Clonidine Decreases Stress Response in Patients Undergoing Carotid Endarterectomy Under Regional Anesthesia: A Prospective, Randomized, Double-Blinded, Placebo-Controlled

Study
Christine E. Schneemilch, MD Holger Bachmann, MD Anke Ulrich, MD Regine Elwert, MD Zuhir Halloul, MD Thomas Hachenberg, MD, PhD
Inadequate analgesia or anxiety may induce an increased stress response in patients undergoing carotid endarterectomy (CEA) under regional anesthesia (RA). Central 2 adrenoceptor agonists have significant sedative and analgesic properties, which may attenuate sympathoadrenal activation during CEA and improve the quality of RA. We randomly assigned 80 patients to 2 groups receiving either RA plus placebo (n 40) or RA plus clonidine 1 g/kg as the initial loading dose followed by 1 g kg1 h1 (n 40). RA was performed as combined deep and superficial cervical plexus blockade. Hemodynamic and neurological variables were assessed before, during, and after CEA. Arterial blood samples were collected at defined time points for the determination of plasma concentrations of epinephrine, norepinephrine, cortisol, and creatinine kinase and creatinine kinase-MB. Throughout the study, all patients responded easily to neurological evaluations. Before and during clamping mean arterial blood pressure and heart rate were not different between the groups, but mean arterial blood pressure was lower in the clonidine group (P 0.01) at skin closure and postoperatively in the intensive care unit. In the placebo group, cortisol, epinephrine, and norepinephrine plasma concentrations were increased significantly (P 0.05) and more patients required antihypertensive treatment (P 0.01). Postoperatively the incidence of hypertension (P 0.001) and development of neurological deficits (P 0.05) was significantly decreased in the clonidine group. We conclude that 1 g kg1 h1 clonidine suppresses the hyperadrenergic response to CEA without adverse effects on hemodynamics or clinical neurological monitoring.
(Anesth Analg 2006;103:297302)

he main cause of carotid stenosis is atherosclerotic disease, which puts patients at risk for cerebral and myocardial complications. Carotid endarterectomy (CEA) is an established surgical procedure and can be performed under general anesthesia (GA) or regional anesthesia (RA). The advantages of GA are myocardial and cerebral protection by IV or inhaled anesthetics, control of airway and alveolar ventilation, and patient comfort. RA may improve hemodynamic stability and allow monitoring of the awake patient to detect neurological deficits during clamping of the carotid artery. Several studies have suggested that RA

From the *Department of Anesthesiology and Intensive Care Medicine and Department of Surgery, Otto-von-GuerickeUniversity, Magdeburg, Germany. Accepted for publication April 11, 2006. Address correspondence and reprint requests to Christine E. Schneemilch MD, Department of Anesthesiology and Intensive Care Medicine, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. Address e-mail to christine.schneemilch@medizin.uni-magdeburg.de. Copyright 2006 International Anesthesia Research Society
DOI: 10.1213/01.ane.0000223673.68072.42

is associated with reduced morbidity and mortality (1 4). However, supplementation of RA is frequently necessary during CEA and inadequate analgesia or patient anxiety may induce an increased stress response with the risk of myocardial ischemia (5,6). Central 2 adrenoceptor agonists attenuate sympathoadrenal activation and provide greater perioperative stability. In patients at risk for myocardial ischemia, perioperative administration of clonidine improved morbidity and mortality. In addition, clonidine (1 to 4 g kg1 h1) has significant sedative and analgesic properties (79). However, there are limited data on supplementation of RA for CEA with IV clonidine and regarding whether clinical neurological monitoring is potentially impaired. The present study was designed to analyze the effects of small dose clonidine infusion (1 g/kg) on sympathoadrenal activation, hemodynamics, neurological performance, and clinical outcome before, during, and after CEA under combined superficial and deep cervical block.

METHODS
After approval of the ethics committee of the Ottovon-Guericke-University, Magdeburg and obtaining
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informed written consent, 40 patients undergoing elective CEA under RA were randomly assigned to one of two groups. The sample size had been calculated from recent studies to detect a difference for plasma norepinephrine and epinephrine concentrations of 20% between the groups with a power of 0.8 and a two-tailed P 0.05. Exclusion criteria were acute symptomatic patients, decompensated cardiopulmonary or endocrinologic disease, and uncooperative patient. The patients were prospectively randomized into two groups receiving a continuous infusion of placebo (n 40) or a continuos infusion of clonidine (n 40). All patients received midazolam (5 to 7.5 mg orally) for premedication 30 min before arrival in the operation room. RA was performed as combined deep and superficial cervical plexus blockade with 40 mL ropivacaine 0.375% plus prilocaine 1% according to standard procedures in our institution. A continuous infusion of electrolyte solution (5 mL kg1 h1) was given for fluid therapy. A radial artery was cannulated before regional anesthesia (RA) for continuous arterial blood pressure monitoring and for blood sampling. Monitoring included heart rate (HR), systolic, mean, and diastolic arterial blood pressure (SAP, MAP, DAP), oxygen saturation, temperature, and continuous clinical evaluation of neurological changes, such as consciousness and strength of the contralateral arm (ability to squeeze a toy) during the operation. A sedation score (0 awake; 1 sedated, but awake; 2 asleep, reacting immediately to verbal commands and able to squeeze a toy; 3 asleep, reacting to verbal commands with delay; 4 asleep, not reacting to verbal commands) was used to detected differences in consciousness during the course of the study. All data were recorded on a computerbased anesthesia recording system (integrated DatexOhmeda monitor system, Instrumentarium Corp., Helsinki, Finland). Supplemental doses of the opioid piritramide (2.5 to 5.0 mg) were given intraoperatively if the patients complained of pain. Patients required no supplemented sedation. Bradycardia (HR 50 bpm) and hypotension (MAP 20% of control) were treated with supplemental doses of atropine (0.5 to 1.0 mg) and the vasopressor cafedrine/theodrenaline (Akrinor, incremental doses of 40/2 mg [2 mL] to 200/10 mg [10 mL]), respectively. Tachycardia (HR 90 bpm) and hypertension (MAP 20% of control) were treated with metoprolol (1 to 5 mg) and the alpha-receptor antagonist urapidil (10 to 50 mg), respectively. In the intensive care unit (ICU) first-line treatment of hypertension was achieved with IV doses of urapidil (10 to 50 mg) and second-line treatment with oral doses of nifedipine (10 mg) in patients with nifedipine as preoperative co-medication. After completion of the RA patients of the clonidine group received an initial loading dose of 1 g/kg clonidine over a period of 15 min followed by a continuous infusion of 1 g kg1 h1 clonidine
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until the end of the operation (skin closure). The doses were predicted to have minor cardiovascular effects as described by Hall et al. (10). In the placebo group NaCl 0.9% was given in equivalent doses. The drug solutions were prepared by an investigator not involved in anesthesia, postoperative patient care, or collection of data. SAP, MAP, DAP, and HR were determined immediately on arrival the operating room (t0), after placement of the cervical block (t1), before skin incision (t2), at skin incision (t3), before cross-clamping (t4), at clamping (t5), 5 min after clamping (t6), 10 min after clamping (t7), at declamping (t8), at skin closure (t9), on arrival to the ICU (t10), 1 h later (t11), and 2 h later (t12). Arterial blood samples were collected before placement of the cervical block (t0), at cross-clamping (t1), at skin closure (t2), and on the morning of the first postoperative day (t3) for assessment of epinephrine, norepinephrine, and cortisol; creatinine kinase (CK) and creatinine kinase-MB (CK-MB). Plasma concentrations of epinephrine and norepinephrine were determined by high performance liquid chromatography (Pharmacia, Uppsala, Sweden) using commercial test kits (Chromsystems, Instruments & Chemical GmbH, Mu nchen, Germany). Reference values were 30 85 ng/L for epinephrine and 185275 ng/L for norepinephrine. Sensitivity was 10 ng/L. Plasma concentrations of cortisol were determined with chemiluminescence immunoassay system (Immulite-System, DPC-Biermann, Bad Nauheim, Germany) with reference values at 200 600 nmol/L in the morning and 100 300 nmol/L in the evening. Sensitivity was 0.2 g/dL. CK and CK-MB were measured using Roche/Hitachi Modular Analytics (Roche Diagnostics, Germany) with reference values 2.34 mol s L1 for CK and 0.4 mol s L1 for CK-MB. All data were analyzed using SPSS (Statistical Package for the Social Sciences, Chicago, IL). Values were tested for normal distribution with the KolmogorovSmirnov test. Kruskal-Wallis one way analysis was used to assess differences between and within the groups. If differences were statistically significant, the Mann-Whitney U-test was used for differences between groups and the Wilcoxon matched-pairs signed-rank test for differences within groups. Students t-test was used to compare patient characteristics. Differences in previous risk factors, vasoactive medication, and postoperative complications were compared with Fishers exact probability test. Spearman correlation coefficient (rs) was used to test the bivariate correlation between measured variables. A value of P 0.05 was considered as statistically significant.

RESULTS
Patient data are summarized in Table 1. There were no significant differences in patient characteristics,
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Clonidine Infusion and Stress Response During Carotid Endarterectomy

Table 1. Patients Characteristics, Risk Factors, Preoperative Morbidity and Medication Placebo group (n 40)
Age (yr) Female/male Height(cm) Weight (kg) Risk factors Carotid artery stenosis (%) Previous stroke or TIA Coronary artery disease Hypertension Diabetes mellitus Co-medication [n] Beta-blocker Calcium channel blocker Nitrates ACE inhibitors Digoxin 65 (3982) 10/30 170 (154186) 75 (49120) 90 (7595) 24 18 38 12 20 7 10 26 5

Clonidine group (n 40)

68 (5483) 11/29 169 (155182) 79 (58120) 90 (8595) 22 22 38 13 19 8 11 26 4

Values are n or median (range). ACE angiotensin-converting enzyme; TIA transient ischemic attack

neurological risk factors, co-morbidity, or comedication between groups. Eleven patients in the placebo group and 9 patients in the clonidine group were shunted because of loss of consciousness, aphasia, and/or hemiplegia after test clamping of the carotid artery. The patient response to name and questions and the ability to squeeze a toy were not impaired during the course of the study in both groups, with the exception of transient neurologic deficits during cross-clamping in 20 subjects. The sedation scores were between 0 and 2 in all patients without any differences between groups (Table 2). There were no differences in the length of ICU stay between groups. No permanent cardiovascular complications were seen in either group postoperatively (Table 3). Five patients in the placebo group developed transient neurological deficits, which persisted for 2 days in four patients and was present in one patient at hospital discharge. No patients in the clonidine group developed new postoperative neurological deficits (P 0.05). The incidence of postoperative hypertension was significantly more frequent in

the placebo group (P 0.01). Seven patients in the clonidine group and 18 patients in the placebo group developed local hematoma, which required surgical revision in 1 patient (Table 3). After declamping, at skin closure, and in the early postoperative course MAP and HR were decreased in the clonidine group as compared with the placebo group (Fig. 1). The dose of theodrenaline/cafedrine was significant larger in the clonidine group (P 0.002) (Table 4). The perioperative CK and CK-MB plasma concentrations were below reference values in all patients. Plasma concentrations of cortisol, epinephrine, or norepinephrine were comparable in both groups at baseline. Cortisol increased significantly in both groups after clamping, which was more pronounced at declamping time in the placebo group (P 0.04). In both groups baseline values were reached on the first postoperative day. Epinephrine and norepinephrine plasma concentrations increased after clamping of the carotid artery, at the end of CEA, and on the first postoperative day (Fig. 2). The

Table 2. Perioperative Characteristics, Neurological Decits During Clamping, and Sedation Score Placebo group (n 40)
Duration of surgery (min) Clamping-time (min) Intraoperative neurological deficits Shuntplacement Sedation Score (range) 90 (55150) 42 (2568) 11 11 02

Clonidine group (n 40)

98 (57168) 43 (2484) 9 9 02

Table 3. Postoperative Complications Placebo group (n 40)

ICU length of stay (days) Postoperative complications Neurological deficits Local hematoma Revision Hypertension Mortality
ICU intensive care unit

Clonidine group (n 40)

1.1 (12) 0 7 (17.5%) 1 (2.5%) 1 (2.5%) 0

P value
0.1 0.03 0.01 0.001

1.2 (13) 5 (12.5%) 18 (45%) 0 12 (30%) 0

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Figure 1. Mean arterial blood pressure (MAP, mm Hg) and heart rate (bpm) in patients undergoing carotid endarterectomy (CEA) under regional anesthesia supplemented with clonidine () or placebo () on arrival the operating room (t0), after placement of the cervical block (t1), before skin incision (t2), at skin incision (t3), before cross-clamping (t4), at clamping (t5), 5 min after clamping (t6), 10 min after clamping (t7), at declamping time (t8), at skin closure (t9), on arrival to the intensive care unit (ICU) (t10), 1 h later (t11) and 2 h later (t12); mean sd; *P 0.05 between groups.

Figure 2. Plasma concentrations of cortisol, epinephrine, and

norepinephrine in patients undergoing carotid endarterectomy (CEA) under regional anesthesia supplemented with clonidine (gray columns) or placebo (white columns) immediately on arrival in the operating room (t0), after placement of the cervical block (t1), at skin incision (t2), before crossclamping (t3), at clamping (t4), at declamping time (t5), at skin closure (t6) at the end of surgery (t7), and 10 min postoperatively (t8). Box plots represent median and range, 25th and 75th percentile. *P 0.05 and ** P 0.01 between groups.

Table 4. Intraoperative Drug Treatment Placebo group (n 40)

Piritramide Dose (mg) Atropine Median dose (mg) Cafedrine/Theodrenaline Before clamping End of surgery Dose (mL) Urapidil Dose (mg) Metoprolol Dose (mg) Bolus dose of clonidine (g) Infusion dose of clonidine (g)
Values are n or median (range)

Clonidine group (n 40)

21 5 (315) 8 0.5 19 10 9 5 (215) 1 5 (5) 1 5 79 (58120) 129 (75221)

P value
0.08 0.1 NS NS 0.002 0.1 0.003 0.001 NS NS

28 9 (230) 7 0.5 5 5 0 4 (28) 10 30 (10100) 1 3

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alterations of catecholamine plasma concentrations were significantly smaller in the clonidine group as compared with the placebo group (P 0.01). No correlations were observed between measured variables, preoperative risk factors, and co-medication.

DISCUSSION
In the present study we analyzed the sympathoadrenal effects of small dose clonidine in patients undergoing CEA under combined superficial and deep cervical block. The main results were that clonidine 1 g/kg followed by a continuous infusion of 1 g kg1 h1 suppressed the hyperadrenergic response to CEA without impairment of clinical neurological monitoring. Postoperatively, the incidence of hypertension and neurological complications was decreased in the clonidine group. Central 2 adrenoceptor agonists have been extensively studied in patients at risk for ischemic heart disease, as an adjunct to GA or RA, and in patients with acute or chronic pain (11). Clonidine decreases peripheral norepinephrine release by stimulation of prejunctional inhibitory 2 adrenoceptors and by inhibition of neural transmission in different brainstem areas, such as the nucleus tractus solitarius and lateral reticular nucleus in the ventrolateral medulla. Hypnotic-sedative, analgesic and anxiolytic actions of clonidine may be modulated via the 2A adrenoceptor subtype. In addition, experimental data suggest that clonidine may have neuroprotective properties. The proposed mechanisms for neuroprotective effects include the attenuation of the excessive release of noradrenaline and glutamate, inhibition of voltageoperated calcium channels, activation of G proteinlinked K channels, and inhibition of adenylate and guanylate cyclase (12,13). On the heart, an attenuated sympathetic tone is associated with decreased myocardial oxygen requirements and improved coronary perfusion, which may reduce the incidence of perioperative myocardial ischemia (14). In the present study, clonidine, in a small dose of 1 g/kg, decreased norepinephrine and epinephrine plasma concentrations by more than 40% and 50% during and after CEA. A decreased sympathetic activity was observed until the first day after CEA and was associated with improved hemodynamic stability. Postoperatively, significantly more patients in the control group had to be treated for hypertension. This effect may be a consequence of the elimination halftime of clonidine, which is approximately 30 hours in healthy volunteers (15). Clonidine also had a suppressive effect on cortisol plasma concentrations, indicating that perioperative stress reactions are affected by central 2 adrenergic agonists. In addition, slightly fewer patients in the clonidine group required supplemental analgesia during CEA; however, the difference was not statistically significant. An increased sympathetic tone in vascular surgical patients with hypertension and tachycardia has been associated with
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more frequent myocardial ischemia and infarction (8,9). Postoperatively, the plasma concentrations of epinephrine and norepinephrine may have been confounded by the more frequent use of nifedipine in the placebo group. In fact, a single oral dose of nifedipine has been shown to induce sympathetic modulation in healthy volunteers, which lasted for 6 hours (16). However, in the present study no nifedipine was used on the first postoperative day and differences of norepinephrine and epinephrine plasma concentrations were probably not influenced by treatment of hypertension. Our results partially confirm data published by Bekker et al. (17), who investigated the effects of dexmedetomidine on hemodynamics and catecholamine plasma concentrations in patients undergoing CEA under RA. Patients receiving dexmedetomidine required less antihypertensive therapy and norepinephrine plasma concentrations were significantly smaller as compared with the control group. However, dexmedetomidine has a different pharmacological profile than clonidine. Supplemental bolus doses of fentanyl, midazolam, or propofol were administered intraoperatively, which may have influenced hemodynamics and stress response. In the dexmedetomidine group, there was a trend for more frequent placement of intraluminal shunts, which may be attributed to alterations of cerebral perfusion (18). However, in the present study slightly more shunts were used in the placebo group and the development of new perioperative neurological deficits was significantly decreased in patients receiving clonidine. Experimental studies have shown that central 2 adrenergic agonists may induce constriction of cerebral arteries and reduction in cerebral blood flow (CBF) (18 20). However, the data from different studies are conflicting. Lee et al. (20) described decreased CBF when clonidine was given for treatment of severe hypertension. In contrast, other investigators demonstrated that the effects of clonidine on CBF were determined by the pretreatment levels of cerebral perfusion and mean CBF did not change. In patients with severe head trauma, clonidine had no influence on local cerebral hemodynamics (21,22). In the present study, a decreased incidence of new postoperative neurological deficits may indicate beneficial effects of clonidine during and after CEA. Clonidine administration induced greater hemodynamic stability in the perioperative course, as documented by a decreased incidence of hypertension and use of antihypertensive drugs. Mortality was infrequent in our patients and biochemical markers of myocardial ischemia were not different between groups. However, the assessment of the potential effects of clonidine on cardiac outcome would require a much larger sample size. Wallace et al. (23) demonstrated that clonidine significantly decreased the incidence of perioperative myocardial ischemia and postoperative mortality in patients at risk for coronary
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artery disease undergoing noncardiac surgery. In that study, an oral dose of clonidine (0.2 mg) was administered the night before surgery and on the morning of surgery and the patients received a 7.0-cm2 transdermal patch of clonidine providing continuous systemic delivery of 0.2 mg/day. Whether clonidine improves cardiac outcome in patients undergoing CEA under RA remains to be shown. The clonidine dose used in the present study was smaller as compared with clinical investigations, in which doses up to 5 g kg1 h1 have been used (24,25). Hall et al. (10) studied 1, 2, and 4 g kg1 h1 clonidine in healthy volunteers. Clonidine infusions had comparable analgetic effects after 60 min, but memory impairment and performance on the digit symbol substitution test were significantly more marked during 4 g kg1 h1 infusion. Although larger clonidine doses may be associated with more pronounced analgesic and sedative effects, the smallest effective dose seemed to be appropriate in our patients to minimize the risk of hypotension before, during, and on the first postoperative day after CEA. In conclusion, CEA under RA is associated with an activation of the sympathoadrenal system. Supplemental clonidine infusion (1 g kg1 h1) suppressed the hyperadrenergic stress response without affecting the patients neurological performance. Postoperatively, the incidence of hypertension and development of new neurological deficits was significantly decreased in the clonidine group. Thus, small dose clonidine may offer advantages as an adjunct during CEA under RA. ACKNOWLEDGMENTS The authors thank Peter Kulka, MD for his helpful comments when preparing the manuscript. REFERENCES
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