Effects of clonidine on the pituitary hormonal response to pelvic surgery

British Journal of Anaesthesia 1997; 78: 134–137 Effects of clonidine on the pituitary hormonal response to pelvic surgery F. M. LYONS, S. BEW, P. SHEERAN AND G. M. HALL Summary We have investigated the effects of the central ␣2 adrenoreceptor agonist, clonidine, given i.v. before induction of anaesthesia, on the haemodynamic and endocrine responses to pelvic surgery. Twenty patients were allocated randomly to receive either clonidine 3 ␮g kg91 or an equivalent volume of 0.9% sodium chloride solution. Arterial pressure, heart rate, and circulating concentrations of cortisol, growth hormone, glucose and lactate were measured during and in the 24 h after total abdominal hysterectomy. Arterial pressure and heart rate decreased significantly in the clonidine group during surgery and in the early postoperative period. There were no differences between groups in serum cortisol or growth hormone concentrations throughout the study. Despite an effective decrease in the cardiovascular response to surgery, clonidine 3 ␮g kg91 i.v. had no significant effect on pituitary hormone secretion. (Br. J. Anaesth. 1997; 78: 134–137) Key words Hormones, glucocorticoid. Hormones, growth. Surgery, gynaecological. Surgery, hormonal response. Sympathetic nervous system, clonidine. Metabolism, glucose. The antihypertensive drug clonidine is a centrally acting ␣2 agonist.1 It is useful as a premedicant because of its sedative, anxiolytic and analgesic effects. Clonidine decreases the amount of isoflurane and fentanyl needed to supplement general anaesthesia and may offer myocardial protection to patients with cardiovascular disease.2 3 Recognized neuroendocrine effects of clonidine include inhibition of sympathoadrenal activity with decreased circulating catecholamine concentrations,4 5 decreased secretion of adrenocorticotrophic hormone (ACTH) and cortisol,6 and decreased secretion of insulin and enhanced growth hormone release (GH).7 8 After i.v. administration of clonidine, the maximum effect occurs within 60–90 min and the terminal elimination half-life is in the range 20–25 h.9 10 Two studies have examined the effects of oral premedication with clonidine on the early haemodynamic and endocrine changes associated with surgery. One study investigated neurosurgical patients and showed a decrease in the cortisol response with clonidine.11 The other showed that clonidine added to diazepam premedication, compared with diazepam alone, did not alter the cortisol and GH response to surgery.12 The purpose of this study was to examine the effects of preoperative i.v. clonidine on the haemodynamic and endocrine responses, during and in the 24 h after pelvic surgery. Patients and methods Approval for the study was obtained from the local Ethics Committee for clinical research (reference No. 94.05.17). Written informed consent was obtained from each patient. We studied 20 patients with benign disease undergoing total abdominal hysterectomy. Patients had no history of endocrine or cardiovascular disease. They were allocated randomly using sealed envelopes to receive either clonidine (n:10) or 0.9% sodium chloride (NaCl) solution (n:10) i.v. before induction of anaesthesia. Previous work indicated that a sample size of 20 patients had a power of 90% to detect a standardized difference of 1.5 in heart rate and systolic arterial pressure, at a significance level of 5%. Patients did not receive premedication. On arrival in the anaesthetic room an i.v. cannula was inserted for drug administration. Non-invasive monitoring of heart rate, arterial pressure and arterial oxygen saturation was commenced. A central venous catheter was inserted, via the antecubital fossa, for fluid administration and blood sampling. Baseline measurements of heart rate, arterial pressure and arterial oxygen saturation were recorded, and a blood sample was obtained for measurement of circulating hormones and metabolites. Patients then received either clonidine 3 ␮g kg91 in 0.9% NaCl solution 20 ml or 0.9% NaCl solution 20 ml, i.v. over 15 min. General anaesthesia was induced in all patients with fentanyl 4 ␮g kg91 and a sleep dose of thiopentone. Vecuronium 0.1 mg kg91 was used to facilitate F. M. LYONS, MB, BCH, BAO, FFARCSI, S. BEW, MA, MB, BS, FRCA, P. SHEERAN, MB, BCH, FFARCSI, G. M. HALL, MB, BS, PHD, FIBIOL, FRCA, Department of Anaesthesia, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE. Accepted for publication: October 17, 1996. Correspondence to: G. M. H. 135 Clonidine and pituitary hormones tracheal intubation. Anaesthesia was maintained with 0.5–1.5% isoflurane and 60% nitrous oxide in oxygen. Mean end-tidal isoflurane concentrations were 0.6 (SEM 0.1) % in the clonidine group and 0.7 (0.1) % in the saline group. All patients received 0.9% NaCl 6 ml kg91 h91 in the intraoperative period and 2 ml kg91 h91 after operation as i.v. maintenance fluid. Blood losses were replaced with an equivalent volume of Gelofusin. After operation, patients received patient-controlled analgesia with morphine. Blood samples were obtained and cardiovascular measurements made at the following times: before administration of placebo or clonidine, at skin incision (0 h) and at 1, 2, 4, 6, 12 and 24 h after skin incision. All samples were analysed in duplicate for blood glucose and lactate concentrations by methods described previously.13 Serum concentrations of cortisol and GH were measured with commercially available enzyme linked immunoassay kits. The sensitivity of the assay was 7.3 nmol litre91 for cortisol (Milenia Cortisol EIA) and 0.11 miu litre91 for growth hormone (Medgenix-HGH-EASIA). Intraassay coefficients of variation were 3.2% for cortisol and 2.1% for GH; inter-assay coefficients of variation were 8% for cortisol and 7% for GH. Packed cell volume (PCV) was measured using a microcapillary method. The investigator undertaking the analysis was unaware of the identity of the sample. Statistical analysis was undertaken using Statview SE; Graphics computer software (Abacus concepts, Berkeley, CA, USA). GH values were not distributed normally and are shown as median (range); values below the sensitivity of the GH assay were ascribed that value. All other hormonal, metabolic and cardiovascular variables are presented as mean (SEM). Differences within groups with respect to baseline samples were assessed by two-way analysis of variance with Dunnet’s test, and between-group differences by one-way analysis of variance. GH data were analysed using Friedman’s two-way analysis of variance and the Kruskal–Wallis test for differences between groups. P:0.05 was accepted as significant. Results The groups were similar in mean age (control 44 (range 36–52) yr, clonidine 46 (37–64) yr), body weight (control 66 (55–82) kg, clonidine 67 (60–86) kg), duration of surgery (control 80 (50–110) min, clonidine 75 (40–110) min) and 24-h morphine consumption (control 46 (19–87) mg, clonidine 54 (33–76) mg). Two patients received atropine 0.3 mg i.v. for bradycardia (heart rate -45 beat min91). CARDIOVASCULAR CHANGES Heart rate was unchanged throughout the study in the control group from the baseline value of 80 beat min91. In the clonidine group, heart rate decreased significantly from the baseline value of 78 beat min91 until 4 h after operation (P:0.05). There was a significant difference in heart rate between the groups at skin incision (P:0.01), and at 1 and 2 h (P:0.05). Systolic arterial pressure decreased significantly from baseline at skin incision and at 4 h (P:0.05) in the control group. In the clonidine group, systolic pressure decreased significantly from baseline at skin incision and at 1, 2, 4, 6 (P:0.01) and 12 h (P:0.05). There was a significant difference in systolic arterial pressure between the groups at skin incision (P:0.01), and at 1 and 2 h (P:0.05). Diastolic arterial pressure did not change from baseline in the control group throughout the study. In the clonidine group, diastolic pressure decreased significantly from baseline at skin incision, 1 h (P:0.01) and 4 h (P:0.05). There was a significant difference between groups at skin incision (P:0.01) and at 2 h (P:0.05). CIRCULATING HORMONES AND METABOLITES (TABLE 1) Serum concentrations of cortisol increased significantly from a baseline value of 603 nmol litre91 at 1, 2, 4 and 6 h (P:0.05) in the control group, and Table 1 Mean (SEM) blood glucose, blood lactate, and serum cortisol concentrations and packed cell volume (PCV). Growth hormone concentrations are presented as median (range). Within group differences: *P:0.05; ** P:0.01. B:Baseline B 0h 1h 2h 4h 6h 12 h 24 h Control vs clonidine 5.3 (0.3) 6.4* (0.2) 6.6** (0.5) 6.4* (0.4) 6.2* (0.4) 6.1* (0.3) 5.9* (0.3) 6.4* (0.6) 6.2* (0.5) 6.3* (0.5) 5.2 (0.4) 6.6* (0.7) P:0.05 at 1 h 0.63 (0.08) 0.71 (0.06) 0.96 (0.14) 0.72 (0.09) 0.72 (0.11) 0.69 (0.08) 0.52*(0.05) 0.77 (0.15) 0.67 (0.11) 0.77 (0.11) 0.74 (0.11) 0.76 (0.08) P:0.05 at 4 h 973* (88) 1036* (57) 1120** (43) 1183**(45) 1016* (101) 935* (163) 1146**(78) 885* (134) 955 (95) 814 (74) 683 (113) 622 (94) ns 6.0* (0.5–131) 13.2** (7.0–45.4) 11.6 (0.3–35) 8.7 (2.0–29.7) 4.5 (0.5–20.1) 3.5 (1.5–11.9) 1.8 (0.3–5.2) 2.7 (0.6–12.9) 6.1 (1.9–23.7) 9.9 (1.1–19.7) 4.7 (2.1–23.5) 4.8 (2.1–19.5) ns 35 (0.9) 35 (1.4) 34 (0.8) 34 (1.4) 34 (1.0) 34 (1.3) 34 (0.7) 34 (1.8) 33 (0.8) 32 (2.3) 33 (0.8) 32 (1.4) ns litre91) Blood glucose (mmol Control 4.3 (0.4) 5.4 (0.4) Clonidine 4.3 (0.2) 5.1 (0.3) Blood lactate (mmol litre91) Control 0.84 (0.08) 0.81 (0.08) Clonidine 0.86 (0.06) 0.65 (0.10) Serum cortisol (nmol litre91) Control 603 (65) 581 (81) Clonidine 536 (69) 501 (69) Serum GH (miu litre91) Control 2.1 11.2* (0.3–17.7) (0.3–85.9) Clonidine 0.6 7.8* (0.3–14.9) (3.4–78.9) PCV (%) Control 39 (0.7) 35 (0.8) Clonidine 40 (1.1) 36 (1.3) 136 from a baseline value of 536 nmol litre91 at 1, 2, 4 (P:0.01) and 6 h (P:0.05) in the clonidine group. However, there were no significant differences between groups. In both groups serum concentrations of GH increased transiently from baseline values at skin incision and at 1 h (P:0.05 in the control group, P:0.05 and :0.01 in the clonidine group). There were no significant differences between groups. Blood glucose values increased significantly at 2 (P:0.01), 4, 6 and 12 h (P:0.05) in the control group and at all times, other than skin incision, in the clonidine group (P:0.05). At 1 h, blood glucose concentration was significantly greater in the clonidine group than in the control group (P:0.05). Blood lactate concentrations did not change significantly throughout the study in the control group. In the clonidine group, blood lactate concentration was significantly lower than baseline at 4 h (P:0.05), and was also significantly lower at this time compared with the control group. PCV decreased from baseline in both groups of patients, but this change was not statistically significant. There was no significant difference between groups. Discussion We have shown that clonidine 3 ␮g kg91 i.v. decreased the cardiovascular, but not the pituitary hormonal, response to pelvic surgery. The physiological response to surgical trauma includes an increase in circulating concentrations of the catabolic hormones, such as catecholamines, cortisol and GH, and a concomitant decrease in plasma concentrations of the anabolic hormones, such as insulin and testosterone.14 Most anaesthetic techniques do not prevent these changes, but high doses of opioids and regional anaesthesia can modify the pituitary and sympathoadrenal response to surgery. In this study, patients treated with clonidine had a decreased haemodynamic response to surgery, as shown by the lower values of heart rate, and systolic and diastolic arterial pressures, for 4 h after surgical incision. Thus the dose and method of administration of clonidine were adequate to test the hypothesis that clonidine could attenuate pituitary hormone secretion in addition to the cardiovascular response. However, we have clearly demonstrated no difference in GH and cortisol values after administration of clonidine. Two previous studies have reported variable effects of clonidine on serum cortisol changes associated with surgery. In a study of 20 neurosurgical patients in which a significant decrease in serum cortisol concentration was reported, no samples were collected before oral administration of clonidine, and patients receiving high doses of steroids for less than 3 days were not excluded.11 Pouttu and colleagues studied 21 patients undergoing breast surgery and found no difference in serum cortisol and GH concentrations when clonidine premedication was used. However, interpretation of the data is complicated by the use of British Journal of Anaesthesia diazepam premedication in the clonidine and control groups,12 as benzodiazepines are known to alter ACTH and GH secretion.15 16 In both of these studies, blood sampling was continued for a maximum of 3 h after surgery. As clonidine has a long half-life, neither study has assessed the effect of clonidine over an appropriate time period. The hyperglycaemic response to surgery is multifactorial and results from increased secretion of catabolic hormones, particularly adrenaline and cortisol. Blood glucose concentrations increased significantly in both groups after surgery. Clonidine did not attenuate the hyperglycaernic response, despite the sympathoadrenal inhibition indicated by the haemodynamic changes. Paradoxically, blood glucose was significantly greater in the clonidine group 1 h after skin incision. A transient glycaemic effect of clonidine with an acute dose has been demonstrated, and clonidine is associated with direct inhibition of insulin secretion.7 9 Our findings suggest that any hypoglycaemic effect of clonidine secondary to decreased sympathoadrenal activity is overcome by a direct inhibitory effect on the ␤-cells of the pancreas, and other catabolic hormones released in response to surgical stress. We conclude that clonidine 3 ␮g kg91 i.v. at induction of anaesthesia failed to alter the pituitary–adrenal response to pelvic surgery. References 1. Jarrott B, Conway EL, Maccarrone C, Lewis SJ. Clonidine: understanding its disposition, sites and mechanism of action. Clinical Experimental Pharmacology and Physiology 1987; 14: 471–479. 2. Maze M, Tranquilli W. Alpha 2 adrenoceptor agonists: defining the role in clinical anesthesia. Anesthesiology 1991; 74: 581–605. 3. Aantaa R, Scheinin M. Alpha2 adrenergic agents in anaesthesia. 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