ONC: Glutamine (2006)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
  • The purpose of the review was to determine the efficacy of any form of enteral or parenteral nutrition support for patients receiving bone marrow transplantation
    • Efficacy is defined in terms of:
      • Time in hospital
      • Complications
      • Change in nutritional status (i.e., body weight)
      • Survival.



Inclusion Criteria:
  • A randomized or quasi-randomized controlled trial
  • Comparison of one type of nutrition support (enteral or parenteral) with another or with an intravenous solution of glucose/saline
  • Subjects had to be bone marrow transplant (BMT) patients of any age.
Exclusion Criteria:
  • Not a randomized or quasi-randomized study
  • No comparison of one type of nutrition support with another or with a glucose/saline solution.
Description of Study Protocol:


  • 35 possible RCTs were identified
  • 24 of the 35 met all inclusion criteria
  • 11 of 35 studies were excluded
    • Eight excluded because not RCTs
    • Two excluded because no form of nutrition support was used as intervention
    • One excluded because subject was not a BMT patient.


  • Search strategy 
    • A computerized search strategy (with no RCT filter) was implemented to identify trials from the following databases:
      • The Cochrane Library (Issue 1, 2000)
      • MEDLINE (1966-2000)
      • Embase (1988-2000)
      • CINAHL (1982-2000).
    • Hand searching included:
      • Nutrition and BMT conference proceedings
      • Reference lists of papers found through electronic search
      • Consultation with experts.
  • Study selection
    • Identified studies were scanned by the lead reviewer and relevant studies retained
      • Relevant studies were independently scanned by the lead and co-reviewers and included or excluded according to pre-determined inclusion criteria.
  • Methodological quality of studies was evaluated for
    • Allocation concealment
    • Blinding
      • Not considered crucial since outcomes were objective measures.
    • Loss to follow-up.

Statistical Analysis

  • For outcomes measured as continuous data
    • Means, mean differences, standard deviation and standard error were used
    • 95% confidence interval.
  • For outcomes measured as dichotomous data
    • Odds ratios were used
    • 95% confidence interval.
  • For meta-analyses (where possible)
    • Fixed effect model was used
    • Summary estimate of outcomes with 95% confidence interval.
  • To detect statistical heterogeneity
    • Chi square test
    • P=0.05, confidence interval 95%
    • If statistical heterogeneity was detected, a random effects model was used to determine a summary statistic
    • 95% confidence interval.
  • Statistical limitations
    • Planned sub-group analysis of adults vs. children, disease type and transplant type could not be performed due to insufficient data
    • Effect of type of allocation concealment, loss to follow-up and 'number needed to treat' could not be assessed due to insufficient data.
Data Collection Summary:

Data collection

  • A data extraction form was designed
    • The form was used to record data on participants, interventions, and outcomes.

Outcome measures assessed

  • Primary outcomes
    • Hospitalization duration (Day Zero to discharge)
    • Mucositis (mean days mucositis from start to end of study)
    • Graft vs. host disease [GVHD] (number of patients who developed >grade two GVHD)
    • Nutritional status (% change in body weight from start to end of study)
    • Duration of nutritional intervention/time to achieve adequate oral intake
    • Neutropenia (mean days to achieve normal neutrophil level from Day Zero of BMT)
    • Line infections (number of patients who developed line infections from start to end of study)
    • Number of positive blood cultures
    • Survival to 100 days
    • Survival beyond 100 days (number of patients who completed study and survived +100 days or two years.)
  • Secondary outcomes
    • Vomiting (mean number patients who had =3 vomits/day from start to end of study)
    • Diarrhea (mean number patients who had =3 bowel movements/day from start to end of study)
    • Veno occlusive disease [VOD] (actual number patients who developed VOD per group)
    • Liver function disturbance (number of patients with abnormal bilirubin levels from start to end of study)
    • Hepatomegaly (number of patients who developed hepatomegaly from start to end of study)
    • Albumin (mean change in albumin from start to end of study between trial groups)
    • Pre-albumin (mean change in pre-albumin from start to end of study between trial groups)
    • Engraftment (mean duration for each group to achieve engraftment from Day Zero of BMT).
Description of Actual Data Sample:

Organization of included studies:

  • 16 of 24 included studies were arranged into four main groups:
    1. Oral glutamine vs. placebo (four studies; 343 patients total)
      • Anderson, 1998
      • Coghlin, Dickson, 2000
      • Jebb, 1995
      • Schloerb, 1999.
    2. Parenteral nutrition with glutamine vs. standard parenteral nutrition (seven studies; 108 patients total)
      • Zeigler, 1992 (four of the seven studies were duplicates of Zeigler, 1992)
      • Brown, 1998
      • Schloerb, 1993.
    3. Standard parenteral nutrition vs. intravenous hydration (two studies; 166 patients total)
      • Lough, 1990
      • Weisdorf, 1987.
    4. Parenteral nutrition vs. enteral nutrition (one full report and two abstracts; 144 patients were identified)
      • Cope, 1997
      • Szeluga, 1987 (abstract)
      • Young, 1997 (abstract).
    5. Eight additional trials compared a variety of nutritional interventions and could not be allocated to one of the above groups (Aldamiz, 1996; Charuhas, 1997; Jimenez, 1999; Lenssen, 1987; Lenssen, 1998; Malhotra, 1996; Mulder, 1989; Muscaritoli, 1998).
Summary of Results:

Findings from the studies

  • Group One: Oral glutamine vs. placebo (four studies; 343 patients total)
    • Adequate data were provided only by Jebb, 1995 and Schloerb, 1999
      • The use of an oral placebo mouth wash reduced days to neutrophil recovery significantly [6.82 days, 95% CI (1.67-11.98), P=0.009] when compared to a glutamine mouth wash.
    • No significant differences in hospital duration, percentage change in body weight, number of positive blood cultures, number of days of nutrition intervention and survival at 100 days.
  • Group Two: Parenteral nutrition with glutamine vs. standard parenteral nutrition (seven studies; 108 patients total)
    • Data was provided for all outcomes by either two or all three authors
    • Most significant finding: Patients who received PN with glutamine had hospital stays 6.62 days shorter than standard PN patients [weighted mean difference; 95% CI (-9.77-3.47), P=0.00004]
    • PN with glutamine patients were less likely to develop positive blood cultures than standard PN patients (odds ratio 0.23)
  • Group Three: Standard parenteral nutrition vs. intravenous hydration (two studies; 166 patients total)
    • The odds of developing a line infection are 21.23 times greater for PN patients than for IV hydration patients [from Lough's data; 95% CI (4.15-108.73), P=0.0002]
    • Mean percentage change in albumin concentration increased for hydration group as compared to PN group [from Lough's data; mean percentage change -5.93, 95% CI (-9.90 to -1.96), P=0.003]
    • PN more effective than hydration at maintaining body weight [from Lough's data; weighted mean difference for percentage change 2.76, 95% CI (1.26-4.26), P=0.0003]
    • No significant difference in survival 200 days post-BMT.
  • Group Four: Parenteral nutrition vs. enteral nutrition (one full report and two abstracts; 144 patients were identified)
    • Due to study design and data collection problems, none of the data could be used.
  • Group Five: Other studies (eight studies)
    • Due to the low power and inability to group these studies, the results could not be utilized.
Author Conclusion:
  • The benefits of oral glutamine mouth wash vs. placebo are unclear
  • Parenteral nutrition with glutamine should be routinely considered for bone marrow patients thought likely to experience prolonged gastrointestinal failure
    • BMT patients receiving PN with glutamine seem to leave the hospital significantly sooner than placebo patients
    • BMT patients receiving PN glutamine seem to have significantly fewer positive blood cultures than placebo patients.
  • PN should be administered with caution due to a highly increased risk of line infection
  • Lack of evidence prevents analysis of effectiveness of enteral nutrition vs. parenteral nutrition.

Suggestions for further research:

  • Another trial of oral glutamine vs. placebo since existing data are scant and inconclusive 
  • A multi-center, four-armed RCT comparing parenteral to enteral nutrition, with and without added glutamine
  • Studies to determine appropriate dose of parenteral glutamine.
Funding Source:
Reviewer Comments:
  • Chi-square statistic has low power to detect heterogeneity when only a small number of studies are analyzed
  • Studies favorable to glutamine-enriched PN suggest a protective effect of glutamine against infections, with subsequently shorter hospital stay. However, appropriate dose of parenteral glutamine has not been determined.
Quality Criteria Checklist: Review Articles
Relevance Questions
  1. Will the answer if true, have a direct bearing on the health of patients? Yes
  2. Is the outcome or topic something that patients/clients/population groups would care about? Yes
  3. Is the problem addressed in the review one that is relevant to dietetics practice? Yes
  4. Will the information, if true, require a change in practice? Yes
Validity Questions
  1. Was the question for the review clearly focused and appropriate? Yes
  2. Was the search strategy used to locate relevant studies comprehensive? Were the databases searched and the search termsused described? Yes
  3. Were explicit methods used to select studies to include in the review? Were inclusion/exclusion criteria specified andappropriate? Wereselectionmethods unbiased? Yes
  4. Was there an appraisal of the quality and validity of studies included in the review? Were appraisal methodsspecified,appropriate, andreproducible? Yes
  5. Were specific treatments/interventions/exposures described? Were treatments similar enough to be combined? Yes
  6. Was the outcome of interest clearly indicated? Were other potential harms and benefits considered? Yes
  7. Were processes for data abstraction, synthesis, and analysis described? Were they applied consistently acrossstudies and groups? Was thereappropriate use of qualitative and/or quantitative synthesis? Was variation in findings among studies analyzed? Were heterogeneity issued considered? If data from studies were aggregated for meta-analysis, was the procedure described? Yes
  8. Are the results clearly presented in narrative and/or quantitative terms? If summary statistics are used, are levels ofsignificance and/or confidence intervals included? Yes
  9. Are conclusions supported by results with biases and limitations taken into consideration? Are limitations ofthe review identified anddiscussed? Yes
  10. Was bias due to the review's funding or sponsorship unlikely? Yes