 | 1259.0 pg/mL | Standard Deviation 91.5 |
Secondary
Mean Heat Shock Proteins Level, HSP70
Levels of the heat shock protein,HSP70, will be measured in ng/mL from baseline to day 28. Higher levels indicate a higher protein presence.
Time frame: Baseline, Day 3, Day 7, Day 14, Day 21, Day 28
Population: The number of participants currently hospitalized are included in each time point analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP70 | Baseline | 52.6 ng/mL | Standard Deviation 6.2 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP70 | Day 3 | 48.1 ng/mL | Standard Deviation 6 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP70 | Day 7 | 52.1 ng/mL | Standard Deviation 7 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP70 | Day 14 | 33.9 ng/mL | Standard Deviation 4.6 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP70 | Day 21 | 30.7 ng/mL | Standard Deviation 4 |
| Glutamine Dipeptide | Mean Heat Shock Proteins Level, HSP70 | Day 28 | 26.3 ng/mL | Standard Deviation 3.1 |
| Standard | Mean Heat Shock Proteins Level, HSP70 | Day 21 | 32.9 ng/mL | Standard Deviation 6.7 |
| Standard | Mean Heat Shock Proteins Level, HSP70 | Baseline | 55.3 ng/mL | Standard Deviation 8.7 |
| Standard | Mean Heat Shock Proteins Level, HSP70 | Day 14 | 33.9 ng/mL | Standard Deviation 4 |
| Standard | Mean Heat Shock Proteins Level, HSP70 | Day 3 | 44.5 ng/mL | Standard Deviation 5.8 |
| Standard | Mean Heat Shock Proteins Level, HSP70 | Day 28 | 25.5 ng/mL | Standard Deviation 3.7 |
| Standard | Mean Heat Shock Proteins Level, HSP70 | Day 7 | 36.4 ng/mL | Standard Deviation 3.1 |