Original

Communications

Protein and Energy Metabolism with Biosynthetic Human Growth Hormone in Patients on Full Intravenous Nutritional Support G. A. PONTING, M.S., F.R.C.S.,* H. C. WARD, F.R.C.S.,t D. HALLIDAY, PH.D., A. J. W. SIM, M.S., F.R.C.S.* From the

*

Academic

1NY and &dag er; Division Harrow HA1 3UJ, United Kingdom

Surgical Unit, St. Mary’s Hospital, London W2

ABSTRACT. Our objective was to examine the effect of biosynthetic human growth hormone (BSHGH) on protein and energy metabolism in patients on full intravenous nutrition (IVN). Fifteen patients who had been established on IVN were allocated at random to receive either BSHGH (0.1 mg/kg/day) or placebo daily for 7 days. All patients received the same feeding regimen which contaminated 14 gN, 1000 kcal of glucose and 1000 kcal of fat (Intralipid) daily. The mean nitrogen balance for days 4 to 7 was significantly more positive with BSHGH (7.0 ± 0.6 gN/day) than with placebo (4.4 ± 0.7 gN/ day). The BSHGH group were lighter (53 ± 4.6 kg body weight) than controls (68 ± 5.1 kg), but the difference was not signifi-

The effects of

growth

hormone administration

on

ni-

trogen excretion were first described in rats by Cuthbertson et all and, later by Young.2 The reduced nitrogen excretion, in rats, was associated with an increase in whole body protein and a decrease in whole body fat.’

Subsequently, purified extracts of human pituitary have in most cases demonstrated improvement in nitrogen balance in man.4-12 One study, however, failed to demonstrate any significant effect in patients undergoing hernia repair. 13 Recent developments in genetic engineering using recombinant DNA techniques in an E. coli host (Somatonorm-KabiVitrum), have led to the synthesis of biosynthetic human growth hormone (BSHGH). Studies of the effects of BSHGH on protein metabolism have demonstrated improved nitrogen balance in healthy human subjects receiving intravenous nutritional support&dquo; (IVN), or in surgical patients after major gastrointestinal operations receiving maintenance fluids&dquo; or hypocaloric nutrition.16 No previous study has investigated the effects of BSHGH in patients receiving IVN. PATIENTS AND METHODS

at

Patients who were established on IVN were allocated random to receive either BSHGH (0.1 mg/kg/day) or

Reprint requests: G. A. Ponting, Academic Surgical Unit, St. Mary’s Hospital, Praed Street, London, W2 1NY, United Kingdom.

AND

of Clinical Sciences, Clinical Research Centre,

Resting energy expenditure (expressed as percentage of day 1) increased throughout the study in patients receiving BSHGH (day 7, 120.8 ± 5.5%), whereas in patients receiving placebo it remained stable (day 7, 98.9 ± 2.7%). The nonprotein respiratory quotients were similar for BSHGH (mean days 4-7, 0.94 ± 0.04) and placebo (mean days 4-7, 0.93 ± 0.01) 0.05). This study demonstrates more positive nitrogen p ( > balance, which may in part be due to different substrate loads, and an increase in energy expenditure in patients receiving BSHGH. ( :437Journal of Parenteral and Enteral Nutrition 14 cant.

441, 1990).

placebo, by daily intramuscular injection for 7 days. Those with diabetes, on corticosteroids, or who had evidence of either sepsis or metastatic malignant disease were excluded. During days 4 to 7 of the study all patients received the same feeding regimen which contained 14 gN, 1000 kcal of glucose and 1000 kcal of fat (Intralipid), in a 3-liter bag infused over 24 hr via a central venous catheter.

Samples of venous blood were drawn for estimation of glucose, plasma free fatty acids, serum insulin, serum somatomedin C, and plasma fibronectin on days 1, 2, 3, 5 and 7. Free fatty acids, insulin and somatomedin C were measured by radioimmunoassay. Fibronectin was measured using a turbidimetric immunoassay. Urine was collected throughout the study, and urinary nitrogen excretion was analyzed using the Kjeldhal technique. Nitrogen balance was calculated by subtracting output from input, without allowance for fecal or inte-

blood

gumentary losses.

Nitrogen turnover was measured on the 4th or 5th day study using a primed continuous infusion of 15Nglycine over 24 hr. Isotope enrichment in urinary urea was measured by mass spectrometry using an aliquot from the second 12-hr urine collection.17 Whole body protein synthesis was derived by subtracting urinary nitrogen excretion from turnover, and whole body protein breakdown by subtracting the nitrogen input from whole body nitrogen turnover. The values for synthesis of the

and breakdown

were

437 Downloaded from pen.sagepub.com at UNIV OF WINNIPEG on August 13, 2015

converted

to

grams of

protein by

438

multiplying by 6.25. Net synthesis was derived by sub- on each of the 7 days, but the difference was only significant on days 3, 4 and 7 (fig. 1). Whole body protein tracting breakdown from synthesis. Oxygen consumption and carbon dioxide production turnover was 12.6% and synthesis 22% higher in the were measured daily using a microcomputer-controlled patients receiving BSHGH, whereas breakdown recontinuous flow indirect calorimeter18 (Calostar 90, Femained virtually unchanged. Although net protein synthesis was significantly greater (p < 0.05), the other nyves and Gut, Basel, Switzerland). The system has been validated using alcohol combustion and gas dilution.19 changes in whole body protein metabolism were not Resting energy expenditure and the non-protein respi- significant (Table III). The resting energy expenditure (expressed as per cent ratory quotient were calculated as described by Frayn.2o Energy expenditure values are expressed as a percentage of day 1) in subjects receiving placebo remained stable of control (day 1). (98.9 ± 2.7% on day 7) (Table IV, Fig. 2), whereas in the Blood samples and indirect calorimetry were performed on day 1 before the administration of BSHGH, and were used as control values. Results are described as the mean ± SEM. Statistical analysis was by the twotailed Mann Whitney U-test. The study was approved by the District Ethical Committee. Informed consent was obtained from all patients.

BSHGH it gradually rose throughout the study to 120.8 ± 5.5% that of initial values. When comparing the daily percentage increase between BSHGH and placebo, these increases were significant (p < 0.05) on days 4, 5, 6 and 7. The non-protein respiratory quotients between days 4 and 7 were similar for placebo (0.93 ± 0.01) and BSHGH (0.94 ± 0.04) (p > 0.05) (Table

subjects receiving

V).

Although the blood glucose levels were higher in patients receiving BSHGH on days 3, 5 and 7 of the study, Seven patients received BSHGH and eight received these differences were not significant (Table VI). Both placebo. Although the subjects receiving placebo (68 ± insulin and somatomedin-C levels increased progres5.1 kg body weight and 44.4 ± 3.1 kg lean body mass sively throughout the study in patients receiving (LBM) were heavier than those receiving BSHGH (53 ± BSHGH. Somatomedin-C appeared to reach maximal 4.6 kg body weight and 37.2 kg LBM), the difference was levels on day 5 (Table VII). Plasma fatty acid levels were not significant (p > 0.05) (Table I). The ages were similar higher in the patients receiving BSHGH (Table VIII), for patients receiving BSHGH (56 ± 6.5 years) and but the control values were also higher in these patients placebo (58 ± 64 years). The placebo group received a than those on placebo. On subsequent days there was no mean of 30.4 ± 2.1 kcal/kg/day (non-protein kcal) and significant differences between the two groups. the BSHGH group 40.5 ± 4.3 kcal/kg/day (p > 0.05). Plasma fibronectin levels, when expressed as per cent No clinically obvious adverse effects were observed from of day 1, were significantly higher with BSHGH on days the administration of either BSHGH or placebo. The 2, 3 and 5 (Table IX). patient details and there diagnoses are indicated in Table I. DISCUSSION The mean daily nitrogen balance for days 4 to 7 was 4.4 ± 0.7 gN (67 mgN/kg/day) for those receiving placebo This is the first study investigating the effects of and 7.0 ± 0.6 gN (146 mgN/kg/day) for those receiving BSHGH in patients on full IVN. A significant improveBSHGH (p < 0.05) (Table II). The daily nitrogen bal- ment in nitrogen balance has been demonstrated. Howance was more positive in the patients receiving BSHGH ever, the smaller body weight in the patients receiving RESULTS

TABLE I

Age, diagnosis, weight and lean body

*

p>

0.05 for all

mass

of the patients studied*

comparisons.

Downloaded from pen.sagepub.com at UNIV OF WINNIPEG on August 13, 2015

439 TABLE II

decrease in breakdown. In the absence of any specific

Nitrogen input, output and balance

Values are the * p < 0.05.

BSHGH

mean

means

±

effect of

growth hormone on glycine metabolism, the assumption that glycine is a representative amino acid as an isotope carrier should be valid. We have demonstrated increases in whole body protein turnover, synthesis and net protein synthesis with BSHGH, although the effects were not marked, and did not reach significant levels. Other studies, particularly during hypocaloric nu-

SEM.

that this group received

a

greater sub-

load, and thus a more positive nitrogen balance would be expected. The differences in LBM were less strate

tritional support, have shown a more marked effect on whole body protein metabolism.1.5.16.22 The gradual increase in energy expenditure without significant changes in the non-protein respiratory quotient in patients receiving BSHGH indicates an overall increase in substrate oxidation without any switch toward fat utilization. This contrasts with the previous studies15,16 using BSHGH in postoperative patients which demonstrated progressive increase in energy expenditure and fat oxidation in patients receiving BSHGH. A possible explanation is the higher levels of insulin seen in this study, which would tend to inhibit

lipolysis. The finding of raised levels of somatomedins in patients receiving BSHGH agrees with previous work.15,16,22 Somatomedins are thought to act as mediators of growth hormone activity23 and, as such, may be involved in the stimulation of protein synthesis in a variety of tissues. 23,24 It has been suggested that somatomedins are indicators of the adequacy of nutritional support25°2s which, if true, implies that in this study the patients receiving BSHGH might be making better use of the infused nutrients. Previous workers have reported a raised plasma glucose and impaired glucose tolerance2’ with the adminissurface area 15-45% ).21 tration of growth hormone. Blood glucose levels were not Changes in nitrogen balance can be brought about by elevated in patients receiving growth hormone, whereas either an increase in whole body protein synthesis or a insulin levels continued to increase throughout the study.

marked than the differences in body weight, indicating that the patients receiving BSHGH had a relatively greater fat mass. The possibility that differences in body weight could, at least in part, explain the improvement in nitrogen balance remains. Previous studies in animals,2,3 patients with burns,g°11 and volunteers&dquo; have all demonstrated significant improvements in nitrogen balance. Greenbaum3 has demonstrated that if growth hormone is continued for 2 weeks, then an increase in whole body protein occurs in rats. Other authors have not shown a significant effect when BSHGH is given within 24 hr of severe burns (burn

or

Downloaded from pen.sagepub.com at UNIV OF WINNIPEG on August 13, 2015

FIG. 1. Nitrogen balance with BSHGH.

placebo

440 TABLE V

TABLE III Whole

*

p




comparison).

TABLE VI

percentage of control

Blood

Values

are

the

glucose levels (mmol/liter)

mean +

SEM

(p

>

0.05 for all

comparisons).

TABLE VII Insulin and somatomedin C levels Values are given ± SEM. * p < 0.05.

Values are the mean ± SEM. * p ~ 0.05.

TABLE VIII

Plasma-free fatty

acids

nMO

p > 0.05 when each group.

comparing

groups, but

no

significant increase

within

TABLE IX Plasma fibronectin (mg/liter)

-

mmmwm

FIG. 2. crol.

Thus

Resting

energy

I

t&dquo;ïé1c.;~UO

expenditure expressed

as

percentage of

growth hormone produced a relative

con-

insulin resist-

&dquo; p

Protein and energy metabolism with biosynthetic human growth hormone in patients on full intravenous nutritional support.

Our objective was to examine the effect of biosynthetic human growth hormone (BSHGH) on protein and energy metabolism in patients on full intravenous ...
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