CI: Supplemental Intravenous Glutamine (2011)


Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition. 1997 Apr; 13 (4): 295-302.

PubMed ID: 9178278
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 test whether the provision of GLN in PN shortens recovery and improves survival in ICU patients who initially are unable to tolerate EN.

Inclusion Criteria:
  • Adult patients (≥16 years)
  • Admitted to a general ICU of a district general hospital
  • Admission Acute Physiological and Chronic Health Evaluation (APACHE) II score of 11 or greater
  • Clinical need to provide nutritional support with an illness expected to be protracted
  • Proven intolerance of enteral feedings over 48 hours or presence of the following contraindications to enteral nutrition:
    • Major intra-abdominal sepsis (peritonitis)
    • Bowel resection
    • Pancreatitis
    • Heavily bile-stained gastric aspirate more than one liter in 24 hours in ventilated patients with major trauma or non-GI sepsis.
Exclusion Criteria:
  • APACHE II score less than 11
  • Age <16 years
  • Pregnancy
  • Clinical severe liver failure
  • Malignant disease unless a satisfactory operative resection had been achieved.


Description of Study Protocol:


Adult subjects admitted to a general ICU of a district general hospital between May 1991 and February 1995 with an admission APACHE II score of 11 or greater and in whom there was a clinical need to provide nutritional support with an illness expected to be protracted.


Prospective, double-blind, block-randomized treatment study

Blinding used

  • Randomization was performed by members of the pharmacy department, who were blinded to the clinical aspects of the study
  • All investigators involved with analysis, the patients and their family members remained blinded until the six month post-ICU follow-up had been completed.


  • PN formulations were isocaloric and isonitrogenous
  • Three-in-one PN formulations were used for both groups with all solutions were matched for energy and nitrogen (isocaloric and isonitrogenous) (15.5 grams protein nitrogen with 2,300 non-nitrogen calories divided 60:40 between glucose and lipid)
    • Same lipid (500mL Eliolipid 20%, Leopold Pharam, Graz, Austria; Oxford Nutrition, Oxford, U.K.)
    • Same carbohydrate (500mL glucose 50%, Baxter Healthcare, Thetford, UK; 500mL glucose 20%, Galen Research Laboratories, Craigavon, U.K.)
    • Same electrolyte, trace minerals and other micronutrients
    • Both amino acid solutions provided more than the recommended daily allowance of all "essential" amino acids and all amino acids (except L-Gln) were more abundant in the control group. Amino acid composition varied between groups as follows:
      • Control group
        • 1,500mL solution-1,000 mL Eloamin 10%, Leopold Pharma-Oxford Nutrition with 500ml sterile water
      • Gln group
        • 1,500mL solution-1,000mL of 2.5% L-Gln solution (25 gram L-Gln) prepared by the hospital sterile production pharmacy was combined with 500mL Eloamin 15% (Leopold Pharma-Oxford Nutrition)
        • The proportions of all other amino acids were reduced to accommodate for the additional Gln in the Gln formulation.

Statistical Analysis

  • SPSS for windows (SPSS Inc., Chicago, IL, USA)
  • Results are presented as medians, ranges and interquartile ranges for non-normally distributed date and as means and standard deviations if confirmed normally distributed
  • Comparisons were made using Mann-Whitney or T-tests if normally distributed
  • Survival analysis was performed using log rank
  • Proportions were tested using Fisher's exact test (chi-square with Yates continuity correction)
  • The relationship of various variables to mortality was examined using multivariate analysis
  • Repeat clinical variables taken in the same patient over a number of days were examined using repeat-measure analysis of variance to test for differences between Gln and the control groups.


Data Collection Summary:

Timing of Measurements

Measurements upon admission to ICU:

  • Age in years
  • Sex
  • Whiston Health Questionnaire (WHQ) pre-morbid health score with completion either by the patient on recovery or prior to that by a close relative
  • Days in hospital prior to feeding
  • Type of admission (emergency medical, emergency surgical, booked surgical)
  • Admission APACHE II score
  • APACHE II risk of death prediction
  • Primary diagnosis was recorded.

Measurements at start of feeding:

  • Plasma glutamine (mmol/L)
  • Serum albumin (g/L) (mean±SD)
  • Mid-arm circumference (cm)
  • Triceps skin-fold thickness (mm)
  • Days from ICU admission to feeding
  • Days with reduced prior nutritional intake (anorexia greater than three and <10 days; anorexia>10 days)
  • Renal support (number of patients)
  • Ventilated (number of patients)
  • Therapeutic Intervention Score System (TISS) score (mean±SD) were recorded daily on all ICU patients during the year one (1993) to determine extent to treatment
  • Whiston Sepsis Score to determine extent of systemic inflammatory response or sepsis.

Measurements during early (days one to five) and late (more than five days) feeding periods:

  • Days fed (range)
  • Total calorie intake per day (including calories from 10% dextrose and 10% lipid propofol)
  • Total parenteral nutrition (TPN) calorie intake per day
  • Nasogastric feeding (NGF) calorie intake per day
  • Nitrogen per day (grams)
  • Glutamine intake per day (grams)
  • Duration feeding greater than five days (range)
  • Other variables:
    • Plasma Gln
    • Plasma albumin
    • Plasma bicarbonate
    • Plasma ammonia
    • Plasma urea
    • Platelet count
    • White cell count
    • Daily TISS score
    • Number of antibiotics
    • Number of inotropes.

Six-months post-ICU discharge:

  • Cause of death was recorded (if occurring within six months of start of feeding), including the organs that failed of cause of death was multiple-organ failure (MOF)
  • Morbidity was assessed by length of stay and from validated, re-worded WHQ form for follow-up.

Dependent Variables

  • Mortality; cause of death determined from hospital records during stay or post-discharge deaths
  • Morbidity as assessed by length of stay and from the re-worded WHQ for follow-up
  • Cost of ICU stay as determined using cumulative daily TISS scores for whole ICU stay
  • Cost of hospital stay as determined based on the hospital's average stay cost of $270 per day.

Independent Variable 

  • PN formula (GLN enriched or control)

Control Variables

  • Nutritional support was continued until death or as long as clinically required (patient able to tolerate a normal diet or full enteral nutrition)
  • Clinicians (who were independent of the investigators) were able to adjust total volumes delivered and the amounts of lipid and electrolytes on a daily basis as judged clinically appropriate using routine laboratory monitoring (whole blood ammonia and plasma clearance of lipids)
  • All nutritional intakes including additional calorie intake in the form of 10% dextrose or 10% lipid-propofol were recorded.
Description of Actual Data Sample:
  • Initial N: 84 (56% male)
  • Attrition (final N): 84 parenterally fed patients met inclusion criteria:
    • 42 to control group
    • 42 to Gln group
  • Age: 
    • GLN-PN 65.5 (22-89)
    • Control 64.5 (22-81)
  • Ethnicity: Not described
  • Other relevant demographics: APACHE II scores for GLN and control groups, respectively: 
    • 18 (11-34)
    • 17 (11-31)
  • Location: Liverpool, UK.
Summary of Results:

 Key Findings

Variable GLN PN (N=42) Control PN (N=42) P-Value
Death by six months 18/42 (43%) 28/42 (67%) 0.049

Cost of Intensive Care and Hospital Stay

  • There was a 25% reduction in total cost of ICU care and 15% reduction in total cost of hospital care for all patients receiving GLN
    • When expressed as cost to produce a survivor at six months, then GLN supplementation reduced cost by 50% over the control group
  • The average number of days of ICU time consumed to achieve a survivor was 25 days for the GLN group vs. 48 days for control; this was due to a reduction in number of late ICU deaths among the GLN group and is important for efficient use of ICU beds.
Author Conclusion:

The authors concluded that in critically ill ICU patients unable to receive enteral feeding, a glutamine-supplemented parenteral feeding will improve the six-month survival, resulting in a more efficient use of ICU resources and a reduction in the cost per survivor. Glutamine should be a constituent of parenteral feeding for severely ill ICU patients.

Funding Source:
Oxfor Nutrition, UK; Leopold-Oharma, Austria
Pharmaceutical/Dietary Supplement Company:
Sir Jules Thorn Charitable Trust
Other: Mersey Regional Research Committee
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) 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? 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? 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? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  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)? Yes
  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? Yes
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