A multicentre study of the dose response effect of human recombinant growth hormone (rhGH) on cumulative nitrogen balance (CNB) in patients after major abdominal surgery

A multicentre study of the dose response effect of human recombinant growth hormone (rhGH) on cumulative nitrogen balance (CNB) in patients after major abdominal surgery

UNSR pmol/(min w Values Control 4.0&0.3’ Controt + vehicle 4.0+0.4 IL-I 7.0+0.3* During this period heart rate (HR) and forearm blood flow (RF) ...

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UNSR pmol/(min

w

Values

Control 4.0&0.3’

Controt + vehicle 4.0+0.4

IL-I 7.0+0.3*

During this period heart rate (HR) and forearm blood flow (RF) were also recorded at intervals. An adrenaline infusion was then commenced at a rate of 25 ng/kg IBW/min and was continued for 90 minutes. The above measurements were repeated during this time.

IL-1 + RU486 4.9 * 0.4

100 g

are mean

i

SEM. n = 0 in each

group.

‘: p < 0.01

Conclusion: The effect of interleukin-1 on hepatic aminoN catabolism for the major part is due to the action of the glucocorticoids that are released by the cytokine.

Results: Hours of Starvation ;: 72

Response of protein synthesis in human skeletal muscle to insulin, assessed with L-[d,])phenylalanine P.80

Hours of Starvation

M.A. McNurlan’, P. Esser?, A. ThorelF, A.G. Calder’, SE. Anderson’. 0. Ljungsqvis?, J. Wernerman and P.J. Garlick’ ’Rowett Institute, Aberdeen, UK and the ‘Department of Surgery, Karolinska Hospital and the Departments of Anesthesiology at 3Huddinge and 4 St. Gorans Hospital, Stockholm, Sweden

:6’ 72

‘p < 0.05,“p <

HR inc beatslmin 17.7+2 9 19.6f2.1 21.0+23 0.01

MR inc J/kg/min 11.4rt1.5 13.0f1.2 18.3f1.6”

Basal HR beatsfmin 62.1 f2.9 67.4f2.9’ 68.3f2.5’

Basal BF mlllO0 ml/min 3.73kO.43 5 13+0.62’ 6.12+0.96’

SF inc mlllOOml/min 3.92kO.59 3.94kO.69 4.97 f 0.72

During early starvation there is evidence of increased sensitivity to infused adrenaline. This is consistent with an increasing importance of sympathoadrenal mediated responses during developing starvation.

Insulin has been shown to stimulate muscle protein synthesis in growing animals while studies in man have not been able to demonstrate this. The flooding technique was used in animals, in contrast to continuous infusion in humans. This disparity in both results and methodology has prompted a study to investigate the effect of insulin on protein synthesis in human muscle studied with the flooding technique. Protein synthesis in quadriceps muscle of 6 postabsorptive young males was assessed immediately prior to and during a hyperinsulinemic (60 pU/ml) normal glycemic (4.5 mmol/l) clamp. Protein synthesis wasestimatedfrom the incorporation of label into protein of a muscle biopsy taken 90 min after injection of a flooding amount of L-[d,]phenylalanine (45 mg/kg, 7.5-l 5 atoms %). Injection of this amount of phenylalanine over 10 min minimizes errors in the estimate of precursor labelling, results in a minimal increase in plasma insulin (average 1 pU/ml over 90 min) and has not been reported to influence muscle protein synthesis. Moreover, there is a substantial analytical advantage allowing the use of gas chromatography-mass spectrometry even at enrichments as low as 0.005 atoms %. The rate of muscle protein synthesis during the control period was 1.65 +_ 0.3 % per day, compared with 1.66 + 0.4 during the clamp. Thus, the improved method, employing L-[d,]phenylalanine, has shown that muscle protein synthesis rate is not acutely sensitive to changes in insulin concentrations within the physiological range in healthyadult man.

P.82 Changes in resting metabolic rate in acute starvation are not related to changes in plasma catecholamines J. Webber and I.A. Macdonald Department of PhysiologyandPharmacology, cal Centre, Nottingham, UK

Queen’s Medi-

During acute starvation there are changes in resting metabolic rate (RMR) which are thought to be mediated via sympathoadrenal pathways. To examine this hypothesis we chose to measure plasma adrenaline and noradrenaline and RMR during starvation. Sixteen non-obese subjects (6 mate), aged 20-30 years were recruited. They attended on 3 occasions having fasted for 12, 36 or 72 hours. During this period they were allowed water ad libitum and consumed 80 mmol sodium chloride and 50 mmol potassium chloride per 24 hours. Arterialized venous blood samples for plasma catecholamine analysis were taken after the subject had been supine for at least 1 hour. RMR was measured by indirect calorimetry using a ventilated canopy system. Duration of starvation (hours) :: 72 ‘p c 0.05, “p

RMR

(J/kg/min) 72.48+1.79 78.29+2.11” 75.23 f 2.00 < 0.01 vs 12 hours

Noradrenaline (nmolll)

Adrenaline (nmolll)

0.71 f0.04 0.67+_0.05 0.86*0.07’

0.20~0.03 0.26+0.03 0.36iO.06”

RMR increases significantly by 36 hours and then decreases towards basal levels. Both adrenalineand noradrenaline levels are not significantly changed at 36 hours, but are increased at 72 hours. There are no significant correlations between the changes in RMR and those in plasma catecholamines during starvation. Thus there is no obvious sympathoadrenal explanation for the changes in RMR.

P.81 The time course of the effects of starvation on the thermogenic and cardiovascular responses to infused adrenaline J. Webber, and I.A. Macdonald Department of Physiology and Pharmacology, Hospital, Nottingham, UK

Basal MR J/kg/min 73.3+2.8 76.9f3 1 75.7Y12.3

University

Considerable adaptations occur in energy metabolism during starvation. These include a reduction in resting metabolic rate (RMR) and a switchover from the use of carbohydrate to that of fat as the main energy substrate. It has been proposed that changes in Sympathetic Nervous System (SNS) activity may be important in bringing about these alterations. We therefore chose to examine whether the responses to exogenous adrenaline changed during the first 72 hours of starvation. 9 healthy non-obese subjects (4 male), aged 20-30 years, were studied on 3 different occasions at 12.36 and 72 hours of starvation, with the studies done in random order. On each visit RMR and Respiration Exchange Ratio (RER) were measured continuously by indirect calorimetry for an hour.

P.83 A multicentre study of the dose response effect of human recombinant growth hormone (rhGH) on cumulative nitrogen balance (CNB) in patients after major abdominal surgery J.H. Lehner’. K. W. Jauch2, G. Berge?, J. Tacke’ and B. Savic4 ’Dept. of Surgery, City Hospital of Dortmund, ‘Dept. of Surgery, University of Munich, 3 Department of Surgery, University of Berlin, FRG and 4 Kabi Pharmacia AB, Sweden It has been shown in several investigations that rhGH has a protein saving effect in the postoperative state. However, an optimal dose has not yet been defined. In this study the effect 75

of different doses of rhGH on CNB was investigated in patients after major abdominal surgery. The study was randomized and comprised 104 patients. 24 patients were excluded from the efficacy analysis, whereof 12 were excluded according to the inclusion/exclusion criteria, 3 due to treatment with high doses of insulin and 9 because of incomplete CNB measurements. The 80 patients (F/M 33/47, age 41-75 years) remaining in the study had either recieved 0.075 (n = 21), 0.15 (n = 19) or 0.30 Ill/kg/day (n = 19) of rhGH (Genotropin, Kabi Pharmacia AB) or placebo (n = 21) for a period of five days, starting on the second day after surgery. All patients received TPN throughout the whole study period starting on the first postoperative day. A regression model was used for statistical analysis. CNB improved significantly (p = ~0.01) in the patients who received rhGH at 0.075 IU/kg/day (-4.2 + 12.8 g) or 0.30 Ill/kg/day (-4.3 k 9.6 g) compared to placebo, (-14.8 + 3.3 g), whereas the patients who received 0.15 Ill/kg/day (-12.7 & 10.0 g) did not demonstrate any significant difference versus placebo. The reason for this is not clear. Conclusion: rhGH treatment in postoperative patients improves CNB. The effect is not clearly related to the dose, and additional studies on dose and duration of treatment are warranted.

circulating levels of specific regulatory hormones in a group of severely injured, highly catabolic, multiple trauma patients (n = 22) and compared with corresponding controls (n = 37). Forty-eight to sixty hrs after injury, when the ebb/shock phase had subsided, an 8 a.m. blood sample was drawn when the patients were receiving maintenance fluids with electrolytes but no calories or nitrogen. The results (mean k SEM) are:

No/Sex Wt. ko Age ($s) BMI (kg/m2) ISS REE (% BEE) N lois IGF-I. ng/ml hGH, ng/ml Insulin, ullJ/ml C-Peptide, ngir Ill Glucose, mg/dl

(gN/d)

No/Sex Wt. kg Age (vrs) BMI (kg/m’) ISS REE (% BEE) N loss (gN/d) IGF-1, ng/ml hGH, ng/ml Insulin, ulU/ml C-Peptide, ng/ml -.

P.84 Effect of human growth hormone (rHGH) on lipoproteins in serum of surgical patients S. Hailer’, K.-W. Jauch* and G. Wolfram’.3

’Institute for Nutrition Department, Clinic Munich, FRG

Science, Weihenstephan, ‘Surgical Grosshadern and 3 Medical Polyclinic,

tillKxw?,

We investigated the effect of rHGH (Genotropin@) supplement to parenteral nutrition on normalization of decreased lipoproteins in catabolic state after operation. 48 metabolic healthy patients were randomized to receive placebo (0) or rHGH in a dosage of 0.075 (1); 0.15 (2); 0.3 (3) IE/kg BW. The parenteral nutrition was 50% carbohydrates, 50% fat (Intralipid 20%@), 0.15 g amino acids/kg BW according to energy expenditure. The study was approved by the Ethic Commission of the University of Munich. Triglycerides (TG), cholesterol (Ch) and apolipoproteins (apo A-l, A-II, B, E) in serum or lipoprotein fractions (VLDL, LDL, HDL) were determined before and on day 1, 4 and 7 after operation. Statistical evaluation was assessed. Serum ;;DL Serum Serum Serum VLDL Serum oay post opl

Group 0 :

7

z : 3

TG

25 :8” 79 1;: 149 208 206

z: 25 6543 102 122

Ch 115 131 107 135 159 149 155 158

ApoA-IApoB :: 85 109 107 :: 101

:: 68 79 112 108 118 104

ApoB 3

: 8

; 10 11

: 10 11

& Medical

Elderly

3M/2F 104k6 47ilO 37k2 30+1 149*13 21.3+4.1 79+7* 0.4+0.1 Ia*4 5.7*1 2 118+8

4M/2F

Controls II

:z 25?1 27f4 134?8 9.7L2.2 ao+10* 0.5+0.1 13+5 4.9+1.3 125+9’ ill

Obese

Elderly

6Ml6F 105*4 46+4 35*1

6Ml5F 8Ok6 69+2 28fl

136516 1 .l kO.6 19+2 3.2kO.5 103+7

;33+15 0.4+0.1 llf2 2.9f0.3 98f3

M. Mjaaland, R-O. Lindsetmo andA. Revhaug Department of Surgery, Tromsm University Hospital, Norway The study objective was to examine whether treatment with the somatostatin analogue SMS 201-995 influenced nitrogen balance after surgery and a postoperative (p.0.) endotoxin injection in an experimental model in pigs. Twelve piglets (19-29 kg) were studied in a paired fashion. They were treated with a continuous infusion of SMS 201-995 (Sandostatin) 24 pg/kg/day or placebo for 2 days preoperatively, peroperatively and the first four p.o. days. On the operation day, they underwent a standardized abdominal surgical procedure. On the second p.o. day, the piglets were given an injection of E. coli endotoxin (3 ngram/kg). On the sixth p.o. day, the piglets were sacrificed. On the operation day and the second p.o. day, the piglets were given saline infusion, the other days they were given parenteral nutrition (28 g nitrogen, 2240 kcal (55% from glucose and 45% from fat)). Throughout the observation period, the piglets were kept in metabolic cages. Urine was collected for nitrogen analysis and cumulative nitrogen balances for the p.o. period calculated. Results: Nitrogen intake in piglets with SMS 201-995 treatment was 4.1 + 0.3 g/kg body weight, with placebo treatment 4.2 + 0.4 g/kg (NS). Nitrogen excretion in SMS 201-995 treated piglets was 2.5 + 0.1 g/kg, in placebo treated 3.0 &- 0.1 (p = 0.07). Nitrogen balance with SMS

P.85 Acute insulin-like growth factor-l (IGF1) deficiency in multiple trauma victims M. Jeevanandam, N.J. Holaday and S.R. Petersen Hospital

;2a+21 2.9IO.6 6+0.6 1 .a+o.2 a5+3

Ill

P.86 SMS 201-995 treatment induced nitrogen retention after abdominal surgery and postoperative endotoxin injection

The results indicate a faster, dose-dependent effect of HGH on normalization of serum and VLDL-TG and apo B and serum apo E, but not of Ch or apo A-l and A-II in the catabolic state after surgery.

Trauma Center, St. Joseh’s Phoenix, AZ, USA

Normal I NOllobese Young 7MJ7F 76rt4 38f3 25+1

II Obese

The hypermetabolic and highly catabolic state of post-trauma is characterized by diminished levels of IGF-1 in a wide spectrum of patients. Inverse relationships of adiposity and aging on IGF-1 levels are seen both in injured and uninjured subjects.

APE

: 3

mg,*l

Trauma Patients I Nonobese Young 8M/3F 7623 30+3 26kl 30+2 143f7 15.4k2.0 113+14* 0.9f0.2’ 9+1* 4.1 iO.5’ 118k5’

Center,

Many of the anabolic effects of growth hormone (hGH) are mediated by IGF-1. The role of this anabolic IGF-1 in the early catabolic flow phase of severe injury as a function of age and adiposity are not established. We have measured the 76