Glutamine

Glutamine

PEP Topic 
Chemotherapy-Induced Diarrhea
Description 

Glutamine is the most abundant amino acid in the body, comprising 60% of the free amino acid pool. Glutamine requirements increase during periods of metabolic stress and, therefore, glutamine is considered a conditionally essential amino acid. Glutamine is the primary fuel for rapidly dividing cells, including enterocytes, colonocytes, fibroblasts, and lymphocytes. Individuals who are deficient in glutamine often present with changes in gastrointestinal morphology, resulting in bacterial translocation, malabsorption, and diarrhea. Individuals deficient in glutamine also may present with impaired wound healing or impaired immune function. Glutamine is available as a dietary supplement without prescription. Glutamine has been studied for the management of diarrhea, mucositis, and peripheral neuropathy.

Effectiveness Not Established

Research Evidence Summaries

Daniele, B., Perrone, F., Gallo, C., Pignata, S., De Martino, S., De Vivo, R., … D'Agostino, L. (2001). Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: A double blind, placebo controlled, randomised trial. Gut, 48(1), 28–33.

doi: 10.1136/gut.48.1.28
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Study Purpose:

To evaluate the effect of glutamine on intestinal absorption and permeability in patients with colorectal cancer

Intervention Characteristics/Basic Study Process:

Patients receiving their first cycle of chemotherapy with 5-fluorouracil (5-FU) and folinic acid (FA) for five days were randomly assigned to receive either 18 g glutamine or placebo for 15 consecutive days, beginning 5 days before chemotherapy initiation. The experimental dose (18 g) was much greater than the normal dietary intake (1 g).
 

Sample Characteristics:

This study reported on 70 patients with colorectal cancer who were chemotherapy naïve. 

Study Design:

This was a randomized, double blind, placebo-controlled, two armed, parallel trial.

Measurement Instruments/Methods:

Intestinal absorption (IA) was measured using d-xylose absorption test and intestinal permeability (IP) using cellobiose-mannitol permeability test.  Both of these tests have been confirmed to be reliable and sensitive in clinical conditions characterized by disruption of the normal small intestinal mucosa (e.g., celiac disease, Crohn’s disease).

Results:

  • For both groups, chemotherapy induced worsening of IA and IP. When pretreatment IA was compared to post-treatment IA, reduction in IA was significantly greater in the placebo group (p = 0.02).
  • The placebo group experienced a higher incidence of diarrhea, but this was not statistically significant (p = 0.09).
  • The placebo group used significantly more loperamide (p = 0.002). No differences were found in episodes of nausea, vomiting, or hematologic toxicity.
     

Conclusions:

Glutamine was shown to reduce changes in IA and IP during 5-FU chemotherapy and may have a protective effect against diarrhea by enhancing the barrier function of the intestine.

Limitations:

  • The sample size needed for statistical analysis was 70, but only 62 patients were included in the final analysis.
  • The findings are applicable to chemotherapy using 5-FU and FA only.

Nursing Implications:

This study used sensitive and reliable tests to evaluate the morphological changes to the intestine that are casually related to diarrhea incidence. The results are consistent with previous studies that have demonstrated the protective effects of glutamine on the intestinal mucosa.

Guideline/Expert Opinion

Gibson, R.J., Keefe, D.M., Lalla, R.V., Bateman, E., Blijlevens, N., Fijlstra, M., … Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). (2013). Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Supportive Care in Cancer, 21(1), 313–326.

doi: 10.1007/s00520-012-1644-z
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Purpose & Patient Population:

To systematically review current evidence for prevention and treatment of gastrointestinal (GI) mucositis in adults and children receiving cancer treatment and to update relevant Multinational Association of Supportive Care in Cancer (MASCC) guidelines

Type of Resource/Evidence-Based Process:

This was an evidence-based guideline developed based on a systematic review of the literature with rating of levels of evidence and identification of study flaws.

Database searched was MEDLINE.

Search keywords were numerous and included all known possible interventions tested.

Inclusion and exclusion criteria were not stated in this article but provided elsewhere in the journal.

Phase of Care and Clinical Applications:

  • Patients were undergoing the active treatment phase of care.
  • The study has clinical applicability for pediatrics.

Results Provided in the Reference:

A total of 1,336 papers were initially retrieved; of these, 146 were reviewed for development of the guidelines.

Guidelines & Recommendations:

  • Probiotics with Lactobacillus spp. may be beneficial for prevention of chemotherapy- and radiotherapy-induced diarrhea in patients with pelvic malignancies. Two studies with positive results were cited.
  • Amifostine may reduce esophagitis because of concomitant radiation and chemotherapy. It is not recommended in other situations because of conflicting evidence.
  • Mesalazine, 5-aminosalicylic acid (5-ASA), and olsalazine are not recommended because they have been associated with increased diarrhea compared to placebo.
  • Sucralfate is not recommended for diarrhea prevention because it is associated with increased GI side effects, including rectal bleeding.
  • Oral sulfasalazine given at 500 mg twice daily is recommended to reduce incidence and severity of radiation-induced enteropathy.
  • No guideline was provided for glutamine, but three new studies were sited that showed promising results.
  • If loperamide has not resulted in diarrhea control with standard or high-dose chemotherapy in HCTY patients, 100 mcg or greater of subcutaneous octreotide twice daily is recommended.

Limitations:

This review had a limited search strategy, as only one database was searched. In addition, most of the suggestions and recommendations provided were based on low-level evidence by the rating system used.

Nursing Implications:

These guidelines provide some suggestions for management of oral mucositis and diarrhea in patients with cancer. They also provide information regarding evidence for mucositis in the entire GI tract.

Systematic Review/Meta-Analysis

Sun, J., Wang, H., & Hu, H. (2012). Glutamine for chemotherapy induced diarrhea: a meta-analysis. Asia Pacific Journal of Clinical Nutrition, 21(3), 380–385.

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Purpose:

To investigate if prophylactic glutamine administration in patients receiving chemotherapy is effective for diarrhea prevention and control with the two major outcomes of duration and severity of diarrhea

Search Strategy:

  • Databases searched were Embase, MEDLINE, Cochrane Library, and BIOSIS.
  • Search keywords were glutamine, diarrhea, chemotherapy, meta-analysis, and prophylactic.
  • Studies were included in the review if they used randomization, with one group receiving glutamine and one group serving as control, and if they included patients receiving bone marrow transplant.
  • Studies were excluded if they were not written in English or Chinese or did not clearly report results.

Literature Evaluated:

  • A total of 20 references were retrieved.
  • Studies were graded using the Jadad 5-point scale with 1 point assigned to each of the following: description of study as randomized, description of appropriate method of randomization, description of double-blind, description of appropriate method of double-blinding, and statement addressing study withdrawals.
  • Review Manager Software was used for quantitative analysis to calculate the odds ratio for the weighted mean differences (WMDs) for continuous data between the study drug group and the control group. The software also was used to perform heterogeneity analysis; data that was not significantly heterogeneous (p > 0.05) were analyzed using a fixed effects model, and heterogeneous data (p < 0.05) were analyzed using a random effects model.
  • Common toxicity criteria grades for diarrhea were defined as follows.
    • Grade 0: No diarrhea
    • Grade 1: An increase of fewer than 4 stools per day from pretreatment
    • Grade 2: An increase of 4–6 stools per day or nocturnal stools
    • Grade 3: An increase of more than 6 stools per day, incontinence, or need for parenteral support for dehydration
    • Grade 4: Physiological consequences requiring intensive care or death.  
       

Sample Characteristics:

  • A total of eight studies were included in the review.
  • The total sample size was 298 patients, with 147 in the treatment groups and 151 in the placebo groups. Sample ranges across all studies were 8–33 in the treatment groups (n = 18) and 8–33 in the placebo groups (n = 19).
  • Cancer diagnoses were gastrointestinal, acute myeloid leukemia, colorectal, advanced breast, autologous and bone marrow transplant, and hematologic.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Results:

  • An overall statistically significant difference was found in duration of diarrhea with glutamine recipients versus patients receiving placebos (WMD, -1; 95% confidence interval [CI], -1.73, -0.26). Oral glutamine scored higher (WMD, -1.06, 95% CI, -2.01, -0.11) compared to intravenous glutamine (WMD, -0.89; 95% CI, -2.07, 0.28).
  • Study findings indicated that glutamine did not improve the severity of diarrhea (WMD, 0.49; 95% CI, -1.36, 0.39).
  • Statistical heterogeneity was found for overall rates (p < 0.00001) with the random effects model (p < 00001).

Conclusions:

According to the results of this meta-analysis, prophylactic administration of glutamine (ranging from 16–30 g oral form daily for periods of up to 20 days and 20-40 g IV administration daily for periods of up to 21 days) reduced the length of chemotherapy-induced diarrhea (CID). However, results did not show reduction in the severity of the diarrhea. Oral glutamine was found to be more effective than IV glutamine.

Limitations:

  • Endotoxin levels were used to assess permeability levels instead of the standard lactulose-mannitol test.
  • Although this was a meta-analysis, the individual RCTs were small.
  • Doses and administration were not standardized across studies, making it difficult to combine results for statistical analysis.

Nursing Implications:

This meta-analysis provided evidence that glutamine, as the most abundant amino acid in humans, could reduce the duration of CID and intestinal permeability and may stimulate mucosal recovery. However, glutamine has not been shown to be beneficial in reducing or limiting the severity of CID. Larger trials are needed.

Prophylactic oral glutamine in patients receiving chemotherapy may be useful in lessening the duration of chemotherapy-related diarrhea. However, without further large trials with standardized doses, routes, and length of administration, glutamine should not be recommended for practice.


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