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ONC: Hematopoietic Cell Transplant (2007)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

 The objective of this study was to determine the effect of increasing nitrogen intake on nutritional and metabolic parameters in Bone Marrow Transplant (BMT) patients.

Inclusion Criteria:
  • Patients admitted to the BMT service of the Ohio State University Hospitals for allogenic or syngeneic bone marrow transplant.
  • Signed an informed consent.
Exclusion Criteria:
The exclusion criteria was not defined.
Description of Study Protocol:

Recruitment: The recruitment process was not detailed. Patients were recruited from October 1987 to November 1988.

Design: Prospective, randomized, double-blinded study. Randomization was stratified by age (more than less than 30 years) and risk category (risk level 1, risk level 2).

  • Risk level 1 included patients treated for acute leukemia in first remission or chronic leukemia in chronic phase.
  • Risk level 2 included patients who were transplanted with advanced disease such as for acute leukemia in accelerated or or blastic phase.

IRB approval was obtained for the study.

 Blinding used: -Double blind-study. Investigators and patients were blinded . The investigators were blinded from the dextrose and crystalline amino acid content of the study TPN formula.

 Intervention: Administration of study TPN formulas were initiated on or before day-1 (1 day prior to BMT) and continued to day 16.

  • 14 patients were assigned to receive a standard nitrogen (S-N) formula, 25% dextrose and 4.25 % crystalline amino acids (CAA) (Travasol 8.5% without electrolytes, Baxter Laboratories, Deerfield, IL).
  • 14 patients were assigned to receive a high-nitrogen (H-N) formula of 23% dextrose and 5.67% CAA.
  • No IV fat was prescribed to either group.
  • The caloric content of study TPN formula were identical, each provided 1.02 total calories/ml.  
  • All patients received a volume solution providing 40 kcal of total calories/kg actual body weight per day. 

Statistical Analysis:

  • Sample size was determined a priori to show the difference in nitrogen balance (NB) of 1.5 g/d.
  • A normal distribution was assumed, resulting in a delta value of 1.1.
  • To test h-null for u(S-N)=u(H-N), at 95% confidence interval, and a power of 80%. 14 patients were required in each treatment group.
  • Chi-square analysis was used to compare risk level and gender.
  • Two-way analysis of variance with repeated measures were used to compare the effect of the study TPN formulas and time on all other dependent variables.
  • Posthoc multiple comparisons using Tukey's procedures were employed when significant time or interaction effects were observed.
  • All values are mean ± SD. 

 

 

Data Collection Summary:

Timing of Measurements

Study TPN formulas were initiated on or before 1 day prior to Bone Marrow Transplant (BMT).  Data was collected before and in 3 periods post-transplant.

Table III: Data Collection Periods

Baseline

Period 1

Period 2

Period 3

 1-2 days prior to BMT

 Days

+3 and +4

 Days

+9 and +10

  Days

+14 and +15
 

 pre-steroid treatment   phase

post-initiation of steroids(methylprednisiolone 0.25mg/kg IV BID through day+14)

 co-insides with recovery of oral intake

Baseline data:

  • Descriptive data (age, sex, diagnosis)
  • Nutritional assessment (BEE, weight)
  • Biochemical data (UUN, TIBC, BUN, Creatinine)

Periods 1, 2 and 3 data:

  • Weight
  • Biochemical measurements (TIBC, UUN, BUN, Creatinine and nitrogen balance)

Between study periods

  • Indirect calorimetry measurements

Dependent Variables

1. Nutritional Outcome

  • Basal energy requirement using the Harris Benedict formula
  • weight
  • TIBC
  • Nitrogen balance measures were obtained using only urine measurements. 

 2. Metabolic Outcome

  • UUN-24 hour urine for for urine urea nitrogen.
  • BUN
  • creatinine

3. Metabolic cart measurements-metabolic gas monitor, MGM2, by Utah Medical were obtained providing quantitative measures of : 

  • total metabolic expenditures
  • CO2 production
  • percent contribution of carbohydrate, fat, and protein to total metabolic expenditure.

    Independent Variables

    • age
    • sex
    • diagnosis

     Control Variables

     

    • Description of Actual Data Sample:

     Initial N: 14 (gender equally distributed)

    Table IV: Baseline patient data

    Variable*

    Standard

    High
    Age (years)

    29.9±6.0

    31.1±7.6
    Weight (kg.)

    72.8±19.0

    73.8±15.7
    BEE (cal)

    1656±359

    1615±269
    Caloric requirement (cal)

    2771±638

    2623±415
    TIBC (µg/dl)

    217±20

    218±40
    UUN (g)

    8.7±3.5

    9.5±4.8
    BUN (mg/dl)

    7.2±3.1

    9.1±4.4
    CrCL (mL/min)

    129±33

    104±36
    Values are reported as mean±SD. *No significance between treatment groups on any variable(p<0.05)

    Attrition (final N): 14 patients

    Age: equally distributed

    Ethnicity: not identified

    Other relevant demographics:

    Table V : Diagnosis of patients receiving standard vs high protein formulas

    Diagnosis

    Standard

    High
    Acute lymphoblastic leukemia (ALL)

    1

    3
    Acute myelogenous leukemia (AML)

    6

    5
    Chronic myelocytic leukemia (CML)

    5

    5
    Nodular Hodgkin's disease

    1

    0
    Nodular small cell lymphoma

    1

    0
    Aplastic anemia

    0

    1
    Number of patients

    14

    14

    Table II: Medical therapies per standardized BMT therapy 
     

    10 days Prior to Transplant

    		  

    After Bone Marrow Transplant

    		  
             
      intrathecal methotrexate  

    intravenous cyclosporine

     

     

    intravenous immune serum globulin

     

    intravenous methylprednisolone

     

     

    intravenous cytoxan

     

    intravenous immune serum globulin

     

     

    oral busulfan

     

    oral immunoglobulin

     

     

    oral sulfamethoxazole with trimethoprim

     

     

     

     

    oral phenytoin

     

     

    		  
             

    Location: Ohio State University Hospitals

     

    Summary of Results:

    Nutritional intake

  • At a 40 kcal dose, patients assigned to the standard -nitrogen formula received 33.3 kcal/kg/d of nonprotein calories and 6.7 kcal/kg/d of protein calories. The nitrogen dose was 280 mg of N/kg/d.
  • At a 40 kcal dose, patients assigned to the high-nitrogen formula received 31.2 kcal/kg/d of nonprotein calories and 8.8 kcal/kg/d of protein calories. The nitrogen dose was 373 mg of N/kg/d. 
  • Patients consumed oral intake at 10.8-20.4% total calories with levels equally distributed between groups.

    Table I: Nutritional intake

    Variables

    Standard

    High
     

     

     
    Estimated caloric requirement (kcal/kg)

    40

    40
    Total caloric intake (kcal/kg)    
    Period 1

    37.6±3.7

    37.2±5.8
    Period 2

    41.1±5.8

    39.2±7.3
    Period 3

    36.6±8.3

    36.7±5.0
    Total nitrogen intake (mg/kg)

     

    		  
    Period 1

    252±16.8

    319±50.4*
    Period 2

    302±50.4¶

    353±67.2¶*
    Period 3

    252±67.2

    319±67.2*

    Values reported are mean±SD * Significantly greater than standard therapy (p<0.01).   ¶ Significantly greater nitrogen intake in period 2 vs periods 1 and 3 (p<0.05).

     Nutritional outcomes

    • Weight increased for all patients from baseline for each study period (p<0.01), but were not significantly different between groups or between periods

    Table VI: Nutritional outcome

    Variable

    Standard

    High
    Weight (kg)    
    Baseline

    72.8±19.0

    73.8±15.7
    Period 1

    75.0±17.0*

    74.7±15.3*
    Period 2

    75.7±17.1*

    75.4±15.4*
    Period 3

    75.0±17.3*

    76.5±15.3*
    TIBC (µg/dL)    
    Baseline

    217±20

    218±40
    Period 1

    272±32*

    266±46*
    Period 2

    256±58*

    277±38*
    Period 3

    271±54*

    269±38*
    NB (g/d)    
    Period 1

    -1.8±6.3

    2.7±4.7¶
    Period 2

    -1.7±4.2

    2.2±3.9¶
    Period 3

    -4.7±5.5

    -0.4±5.8¶

    Values reported are mean±SD.  *Significantly greater than baseline values. ¶ An overall group effect shows the high group had significantly more positive values. There were no significant differences between groups for any individual period.                            

    Nitrogen balance

    • HN group had more positive NB values (p<0.01)
    • HN group had more positive measures versus SN group (62.5% vs. 32.4%, p<0.01).
    • Both groups had more negative NB values for the 3rd period vs the 1st period (p<0.01).

    Table VII: Metabolic outcome

     Variable

     Standard

     High
     UUN (g/d)    
     Baseline

     8.7±3.5

    9.5 ±4.8
     Period 1

     16.8±17.4*

     17.1±5.9*
     Period 2

     18.6±6.5*

     19.7±7.1*
     Period 3

     19.7±6.9*

     20.8±8.5*
     BUN (mg/d)    
     Baseline

     7.2±3.1

     9.1±4.4
     Final

     34.4±16.9*

     30.9±15.6*
     CrCL (mL/min)    
     Baseline

     129±33

     104±36
    Final

    106±36¶

    95±42¶

    Values reported as mean±SD. *Significantly greater than baseline values (p<0.01). ¶ Significantly less than baseline values (p<0.01).

    Table VIII: Metabolic cart measurements

     Variable*

     Standard

     High
     Metabolic expenditure (cal/d)    
     Measurement 1

     2187±834

     1964±478
     Measurement 2

     2147±749

     2318±406
     Respiratory quotient    
     1

     1.06±0.08

     1.07±0.06
     2

     1.08±0.05

     1.08±0.06
     O2 consumption (VO2 ,ml/min)    
     1

     301±114

     270±65
     2

     295±100

     318±66
     CO2 consumption (VCO2 ,ml/min)    
     1

     321±121

     298±80
     2

     322±117

     347±66
     Contribution of carbohydrate    
     to metabolic expenditure(%)    
     1

     68±18

     69±9
     2

     70±8

     73±7
     Contribution of protein to    
     metabolic expenditure(%)    
     1

     26±18

     24±7
     2

     26±8

     22±6
     Contribution of fat to metabolic    
     expenditure(%)    
    1

    6±2

    7±6
    2

     5±2

     5±2
     Values reported as mean±SD. Metabolic cart measurements were obtained between periods 1 and 2, and between periods 2 and 3 (measurements 1 and 2, respectively). Measures were completed consistently by one respiratory therapist using identical procedures for each patient.* There were no significant differences by therapy for any of the metabolic cart measures.

    • total measured caloric expenditure was less than actual caloric intake for all patients (p<0.01)

    Other Findings

    Nitrogen balance values at periods 1, 2, and 3 (posttransplant days +3 and +4, +9 and +10 and +15, respectively). Isocaloric TPN formulas with different protein doses were administered. Results are mean±SD. 

    Table IX: Nitrogen balance
    Period 1 Period Period 2 Period 2 Period 3 Period 3
    SN Group HN Group SN Group HN Group SN Group HN Group
     -1.8±6.3 g  2.7±4.7 g  -1.7±4.2 g  2.2±3.9 g  -4.7±5.5 g  -0.45±5.8 g
    S-N Standard nitrogen                  H-N High nitrogen

    Length of TPN not different between groups (26.6±11.9 days SN vs 29.1±10.4 days HN)

    Length of hospitalization not different between groups (42.6±15.1 days SN vs. 42.4±14.2 days)

    Clinical complications (not statistically analyzed due to small sample size):

    •  Acute GVHD (7 patients SN, 6 patients HN)
    • Chronic GVHD (8 patients SN vs 7 patients HN)
    • Infections (12 patients SN vs 13 patients HN)
    • Sepsis (2 patients SN vs 3 patients HN)

    Relapse (also not analyzed):

    • No difference between groups, 3 patients SN and HN

    Survival (not analyzed):

    • 50 days (14/14 SN; 13/14 HN)
    • 100 days (13/14 SN; 12/14 HN)
    • 300 days (10/14 SN; 7/14 HN)
    • Author Conclusion:
    • The high nitrogen formula was more effective in reducing the loss of lean body mass without causing metabolic effects in Bone Marrow Transport (BMT) patients.
    • The high nitrogen formula did not adversely affect metabolic or respiratory parameters.
    • BMT patients do undergo catabolic stress as evidenced by a doubling in UUN from baseline in both groups.
    • The study results indicate that it does not appear necessary to provide a total caloric intake greater than 35/kg/d to meet metabolic demands. Authors recommend 30-35 kcal/kg/day.
    • Nitrogen balance values were not significantly different between groups at any study periods, but were more negative in both groups at period 3. This was attributed to the methylprednisolone administration beginning on day 7 post-transplant.
    • The authors reported that pertinent clinical outcomes including length of stay, relapse rate, and survival was monitored, but no conclusion could be drawn from this study.
    Funding Source:
    University/Hospital: Ohio State University
    Reviewer Comments:
    • Small sample size
    • No mention of dropouts
    • Authors state that body composition was preserved, however no measures of body composition (except weight) were measured to assess if there were changes in body fat or protein. They make the assumption that positive nitrogen balance equates to maintenance of lean body mass.
    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? No
      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? N/A
      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? No
      4.1. Were follow-up methods described and the same for all groups? No
      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%.) No
      4.3. Were all enrolled subjects/patients (in the original sample) accounted for? No
      4.4. Were reasons for withdrawals similar across groups? No
      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? No
      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)? ???
      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? N/A
    9. Are conclusions supported by results with biases and limitations taken into consideration? No
      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