Continuous versus cyclic parenteral nutrition during bonemarrow transplantation: assessment and follow-up

Clinical Nutrition (1996) 15:333-336 © Pearson Professional Ltd 1996

Continuous versus cyclic parenteral nutrition during bone marrow transplantation: assessment and follow-up L. ALDAMIZ-ECHEVARRIA, M. P. BACHILLER*, M. C. ARIZ*, A. GIMENEZ*, M. J. BARCIA* and M. MARIN t Department of Nutrition, *Department of Pharmacy, tDivision of Hematology, Hospital Ntra, Sra. de Aranzazu, p° Dr. Beguiristain s/n, 20.014 San Sebastian. Spain (Reprint requests and correspondence to L. A.-E.) ABSTRACT--The aim of this prospective, randomized clinical trial was to compare the efficacy of parenteral nutrition (PN) in adult bone marrow transplant (BMT) patients on a continuous (CON) versus a cyclic (CYC) regimen. Twelve patients received CON PN and 12 CYC PN. The groups were homogeneous. CON PN received 27.2 _+3.7 kcal/kg/day and for CYC PN 25.9 +__4.2 kcal/kg/day (P = 0.45). The duration of PN was 20.4 +_7.9 days and 27.3 _+ 13.4 days respectively (P = 0.14). There were no differences between initial and final body weights, either within or between groups. The initial pre-albumin levels were 16.1 +_ 7.5 mg/dl and 20.1 _+4.9 mg/dl in CON PN and CYC PN, respectively (P= 0.22), and these were maintained throughout the study. Blood glucose levels did not differ between groups. Measures of liver function were moderately increased, but with no significant differences between groups. There were no significant differences regarding the efficacy of PN or the appearance of complications between CON PN and CYC PN in patients with BMT.

Introduction

incidence of hepatic changes by lowering hepatocyte of triglyceride levels and favouring the synthesis of albumin (8). The aim of this trial was to compare the efficacy of PN in patients with BMT on a continuous infusion regimen (CON) versus cyclic regimen (CYC) and to assess the complications associated with PN.

The use of bone marrow transplantation (BMT) has been steadily increasing as part of the treatment for haematological diseases and solid tumours (1). Those responsible for the care of such BMT patients are members of multidisciplinary teams and the assessment and application of nutritional support is an important component of the overall treatment programme. The BMT recipient often manifests prior malnutrition, characterized by a decrease in cellular mass and an increase in extra cellular volume (2). BMT produces changes in metabolism with a moderate degree of hypercatabolism, which leads to a greater risk of morbidity and mortality during the post-transplantation period (3). Vomiting, diarrhoea and mucositis in the digestive tract, which may last for 3 or 4 weeks (4), results in insufficient oral intake. Nutritional support is often carried out by parenteral nutrition (PN) particularly in cases of allogeneic BMT. PN has been shown to have a beneficial effect on the survival of BMT patients because protein synthesis is maintained, although it has no significant effect on the duration of hospitalization, episodes of bacteremia or graft-versus-host disease (GVHD) (5, 6). During the post-transplantation period the administration of both multiple blood and derivative transfusions and medication is necessary, which requires a central line for prolonged periods. This may give rise to technical difficulties linked to the availability of such central lines. Continuous PN (CON) (24 h) may aggravate the problem, such that administering PN cyclically (CYC) (12 h) may be beneficial because it allows availability of the line for other therapies (7). In addition, CYC PN has been linked to a lower

Materials and methods Patients

A prospective clinical trial was carried out with 24 consecutive patients who had undergone BMT in our hospital between June 1993 and July 1994. They were randomized to receive either CON PN or CYC PN. Those patients below 15 years of age and those with renal failure, insulindependent diabetes mellitus and cardiac conditions prior to BMT were excluded. Those whose PN was interrupted for more than 5 days and/or those with cardiac insufficiency were excluded. Nutritional support

Thirty-five kcal/kg/day (29 non-protein kcal of which 65% were carbohydrates and 35% lipids) were administered as 140 non-protein kcal/g of nitrogen and with an energy content of 1 kcal/ml. Daily support was: nitrogen 0.22 g/kg, glucose 4.9 g/kg and lipids 1.12 g/kg. Electrolytes, trace elements and vitamins were given according to individual requirements. PN was initiated 24 h after transplantation, mad administered by a central line reservoir with an infusion pump over 24 h and 12 h periods for the CON PN and CYC PN groups, respectively, as described by Bennett et al (9). 333

334 PN DURINGBONE MARROW TRANSPLANTATION

Clinical trial variables The following parameters and clinical data were obtained: age, sex, daily weight, BMT, presence of GVHD, hepatic veno-occlusive disease (HVOD), catheter infection, feverish episodes and neutropenia time. The total number and volume of blood transfusions, platelets and plasma administered during the trial, the use of hematopoietic growth factors, nutritional support, duration of PN and the posttransplantation hospitalization period were also recorded.

Plasma biochemistry Glucose, urea, sodium, chlorine, potassium, phosphorous, calcium, magnesium, uric acid, creatinine, cholesterol, triglycerides, aspartate aminotransferase (SGOT), alanine aminotransferase (GPT), gamma glutamyl transferase (GGT), alkaline phosphatase (FA), total bilirubin (BT), total protein, albumin and pre-albumin were determined at the start and end of PN and weekly throughout the study.

Statistical methods Quantitative variables are described by mean and standard deviations, and qualitative variables by proportion. The comparison of parameters at the beginning, during, and at the end of PN was carried out by the non-parametric Wilcoxon test. The Mann-Whitney test was used to establish any association between the type of nutrition and the change in quantitative parameters. The association between qualitative variables and type of nutrition was carried out using the Chi-squared test.

Results Twelve patients received CON PN and 12 patients CYC PN. Their characteristics are shown in Table 1. There were no significant differences between groups with regard to age, sex, initial weight and type of transplant. All the patients completed the trial. PN support provided 27.2 _+ 3.7 kcal/kg/day in the CON PN group and 25.9 _+4.2 in the CYC PN group (P = 0.45). The duration of the PN was 20.4 _+ 7.9 days for CON PN and 278.3 _+ 13.4 days for CYC PN (P = 0.14). There were no significant differences in weekly weight change in either group. The difference in weight between the beginning and end of PN was -1.4 _+_1.7 kg for CON PN and 0.1115 +_2.6 kg for CYC PN (P = 0.12).

Table 1

Characteristics of bone-marrow transplant patients

Group

n

Gender

Age (years)

Weight (kg)

Type

CON PN

12

37 + 9.3

62.6 - 12.9

CYCPN

12

7M 5F 5M 7F

35.4_+11.1

67.1_+14.6

4 AL 8 AUT 2AL 10 AUT

M: male, F: female, AL: allogeneic, AUT: autologous.

There were no significant differences in neutropenia time (19.6 + 11.7 days for CON PN and 22.5 _+ 7.6 days for CYC PN (P = 0.55)), the use of hematopoietic growth factors (CON PN = 7 cases, CYC PN = 9 cases), the incidence of HVOD (CON PN = 2 cases, CYC PN = 2 cases), the incidence of GVHD (one case in each group), oral intakes, the frequency and quantity of blood products required and the post-transplantation hospitalization period (CON PN 29-8 _+ 18.1 days, CYC PN 31 _+ 15.3 days). In no case was infection of the giving set detected and there were 7 cases of fever in each group. The plasma biochemical parameters - urea, sodium, chlorine, potassium, phosphorous, calcium, uric acid and creatinine - in both groups were within the normal range, both at the beginning and in subsequent analyses. Magnesium levels at the beginning (CON PN 1.5 _+ 0.5 mg/dl, CYC PN 1.5 _+0.3 mg/dl, P = 0.93) were normal in 3 patients from the CON PN group and in 1 from the CYC PN group. Values were low in the other cases. These levels remained low during the trial without showing any significant differences between groups. Glucose levels at the beginning (CON PN 110.8 + 27.1 mg/dl, CYC PN 119.6 + 35.7 mg/dl) and during the trial (CON PN 153.4 +__ 40.9 mg/dl, CYC PN 158.0 + 64.2 mg/dl) showed no significant differences, (P -- 0.50 and P = 0.8, respectively). No episodes of hypoglycaemia were observed in any patient. Plasma levels of cholesterol and triglycerides were not significantly different between groups at the beginning of the study. For cholesterol the levels were 154.5 + 25.7 mg/dl (CON PN) and 172.7 _+ 42.9 mg/dl (CYC PN) (P = 0.31) and for triglycerides they were 124.5 + 42.1 mg/dl (CON PN) and 155.7 + 105.9 mg/dl (CYC PN) (P = 0.44). Cholesterol and triglyceride levels remained normal for both groups throughout the trial. Total protein levels at the beginning were CON PN = 5.4 _+ 0.5 g/1 and for CYC PN 5.8 _+ 0.5 g/1 (P = 0.05). By the end of PN values were CON PN = 5.5 + 0.8 g/1 and CYC P = 6.2 + 0.7 g/1 (P = 0.07). With respect to albumin, significant differences were noted between groups only in initial levels: CON PN = 2.85 _+0.32 g/l, CYC PN = 3.16 _+ 0.26 g/1 (P = 0.02). The final levels were CON PN = 3.01 _+ 0.62 g/1 and CYC PN = 3.46 _+ 0.49 g/1 (P = 0.06). There was no evidence of any significant differences between groups or increase in values in either group: CON PN = 0.4 + 0.8, CYC PN = 0.3 + 0.5 (P = 0.74). Initial prealbumin levels were CON PN = 16.1 + 7.5 mg/dl and CYC PN -- 20.1 _+ 4.9 mg/dl (P = 0.22). Throughout the trial levels remained above 15 mg/dl in all determinations for both groups. Final levels were CON PN, = 18.7 _+ 5.9mg/dl and CYC PN = 21.6 _+ 6.1mg/dl (P = 0.35). Average hepatic parameters at the beginning, end and during the different periods are shown in Table 2. No statistically significant differences in either group were noted. Significant differences were, however, evident in cholestasic parameters (GGT, FA) for initial and final values in both groups (P = 0.0001 and P = 0.0021).

CLINICALNUTRITION 335 Table 2

Hepatic parameters Beginning

1st Week

2nd Week

Month

SGOT CON CYC

27.6±16.9 76.2±116.3

21.5±14.61 18.9±8.50

19.5±10.51 3.5±7.7

28.0±13.4 22.2±0.5

GPT CON CYC

43±57.7 74.3±98.9

38.5±39.9 41.5±39.1

42.1±34.4 34.9±17.1

70.3±42.5 22.6±6.8

GGT CON CYC

20.9±10.6 40.4±48.8

47.6±40.9 78.2±68.1

88.3±86.8 131.4±81.5

192±59.2 124.4±9t.3

FA CON CYC

72.9 + 42.2 97.7 ± 72.4

73.3 ± 35.2 97.8 ± 52.1

86.0 + 56.9 125.6 + 44.8

156 + 124.2 114.0 ± 62.5

BT CON CYC

0.5±0.2 0.6±0.3

0.8±0.5 0.5±0.1

0.8±0.5 0.7±0.3

0.7±0.1 0.84±0.5

CON: continuous infusion, CYC: cyclic infusion, SGOT: aspartate aminotransferase (U/l), GPT: alanine aminotransferase (U/l), GGT: gamma glutamyl transferase (U/l), FA: alkaline phosphatase (U/l), BT: total bilirubin (mg/dl).

Discussion This prospective, randomized clinical trial shows that both CON and CYC PN management regimens are safe and efficient methods of nutritional support in patients with BMT, with no significant differences existing between the groups. No significant variations in weight were observed in either group throughout the application of PN, or with regard to the quantity and quality of concomitant oral intakes. However, weight alone is not a very sensitive parameter because of significant changes in body composition in BMT patients (10). For this reason other anthropometric parameters (arm circumference, triceps skinfold) are also of limited use (11). Nitrogen balance is an excellent nutritional indicator but precise calculation is limited by episodes of vomiting and diarrhoea and by the difficulties in adequate urine collection. Despite this, there have been clinical trials in which no significant differences in nitrogen balance according to means of administering PN used have been reported (12,13). In BMT prealbumin is considered to be a more sensitive nutritional indicator for identifying acute changes in metabolic needs (14). In our study prealbumin levels were above the normal lower limit in both groups and there were no differences between initial and final levels within each group. In accordance with other authors (15-17) we consider that energy intakes of between 30 and 35 kcal/kg/day are adequate and are not significantly influenced by the means of application of PN (18). Levels of total protein and albumin improved in both groups and by the same magnitude throughout the trial. However, concentrations are influenced by hydration and infusion of blood products, and so despite the increase they

cannot be considered as useful nutritional indicators (13, 19, 20). Blood glucose levels were the same in both groups. Although those in the CYC PN group tended to have higher average levels, these remained within the normal. The results indicate that CYC PN does not significantly alter blood glucose levels (21-23). Patients who have undergone BMT often need at least 15-20 days of PN depending on their nutritional status. PN makes them especially susceptible to hepatic changes (24). The causes are diverse and among them must be emphasized the nature of the conditioning regimens, infections prior to BMT immunosuppressive medication, HVOD and parenteral nutrition itself (25-28). The increase in enzyme levels often takes place after 1-4 weeks following the initiation of PN (29). GGT, FA, SGOT and GPT are sensitive indicators of hepatic malfunction (30, 31). CYC PN, in contrast to CON PN, is associated with a circadian rhythm in the metabolism of glucose and lipids. This is characterized by oxidation mostly of lipids during the period off PN. This is associated with changes in the glucagon:insulin ratio, and liver triglyceride level, which were 2.5 times less than in CON PN (32-34). In this study, the incidence of HVOD and GVHD did not differ between the groups, nor did hepatoxicity and cholestasis. Although most patients showed a rise in temperature during the study, there was no evidence of fever related to PN or the catheter and we conclude that CYC PN did not involve a greater risk of infection (35). The application of CYC PN has enabled use of the central line for other purposes for a proportion of each day and avoids the use of another line, which is required in patients who receive CON PN. We suggest that the daytime interruption of PN could favour oral intake, although no significant differences existed in our patients since mucositis was very probably the limiting factor. Our data show that the mode of application of PN in this group of patients does not significantly influence nutritional parameters, secondary complications in PN, or therapy and clinical outcomes. In conclusion, CYC PN is as good as CON PN from a medical point of view, has practical advantages and is more comfortable for patients.

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