ONC: Glutamine (2006)
Coghlin Dickson TMC, Wong RM, Negrin RS, Shizuru JA, Johnston LJ, Hu WW, Blume KG, Stockerl-Goldstein KE. Effect of oral glutamine supplementation during bone marrow transplantation. J Parenteral Enteral Nutr. 2000;24:61-66.
PubMed ID: 10772184
To evaluate the role of oral glutamine supplementation in bone marrow transplant patients.
- Bone marrow transplant (BMT) patient
- Peripheral blood progenitor cell transplant (PBPCT) patient
- Met criteria to receive the transplant
- Signed consent forms.
Recruitment
- Enrolled from June 1995 to August 1997 from the Stanford University Medical Center.
Design
- 58 BMT or PBPCT patients were enrolled into a prospective, double-blinded RCT with 29 receiving gln and 29 getting placebo.
Blinding used
- BMT or PBPCT patients were registered with data managers
- Randomized to receive glutamine or placebo. Matched according to:
- Graft
- Allogeneic
- Autologous.
- Preparative regimen
- Fractionated total body irradiation (FTBI)
- No FTBI.
- Graft
- Data collection from medical record review also blinded from study drug.
Intervention
Intervention/placebo was initiated the first day of the preparative regimen and continued until discharge or no later than 28 days after transplant.
- Intervention
- 30 g of pharmaceutical grade glutamine powder administered daily in 10 g doses
- Powder (supplied by Ajinomoto USA, Inc, Teaneck, NJ) was mixed in a liquid or soft solid food chosen by the patient.
- Placebo
- Received powdered sugar mixed in a manner similar to that of the intervention.
- Glutamine or placebo was stopped if a patient was not able to take oral intake until they were able to continue (it was usually not restarted).
- Planned dose modification and withdrawal was not needed for this study.
- TPN
- Initiated when intake reached half their estimated needs.
- Supplied 1.5 times basal energy requirements (calories)
- Supplied 1.5 g protein/kg body weight per day
- TPN was discontinued when patient consistently tolerated oral intake at least 50% of estimated calorie needs.
- Mucositis Grading
- Stanford University BMT toxicity scale
- 0-1: Not considered significant
- 2-4: Mucositis
- Only grades 2-4 were used for # days of mucositis.
- Other information collected
- Daily stool output measurements >500 mL in 24 hours = diarrhea
- Amount of glutamine taken daily recorded by patients and staff
- Length of time to WBC engraftment (WBC>1000/mL3)
- Whether or not resolution of mucositis occurred at the time of WBC engraftment
- Lowest serum albumin
- Cost of therapy
- Tolerance and consumption of glutamine.
Statistical Analysis
- Patient’s characteristics and outcomes of the two groups
- All tests used:
- Two-sided alternative hypothesis
- Alpha level of 0.05
- Wilcoxon’s rank sum test
- Pearson’s ?2 test
- Fisher’s exact test.
- All tests used:
- Probabilities of survival and relapse estimated with:
- Product-limit method of Kaplan and Meier
- Log-rank statistic.
- Pearson’s correlation coefficient for correlation between glutamine dose and length of stay and days of TPN.
- IRB approval.
Timing of Measurements
- After consent: Complete medical history, physical exam and labs taken.
- Various measures/outcomes evaluated daily for duration.
- Drug consumption recorded daily during hospitalization.
- All other information was obtained from medical record after discharge.
Dependent Variables
- Glutamine supplementation.
Independent Variables
- Number of days and highest level of mucositis
- Duration of TPN
- Length of hospital stay (LOS)
- White blood cell count
- Stool output (volume and number of days)
- Serum albumin.
Control Variables
- Graft type (autologous vs. allogeneic)
- Preparative Regimen (FTBI vs. no FTBI).
- Initial N: 58
- Attrition (final N): None withdrew; final N=58
- Age: 17- 59
- Location: Stanford University Medical Center inpatient and outpatients.
Subject Characteristics
|
Placebo (N=29) |
Glutamine (N=29) |
P-value |
Disease |
|
0.83 | |
Acute lymphocytic leukemia |
1 |
1 |
|
Acute nonlymphocytic leukemia |
2 |
2 |
|
Chronic myelogenous leukemia |
3 |
5 |
|
Myelo dysplastic syndrome |
2 |
0 |
|
Multiple myeloma |
12 |
10 |
|
Non-Hodgkins lymphoma |
9 |
12 |
|
Admission weight (kg) |
82.9 (54.5-12.5) |
69 (42.5-114.1) |
0.42 |
Median Age (y) |
48 (21-59) |
46 (17-58) |
0.86 |
Sex |
|
|
0.43 |
Female |
11 |
15 |
|
Male |
18 |
14 |
|
Regimen Type |
|
|
1.0 |
Non-FTBI |
1 |
1 |
|
FTBI |
28 |
28 |
|
Graft type |
|
|
0.79 |
Allogeneic |
13 |
11 |
|
Autologous |
16 |
18 |
|
Disease Status |
|
|
0.98 |
Early (1 chronic remission/1 chronic phase) |
5 |
5 |
|
Advanced (>1 chronic remission/1 chronic phase) |
8 |
10 |
|
Multiple myeloma |
12 |
10 |
|
Unknown |
4 |
4 |
|
[Adapted from Table I presented in publication.]
|
Placebo (N=29) |
Glutamine (N=29) |
P-value |
TPN (d) |
13 (0-33) |
12 (0-36) |
|
Days oral intake >1 L |
7.5 (0-29) |
11 (0-30) |
|
LOS (d) |
19 (3-53) |
21 (4-41) |
|
Days of mucositis |
13 (0-31) |
13 (0-37) |
|
Mucositis grades |
2 (0-4) |
3 (0-4) |
|
Mucositis grades 2-4 (%) |
62 |
66 |
0.79 |
Days of stool >500 mL |
2 (0-14) |
3 (0-9) |
0.79 |
Stool volume in mL |
3170 (2075-22535) |
3900 (0-11215) |
|
Total consumed (g) |
210 (10-840) |
180 (0-550) |
0.48 |
Lowest albumin (mg/dL) |
2.8 (1.5-3.4) |
2.9 (2.1-3.7) |
0.75 |
Highest creatinine (mg%) |
1.1 (0.5-5.5) |
1.1 (0.5-4.8) |
0.54 |
Highest total bilirubin (mg/dL) |
1.1 (0.4-37.9) |
1.4 (0.5-19.3) |
0.94 |
Days to WBC engraftment |
10 (7-29) |
9 (7-29) |
0.43 |
Follow-up (mo) median |
21 |
13 |
0.3 |
2-year survival |
70% |
45% |
0.31 |
Number relapsed |
37% |
51% |
0.35 |
Autoanalogous |
|
|
|
N |
16 |
18 |
|
TPN (d) |
7.5 (0-24) |
10.5 (0-36) |
0.7 |
LOS (d) |
17 (3-30) |
18 (4-41) |
0.55 |
Allogenic |
|
|
|
N |
13 |
11 |
|
TPN (d) |
22 (9-33) |
22 (9-36) |
0.84 |
LOS (d) |
32 (17-53) |
31 (16-39) |
0.58 |
Other Findings
- No significant differences between placebo and glutamine groups were demonstrated
- Some nonsignificant trends in patients who consumed >0.285 g glutamine/kg daily toward (that are consistent with other results that show the response to gln is dose related):
- Decreased length of stay by six days
- Decreased median days of TPN by 3.5 days.
- It “seemed” that FTBI limited the patient’s ability to take the glutamine throughout study.
- The appropriate timing, duration and route of administration of oral glutamine supplementation along with the clinical tools for evaluating effectiveness remain to be determined.
- There was difficulty in maintaining oral intake and tolerance of gln.
- A combination of gastrointestinal “tolerance” measures will need to be considered in future studies:
- Volume and number of days of diarrhea
- Antidiarrheal medicine type and amount used
- Grades of and number of days of mucositis
- Amount and type of pain medicine used for mucositis
- Number of days of TPN
- Number of days until oral intake returns to a standard level
- LOS.
University/Hospital: | Small Grants Program, Stanford University Hospital's Nursing Management Department |
- Hypothesis was not clearly stated, although the roles of glutamine being investigated was inferred from statistical analysis/results discussion.
- The purpose of recording the various outcomes described in the results was not clearly explained.
- Funding source was a small grants program of Stanford University Hospital's Nursing Management Dept.
Positive points
Limitations
Quality Criteria Checklist: Primary Research
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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) | No | |
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? | 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? | 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)? | 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? | No | |
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 | |