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OBJECTIVE: To study the effects of growth hormone (GH) and insulinlike growth factor 1 (IGF-1) on whole body and gastrointestinal (GI), hepatic, femoral, and renal glutamine (GLN) uptake and release in septic piglets. SUMMARY BACKGROUND DATA: The GI metabolism of GLN is impaired during sepsis, and this may contribute to a breakdown of the gut's mucosal barrier. GH treatment has produced increased GI GLN uptake in surgical stress. Little is known about the effects of GH and IGF-1 in sepsis. METHODS: Twenty-four piglets were randomized to three groups of eight each: a GH group received a bolus of 16 IU of Genotropin; an IGF-1 group received a continuous infusion of 1.3 mg/hour of IGF-1; and a control group received saline. After surgical preparation, sepsis was induced with live Escherichia coli bacteria. Using isotope technique, whole body turnover and organ-specific absolute uptake and release were measured before and 4 hours after sepsis. RESULTS: After sepsis, both GH and IGF-1 treatment increased GI GLN uptake compared with controls and induced hepatic release of GLN. GLN release from skeletal muscle was diminished in all groups after sepsis. Whole body GLN turnover was increased in the GH and IGF-1 groups compared with the controls, before and after sepsis. CONCLUSIONS: GH and IGF-1 treatment induced increased GI net uptake of GLN. GH and IGF-1 treatment also promoted absolute and net release of GLN from the liver. This release might facilitate increased GI uptake despite reduced hindleg release in the early phase of sepsis.

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BACKGROUND: Insulin-like growth factor 1 (IGF-1) mediates anabolic actions in catabolic states and also influences the immune system. Endogenous IGF-1 production is suppressed in sepsis; replacement therapy is therefore a natural approach to obtain the protein anabolic and potentially immune-stimulating effects of IGF-1. METHODS: Twenty-two piglets were randomized to three groups: an IGF-1 group (n = 8) receiving a continuous infusion of 1.3 mg/h of IGF-1, a nontreated septic control group (n = 8), and a nonseptic control group (n = 6) receiving saline. Phagocytosis and respiratory burst in porcine neutrophils were evaluated by flow cytometry (FCM); tumor necrosis factor (TNF) levels were measured in serum during the septic period. In addition, human neutrophils and monocytes were primed in vitro with IGF-1 and subsequently were stimulated with phorbol myristate acetate (PMA) or Escherichia coli; phagocytosis and respiratory burst were evaluated by FCM. RESULTS: Under nonseptic conditions, pretreatment with IGF-1 suppressed the ability of neutrophils to ingest bacteria (ie, the level of phagocytosis) 43.4% +/- 2.7% (IGF-1-treated) vs 55.8% +/- 3.4% (nontreated septic controls) and 57.3% +/- 3.34% (nonseptic controls) (p = .01). When challenged by live E. coli infusion, phagocytosis increased in the IGF-1 group to the levels of the nontreated group. The respiratory burst showed a convincing priming effect of IGF-1. After 4 hours of sepsis, the mean fluorescence intensity was 63.1 +/- 6.9 in the IGF-1 group and 40.7 +/- 3.0 in nontreated septic controls. The serum levels of TNF-alpha in the nontreated septic control group were twice those in the IGF-1-treated group, ie, 65.7 +/- 13.1 pg/mL in the nontreated septic controls and 31.5 +/- 7.5 pg/mL in the IGF-1 group (p = .03). In vitro priming of human neutrophils and monocytes with IGF-1 and subsequent stimulation with PMA or E. coli demonstrated that IGF-1 enhanced both phagocytosis and respiratory burst. CONCLUSIONS: IGF-1 serves as a priming agent for biologic functions of leukocytes.

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Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may be beneficial against the protein catabolism seen in injury and septicemia. Further understanding of their effects on carbohydrate metabolism is needed. In a septic porcine model receiving total parenteral nutrition, pretreatment with GH or IGF-1 (or no treatment in controls) was followed by an infusion of live Escherichia coli bacteria. Endogenous glucose production, carbohydrate oxidation, glucose and lactate fluxes over the liver, gastrointestinal organs, kidney, and hindleg were determined. Endogenous glucose production increased during septicemia in the GH group. The metabolic acidosis induced by septicemia was augmented by GH, but attenuated by IGF-1. The alanine and lactate levels were significantly higher in the GH- than in the IGF-1 treated animals during septicemia. IGF-1 pretreatment appeared to induce favorable effects while GH pretreatment might produce unfavorable effects on carbohydrate metabolism in septic piglets.

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OBJECTIVE: To investigate if growth hormone (GH) or its main mediator insulin-like growth factor-1 (IGF-1) alters the response to infusion of live Escherichia coli in injured pigs. DESIGN: Controlled experiment. SETTING: University laboratory, Norway. SUBJECTS: 30 piglets. INTERVENTIONS: The response to infusion of Escherichia coli was compared after a bolus of GH 16 IU (n = 8) or a continuous infusion of IGF-1 1.3 mg/hour (n = 8) in injured piglets. A group with trauma (surgery) and Escherichia coli infusion (n = 8) and a group with trauma only (n = 6) served as controls. MAIN OUTCOME MEASURES: Systemic and regional haemodynamics, oxygen consumption, and acid-base regulation; and circulating concentrations of catecholamines, free fatty acids (FFA), glucose, and lactate Results: After infusion of Escherichia coli, cardiac output was lower and heart rate was higher in the GH than in the IGF-1-treated group. Aortic pH was lower in the GH group compared with the septic controls, whereas aortic pH was higher in the IGF-1 group compared with the septic controls. Portal vein pH was lower in the GH group than in the other three groups. Free fatty acids and lactate concentrations were higher in the GH group than in the other three groups. Glucose concentrations were lower in the IGF-1 group than in the other three groups. Renal artery flow was higher in the IGF-1 than in the GH group and the septic controls. Circulating concentrations of dopamine was higher in the IGF-1 group than in the other three groups, whereas that of noradrenaline was higher in the GH group than in the IGF-1 group. (For all differences stated, p < 0.05). CONCLUSIONS: Acute treatment with GH increased the circulatory and metabolic response to Escherichia coli infusion, in contrast to treatment with IGF-1, which reduced the response

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The aim of this study was to assess the influence of growth hormone (GH) in sepsis on the immune system represented by the circulating TNF-levels and the neutrophil leukocytes phagocytic capacity and respiratory burst, 22 piglets were randomized to 3 groups; pretreatment with GH (16 i.u.) before sepsis (n = 8), non-treated septic controls (n = 8), and non-septic controls (n = 6). Sepsis was induced by a standardized infusion of live E. coli. TNF was measured by a cytotoxic bioassay, while neutrophil function tests were carried out by flowcytometric assays. In brief, phagocytosis was evaluated by the neutrophils' ability to ingest FITC-labelled (fluorescein isothiocyanate) E. coli and intracellular release of oxygen metabolites was detected by the oxidation of 2',7'-dichlorofluorescin (DCFH) to the fluorescent 2',7'-dichlorofluorescein (DCF). Our data show a suppression of phagocytosis in the GH-treated group before sepsis; however, when challenged with Gram-negative bacteria, the phagocytic capacity was similar to that of the non-treated animals. The serum levels of TNF in the non-treated septic control group were twice the levels of those in the GH-treated group, 65.7 pg/ml (septic controls) vs 32.8 pg/ml (GH). Pretreatment with a single dose of GH few hours prior to sepsis does not seem to entail any further imbalance of the neutrophil function in sepsis. Lowering of the circulating TNF-levels is a presumptive favourable effect of GH in sepsis.

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OBJECTIVE: The authors studied the effect of exogenous glutamine (GLN), with and without growth hormone (GH), pretreatment, on gastrointestinal, hepatic, femoral, and renal GLN fluxes. SUMMARY BACKGROUND DATA: Growth hormone treatment increases gastrointestinal uptake of GLN despite a reduced skeletal muscle and whole body release. METHODS: Piglets were randomized to a GH + GLN group (n = 8), a GLN group (n = 8), a GH group (n = 8), and a control group (CON; n = 8). Genotropin (Pharmacia, Stockholm, Sweden; 24 international units; correspondingly saline in the GLN and the CON group) was given daily 3 days before and at the onset of trauma (surgery). Organ fluxes and whole body release of GLN were determined 1 and 5 hours after surgery. An infusion of GLN 36 micrograms/kg per minute was started after the first measurement in the GH + GLN and the GLN groups. RESULTS: Both GH treatment and exogenous GLN increased gastrointestinal GLN uptake (p = 0.001 and p = 0.02, respectively). Growth hormone treatment reduced hepatic GLN uptake (p = 0.001). Hepatic GLN uptake was lower in the GH + GLN group versus the GH group (p = 0.02), but not in the GLN group versus the CON group (p = 0.98). Growth hormone treatment reduced femoral and whole-body GLN release (p = 0.0001 and p = 0.02, respectively). Renal GLN uptake was higher in the two GH-treated groups (p = 0.003). CONCLUSION: Both exogenous GLN and GH increased gastrointestinal GLN uptake, and the combination was additive. In contrast to exogenous GLN, GH reduced hepatic uptake and consequently facilitated the increased gastrointestinal GLN uptake that occurred despite reduced femoral and whole-body release.

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OBJECTIVE: To study hemodynamic effects of growth hormone (GH) and its main mediator, insulin-like growth factor-1, in a model of critical illness. DESIGN: Randomized experiment in traumatized and septic piglets. MATERIALS AND METHODS: Hemodynamics and blood gases before and sustained volume loss during a controlled, fatal hemorrhage were recorded in a GH treated group (n = 8), an insulin-like growth factor-1 treated group (n = 8), a control group with trauma and sepsis (n = 8), and a control group with trauma only (n = 6). MEASUREMENTS AND MAIN RESULTS: Sustained volume loss before cardiac arrest was lower in the GH group. The GH group was characterized by metabolic acidosis. During the hemorrhage, visceral blood flow (portal and renal) as a fraction of cardiac output (fractional flow) was lower and peripheral fractional flow higher in the GH group. Fractional renal artery flow was higher in the insulin-like growth factor-1 group (p < 0.05 for the comparisons stated). CONCLUSION: GH promoted metabolic acidosis in traumatized sepsis and impaired compensation of a subsequent hemorrhage.

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Gastrointestinal, hepatic, and hindleg oxidation of 3H-labelled oleic acid and 14C-labelled glucose based on arterial-venous differences in 3H2O and 14CO2 were studied before and after an intravenous injection of 24 IU of growth hormone in 10 piglets. Hepatic oleic acid oxidation increased transiently while gastrointestinal oleic acid oxidation decreased correspondingly, maintaining a constant splanchnic oleic acid oxidation. Administration of a growth hormone led to a transient, parallel decrease in both hepatic and gastrointestinal glucose oxidation. We conclude that, in contrast to the growth hormone effect on splanchnic glucose oxidation, growth hormone effect on splanchnic fat oxidation appears to be organ specific.

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The aim of this study was to assess whether the protein sparing effects associated with administration of growth hormone (GH) and glutamine in the early post traumatic period deprive the gastrointestinal tract of substrates. Sixteen piglets were randomized to receive GH treatment (n = 8) for 3 days prior to surgery whilst a control group (n = 8) received no growth hormone. Organ fluxes of glucose, lactate, pyruvate, alanine and glutamine were measured at 1 and 5 h after surgery. An infusion of glutamine (36 microg/kg/min) was started after the first measurement in both groups. In the GH group (5 h after surgery), hindleg release of glutamine and alanine was found to be lower than in the control group, whilst intestinal glutamine uptake was higher and that of alanine was lower. Hepatic alanine uptake was reduced whilst hepatic glutamine exchange switched from uptake to release. Intestinal glucose consumption was lower in the GH group (P < 0.05). It is concluded that GH pre-treatment in combination with exogenous glutamine administration induced a shift in gastrointestinal fuel selection which was associated with reduced glucose consumption and increased glutamine consumption. The effect of GH in inducing hepatic release of glutamine compensated for its effect on muscle which results in reduced peripheral glutamine release.

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Endothelin-1 belongs to a family of potent vasoconstrictors, recently isolated from endothelial cells. Endothelin-1 has a variety of hepatic effects and hepatic clearance from the circulation is important. Elevated plasma concentrations of Endothelin-1 are found after orthotopic liver transplantation and in cirrhosis with ascites. This study in piglets on hepatic bloodflow was designed to compare differences in effects between central venous and intraportal injection of endothelin-1, and to evaluate effects of repeated injections. Central venous injection of endothelin-1 caused a larger reduction in portal vein flow, while intraportal injection caused a larger increase in portal vein pressure. Repeated injections resulted in a reduction in portal vein flow and an increase in portal vein vascular resistance.

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OBJECTIVE: To clarify the effects of growth hormone (GH) given three days before and at the start of a standard abdominal operation or at the start of the abdominal operation alone in piglets. DESIGN: Randomised experiment. SETTING: University hospital, Norway SUBJECTS: Twenty-four piglets. INTERVENTIONS: GH 24 IU was given intramuscularly for either three days before and on the morning of the operation or on the morning of a standard abdominal operation only (n = 8 in each group) A further 8 piglets acted as untreated controls. MAIN OUTCOME MEASURES: Diameter of fibres in the soleus and gastrocnemius muscles; urinary nitrogen excretion; and fat and carbohydrate oxidation measured by indirect calorimetry. RESULTS: Nitrogen excretion was reduced (in the three days group the mean (SEM) was 30.8 (4.2) mg/kg, corresponding figures from the one day group and the controls were 37.6 (5.8) and 55.4 (3.1) mg/kg, respectively, p = 0.004). Fat oxidation increased (for the whole period: p = 0.014) and carbohydrate oxidation decreased (p = 0.02) in the one day group only. The diameter of type I muscle fibres was increased in both muscles (soleus, three day group, mean (SEM) 37.5(1.4) microns compared with control, 30.4(0.6) microns, p = 0.001, and gastrocnemius, three day group 38.6(1.3) microns compared with control, 30.8(1.4) microns, p = 0.01). CONCLUSIONS: Three days treatment with GH enhanced nitrogen sparing and attenuated changes in fat and carbohydrate oxidation induced by one day treatment, but induced hypertrophy of type I muscle fibres.

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This study examined whether growth hormone treatment deprived the intestinal tract of glutamine after trauma. Piglets were treated with growth hormone 24 units daily 3 days before and at the start of the trauma (GH-3, n = 8) or at the start of the trauma only (GH-1, n = 8). Eight piglets acted as non-treated controls. The trauma consisted of a standardized abdominal surgical procedure. Primed constant infusions of U-14C-glutamine were given. Intestinal, hepatic, renal and hindleg glutamine fluxes were measured. Growth hormone treatment increased mean(s.e.m.) net intestinal glutamine uptake: GH-3, 39.7(9.4) and 48.7(12.7) mumol/min; GH-1, 33.2(5.5) and 25.7(12.3) mumol/min; controls, 19.5(10.3) and 2.0(15.3) mumol/min at 1 h and 5 h after trauma, respectively, (P = 0.02). The treatment increased glutamine oxidation (P = 0.025), and decreased hindleg glutamine net (P = 0.0052) and absolute release (P = 0.0063), glutamine rate of appearance (P = 0.01), and percentage of glucose coming from glutamine (P = 0.05). Growth hormone treatment before trauma increased intestinal glutamine uptake.

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OBJECTIVE: The study clarified the effects of growth hormone treatment on forearm amino acid efflux in patients with full nutritional support after gastrointestinal surgery. SUMMARY BACKGROUND DATA: Growth hormone attenuates net nitrogen loss after surgical trauma. An increase in net protein synthesis has been described, whereas the results regarding protein breakdown have been conflicting. METHODS: Elective patients undergoing abdominal surgery were double blindly randomized to treatment with recombinant human growth hormone (GH, n = 9) 24 IU or placebo (PL, n = 10) the first 5 postoperative days. All received parenteral nutrition (nitrogen = 5.7 +/- .1 g/m2, energy = 1018 +/- 12 kcal/m2 (125 +/- .7% of BMR) and epidural analgesia. Amino acid plasma levels and forearm fluxes were measured. RESULTS: The second postoperative day, growth hormone abolished forearm efflux of total amino acid nitrogen (GH: 170 +/- 117, PL: -785 +/- 192 nmol/100 mL/min, p = .0007) due to reduced losses of both essential and nonessential amino acids. Glutamine release was abolished (13 +/- 15 vs. -137 +/- 43 nmol/100 mL/min, p = .007) and alanine release attenuated (-61 +/- 17 vs. -211 +/- 51 nmol/100 mL/min, p = .01). 3-Methyl-histidine release was attenuated (-.20 +/- .11 vs. -.62 +/- .09 nmol/100 mL/min, p = .04). Growth hormone also induced decreased venous plasma amino acid levels. CONCLUSIONS: When given after gastrointestinal surgery in patients treated with total parenteral nutrition, growth hormone treatment abolished glutamine, 3-methylhistidine, and total amino acid nitrogen loss from forearm tissue. Alanine loss from forearm tissue was attenuated.

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Patients undergoing elective abdominal surgery were double-blindly randomized for treatment with growth hormone (GH) 24 IU (n = 9) or placebo (n = 10) the first 5 postoperative days while receiving total parenteral nutrition (nitrogen, 5.7 +/- .1 g/m2; energy, 1,018 +/- 12 kcal/m2, ie, 125% +/- .7% of basal metabolic rate [BMR]). Carbohydrate and fat metabolism were evaluated from indirect calorimetry, daily blood samples, and forearm substrate-flux studies. Hormone levels in plasma or blood were also determined. GH decreased carbohydrate oxidation, increased fat oxidation, and increased resting energy expenditure (REE). Free fatty acids (FFA), glycerol, and beta-hydroxybutyrate (beta-OH-B) levels increased in both arterial and venous plasma, and forearm release of FFA and glycerol increased. GH, insulin-like growth factor 1 (IGF-1), and glucagon levels in venous blood were also increased in GH-treated patients. Thus, GH induced mobilization and utilization of fat, and fat was preferred to glucose for energy requirements in patients after abdominal surgery with nutritional support.

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Nineteen patients undergoing elective gastrointestinal surgery were randomised to receive recombination human growth hormone (n = 9) or placebo (n = 10) for the first five postoperative days. All received epidural analgesia and total parenteral nutrition during the same period (energy supply 125% of basal metabolic rate, mean nitrogen (+/- SEM) 5.7 (+/- 0.1) g/m2). Nitrogen and potassium retention was induced in the growth hormone group compared with the placebo group (cumulative nitrogen balance 4.1 (+/- 1.1) g/m2 in the growth hormone group and -3.1 (+/- 1.8) g/m2 in the placebo group, p less than 0.01; cumulative potassium balance 80.8 (+/- 4.7) mmol/m2 in the growth hormone group and 43.1 (+/- 11.4) mmol/m2 in the placebo group, p less than 0.01). In the growth hormone group, serum glucose concentrations increased each evening and mean serum albumin concentrations were reduced throughout the period; the morning pulse rates were decreased, and the patients gained weight compared with the placebo group.

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Thromboplastin activity of monocytes from blood of seven patients with total hip replacement was investigated. At 24 h and 48 h after surgery, thromboplastin activity was significantly increased compared to the activity before surgery. Thromboplastin activity of endotoxin-stimulated monocytes was significantly increased at 24 h after surgery. There were no significant changes in Factor V after surgery, Factor VII was significantly lowered at 24 h after surgery, while Factor VIII and fibrinogen were significantly increased at 72 h after surgery. The results indicate that monocyte thromboplastin may be a thrombogenic factor after total hip replacement surgery.

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Gut motility research is a field where rapid progress is being made. We expect that, in future, diagnosis and treatment of motility disorders will become an important part of gastroenterology. Various techniques are now available for studying motility. This paper reviews one of them, namely recording and interpreting gastrointestinal myoelectric activity.

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The results of lateral retinacular release were evaluated in 28 patients with idiopathic chondromalacia patellae. Follow-up was performed 3-5 years after the operation. At follow-up 13 patients were improved, while the symptoms were equal or intensified in 15 patients. However, compared with the situation before the operation, the levels of activity were increased in only two patients, while the levels of activity were unchanged or reduced in the remaining 26 patients. From this study it is concluded that the results of lateral retinacular release for idiopathic chondromalacia patellae are poor with regard to relief of symptoms, and especially with regard to improvement in ability to perform physical activities.

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