CI: Supplemental Intravenous Glutamine (2011)


Déchelotte P, Hasselmann M, Cynober L, Allaouchiche B, Coëffier M, Hecketsweiler B, Merle V, Mazerolles M, Samba D, Guillou YM, Petit J, Mansoor O, Colas G,Cohendy R, Barnoud D, Czernichow P, Bleichner G. L-alanyl-L-glutamine dipeptide-supplemented total parenteral nutrition reduces infectious complications and glucose intolerance in critically ill patients: The French controlled, randomized, double-blind, multicenter study. Crit Care Med. 2006 Mar; 34(3): 598-604.

PubMed ID: 16505644
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 evaluate the effect of glutamine (GLN) dipeptide-supplemented total parenteral nutrition (TPN) on clinical outcome in critically ill patients.

Inclusion Criteria:
  • 18 years old or older
  • Admitted to intensive care unit (ICU) between January 1996 and December 2000
  • Required TPN for at least five days due to contraindication for or failure of enteral nutrition
  • One of the following:
    • Therapeutic intervention scoring system (TISS) score of 16 or more
    • Injury severity score of 10 or more (for multiple trauma patients)
    • Simplified acute physiology score II (SAPS II) of 22 or more (for patients with complications after surgery or pancreatitis).
Exclusion Criteria:
  • Malnutrition
  • Severe obesity (body mass index less than 18.5 or more than 35kg/m2)
  • Pregnancy or lactation
  • Persistent hemodynamic failure (systolic blood pressure less than 80mm Hg)
  • Renal insufficiency (serum creatinine level 250μmol per L or more)
  • Hepatic failure (prothrombin time more than 23.7 seconds and hepatic encephalopathy)
  • Severe or uncontrolled sepsis
  • Persistent metabolic acidosis
  • Hypertriglyceridemia (more than three N)
  • Head trauma (Glasgow score less than five at admission)
  • Steroid therapy (more than 0.3mg per kg per day)
  • Immunosuppressive therapy or constitutive immune deficiency
  • Human immunodeficiency virus infection
  • Enrollment in another study
  • Life expectancy less than seven days.
Description of Study Protocol:


Eligible patients were recruited from the intensive care units of 16 centers.


Prospective, double-blind, controlled, randomized trial.

Blinding Used

  • Treatments were randomly assigned to patient numbers at each study site
  • Patients were randomized on a 1:1 basis, by means of a computer program (SAS, Chicago)
  • Randomization envelopes were held by the pharmacist and were assigned in strict chronological ascending order within each treatment group
  • alanyl-glutamine (Ala-GLN) and alanine (Ala) and proline (Pro) containing TPN were labeled identically
  • Patients, investigators, coworkers were unaware of treatment allocation and remained blinded to treatment allocation until final statistical evaluation was completed.


Isocaloric isonitrogenous TPN via a central venous catheter providing 37kcal per kg per day and 1.5g amino acids per kg per day (0.35g N per kg per day) supplemented with either:

  • L-alanyl-L-glutamine dipeptide (0.5g per kg per day) Ala-Gln group
  • L-alanine and L-proline (0.7g per kg per day) control group.

Statistical Analysis

  • Performed by intention to treat (ITT) and per protocol with use of BMDP program 7.0 (University of California Press, Berkeley, CA)
  • Patients with less than four days of TPN were not eligible for efficacy evaluation
  • Quantitative variables were analyzed with Student's T-test if criteria were normally distributed in each group and comparable variances between both groups were met
  • Non-parametric Mann-Whitney test was used for variables that did not meet the requirements for analysis by the Student's T-test
  • For repeated assessments, repeated-measures analysis of variance (ANOVA) was used
  • Qualitative variables were compared with chi-square tests and Yates correction if necessary
  • Statistical significance with P < 0.05
  • No correction for multiple testing was performed for secondary efficacy and tolerance outcomes
Data Collection Summary:

Timing of Measurements

  • Day one, three and six of TPN (laboratory values)
  • Duration of TPN feeding (major complications)
  • Six-months after initiation of TPN (six-month mortality)
  • Duration of ICU and hospital stay (LOS).

Dependent Variables

  • Occurrence of a major complication over the duration of the TPN feeding
    • Nosocomial infection
    • Wound infection
    • Days on mechanical ventilation
  • ICU and total hospital length of stay (LOS)
  • Six-month mortality rate
  • Transthyretin (TTR)
  • Retinol binding protein (RBP)
  • Albumin
  • α-1 acid glycoprotein (AGP)
  • C-reactive protein (CRP)
  • Prognostic inflammatory and nutritional index
  • Daily diuresis
  • Urinary nitrogen content
  • Nitrogen balance
  • Urinary 3-methylhistidine
  • Creatinine
  • Plasma amino acid profile.

Independent Variables

  • Ala-GLN supplemented TPN
  • Ala + Pro supplemented TPN.
Description of Actual Data Sample:

Initial N

114 patients randomized (analyzed by intention to treat).

Attrition (final N)

  • 104 patients (analyzed per protocol)
  • 100 patients (completed study).


  • Ala-GLN group: 51.0±17.9 years
  • Control group: 54.7±18.9 years.

Other Relevant Demographics:

  • Ala-GLN group:
    • 41 men (70.7%), 17 women (29.3%)
    • TISS = 25 (16 to 51)
    • Multiple trauma (N=17)
      • TISS = 30 (20 to 51)
      • ISS = 43 (22 to 75)
    • Complications post-surgery (N=34)
      • TISS = 24 (16 to 32)
      • SAPS II = 29 (22 to 37)
    • Pancreatitis (N=7)
      • TISS = 20 (17 to 30)
      • SAPS II = 28 (25 to 37)
  • Control group:
    • 43 men (76.8%), 13 women (23.2%)
    • TISS = 25 (16 to 43)
    • Multiple trauma (N=21)
      • TISS = 25 (19 to 35)
      • ISS = 39 (17 to 75)
    • Complications post-surgery (N=31)
      • TISS = 27 (18 to 43)
      • SAPS II = 30 (22 to 43)
    • Pancreatitis (N=4)
      • TISS = 18 (16 to 19)
      • SAPS II = 26 (19 to 45).


  • Ala-GLN group:
    • Weight (kg) = 69.5±13.4
    • Body Mass Index = 24.5±4.3
  • Control group:
    • Weight (kg) = 74.7±13.9
    • Body Mass Index = 25.5±3.7.


  • 16 hospitals in France.
Summary of Results:

Key Findings

Variable (intent-to-treat analysis) Control Group GLN Group P-Value
Nosocomial infections (number per patient) 0.71 0.45 P<0.05
Death at six months [N (%)] 9 (16%) 16 (27%) NS
ICU length of stay (days) 11.5 12.5 NS
Hospital length of stay (days) 26 30 NS
Mechanical ventilator (days) 5 2 NS


  • Proportion of patients with a complicated clinical outcome was significantly lower among those receiving Ala-GLN than among the control group :
    • 41% (95% CI: 29% to 54%) vs. 61% (95% CI: 48% to 74%), P<0.05 in ITT analysis
    • 39% (CI: 25% to 52%) vs. 64% (CI: 50% to 77%), P<0.02 in per protocol analysis
  • Patients receiving Ala-GLN had fewer nosocomial infections
    • P<0.06 in ITT
    • P<0.02 in per protocol analysis
    • Decrease in nosocomial infections related primarily to decrease in incidence of pneumonia (P<0.05)
    • Indicative post hoc observation of each sub-group (multiple trauma, complications after surgery, pancreatitis) showed that nosocomial infections were markedly reduced in multiple trauma patients receiving Ala-GLN [Eight of 17 patients (47.1%) vs. 17 of 21 patients (81%) in the control group; P<0.05]
  • Number of episodes of nosocomial infection per patient was lower in the Ala-GLN treated group than in the control group
  • Number of adverse events per patient was significantly lower in the Ala-GLN group (2.0 vs. 2.8; P<0.01)
  • Number of patients with hyperglycemia was significantly lower in the Ala-GLN group (20 patients) vs. the control group (30 patients), P<0.05
    • Number of patients requiring insulin to treat the hyperglycemia was lower in the Ala-GLN group (14 patients) vs. the control group (22 patients), P<0.05
  • 3-methylhistidine/creatinine ratio remained stable in the Ala-GLN group but decreased in the control group, P<0.05
  • Total plasma amino acids increased in both groups but increase more markedly in the control group, P < 0.01; the increase was mainly in relation to the plasma accumulation of proline, P<0.01

Other Findings

  • No significant difference between groups for
    • Supply of amino acids, carbohydrates and lipids
    • Duration of TPN
    • Wound healing alterations and death during the study period
    • Number of deaths over six months
    • Overall incidence of infections other than nosocomial infections
    • Days of mechanical ventilation
    • TISS value over time
    • Median LOS in the ICU
    • Median LOS in the hospital
    • the following nutritional, inflammatory and biochemical markers and plasma amino acid concentrations:
      • PINI
      • CRP
      • TTR
      • RBP
      • Nitrogen balance
      • Glutamine
      • Alanine
      • Glutamic acid
      • Arginine
      • Citrulline
      • Ornithine.
Author Conclusion:
  • In this multicenter, prospective, double-blind trial, GLN dipeptide-supplemented TPN reduces the clinical complications of critically ill patients, mainly through a lower incidence of pneumonia, and better metabolic tolerance. Results of the per protocol analysis were in agreement with those of the intention to treat analysis.
Funding Source:
Fresenius Kabi France
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:
  • Overall well-designed and conducted trial
  • Author's conclusions seem overstated considering that only three of nine clinical outcome measures (including one of five types of infectious episodes and two of five types of metabolic and nutritional disorders) were statistically significant between the groups.
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%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  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? No
  6.6. Were extra or unplanned treatments described? No
  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? No
  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