ONC: Hematopoietic Cell Transplant (2006)

Citation:

Lenssen P, Cheney CL, Aker SN, Cunningham BA, Darbinian J, Gauvreau JM, Barale KV.  Intravenous Branched Chain Amino Acid Trial in Marrow Transplant Recipients. Journal of Parenteral and Enteral Nutrition, 1987; 11(2):112-8

PubMed ID: 3295317
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To compare the effects of a high-leucine 45% branched-chain amino acid (BCAA) vs a standard 23% BCAA intravenous solution on nitrogen balance, urinary 3-methylhistidine (3-MH)-to-creatinine excretion ratio, upper arm anthropometry, serum prealbumin, and peripheral marrow engraftment in adult patients with leukemia treated by chemoradiotherapy and marrow transplantation during the first month posttransplant.
Inclusion Criteria:
*    > 18 years of age

*   No other criteria specified.
Exclusion Criteria:
*   None specified.
Description of Study Protocol:

Recruitment:  40 consecutive patients with leukemia and > 18 years of age.

 

Design:  Prospective, randomized, double blind intervention

 

Blinding used (if applicable):  Double blinding

 

Intervention (if applicable):

  • TPN treatment plans identical except in the composition of the amino acid formula:  45% Branched Chain Amino Acid (BCAA) (high leucine) vs. 23% BCAA.
  • Provided 0.24 g nitrogen/kg ideal body weight,  155-165% of basal energy expenditure; 25-30% to total kcal as lipid (Liposyn 10% and 20%), a standard profile of vitamins and trace elements, and electrolytes in amounts determined by the primary care physician.
  • A standard resistive exercise program was provided 5 days/week to all study patients by a physical therapist.  Some patients were treated in laminar air flow environments and restriced from ward ambulation. 

 

Statistical Analysis:

  • Cases with fewer than four observations for any week were amitted from analysis for that week.
  • Significance of differences between groups as a whole and stratified by stress categories was determined by the chi-square test or Fisher's exact test for qualitative variables, and by both Student's t-test and athe Wilcoxon ran sum test for quantitative variables.
  • Probability functions of times to engraftment were calculated by the Kaplan-Meier acturial estimate and utilized observations throughout the transplant course.
  • Medians and results of Wilcoxon rank test are presented regardless of sample size.
  • p-values adjusted by Bonferroni's procedure.

 

 

Data Collection Summary:

Timing of Measurements:


Nitrogen balance:                                     Measured daily
Urinary 3-methylhistidine (MH):                Days 1-3, 13-15, 26-28
Serum albumin:                                        Weekly
CBC:                                                         Daily
Upper arm anthropometry:                       Prior to treatment, day of transplant, days 14 and 28 post-transplant
Plasma samples for amino acid analysis:  Pretreatment and weekly
Stress level:                                              Weekly and At study end

 

Dependent Variables

  • Nitrogen balance:  Difference between actual infused intravenous nitrogen plus weighed oral nitrogen itake and Kjeldahl analysis of total nitrogen in urine and mixed urin-stool plus 2 g if the patient had any additional stool.  Nitrogen balance was corrected for changes in the urea pool.
  • Urinary 3-MH:  average of 3-day collections;  expressed as a ratio to baseline creatinine excretion in g to standardize for muscle mass.
  • Serum prealbumin:  radial immunodiffusion
  • Routine laboratory tests:  analyzed on automated equipment
  • Marrow engraftment:  attainment of a peripheral granulocyte count of >500/mm3
  • CBC: hand counted daily
  • Upper arm anthropometry:  standard methods
  • Amino acid analysis:  plasma samples collected in heparinized tubes, refrigerated on ice immediately, and within 30 minutes of collectioncentrifuged at 4oC at 3500 rpn for 15 minutes.  The supernatant was extracted and stored at -70oC until analyzed on a Beckman model 121-M amino acid analyzer.
  • Stress Classification:   Moderate or severe
    • Severe stress:  sepsis (two consecutive positive blood cultures or one blood culture with a source), fever >38.5oC for at least 4 out of 7 days, pneumonia, acute GVHD grade of at least three in skin, liver, or gastrointestinal tract, elevated liver function tests (bilirubin> 8 mg/dl, SGOT > 200 IU/dl, alkaline phosphatase > 400 IU/dl), administration of high dose steroids (>2 mg/kg daily) or renal failure requiring dialysis.

Independent Variables:  TPN:  45% (high leucine) BCAA intravenous solution vs 23% BCAA solution

 

Control Variables:  None specified

 

Description of Actual Data Sample:

 

Initial N: 40 (21 Male; 19 Female)

Attrition (final N):  19 (8 in 45% BCAA group; 11 in 23% BCAA  group)

Age:  Median age = 28.5 ( range: 18-49)

Ethnicity:  Not specified.

Other relevant demographics:

Anthropometrics  Data not given.

Location: USA

 

Summary of Results:
  • There were no significant differences between groups in patient characteristics.  However, the proportion of patients with chronic leukemia was higher in the 45% BCAA group.
  • Those who remained in the study were more likely to have been placed in laminar air flow isolation and to have a later engraftment.  No other factor ((sex, age, diagnosis, disease status, degree of stress,  BCAA solution) was related to study completion.
  • There were no apparent differences in stress stratification by week or types of complications experienced.  Patients in the 23% BCAA group experienced a higher incidence of renal failure .  Patients in the 45% BCAAA group experienced more liver dysfunction in study week 4.

Nitrogen (N) Balance:

  • did not differ between groups.
  • In study week 4, median net N loss of the 45% BCAA group was greater (-11.3 g) than 23% BCAA (- 3.9 g) and suggestive of a difference (p=0.08).  The trend was also observed in moderately stressed and severely stressed patients.
  • Nitrogen and nonprotein calorie intake did not differ between groups:    In study week 4:             
  •                    The median nitrogen per kg ideal weight in 45% BCAA group was 0.23 g for moderate and 0.21 g for severe categories, respectively;  the median nitrogen per kg ideal weight in 23% BCAA was0.22 and 0.19 g for moderate and severe categories, respectively.
  •                    The median nonprotein calories in the 45% BCAA were 36 and 31 calories per kg respectively for moderate and severe stress groups; those in the 23% BCAA received 30 and 29 calories per kg for moderate and severe stress groups, respectively. 

Urinary 3-MH to creatinine excretion ratio 

  •    was similar between groups at baseline and study midpoint. 
  •    was greater in 45% BCAA group at study end, but not significantly. 
  •    was significantly greater in the severely stressed group (p=0.045)

Arm muscle area as a percent of baseline

  • Changes were similar   
  • Those patients remaining in the 45% BCAA group appeared to suffer more loss.

Median day postttransplant of >500/mm3 granulocytes 

  •   Day 18 for both groups

Median day when oral protein intake was> 10 g

  • Day 24 for 45% BCAA and day 26 for 23% BCAA (n.s.)

Weekly prealbumin:  No differences

  • Baseline prealbumin levels were 33.5 (13-40)mg/dl  in 45% BCAA and 32.5 (6-40) mg/dl in the 23% BCAA
  • Lowest levels in both groups were at the end of the study week 2:  13.0 (8-40) mg/dl in the 45% BCAA and 15.2 (7-40)mg/dl in the 23% BCAA group
  • Study week 4 values were 30.0 (12-40) mg/dl in the 45% BCAA and 39.6 (16-40) in the 23% BCAA group

Plasma amino acids:  significant differences between groups occurred only in

  • plasma glycine on day of transplant (week 1) and weeks 2 and 3 posttransplant; 
  • plasma leucine and valine on day of transplant and all posttransplant intervals;
  • plasma isoleucine on weeks 1 and 4 posttransplant. 
  • Differences in plasma amino acids appeared to reflect differences in the amino acid solution content.  

 

 

 

Other Findings

 

Author Conclusion:
These results suggest that these expensive amino acid formulations are not routinely indicated in the immediate period following marrow transplantation.
Funding Source:
Government: National Cancer Institute, DHHS
Industry:
Kendal McGaw
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:

*  To varying degrees at each weekly interval, study size limited detection of differences in nitrogen balance.  However, the authors comment that it is unlikely that the true difference exceeds 2.5 g at week 1 and 4.0 g thereafter.

*  The authors comment that this population was in greater stress than described in most previous BCAA studies of postoperative patients.

*  In study week 3, high dose steroids were used in 3 of 17 patients in the 45% BCAA group vs none in the 23% BCAA group.  This may have influenced ability to evaluate nitrogen balance in the analysis comparing the severely stressed and overall 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
  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
  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
  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
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
  1. Was the research question clearly stated? Yes
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. 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
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  2. Was the selection of study subjects/patients free from bias? 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
  2.1. 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
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? 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
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  3. Were study groups comparable? 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
  3.1. 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
  3.2. 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
  3.3. 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
  3.4. 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
  3.5. 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
  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. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? 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
  4.2. 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
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? 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
  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. 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
  5.1. 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
  5.2. 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
  5.3. 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
  5.4. 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
  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. 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
  6.1. 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
  6.2. 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
  6.3. 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
  6.4. 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
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments 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
  6.7. 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
  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. 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
  7.1. 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
  7.2. 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
  7.3. 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
  7.4. 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? ???
  7.5. Was the measurement of effect at an appropriate level of precision? ???
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? 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. 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
  8.1. 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
  8.2. 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
  8.3. 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)? N/A
  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)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  8.6. Was clinical significance as well as statistical significance reported? 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? N/A
  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. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? 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. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes