CI: Supplemental Intravenous Glutamine (2011)


Fuentes-Orozco C, Cervantes-Guevara G, Muciño-Hernández I, López-Ortega A,Ambriz-González G, Gutiérrez-de-la-Rosa JL, Gómez-Herrera E, Hermosillo-Sandoval JM, González-Ojeda A. L-alanyl-L-glutamine-supplemented parenteral nutrition decreases infectious morbidity rate in patients with severe acute pancreatitis. J Parenter Enteral Nutr. 2008 Jul-Aug; 32 (4): 403-411.

PubMed ID: 18596311
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
  • To determine whether the early administration (within the first 48 hours of the onset of severe acute pancreatitis) of parenteral L-alanyl-L-glutamine improves nutrition status and immune function in patients with acute pancreatitis
  • To determine the ability of the early administration (within the first 48 hours of the onset of severe acute pancreatitis) of parenteral L-alanyl-L-glutamine to reduce morbidity, mortality and the duration of hospital stay in patients with acute pancreatitis.
Inclusion Criteria:
  • Admitted to intensive care unit (ICU) with acute pancreatitis determined by:
    • Increase in serum amylase concentrations to a level three-fold greater than basal levels 
    • Abdominal pain and findings typical of acute pancreatitis upon abdominal ultrasound or computed tomography (CT).
Exclusion Criteria:
  • Renal failure (creatinine>180mol/L)
  • Hepatic failure (bilirubin>40mol/L, alanine aminotransferase [ALT]>100U/L, aspartate aminotransferase [AST]>100U/L)
  • Severe neutropenia (<500 cells/mm3)
  • Receiving cytotoxic, radiation or steroid therapy
  • Hemodynamic instability resistant to aggressive fluid resuscitation
  • Received nutrition support or surgical treatment before admittance.
Description of Study Protocol:


All patients admitted to intensive care unit (ICU) between April 2003 and October 2005 who met inclusion criteria were asked to participate and provide informed consent.


Randomized, controlled trial utilizing two treatment groups

Blinding used

  • Double-blind
  • Enrolled patients received a serial number allocated in ascending order of enrollment
  • Based on number, patients were assigned to one of the study groups
  • Patient number appeared on patient's prescription and was used to prepare all-in-one bag for patient
  • All investigators involved with analysis, patients and relatives of patients were blinded to randomization until 10-day follow-up had been completed for all subjects.


  • Standard parenteral nutrition (PN)
    • Supplied 30kcal per kg per day
    • Non-protein calories derived from carbohydrates (50% hypertonic glucose) and lipids (20% fatty acids) in ratio of 60:40
    • Protein calories derived from amino acids (8.5%; 1.5g per kg per day)
  • L-alanyl-L-glutamine (GLN) supplemented parenteral nutrition (PN)
    • Supplied 30kcal per kg per day
    • Non-protein calories derived from carbohydrates (50% hypertonic glucose) and lipids (20% fatty acids) in ratio of 60:40
    • Protein calories derived from amino acids (8.5%; 1.1g per kg per day)
    • GLN provided at 0.40g per kg per day for total protein of 1.5g per kg per day
  • PN formulas were isonitrogenous and isocaloric
  • PN commenced between 24 and 48 hours after admittance to ICU
  • Adjusted body weight considered for caloric estimations
  • PN initially infused at 80% of calculated energy requirements then increased over 48 hours to achieve 100% of target energy rate
  • PN continued until death or as long as clinically required (normal diet or full enteral nutrition)
  • Clinicians allowed to adjust total volume of PN delivered and amount of water and electrolytes administered on daily basis as judged clinically appropriate
  • All patients received IV crystalline insulin according to serum or capillary glucose levels.

Statistical Analysis

  • Comparison between normally distributed means assessed using ANOVA or unpaired Student's T-test
  • Comparison between data that was not normally distributed assessed using Mann-Whitney U test
  • Qualitative values expressed as proportions; comparison between proportions assessed using Χ2 test or Fisher's exact test
  • Analysis performed using SPSS (release 10.0 for Windows; SPSS Inc., Chicago, IL)
  • P value<0.05 considered significant
  • To evaluate effectiveness of GLN-supplemented PN in preventing deaths, the absolute risk reduction, the relative risk reduction, and the necessary number of patients to treat to prevent a death were calculated.
Data Collection Summary:

Timing of Measurements

  • Hematology and biochemistry measurements
    • Baseline
    • Protocol day five
    • Protocol day 10.

Dependent Variables

  • Primary efficacy variables
    • Infectious morbidity (including intra abdominal and extra-abdominal infections)
    • Nitrogen Balance
    • Leukocytes
    • Counts of leukocytes
    • Lymphocytes
    • CD4 and CD8 sub-populations
    • Immunoglobulin A (IgA)
    • Total protein
    • Albumin
    • C-reactive protein
    • Interleukin-IL-6
    • IL-10
    • Systemic inflammatory response syndrome
    • Sepsis
    • Septic shock
    • Multiple organ failure syndrome
  • Secondary efficacy parameters
    • Duration of hospital stay
    • Duration of ICU stay
    • Duration of ventilatory support
    • Incidence of mortality.

Independent Variables

  • PN formula 
    • Standard parenteral nutrition
    • L-alanyl-L-glutamine supplemented parenteral nutrition.

Control Variables

  • Control and GLN PN formulas were isocaloric and isonitrogenous
  • All patients managed with gastric drainage through nasogastric tube
  • All patients received treatment with proton pump inhibitors (40mg per day omeprazole)
  • Prophylactic antibiotic treatment with IV imipenem and cilastin at doses of 500mg each were administered every eight hours after presence of pancreatic necrosis was established using contrast-enhanced CT scanning.


Description of Actual Data Sample:
  • Initial N: 44 subjects
    • 22 in GLN supplemented PN group
    • 22 in control PN group
  • Attrition (final N): All participants were accounted for at end of study period
  • Age:
    • GLN supplemented group
      • 43.8±14.4 years (mean±SD)
    • Control group
      • 41.5±14.2 years
  • Ethnicity: Not provided
  • Other relevant demographics:
    • GLN supplemented group
      • 12 men (54.5%); 10 women APACHE II score=10.3±1.6
      • CT severity index=7.0±1.9
      • Etiology
        • Biliary=13
        • Alcohol=6
        • Other etiologies=3
    • Control group
      • 12 men (54.5%); 10 women
      • APACHE II score=10.7±1.9
      • CT severity index=7.1±1.8
      • Etiology
        • Biliary=16
        • Alcohol=4
        • Other etiologies=2
  • Anthropometrics:
    • GLN supplemented group
      • Weight (kg)=72.3±9.4
      • BMI=26.4±2.68
    • Control group
      • Weight (kg)=70.5±13.6
      • BMI=26.69±5.35
  • Location: Western Medical Center, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico.
Summary of Results:

Key Findings


Control Group (N=22)(mean±SD)

GLN Group (N=22) (mean±SD)


Mortality 5/22 (22.7%) 2/22 (9%) P=0.20
Infectious Complications    16/22 (72.7%)  9/22 (40.9%)  P=0.03
ICU LOS (days)  11.14±7.41  11±11.7  P=0.97
Hospital LOS (days)   26.59±13.3  30.18±10.42  P=0.31
Ventilator Days   9.23±6.45  8.27±6.45  P=0.62

Leukocytes (109/L) 

 14.87±4.88  11.43±6.18  0.04

Lymphocytes (mm3) 

 1,063±638  1,408.36±433  0.04

Lymphocytes CD4 (mm3)

 570±366.2  791.41±314.72  0.03
Lymphocytes CD8 (mm3)   365.77±170.88  526.59±293.11  0.03
C-reactive protein (g/dL)   95.27±60.9  52.04±31.9  0.005
IL-6 (pg/mL)   113.62±80.78  65.90±64.08  0.03
IL-10 (pg/mL)   32.57±19.75  50.62±30.12  0.02
IgA (mg/dL)   321.41±159  407.27±114.33  0.01
Proteins (g/L)   5.7±1.19  6.39±1.0  0.03
Albumin (g/L)   2.31±0.62  2.69±0.51  0.01
Nitrogen balance (g)   -2.06±5.0  3.4±3.17  0.04

Other Findings

No significant differences between groups for calories per day, protein per day or nitrogen per day.


Author Conclusion:
  • Parenteral GLN dipeptide supplementation decreases the incidence of infectious complications in patients with acute pancreatitis
  • Parenteral GLN dipeptide supplementation did not impact mortality in patients with acute pancreatitis.
Funding Source:
Other: No financial support information provided.
Reviewer Comments:
  • Overall well-conducted study
  • Relatively small number of subjects in control and intervention groups
  • Inclusion criteria scattered throughout article including results and discussion sections making exact inclusion criteria difficult to determine.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? ???
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? Yes