Department of Anaesthesia, Hôpital lArchet, 151 Route de Saint Antoine de Ginestière BP, F-3079-06202 Nice, Cedex 3, France
Corresponding author. E-mail: anesthesiologie@chu-nice.fr This article is accompanied by Editorial II.
Accepted for publication: November 8, 2002
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Abstract |
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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 5.511.1 mmol litre1. 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: 4349
Keywords: blood, glucose; complications, diabetes; metabolism, hyperglycaemia; sympathetic nervous system, catecholamines; sympathetic nervous system, clonidine
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Introduction |
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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 (510%).3 Perioperative blood glucose may also be controlled by reducing the intensity of the hormonal and metabolic responses to surgical stress.4 Clonidine, an 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 pituitaryadrenocortical 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.
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Patients and methods |
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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 patients weight: 225 µg if the weight was less than 55 kg; 300 µg if it was 5574 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 h1 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 h1 (6.25 g h1). 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 litre1. If the concentration was less than 5.5 mmol litre1, the rate of glucose infusion was briefly increased; if it was greater than 11.1 mmol litre1, additional insulin (5 units) was given as an i.v. bolus until blood glucose was less than 11.1 mmol litre1. In both groups, when blood glucose exceeded 11.1 mmol litre1 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 11.114.0 mmol litre1; 7 units if blood glucose was in the range 14.017.0 mmol litre1; 10 units if blood glucose was greater than 17.0 mmol litre1.
Anaesthesia was induced with thiopental 5 mg kg1 and tracheal intubation was facilitated with vecuronium 0.1 mg kg1. Fentanyl was used at induction 2 µg kg1 and during anaesthesia. Anaesthesia was maintained with 0.81% 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 litre1, 5.5 nmol litre1 and <0.1 mU litre1, 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 litre1, 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 Friedmans two-way analysis of variance and the KruskalWallis 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 Bonferronis 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.
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Results |
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Discussion |
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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. 2-Adrenoceptor agonists inhibit the release of catecholamines through the activation of central presynaptic inhibitory
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
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 kg1 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 litre1 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 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
-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.
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References |
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