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It has been suggested that the incidence of early graft occlusion after arterial reconstructive surgery to the leg may be decreased by epidural analgesia. This effect may be mediated by the suppression of the usual cortisol response to surgery, which results in increased circulating plasminogen activator inhibitor-1 with consequent adverse effects on fibrinolysis. To investigate this and other potential mechanisms, 30 patients undergoing arterial reconstructive surgery to the leg were randomized to receive either general anaesthesia or general anaesthesia plus epidural analgesia. Post-operative analgesia was provided by morphine infusion or epidural analgesia, respectively. Blood samples were collected at 0, 2, 4, 6, 12 and 24 h, and 2, 3 and 5 days and analysed for cortisol, plasminogen activator inhibitor-1 antigen, interleukin-6 and beta thromboglobulin. The incidence of graft-related and systemic complications was recorded for 30 days. Only one patient developed early graft occlusion that required embolectomy and eventually amputation. There were no significant changes from control values in either group of patients in circulating cortisol, plasminogen activator inhibitor-1 and beta thrombogobulin (a marker for platelet degranulation). Interleukin-6 values increased significantly in both groups after 4 h and remained elevated until day 3. There were no significant differences between the groups in any variable measured. We conclude that any effect of epidural analgesia on early graft patency is unlikely to be mediated by fibrinolysis or platetlet degranulation.

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In vitro studies suggest that volatile anaesthetic agents may directly inhibit insulin secretion. It is unclear if supplementation of anaesthesia with isoflurane impairs insulin secretion. We performed a 5-g i.v. glucose tolerance test in 21 patients before and during anaesthesia which was maintained with either 1 or 2 MAC of isoflurane in nitrous oxide, or no volatile agent. The study was carried out before surgery to avoid the influence of hormonal responses to trauma. A significant glycaemic response occurred during both i.v. glucose tolerance tests in all three groups of patients. Serum insulin concentrations were measured and the acute increase in insulin concentration at 3 min and area under the curve for 15 min were calculated. Both variables decreased significantly in all three groups during the tests performed under anaesthesia compared with tests carried out before anaesthesia.

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BACKGROUND: The endocrine and immune changes associated with surgery are well documented, but the interaction between them has not been fully evaluated. Cortisol production during surgery can be suppressed by etomidate and we have used this to investigate the relationship between the cortisol response and immune changes in the perioperative period. METHODS: We have measured the cortisol, interleukin-6 and white cell responses to elective abdominal hysterectomy in 8 healthy female patients, who received etomidate 0.3 mg kg-1 for induction of anaesthesia. A control group of 8 subjects received thiopentone. Both groups of patients received vecuronium and fentanyl 2 micrograms kg-1 and anaesthesia was maintained with nitrous oxide in oxygen and isoflurane 0.5-1.0%. Venous blood samples were collected before and during surgery and up to 24 h in the postoperative period. RESULTS: Serum interleukin-6 values were significantly greater at 6 and 12 h (P < 0.05) in those patients who received etomidate. Inhibition of the serum cortisol response to surgery in the etomidate group was also associated with less marked lymphopenia at 4 h (P < 0.05). There was no significant difference in neutrophil granulocyte counts between the two groups. CONCLUSION: In conclusion, endogenous corticosteroids modulate the interleukin-6 response to surgery.

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We have investigated the hormonal and metabolic effects of thoracic extradural analgesia with bupivacaine in addition to sufentanil 20 micrograms kg-1 in nine patients undergoing coronary artery bypass surgery. A control group received general anaesthesia alone. The catecholamine response was inhibited for 24 h after surgery in patients who had received extradural analgesia, and the cortisol response was suppressed during cardiopulmonary bypass. Blood glucose values were unchanged until 24 h after surgery in the extradural group. There were no significant differences in cardiac index between the two groups of patients, although heart rate and mean arterial pressure decreased before surgery in patients who received extradural analgesia. The benefits of this technique in terms of a reduction in postoperative morbidity remain to be determined.

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Pharmacological doses of growth hormone (GH) in humans and rats increase plasma and muscle glutamine values. As major surgery results in a physiological rise in serum GH concentration, we investigated whether this physiological increase in GH altered glutamine metabolism. Eighteen patients undergoing coronary artery bypass graft (CABG) surgery were randomly assigned to receive somatostatin, 100 micrograms subcutaneously at induction of anaesthesia and 8 hourly for 48 h, or placebo. Somatostatin effectively blocked the physiological surge of GH following injury but did not affect plasma or muscle glutamine concentrations, which fell significantly in both groups. Plasma glutamine decreased by 31% (P < 0.01) and 28% (P < 0.01) in the control and somatostatin groups respectively. Muscle glutamine was reduced 45% (P < 0.001) in the control group and 50% (P < 0.001) in the somatostatin group. There was no difference in muscle or circulating glutamate, alanine or branched chain amino acid concentrations or in metabolite values between the somatostatin-treated patients and the control group. There was no relationship between the GH response to surgery and glutamine metabolism following major surgery.

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Serum concentrations of the cytokine, interleukin-6 (IL-6), increase after surgical trauma. IL-6 mediates the synthesis of acute phase proteins and stimulates secretion of pituitary hormones. We have examined the time course of circulating IL-6, and cortisol and growth hormone responses in patients undergoing hysterectomy to determine if IL-6 contributes to the early pituitary hormone changes found during surgery. One group (n = 8) received a standardized general anaesthetic while the remaining patients (n = 8) received extradural analgesia to T4-S5 in addition to a similar general anaesthetic. In the general anaesthesia group, there was a significant increase in serum cortisol and growth hormone concentrations before any changes in IL-6 were detected. Furthermore, in the extradural group, in whom these hormonal responses were attenuated, circulating IL-6 concentrations did not differ significantly from the general anaesthesia group. There were no significant differences between the groups in the acute phase response, as measured by circulating concentrations of C-reactive protein and zinc, but the expected effects of extradural block on circulating metabolites and white cell count were demonstrated. We conclude that IL-6 is unlikely to contribute to the initial increases in secretion of pituitary hormones found during surgery, but a later effect of the cytokine on endocrine responses cannot be excluded.

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Cholinergic blockade markedly reduces the growth hormone (GH) response to most stimuli, with the exception of insulin induced hypoglycaemia. We have administered the cholinergic antagonist, atropine, known to cross the blood brain barrier, to eight healthy female patients prior to elective surgery in order to investigate the role of cholinergic pathways in the GH response to surgery. Additionally, eight patients received the octapeptide analogue of somatostatin, octreotide, known to suppress GH secretion. A control group matched for age and weight received no injection. The GH response to surgery was assessed by peak values and areas under curves. Octreotide resulted in a significant inhibition of GH secretion compared with the control group (p < 0.01 for both parameters). In contrast, atropine did not significantly inhibit the GH response to surgery. In conclusion, octreotide completely suppressed GH secretion during surgery, whereas cholinergic blockade was ineffective. Thus surgery is similar to insulin induced hypoglycaemia poglycaemia in that the GH response is not decreased by cholinergic blockade.

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We have investigated the effects of isoflurane on insulin secretion in vitro from rat isolated islets of Langerhans and found a significant, dose-related and reversible inhibition of insulin secretion. Isoflurane 2% decreased insulin secretion stimulated by glucose 20 mmol litre-1 to basal, nonstimulated values. In other studies to identify the stage in the stimulus secretion pathway for insulin at which the anaesthetic may exert an inhibitory action, we have stimulated insulin release using glyceraldehyde and a phorbol ester. Insulin secretion induced by these secretagogues was also blocked by isoflurane. This suggests that the inhibitory effect of the anaesthetic agent may be at a site distal to stimulation of insulin secretion by glyceraldehyde and phorbol esters.

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Isolated, cultured rat pancreatic islets of Langerhans were incubated in medium containing glucose 2 or 20 mmol litre-1 and with glucose supplemented with midazolam 10, 100 or 1000 ng ml-1. Glucose 20 mmol litre-1 with the addition of noradrenaline 10 mumol litre-1 was used as a control. In contrast with noradrenaline, midazolam did not inhibit glucose-induced insulin secretion. Noradrenaline 10 mumol litre-1 inhibited secretion to basal values in response to glucose 20 mmol litre-1 (P < 0.001).

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We have investigated the effects of midazolam on circulating concentrations of pituitary and pancreatic hormones in eight healthy patients during cholecystectomy and compared the changes with those in a control group of eight patients. Anaesthesia was induced either with midazolam 0.42 mg kg-1 i.v. followed by an infusion of midazolam 0.125 mg kg-1 for 1 h, or with a sleep dose of thiopentone. All patients received vecuronium, and the lungs were ventilated with 0.5-1.0% halothane and 70% nitrous oxide in oxygen. The use of midazolam was associated with a significant decrease (P less than 0.05) in secretion of cortisol and insulin during surgery. Serum growth hormone secretion was augmented, but this did not reach statistical significance. There was little difference in the concentrations of circulating metabolites between the two groups, except for a significant decrease in blood glucose (P less than 0.05) in the midazolam group after 60 min. There were no marked differences in cardiovascular variables between the two groups of patients.

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We have measured plasma histamine concentrations, systemic vascular resistance, cardiac output and arterial pressure during laparotomy in a patient with systemic mastocytosis. The patient developed vasodilation and hypotension during surgery, associated with a massive increase in plasma histamine concentration.

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We have investigated the effect of the addition of somatostatin and trimetaphan to sufentanil 20 micrograms kg-1 on the hormonal responses to cardiac surgery and compared the changes with a control group receiving sufentanil and sodium nitroprusside. Eighteen patients undergoing elective valve replacement surgery were studied. Patients who received somatostatin and trimetaphan in addition to sufentanil had significantly smaller serum growth hormone and plasma glucagon concentrations compared with those who received sufentanil and sodium nitroprusside. The cortisol response to surgery was inhibited in both groups. There were no significant differences in catecholamine concentrations between the two groups. There was no effect of the additional inhibition of glucagon and growth hormone on circulating concentrations of glucose and lactate, but plasma concentrations of non-esterified fatty acids increased significantly. Thus the addition of somatostatin increased the suppression of the hormonal response to cardiac surgery by sufentanil.

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We have studied the metabolic and hormonal responses to surgery, and the pain scores and analgesic requirements in 24 patients undergoing cholecystectomy, allocated randomly to three groups to receive either general anaesthesia alone, or general anaesthesia with extradural diamorphine 0.1 mg kg-1, or general anaesthesia with extradural somatostatin to a total dose of somatostatin 3 mg. The only significant effect of extradural diamorphine was a decrease in the glucose response to surgery. Somatostatin 3 mg by the extradural route caused a significant increase in the concentration of circulating somatostatin which resulted in a significant decrease in plasma growth hormone and insulin after 60 min of surgery, together with an increase in plasma glycerol concentration. Patients in the diamorphine group required significantly less i.v. analgesia in the postoperative period than the other two groups. Intraoperative somatostatin failed to provide any postoperative analgesia.

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