Different pharmacologic actions of preanaesthetic medication may be desirable depending upon specific perioperative conditions such as patient selection and surgical procedure. Consequently, a variety of drugs are prescribed, although benzodiazepines are probably still most frequently used. Recently, there has been growing interest in alpha-2 adrenoceptor agonists as preanaesthetic medications. Alpha-2 adrenergic stimulation produces several useful effects that make these drugs an interesting alternative [1,2]. Alpha-2 agonists have been shown to induce sedation and anxiolysis, increase haemodynamic stability and attenuate adverse haemodynamic responses to surgical stress, reduce anaesthetic and analgesic requirements and decrease postoperative pain and shivering [2,3]. However, studies investigating alpha-2 agonists for premedication revealed controversial results depending on particular study designs. Although some authors reported no marked effects or even discouraged the use of alpha-2 agonists as preanaesthetic medication [4,5], others recommend these drugs as an alternative to benzodiazepines [1,6,7]. Therefore, despite increasing use, the distinct value of alpha-2 agonists for preanaesthetic medication remains to be elucidated.
Clonidine is the alpha-2 adrenoceptor agonist most widely used for premedication and can be administered orally with nearly complete absorption . It has been shown that prophylactic perioperative administration of clonidine can be used to reduce the risk of perioperative cardiac mortality in patients with or at risk for coronary artery disease undergoing noncardiac surgery . However, the value of routine administration of clonidine for premedication still remains unclear. The present study was designed to investigate the effect of routine administration of clonidine compared with a standard dose of midazolam for preanaesthetic medication in healthy individuals.
After approval of the local Ethics Committee and written informed consent, 60 patients, ASA physical status I or II, scheduled for elective ear, nose and throat surgery were enrolled. A randomized, double-blind, placebo-controlled prospective study design was used that corresponded to the respective good clinical practice criteria. The study has been registered at www.clinicaltrials.gov NCT00638729 Clonidine Versus Midazolam for Premedication. Exclusion criteria were as follows: age less than 18 or more than 75 years, weight less than 50 or more than 100 kg, cardiovascular disease and pregnancy. Patients were enrolled on the day before surgery (DBS) after obtaining general information regarding anaesthesia, and each patient was assigned to one of the three study groups by opening of a sealed envelope. All patients were premedicated with dipotassiumchlorazepate (Tranxilium, Sanofi-Aventis, Frankfurt, Germany, 20 mg orally) the evening before surgery. On the day of surgery 60–90 min prior to the estimated anaesthesia induction time, group M (n = 20) received midazolam (Dormicum, Roche Pharma, Grenzach-Wyhlen, Germany, 7.5 mg orally), group C (n = 20) was premedicated with clonidine (Catapresan, Boehringer Ingelheim, Ingelheim, Germany, 150 μg orally) and group P (n = 20) received an inert tablet. On arrival at the anaesthesia induction room, all patients were continuously monitored with ECG, noninvasive blood pressure, pulse oximetry and bispectral index (BIS XP, Aspect Medical Systems, Natick, Massachusetts, USA) until discharge from the postanaesthesia care unit (PACU). For induction of anaesthesia, sufentanil (0.3 μg kg−1 intravenously) was administered. Thirty milligram of propofol was then given every 10 s until loss of eyelash reflex, and the total propofol dose needed was recorded. After muscle relaxation with rocuronium (0.6 mg kg−1 intravenously), tracheal intubation and controlled mechanical ventilation with an oxygen–air mix was performed. Anaesthesia was maintained by continuous infusion of propofol aimed at BIS values of 40–50 during the surgical procedure. Sufentanil was administered according to the routine clinical judgement of the attending anaesthesiologist (unaware of the study groups) to treat hypertension or tachycardia. Cumulative doses of sufentanil and propofol administered for anaesthesia were recorded at the end of the surgery. After tracheal extubation, patients were transferred to the PACU. Metamizol (1 g intravenously) and piritramide (3.75 or 7.5 mg intravenously) were administered on demand for postoperative analgesia according to the prescription of the attending anaesthesiologist. The number of requests for analgesic treatment was noted as well as the incidence of postoperative nausea and vomiting (PONV) or shivering. All patients were evaluated with the Aldrete postanaesthesia recovery scoring system . The day after surgery, each patient was visited and asked regarding satisfaction with anaesthesia and complaints about postanaesthesia side effects using a standardized postoperative questionnaire.
On the DBS, study course and timetable were explained to each patient. Patients were familiarized with all measurement procedures applied during the study. On the day of surgery, five time points were defined for data collection: baseline, prior to study medication; PRE-IN, immediately prior to induction of anaesthesia, 60–90 min following study medication; R-0, on arrival at the PACU; R-60, 60 min after arrival at the PACU; and R-120, 120 min after arrival at the PACU. Data collection was performed by a blinded investigator.
Noninvasive mean arterial blood pressure (MAP) and heart rate (HR) were recorded while patients remained in the supine position. The mean of three measurements was recorded for further analysis. Body temperature was assessed at baseline and R-0 with a tympanic thermometer (Genius 2 Tympanic Thermometer; Covidien, Hamilton, Bermuda). For determination of BIS, electrodes were placed at the forehead of the patients according to the manufacturer's specification and connected to a BIS XP monitoring system. During measurement and while being awake, patients were asked to lie calmly with closed eyes in the supine position. Visual analogue scales (VAS, 0–10 cm) were used to assess the intensity of pain and anxiety (0, no pain or anxiety at all, 10, maximum intensity of pain or anxiety, respectively). Sedation was assessed using a five-point scale: 1, awake and alert; 2, awake but drowsy; 3, asleep but prompt response to a voice command; 4, asleep and delayed response to a voice command; 5, asleep, arousable to stimulation but unarousable to verbal command. To assess cognitive function following premedication and during the postanaesthesia recovery period, each patient was asked to complete two neuropsychological tests: the digit symbol substitution test (DSST; a subtest of the Wechsler adult intelligence scale-revised)  and the Trieger's dot test (TDT). The DSST involves pairing of numbers with corresponding symbols according to a code that is visible to the patient. It is widely used as a component of a comprehensive neuropsychological assessment battery to assess specific domains of cognitive function and has been shown to be sensitive even to small degrees of sedation [12,13]. The TDT is a measure of psychomotor function that requires a patient to connect printed dots on a paper within 1 min. A score is assigned according to the number of missed dots. It is used widely in clinical evaluations for assessment of recovery from anaesthesia [14,15]. Because learning effects may influence neuropsychological testing, each patient was asked to perform both tests on the DBS and on the day of surgery at baseline. The best neuropsychologic test result was scored as 100% (baseline), and further results during the study period are expressed as a percentage of baseline.
Analysis of stress hormones was performed as described earlier . Briefly, a HPLC technique was used to measure catecholamines (autosampler: AS 2000, Merck-Hitachi, Darmstadt, Germany; software: HPLC-Manager D-6000 A interface, Merck); normal values for epinephrine and norepinephrine in unpremedicated patients were less than 84 pg ml−1 and less than 420 pg ml−1, respectively. For detection of adrenocorticotropic hormone (ACTH), immunoluminometric assay (LUMItest; BRAHMS Inc., Henningsdorf, Germany) was used; normal values were 5–60 pg ml−1. Competitive immunoassay (IMMULITE; Diagnostic Products Corp., Los Angeles, California, USA) was used for cortisol; normal values were 5–25 μg dl−1. Blood samples for analysis of circulating stress hormones were taken on the DBS to determine baseline levels before dipotassiumchlorazepate, at PRE-IN to determine plasma levels following premedication, on skin incision reflecting a painful intraoperative stimulus and at R-60.
Statistical analysis was performed using SPSS for Windows 10.0 (SPSS Inc., Chicago, Illinois, USA) and GraphPad Prism 4.03 for Windows (GraphPad Software, San Diego California, USA). Sample size was calculated on the basis of BIS as the primary endpoint. We chose a BIS difference of at least 3 as a potentially meaningful difference. For an α = 0.05 and a β = 0.2, a sample size of 16 patients in each group was calculated. To compensate for dropouts, 20 patients were enrolled in each group.
Results are presented as mean ± SEM for parametric data (haemodynamic and demographic data). One-way analysis of variance (ANOVA) with Tukey's posttest was used to test for differences between groups. Differences over time within a group were analysed using ANOVA for repeated measures followed by Tukey's posttest. Nonparametric data are expressed as median (25th–75th percentiles). The Kruskal–Wallis nonparametric ANOVA was used to test for differences between the treatment groups followed by Mann–Whitney U test. To detect changes over time within the same group, Friedman test followed by appropriate posttesting (to compare vs. baseline, prior to study medication) was performed. When appropriate (VAS, neuropsychological tests), Fisher's exact test was performed to test for differences between groups. The Bonferroni correction was used to correct for multiple comparisons. A P value of less than 0.05 was considered statistically significant.
Groups did not differ with respect to weight and ASA status. Patients in group M were younger than patients in groups C and P (P < 0.05; Table 1). Duration of surgery and cumulative doses of sufentanil and propofol administered during anaesthesia did not differ significantly between groups (Table 1). Body temperature was similar between groups at baseline (group M, 36.3 ± 0.1°C; group C, 36.0 ± 0.1°C; group P, 36.3 ± 0.1°C) and did not differ significantly from R-0 values (group M, 36.1 ± 0.1°C; group C, 35.9 ± 0.2°C; group P, 36.1 ± 0.1°C). MAP was comparable at baseline in all groups (group M, 91 ± 2.5 mmHg; group C, 91 ± 3.1 mmHg; group P, 95 ± 1.9 mmHg). Highest values for MAP were recorded on arrival at the PACU (R-0; group M, 100 ± 4.7 mmHg; group C, 96 ± 3.4 mmHg; group P, 98 ± 3.0 mmHg). MAP displayed neither significant changes over time within groups nor significant differences between the different study regimens (data not shown). HR did not change significantly over time within group M and group C (Fig. 1). In contrast, patients receiving placebo showed a significant increase in HR after transfer to the anaesthesia induction room prior to induction of anaesthesia. HR at PRE-IN was significantly higher for patients in group P than for patients in group C (Fig. 1; P < 0.01). BIS was significantly reduced following premedication (PRE-IN) in groups M and C compared with baseline (P < 0.05 vs. baseline; Table 2) but not in group P. During the postanaesthesia period, BIS remained reduced in all patients at R-0 (P < 0.05 vs. baseline) and R-60 (P < 0.05 vs. baseline) and reached baseline values in groups P and M at R-120. In contrast, BIS remained significantly reduced in group C at R-120 (P < 0.05 vs. baseline). Comparing the three premedication regimens, BIS values differed significantly between groups at PRE-IN, R-0 and R-60. At these time points, BIS was lowest in patients receiving clonidine, whereas highest values were recorded for placebo patients (P < 0.05 for groups C vs. P, C vs. M and M vs. P). At R-120, group C still displayed reduced BIS values compared with group P (P < 0.05). For induction of anaesthesia, less propofol was administered until loss of eyelash reflex in patients premedicated with clonidine (94.4 ± 4.5 mg) than in patients in group M (116.4 ± 5.9 mg; P < 0.05 vs. group C) and group P (116.8 ± 8.3 mg; P < 0.05 vs. group C). Sedation score did not change significantly compared with baseline within groups following study medication (baseline vs. PRE-IN, P > 0.05; Fig. 2). However, at PRE-IN, only five of 20 placebo patients exhibited clinically detectable sedation, whereas nine of 20 patients following midazolam and 12 of 20 clonidine patients were sedated. Sedation scores increased during the postanaesthesia period and reached baseline values at R-120. Sedation score was not different between treatment groups. VAS for anxiety was comparable between groups at baseline and did not change significantly after study medication (Fig. 3). VAS for anxiety decreased after surgery without differences between the study regimens. VAS for pain was similar in all groups during the preoperative period (Fig. 4). During the postanaesthesia period, VAS for pain increased in all groups compared with baseline. However, clonidine patients tended to display lower VAS values than groups P and M at R-0. VAS for pain was not different between treatment groups. In the recovery period, Aldrete score showed a median of 8 [(8–9) in groups M and C] and 9 [(8–9.75) in group P], respectively, and increased to 10 (9.25–10) in all groups at R-120 with no differences between treatment regimens (data not shown). Neuropsychological tests revealed a characteristic pattern during the study period. Performance progressively decreased, displaying a minimum at R-0, and increased afterwards (Table 3). Neither DSST nor TDT displayed significant differences between the treatment regimens. Plasma levels of stress hormones displayed a minimum during anaesthesia at skin incision and increased afterwards at R-60. Plasma concentration of ACTH was significantly lower in clonidine patients than in placebo patients at PRE-IN (P < 0.05 group P vs. group C; Fig. 5). Epinephrine, norepinephrine and cortisol did not differ between groups (data not shown). Incidence of shivering was nine out of 20 patients (45%) in group M, two out of 20 patients (10%) in group C and five out of 20 patients (25%) in group P. Incidence of PONV was nine out of 20 patients (45%) in group M, one out of 20 patients (5%) in group C and four out of 20 patients (20%) in group P. Differences between groups with respect to the incidence of shivering and PONV did not reach statistical significance. The 24-h follow-up interview revealed no differences in patient satisfaction with anaesthesia or complaints about postanaesthesia side effects.
The main findings of our study are as follows. First, routine administration of low-dose clonidine was associated with lower BIS values compared with a standard dose of midazolam or placebo. Second, effects of preanaesthetic medication on BIS monitoring did not translate into subjective reduction of perioperative anxiety or increased sedation scores. Third, clonidine reduced anaesthetic requirements for induction of anaesthesia. Fourth, low-dose clonidine increased perioperative haemodynamic stability by preventing increases in HR during the preoperative period. Additionally, clonidine partially prevented increases in plasma levels of circulating stress hormones (ACTH) during the preoperative period. And finally, clonidine did not delay the recovery of cognitive function during the postanaesthesia period.
The rationale for preanaesthetic medication is equivocal, although most experts agree on terms such as sedation and reduction of anxiety. Traditional methods to assess anxiety and sedation rely on more or less subjective evaluations with inherent problems of subjective differences in clinical interpretation and self-reporting bias . Thus, a more objective tool would be favourable. BIS is a variable derived from the electroencephalography that has been well validated as an indicator of anaesthetic depth . In contrast, BIS has been reported to be less reliable as a measure of sedation in ICU patients . Nonetheless, previous studies suggested that BIS appears to be a useful parameter for assessing midazolam-induced sedation [20–22] and can be used to objectively evaluate sedative effects of preanaesthetic medication . This is supported by the results of the present study showing that BIS significantly declined following preanaesthetic medication with clonidine and midazolam. In contrast, BIS was not changed in placebo patients, suggesting that BIS reflects the sedative properties of premedication. Accordingly, BIS displayed a progressive increase during the recovery period that paralleled corresponding changes in the Aldrete postanaesthesia recovery score and the sedation score. As assessed by BIS, clonidine, compared with midazolam and placebo, provided increased sedation in the present study. The sedative properties of alpha-2 agonists have been proved in numerous studies [2,24] and may contribute to their well known anaesthetic-sparing effect [2,6]. Correspondingly, in the present study, clonidine, but not midazolam, significantly reduced the dose of propofol needed until loss of eyelash reflex.
Despite the effects on BIS, preanaesthetic medication did not alter sedation score. The reason for this discrepancy remains unclear. However, this finding is in accordance with the results of the study by Brosius and Bannister  showing significant decreases in BIS following midazolam premedication, whereas only 40% of their patients exhibited clinically detectable sedation. In the present study, sedative effects were evident in 45% of the midazolam-treated patients and in 60% of the patients receiving clonidine. Nevertheless, 25% of patients receiving placebo were also judged as sedated. This may have resulted from confounding effects of the benzodiazepine premedication on the evening before surgery, and this baseline sedation may have precluded significant differences between the treatment regimens. We accept this as a general limitation to our study; however, this study was designed to reflect routine clinical practice that usually includes premedication the evening before surgery. Moreover, subjective assessment of sedation may be confounded by inherent methodological limitations such as the five-point scale used in the present study that may not be differentiated enough to detect differences between the treatment regimens. Our study suggests that BIS may be very sensitive in monitoring sedative properties of preanaesthetic medication.
Although anxiolytic effects have been reported for midazolam and clonidine [2,5,25], the present study failed to demonstrate significant influences of preanaesthetic medication on the intensity of anxiety. Common methods to measure anxiety are the use of psychological assessment scores or self-rating scales [26,27]. We decided to use the VAS because it is less time-consuming and widely used for the determination of anxiety in the perioperative period [26,28]. Previous studies concluded that VAS and more complex scales such as state-trait anxiety inventory or the hospital anxiety and depression scale are equivalent in their assessment of anxiety before surgery . However, determination of anxiety represents a complex issue, and emotional states vary widely with time and situation during the perioperative period. Previous studies revealed that tools for assessment of anxiety failed to reliably determine perioperative anxiety, and results may be confounded by consistent self-reporting bias of patient responses [17,28].
Particularly, patients at cardiac risk seem to benefit from a reduction in perioperative stress and preservation of haemodynamic stability during the perioperative period. Previous studies have shown that intraoperative circulatory responses, especially tachycardia, are related to postoperative complications and placed emphasis on sympathetic activation as a key issue with respect to cardiac risk [2,29]. Alpha-2 agonists such as clonidine have been shown to effectively reduce the concentration of circulating stress hormones, attenuate adverse circulatory responses to stressful stimuli and increase haemodynamic stability [1,6,30]. Correspondingly, in the present study, clonidine, but not midazolam, prevented increases in HR observed in placebo patients immediately prior to induction of anaesthesia. Additionally, clonidine was able to block increases in ACTH as a marker for preoperative stress. We did not observe significant differences between treatment regimens with respect to epinephrine, norepinephrine or cortisol plasma levels. There are several reasons that may account for this discrepancy. A limitation to our study may be lack of power. The study was planned to assess sedative properties of preanaesthetic medication by BIS, and power analysis was based on estimated differences in BIS. Thus, significant differences in other parameters such as VAS or stress hormones may have not been detected because of the lack of power. Another general criticism may be that the doses of clonidine and midazolam administered in our study were inadequate. Actions of alpha-2 agonists and benzodiazepines have been shown to be dose-dependent [24,25,30]. However, a general consensus on the doses of clonidine or midazolam administered for premedication does not exist, and dose regimens vary widely. Low-dose clonidine failed to attenuate stress response to laryngoscopy in patients undergoing coronary artery bypass grafting . In contrast, dose–response studies reported an increased incidence of hypotension with clonidine (300 μg orally), and the authors urged caution in its use [5,31]. Previous studies showed that midazolam in a dose comparable to the present study exerted an anxiolytic effect  and provided sufficient or good quality of premedication in a vast majority of patients . In contrast, higher doses may be associated with delayed emergence after general anaesthesia . Consequently, we chose to investigate low doses of clonidine and midazolam. In routine clinical anaesthesia, oral administration of drugs is preferred, and preanaesthetic medication is usually prescribed depending on available drug preparations. Therefore, patients were premedicated with one tablet (150 μg) of clonidine compared with a standard low dose of one tablet (7.5 mg) of midazolam. The present study was designed to reflect routine clinical practice. Although we do not claim pharmacological equipotency, the doses chosen in our study represent standard low doses of midazolam and clonidine that have been shown to exert comparable premedication effects in a previous study .
Because of its long elimination half-life (8–12 h) , it is likely that oral clonidine premedication affects the postoperative recovery. This was reflected by BIS that was still reduced 120 min after arrival at the PACU in clonidine patients but not in patients who received midazolam or placebo, suggesting residual sedative effects. However, variables more important to discharge eligibility, such as the Aldrete score, were similar in all treatment groups. Particularly, recovery of cognitive function was not significantly delayed by clonidine premedication compared with placebo or midazolam. Therefore, clonidine did not adversely influence postoperative recovery. In contrast, patients receiving clonidine exhibited a decreased incidence of shivering (10 vs. 45% in group M and 25% in group P). Antishivering properties of alpha-2 agonists are well known . However, probably because of the lack of power, this did not reach statistical significance. In addition, PONV was low in clonidine patients but not significantly different compared with placebo and midazolam.
The results of our study indicate that in patients receiving a benzodiazepine the evening before surgery, routine premedication on the day of surgery with clonidine offers advantages compared with midazolam and placebo in healthy individuals. One could argue that our study merely evaluates surrogate parameters instead of true outcome. However, in order to reliably detect small, but potentially important, outcome improvements, large randomized studies including up to thousands of patients are required. This can only be achieved by a multicentre approach . Further studies are needed to confirm the results of the present investigation particularly in patients at cardiac risk who may benefit from alpha-2 agonists even to a greater extent.
The authors thank Dr A. Caliebe, Institute for Medical Statistics and Informatics, University of Kiel, for her valuable contributions to the statistical analysis.
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Keywords:© 2009 European Society of Anaesthesiology
alpha-2 agonists; benzodiazepines; bispectral index; clonidine; cognitive function; midazolam; postoperative recovery; premedication; sedation; stress hormones