CI: Supplemental Intravenous Glutamine (2011)


Ziegler TR, Ogden LG, Singleton KD, Luo M, Fernandez-Estivariz C, Griffith DP,Galloway JR, Wischmeyer PE. Parenteral glutamine increases serum heat shock protein 70 in critically ill patients. Intensive Care Med. 2005 Aug; 31 (8): 1,079-1,086. Epub 2005 Jun 23.

PubMed ID: 15973519
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 examine whether IV GLN as a component of PN supports increased serum heat shock protein 70 (HSP-70) levels in critically ill adults admitted to a SICU
  • To determine the relationship between serum HSP-70 responses and important clinical outcomes in these individuals.
Inclusion Criteria:
  • Signed informed consent
  • Age 18-80 years
  • Surgical intensive care unit (SICU) care required after pancreatic, coronary artery bypass grafting (CABG), cardiac valve, non-neurological vascular, or colonic surgery
  • Subject without evidence of acute, uncontrolled infection or history of clinical sepsis in previous 24 hours
  • No evidence of active malignancy, significant hepatic dysfunction (total bilirubin >4.0mg/dl or more than five-fold elevation in serum transaminase concentrations) or significant renal dysfunction (evolving acute renal failure or on dialysis).
Exclusion Criteria:
  • Study PN not given for five or more consecutive days after initiation
  • Evidence of developing hepatic failure.
Description of Study Protocol:


Subjects were postoperative patients requiring admission to a surgical intensive care unit (SICU) necessitating PN at Emory University Hospital (EUH) and were selected based on the availability of serum for analysis for HSP-70.


Randomized, controlled, double-blind study

Blinding used

Double-blind analysis


  • Control subjects received standard, Gln-free PN for seven days or more
    • Given at a daily does of 1.5 grams per kg
  • Experimental subjects received isocaloric isonitrogenous, Gln dipeptide-supplemented PN for seven days or more
    • Containing 0.5g per kg per day L-alanyl-L-Gln dipeptide
    • Provides 23g L-Gln daily for a 70kg subject
  • Feeding goals for both groups:
    • Total daily calorie intake of 1.3 x basal energy expenditure (predicted by the Harris-Benedict equation) from PN plus enteral intake
    • Total daily amino acid/protein intake of 1.5mg/kg
    • PN dextrose comprised 70% of PN non-AA kilocalories and fat emulsion and 30% of PN non-AA kilocalories.

Statistical Analysis

  • T-tests
  • Pearson's X2 tests
  • Spearman's rank correlation coefficients.
Data Collection Summary:

Timing of Measurements

  • Blood for serum creatinine and bilirubin levels was drawn at enrollment and several times weekly
  • After enrollment blood was also drawn in the morning between 0800 and 1000 hours for baseline plasma Gln levels, C-reactive protein, and HSP-70 concentrations
  • Seven days after entry, blood was drawn again for assessment of plasma Gln levels, C-reactive protein, and HSP-70 concentrations.

Dependent Variables

  • Hospital and intensive care unit (ICU) length of stay
  • Days on mechanical ventilation 
  • Serum HSP-70 levels.

Independent Variable

GLN dipeptide-supplemented PN

Control Variables

Standard, GLN-free PN

Description of Actual Data Sample:
  • Initial N:
    • 59 (male=40; female); 68% male
    • 29 (male=19; female; 65% male) of the original study group were randomly selected for additional serum analysis for HSP-70
  • Attrition (final N): Zero (59)
  • Age: 53-60 years
    • HSP-70 subgroup
      • Gln-PN group: 53.2±3.9
      • Control-PN group: 52.4±3.8
    • Overall group
      • Gln-Pn group: 56±3
      • Control-PN group: 57±3
  • Ethnicity: Not specified
  • Other relevant demographics:
    • GLN-PN and control-PN groups were well-matched at study entry with respect to age, serum CRP concentration, body mass index, and hospital day at entry to study
    • There were no significant differences in the type of surgery between groups and the APACHE II scores were nearly identical
    • There were no differences with regard to the average number of days PN was provided, intravenous total and protein calories or enteral intake
  • Anthropometrics: There were no significant differences in body mass index between the GLN-PN and control-PN groups
  • Location: Surgical intensive care unit (SICU), Emory University Hospital, Atlanta, Georgia.


Summary of Results:

Key Findings

Variables GLN-PN Group
Median (IQR)
Control-PN Group
Median (IQR)
Statistical Significance of Group Difference
Hospital length of stay 29.7
Intensive care length of stay 15.7 
Days on mechanical ventilation 11.1 
Serum HSP-70 levels in ng/ml (seven-day HSP/baseline HSP) 6.91



Author Conclusion:

These data indicate that PN supplemented with alanyl-Gln dipeptide at a daily dose of 0.5mg/kg can increase serum concentrations of HSP-70 after seven days in critically ill patients. The data indicate that Gln-mediated increases in HSP-70 over baseline levels are significantly correlated with decreased ICU length stay and days on mechanical ventilation.

Funding Source:
Government: National Institutes of Health; General Clinical Research Center
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:
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) N/A
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? N/A
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? N/A
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
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? Yes
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? Yes
  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.) Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? Yes
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%.) Yes
  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? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
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? N/A
  6.6. Were extra or unplanned treatments described? N/A
  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? Yes
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)? ???
  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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes