Clonidine premedication improves metabolic control in type 2 diabetic patients during ophthalmic surgery{dagger}

M. Belhoula, J. P. Ciébiéra, A. De La Chapelle, N. Boisseau, D. Coeurveille and M. Raucoules-Aimé

Department of Anaesthesia, Hôpital l‘Archet, 151 Route de Saint Antoine de Ginestière BP, F-3079-06202 Nice, Cedex 3, France

Corresponding author. E-mail: anesthesiologie@chu-nice.fr
{dagger}This article is accompanied by Editorial II.

Accepted for publication: November 8, 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. In stressful conditions, increasing blood glucose concentrations are closely related to an increase in catecholamines and cortisol release. Clonidine, a centrally acting {alpha}2-adrenoceptor agonist, has neuroendocrine effects, including inhibition of sympathoadrenal activity. We therefore evaluated the effect of clonidine on blood glucose control and insulin requirements during ophthalmic surgery when given as premedication in type 2 diabetic patients.

Methods. After randomization, patients were premedicated with clonidine or flunitrazepam (control). Patients were given insulin by continuous i.v. infusion to maintain blood glucose in the range 5.5–11.1 mmol litre–1. Blood glucose concentrations were measured every 15 min during surgery, and hourly for 6 h after surgery. Plasma C-peptide and counter-regulatory hormones were also measured.

Results. Glycaemia was significantly lower in the clonidine group (P<0.01) and the median amount of insulin administered was significantly reduced: clonidine group 9.0 (interquartile range 5.1) units; control 18.6 (10.2) units; P<0.01). Plasma catecholamine concentrations were lower in patients given clonidine (P<0.05) but there was no difference in cortisol concentrations.

Conclusion. Premedication of type 2 diabetic patients with clonidine 90 min before surgery improves blood glucose control and decreases insulin requirements during ophthalmic surgery.

Br J Anaesth 2003; 90: 434–9

Keywords: blood, glucose; complications, diabetes; metabolism, hyperglycaemia; sympathetic nervous system, catecholamines; sympathetic nervous system, clonidine


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In stressful conditions, and particularly in diabetes mellitus, the release of epinephrine and norepinephrine results in excessive hyperglycaemia. The pivotal role of catechol amines manifests itself in their glycogenolytic and lipolytic effects, in suppressed insulin activity and in stimulation of the pituitary–adrenocortical axis.1 Catecholamines increase the hepatic production of glucose, and this response is intensified by the increased sensitivity of the tissues of diabetic patients to catecholamines.2 Cortisol prolongs and amplifies the hyperglycaemic effects of catecholamines by stimulating gluconeogenesis, and by increasing insulin resistance.1

In patients with diabetes mellitus undergoing surgery, the therapeutic strategy must be to mimic normal metabolism as closely as possible. The administration of exogenous insulin, which suppresses endogenous glucose production (both glycogenolysis and gluconeogenesis) and stimulates glucose use, counteracts the metabolic effects of hormonal changes caused by surgical stress. However, insulin therapy, whatever the insulin regimen used, exposes the patient to the risk of hypoglycaemia (5–10%).3 Perioperative blood glucose may also be controlled by reducing the intensity of the hormonal and metabolic responses to surgical stress.4 Clonidine, an {alpha}2-adrenoceptor agonist, reduces sympathetic tone and the release of norepinephrine from nerve terminals.5 6 There is controversy concerning the effect of clonidine on the pituitary–adrenocortical system, but decreased release of adrenocorticotrophic hormone (ACTH) and cortisol has been reported.7 8 The use of clonidine during ophthalmic surgery has been proposed as a way of improving perioperative haemodynamics, decreasing both the intraocular pressure and anaesthetic requirements.9 10 We postulated that clonidine given as premedication would reduce insulin requirements and improve blood glucose control in type 2 diabetic patients undergoing ophthalmic surgery.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study was conducted on 40 patients with type 2 diabetes mellitus undergoing elective surgery and general anaesthesia. Twenty-six patients were taking oral hypoglycaemic agents (sulfonylurea hypoglycaemics, biguanides). Six patients controlled their blood glucose concentration by diet alone, and eight patients were treated with insulin. Three types of procedure were performed: vitrectomy (n=12), cataract extraction (n=20), and glaucoma surgery (n=8). The study was approved by the Ethics Committee of the University Hospital Centre (CCPPRB), Nice, and informed consent was obtained from all patients. Those with autonomic nervous system dysfunction (Valsalva manoeuvre, respiratory sinus arrhythmia, isometric hand grip test, changes between recumbent and erect arterial pressure values), diabetic ketoacidosis during the preoperative period, bradycardia, impaired renal function (creatinine >100 µmol litre–1), or impaired hepatic function (based on routine liver function tests) were excluded from the study. None of the patients received ß-blockers, antidepressants, neuroleptics, corticosteroids, catecholamines or non-steroidal anti-inflammatory agents before or during surgery. No patients were treated with {alpha}2-adrenoceptor agonists before surgery. Insulin and sulfonylurea hypoglycaemics were discontinued the night before surgery, and biguanides 72 h before surgery. Patients fasted from the night before surgery (i.e. for 12–14 h). Surgery began before 10:00 a.m.

Patients were randomized to receive oral premedication with either clonidine or flunitrazepam (control). Clonidine (Catapressan, Boehringer Ingelheim, France) was given as a function of the patient’s weight: 225 µg if the weight was less than 55 kg; 300 µg if it was 55–74 kg; 375 µg if it was over 75 kg. In the control group, 1 mg of flunitrazepam (Rohypnol, Roche, France) was given to patients weighing less than 60 kg and 2 mg to patients over 60 kg. All patients were premedicated 90 min before surgery.

Insulin therapy was started just before induction of anaesthesia. Patients received a short-acting insulin (Actrapid HM, Novo, France) 1.25 units h–1 by continuous i.v. infusion from a pump-driven syringe (40 units in 31 ml 0.9% saline solution; 1.25 units=1 ml) through a separate peripheral cannula. The problem of insulin adsorption in the syringe was overcome by using high concentrations of insulin and allowing the first 4 ml to flush through the apparatus. Concurrently, a continuous infusion of 5% glucose was given via the same venous cannula at 125 ml h–1 (6.25 g h–1). A second venous cannula was used to infuse other medications or 0.9% saline for volume expansion. (Fluids containing glucose and lactate were prohibited.) Anaesthesia was induced when the blood glucose was between 5.5 and 11.1 mmol litre–1. If the concentration was less than 5.5 mmol litre–1, the rate of glucose infusion was briefly increased; if it was greater than 11.1 mmol litre–1, additional insulin (5 units) was given as an i.v. bolus until blood glucose was less than 11.1 mmol litre–1. In both groups, when blood glucose exceeded 11.1 mmol litre–1 during or after surgery, an additional i.v. bolus of insulin was given in the following fashion: 5 units if blood glucose was in the range 11.1–14.0 mmol litre–1; 7 units if blood glucose was in the range 14.0–17.0 mmol litre–1; 10 units if blood glucose was greater than 17.0 mmol litre–1.

Anaesthesia was induced with thiopental 5 mg kg–1 and tracheal intubation was facilitated with vecuronium 0.1 mg kg–1. Fentanyl was used at induction 2 µg kg–1 and during anaesthesia. Anaesthesia was maintained with 0.8–1% isoflurane in 50% nitrous oxide in oxygen. Muscle relaxation was maintained with vecuronium. In response to hypertension and/or tachycardia, supplementary doses of i.v. fentanyl 50 µg were given. Ventilation was controlled to maintain end-tidal PCO2 between 35 and 40 mm Hg. Muscle relaxation was not reversed after surgery.

The study began just before induction and ended 6 h after surgery. Capillary concentrations of glucose were measured every 15 min during surgery and hourly in the postoperative period using reagent strips (Glucotrend glucose, Roche, France) and an automatic glucose analyser (Glucotrend, Boehringer Mannheim, Germany). Plasma C-peptide, catecholamines, cortisol and growth hormone were measured in venous samples just before induction (S1), 2 min after tracheal intubation (S2), during surgery (S3), immediately after the completion of surgery and tracheal extubation (S4), and at 3 and 6 h (S5 and S6) after surgery. All venous blood samples were collected from an antebrachial vein catheter in the arm not used for the infusion. Plasma C-peptide, cortisol and growth hormone were analysed by radioimmunoassay using commercial kits (Specific C-peptide radioimmunoassay kit, Bio-Rad; ADVIA Centaur Cortisol, Bio-Rad; growth hormone IRMA, Immunotech) with coefficients of variation (interassay) of 2.5%, 3.0% and 1.1%, respectively. Sensitivities were 0.05 pmol litre–1, 5.5 nmol litre–1 and <0.1 mU litre–1, respectively. Epinephrine and norephinephrine were measured by high-pressure liquid chromatography and electrochemical determination, with a 2% coefficient of variation for concentrations tested (interassay). Sensitivities were 0.1 and 0.3 nmol litre–1, respectively. Laboratory glucose concentrations at S1 were determined by the hexokinase-glucose-6-phosphate dehydrogenase method (DuPont Instruments, USA), with a 1.4% coefficient of variation (interassay) for the concentrations tested. Haemoglobin A1c (HbA1c) was measured by chromatography.

The following variables were analysed: systolic and mean arterial pressure and heart rate (measured every 5 min during surgery); capillary glucose concentrations (measured before induction of anaesthesia, every 15 min during anaesthesia and hourly for 6 h after surgery); the total amount of insulin and the number of additional boluses administered, plasma C-peptide and counter-regulatory hormone concentrations from S1 to S6.

Statistics
Statistical analyses of the differences among the various sample times and in the capillary glucose concentrations were made using two-way ANOVA for repeated measurements. An unpaired two-tailed t-test was used to compare values between the groups. Comparisons in one group between two time points were performed using a two-tailed t-test for paired data. The total amount of insulin and the number of additional boluses of insulin used were analysed using non-parametric statistical tests. Hormonal values were not distributed normally and were analysed using Friedman’s two-way analysis of variance and the Kruskal–Wallis test for differences between groups. Values below the sensitivity of the assay (epinephrine and norepinephrine) were ascribed these values. The resulting P values were adjusted by Bonferroni’s method. Results are expressed as mean (SD) or as median and interquartile range (IQR). P<0.05 was considered statistically significant. Statistical analysis was performed using the STATVIEW statistical program.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The two groups were similar with respect to surgical procedure (Table 1), duration of diabetes (clonidine group 10.7 (SD 1.2) yr; control group 11.1 (1.5) yr), and preoperative control of glycaemia, as determined by HbA1c (clonidine group: 8.4 (0.5)%; control group: 8.1 (0.6)%), capillary glucose concentrations measured just before the induction of anaesthesia (S1) or treatment used. The doses of fentanyl given to the two groups were not significantly different (clonidine group: 115 (32) µg; control group: 138 (31) µg; P=0.617).


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Table 1 Patient data, blood glucose concentrations just before induction of anaesthesia (S1) and duration of surgery. Data are numbers or means with SD or range in parentheses
 
Blood glucose concentrations were significantly lower in the clonidine group (two-way repeated ANOVA) during surgery (P<0.01) and during the 6 h after surgery (P<0.01) (Fig. 1). The time courses for changes in the concentrations were significantly different (P<0.01), and there was a significant interaction between the group and time variables (P<0.01). Similarly, patients given clonidine required significantly less insulin to maintain blood glucose concentrations in the range 5.5–11.1 mmol litre–1. Over the whole study period, the median amount of insulin administered was 9.0 (IQR 5.1) units and 18.6 (10.2) units (P<0.01) for the clonidine and the flunitrazepam groups, respectively. The number of additional boluses given was 0.0 (IQR 1.0) and 2.0 (1.0), respectively (P<0.01). No hypoglycaemic episode (blood glucose concentrations <3.3 mmol litre–1) was noted in the two groups but 45 glucose values below 5.5 mmol litre–1 were noted in the clonidine group (mean 4.7 mmol litre–1, range 3.7–5.4 mmol litre–1) and none in the control group (P<0.001).



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Fig 1 Mean (SD) blood glucose concentrations in the clonidine and control groups during surgery and the 6 h after surgery. *P<0.01 for comparisons between groups.

 
The plasma catecholamine concentrations of patients given clonidine were lower (P<0.05) before anaesthetic induction (S1) and during the course of the study (Table 2). The time courses for changes in the concentrations were significantly different (P<0.01) and there was an interaction effect between the group and time variables for epinephrine (P<0.05). There was no difference in cortisol concentrations (P=0.32) (Table 2). During the course of surgery (Table 2) plasma growth hormone concentrations were higher in patients given clonidine (P<0.01). The time courses for changes in the concentrations were significantly different (P<0.01) and there was an interaction effect between the group and time variables (P<0.05). The plasma C-peptide concentrations of the two groups were similar just before induction of anaesthesia (S1). In the clonidine group, plasma C-peptide concentrations decreased during the course of the study (P<0.01); the difference was significant between the groups only for the postoperative period (P<0.01) (Table 2). The time courses for changes in the concentrations were significantly different (P<0.01) and there was an interaction effect between the group and time variables (P<0.01).


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Table 2 Hormone values before surgery (S1), 2 min after tracheal intubation (S2), during surgery (S3), after tracheal extubation (S4), and at 3 and 6 h after surgery (S5, S6). Data are medians with interquartile range in parentheses. NS, not significant
 
The systolic and mean arterial pressures in the control group were significantly higher before and during surgery (P<0.01). The heart rate was lower after tracheal intubation and during surgery in the clonidine group (P<0.05).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The increase in blood glucose in diabetic patients during the first hours of a stressful event is closely related to an increase in catecholamines.11 This study shows that clonidine given as premedication decreases the requirement for insulin and improves blood glucose control during ophthalmic surgery. This improved metabolic control is associated with lower plasma concentrations of catechol amines.

Hyperglycaemia must be avoided in diabetic patients during surgery because sustained hyperglycaemia produces glycosuria and a subsequent osmotic diuresis, which results in fluid and electrolyte imbalances. A rise in serum osmolality results in hyperosmolar states, accompanied by hyperviscosity, thrombogenesis, and impaired central nervous system function.12 Published data also suggest that impaired wound healing and strength and impaired phagocytic function may also occur with hyperglycaemia. A high plasma concentration of free fatty acids increases the incidence of cardiac arrhythmia during anaesthesia,12 and provides a substrate for hepatic ketogenesis. Tight peri operative metabolic control has therefore been proposed to reduce this morbidity.13 Insulin infusion counteracts the metabolic effects of hormonal changes induced by surgery,11 but insulin regimens expose the patient to hypoglycaemic reactions3 and have no action on insulin resistance resulting from the release of catecholamines. In our study, in spite of increased amounts of insulin, the increase in blood glucose in the control group gave evidence of this insulin resistance. The use of clonidine to suppress increased catecholamine release and thus improve blood glucose control during surgery is a rational approach. {alpha}2-Adrenoceptor agonists inhibit the release of catecholamines through the activation of central presynaptic inhibitory {alpha}2-adrenoceptors and there is a dose-dependent reduction in the plasma catecholamine concentration after oral clonidine.6 This central and peripheral effect of clonidine may explain the improvement in metabolic control that we observed. In non-diabetic patients the effects of {alpha}2-adrenoceptor agonists on glucose concentration are variable and depend on the type of surgery14 15 and the dose administered.7 16 Low doses of clonidine can cause hyperglycaemia,14 17 while at doses of about 4.0 µg kg–1 and over the hyperglycaemic response becomes suppressed.7 16 Our study confirms that in diabetic patients high-dose clonidine attenuates the glycaemic response to surgery. No hypoglycaemic reaction occurred in the clonidine group but we noted that the number of blood glucose concentrations below 5.5 mmol litre–1 was increased. We cannot exclude a potential risk for hypoglycaemia when clonidine is systematically associated with administration of insulin.

Previous studies have reported variable effects of clonidine on serum cortisol changes associated with surgery and these differences were not explained by the dose of clonidine used.7 8 14 In the study of Gaumann and colleagues,7 a significant decrease in serum cortisol was found but no samples were collected before oral administration of clonidine, and patients receiving high doses of steroids were not excluded. On the other hand, Pouttu and colleagues8 and Lyons and colleagues14 found no difference in serum cortisol after clonidine premedication. More recently Venn and colleagues18 have shown that dexmedetomidine, a new potent and highly selective {alpha}2-adrenoceptor agonist, does not inhibit adrenal steroidogenesis. We did not find any changes in plasma cortisol concentration, but interpretation of our data is complicated by the use of flunitrazepam premedication in the control group. Benzodiazepines are known to alter ACTH secretion.19 Clonidine stimulates the release of growth hormone, and oral clonidine has been proposed as a growth hormone stimulation test. We observed an increase in plasma growth hormone concentration but this increase did not alter glycaemic control. This may seem surprising, but the deleterious effect of increased growth hormone concentrations on blood glucose in diabetic patients during surgery is probably not as pronounced as the effect of catecholamines or cortisol.16 However, our study was relatively short and we cannot exclude the possibility that a change in glycaemic control could occur later in the postoperative period, because the effects of growth hormone on glucose homeostasis take several hours to develop.1 13 Plasma C-peptide concentrations are lower in patients receiving clonidine. Several explanations are proposed. The first is that clonidine inhibits insulin release by a direct peripheral {alpha}-agonist pancreatic effect.1 The second hypothesis is that the lower blood glucose concentrations obtained after clonidine administration are a less powerful stimulus to insulin release. A third hypothesis is that clonidine decreases insulin resistance via a reduced catecholamine release, and so decreases endogenous and exogenous insulin need.1

Clonidine given as a premedication improves cardiovascular stability and blunts the cardiovascular response to laryngoscopy, intubation and surgery,10 and our results are consistent with this. Clonidine also seems to improve perioperative myocardial ischaemia.20 These properties are useful in diabetic patients undergoing ophthalmic surgery. These patients frequently have cardiovascular disorders such as hypertension, ischaemic heart disease and left ventricular dysfunction. Clonidine also reduces intraocular pressure and prevents an increase in intraocular pressure resulting from the acute hypertension that occurs during both local and general anaesthesia.9

In conclusion, premedication of type 2 diabetic patients with clonidine 90 min before ophthalmic surgery greatly decreases insulin requirements during surgery. This decrease is associated with improved blood glucose control.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 Weissman C. The metabolic response to stress: An overview and update. Anesthesiology 1990; 73: 308–27[ISI][Medline]

2 Shamoon H. Influence of stress and surgery on glucose regulation in diabetes: Pathophysiology and management. In: Oyama T, ed. Endocrinology and the Anaesthesist. Amsterdam: Elsevier Science Publishers, 1983; 95–122

3 Raucoules-Aimé M, Ichai C, Roussel LJ et al. Comparison of two methods of i.v. insulin administration in the diabetic patient during the perioperative period. Br J Anaesth 1994; 72: 1–6[ISI][Medline]

4 Barker JP, Robinson PN, Vafidis GC, Burrin JM, Sapsed-Byrne S, Hall GM. Metabolic control of non-insulin-dependent diabetic patients undergoing cataract surgery: comparison of local and general anaesthesia. Br J Anaesth 1995; 74: 500–5[Abstract/Free Full Text]

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7 Gaumann D, Tassonyi E, Rivest RW, Fathi M, Reverdin AF. Cardiovascular and endocrine effects of clonidine premedication in neurosurgical patients. Can J Anaesth 1991; 38: 837–43[Abstract]

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9 Kumar SM, Bose S, Bhattacharya A, Tandon P, Kundra P. Oral clonidine premedication for elderly patients undergoing intraocular surgery. Acta Anaesthesiol Scand 1992; 36: 159–64[ISI][Medline]

10 Engelman E, Lipszyc M, Gilbart E, et al. Effect of clonidine on anesthetic drug requirements and hemodynamic response during aortic surgery. Anesthesiology 1989; 71: 178–88[ISI][Medline]

11 Raucoules-Aimé M, Roussel LJ, Rossi D, Gastaud P, Dolisi C, Grimaud D. Effect of severity of surgery on metabolic control and insulin requirements in insulin dependent diabetic patients. Br J Anaesth 1995; 74: 231–3[Abstract/Free Full Text]

12 Milaskiewicz RM, Hall GM. Diabetes and anaesthesia: the past decade. Br J Anaesth 1992; 68: 198–206[ISI][Medline]

13 Hirsch IB, McGill JB, Cryer PE, White PF. Perioperative management of surgical patients with diabetes mellitus. Anesthesiology 1991; 74: 346–59[ISI][Medline]

14 Lyons FM, Bew S, Sheeran P, Hall GM. Effects of clonidine on the pituitary hormonal response to pelvic surgery. Br J Anaesth 1997; 78: 134–7[Abstract/Free Full Text]

15 Novak-jankovic V, Paver-Eren V, Bovill JG, Ihan A, Osredkar J. Effect of epidural and intravenous clonidine on the neuroendocrine and immune stress response in patients undergoing lung surgery. Eur J Anaesthesiol 2000; 17: 50–6[CrossRef][ISI][Medline]

16 Nishina K, Mikawa K, Maekawa N, Shiga M, Obara H. Effects of oral clonidine premedication on plasma glucose and lipid homeostasis associated with exogenous glucose infusion in children. Anesthesiology 1998; 88: 922–7[CrossRef][ISI][Medline]

17 Swislocki AL, Vestal RE, Reaven GM, Hoffman BB. Acute metabolic effects of clonidine and adenosine in man. Horm Metab Res 1993; 25: 90–5[ISI][Medline]

18 Venn RM, Bryant A, Hall GM, Grounds RM. Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in post-operative patients needing sedation in the intensive care unit. Br J Anaesth 2001; 86: 650–6[Abstract/Free Full Text]

19 Gram LF, Cristensen L, Kristensen CB, Kragh-Sorenson P. Suppression of plasma cortisol after oral administration of oxazepam in man. Br J Clin Pharmacol 1984; 17: 176–8[ISI][Medline]

20 McSPI. Europe Research Group. Perioperative sympatholysis. Anesthesiology 1997; 86: 346–63[ISI][Medline]