Oncology

Randomized Controlled Trial

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 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.

• Patients admitted to the BMT service of the Ohio State University Hospitals for allogenic or syngeneic bone marrow transplant.
• Signed an informed consent.

The exclusion criteria was not defined.

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. 

 

 

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

 

 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

 

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)

• 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.

University/Hospital:

Ohio State University

• 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.