Clonidine, an α2-adrenergic receptor agonist, produces both preoperative sedation and anxiolysis (1). Therefore, oral clonidine premedication might be expected to delay recovery from anesthesia. There is controversy, however, as to whether oral clonidine premedication delays emergence from anesthesia. Oral clonidine premedication was associated with delayed emergence from isoflurane or propofol anesthesia in some studies (2–4), but not in others (5–7). In these studies, the equivalent concentration of propofol was not determined, although the blood propofol concentration should be steadily maintained before discontinuation. This study was designed to investigate whether oral clonidine premedication delays emergence from total IV anesthesia (propofol/fentanyl). To eliminate the confounding effects of blood propofol, fentanyl, and clonidine concentrations in the emergence from propofol/fentanyl anesthesia, we used a computer-assisted target-controlled infusion (TCI) to maintain stable concentrations of propofol and fentanyl and measured the blood concentrations of propofol and clonidine in patients waking from anesthesia, to investigate the pharmacodynamic interactions between propofol and clonidine.
Written, informed consent was obtained from each patient after the study was approved by the Local Clinical Research Ethics Committee. Healthy male patients (n = 72) were recruited. Patients were eligible for the study if they were scheduled for elective body surface area surgery, such as orthopedic, oral, and otolaryngologic surgery, expected to last 2 h; were classified as ASA physical status I; were 19 to 55 yr old; and had no known contraindication to using propofol. Patients were excluded if they were taking any medications; had central nervous system or psychiatric disorders; had liver, renal, or metabolic disease; or were significantly obese (body mass index >35 kg/m2). Patients were randomly assigned to one of three groups: Control group, 2.5 μg/kg Clonidine group, and 5.0 μg/kg Clonidine group (n = 24 each). Nothing was administered to the Control group. Clonidine (2.5 or 5.0 μg/kg) was orally administered 90 min before the induction of anesthesia in the Clonidine groups. Because clonidine is available only in tablets of 75 or 150 μg in Japan, doses were determined by choosing the dose closest to half, one-third, and a quarter of a tablet.
Upon arrival of the patient in the operating room, an 18-gauge venous cannula was inserted to infuse propofol and fentanyl and to replace acetated Ringer’s solution. Under local anesthesia, a 20-gauge radial artery catheter was inserted for blood sampling and for measuring arterial blood pressure. Heart rate, blood pressure, end-tidal carbon dioxide, oxyhemoglobin saturation, and rectal temperature were monitored continuously during the study. Body temperature was maintained at 36°C to 37°C by use of a forced-air warming blanket (Snuggle Warm; Smiths Industries, Irvine, CA). To maintain the blood concentration of propofol and fentanyl, propofol and fentanyl were administered via a Graseby 3500 syringe pump (SIMS Graseby Ltd., Herts, UK) by using the infusion program RUGLOOP (written by T. De Smet and M. Struys, Ghent University, Gent, Belgium) (8). We used the program to incorporate an effect-site equilibration constant of 0.25 per minute with the pharmacokinetic data of Marsh et al. (9). for propofol. For fentanyl, we used the pharmacokinetic data of Shafer et al. (10).
Anesthetic protocol, an end point for awakening, and the method for defining the awakening concentration were determined with a modification of the method reported by Kazama et al. (11). In all groups, anesthesia was induced with a target (effect compartment) propofol concentration of 5 μg/mL and a fentanyl concentration of 2 ng/mL, with intubation facilitated by 0.1 mg/kg vecuronium. Ventilation was controlled with a tidal volume of 8 to 10 mL/kg, and the ventilatory rate was adjusted to maintain an end-tidal CO2 of 35 to 40 mm Hg. Vecuronium, in 1- to 3-mg IV bolus doses, was administered as required. At least one or two twitch responses to train-of-four stimulations were always present, as measured by a peripheral neuromuscular function monitor. At the end of the surgical procedure, 2.0 mg of neostigmine and 1.0 mg of atropine were administered IV. Propofol and fentanyl target (effect compartment) concentrations were maintained in ranges of 3 to 5 μg/mL and 1.5 to 3 ng/mL, respectively, during most of the surgery, to maintain systolic blood pressure within ±20% of baseline. Propofol and fentanyl target (effect compartment) concentrations were rigidly controlled at 3 μg/mL and 1 ng/mL, respectively, for at least the final 20 to 30 min of surgery. To ensure equivalent concentration sampling, target propofol and fentanyl concentrations were kept steady for at least 45 min before blood samples were obtained. After confirmation of the reversal of neuromuscular block, arterial blood for the propofol concentration was sampled immediately before the discontinuation of propofol in all patients. After abrupt discontinuation of propofol, patients’ responses to a verbal command to open their eyes after having their names called in a normal voice was evaluated every 30 s, and arterial blood samples for propofol and clonidine concentrations were taken when patients opened their eyes, which was recognized as a positive response. Propofol and fentanyl target concentrations were controlled throughout anesthesia by one of the authors (HH), who was blinded to the treatment of the patient. The responses to a verbal command were also identified by the same author. The time from termination of propofol to a positive response to verbal command was recorded.
Blood samples were allowed to clot and were then centrifuged at 3000 rpm for 10 min, and the serum was frozen at −4°C until assayed. The serum concentration of propofol was determined in our laboratory by using high-performance liquid chromatography with a fluorescence detection wavelength of 310 nm and an excitation wavelength of 276 nm (RF550; Shimadzu, Kyoto, Japan), as described previously (12). The area under the chromatographic peak was measured with an integrator (PowerChrom; AD Instrument, Tokyo, Japan). The propofol concentration was estimated from a peak/area ratio to the internal standard, thymol. Linear relationships were obtained between propofol and the internal standard peak/area ratios. The correlation coefficient was greater than 0.997 in the range of 50 ng/mL to 10 μg/mL. The detection limit of propofol was 10 ng/mL. The repeatability coefficients of the variation in serum were 4.6% and 2.1% at concentrations of 1 and 10 μg/mL, respectively, and 2.2% between days (10 μg/mL). The serum concentration of clonidine was measured in an outside laboratory by using a radioimmunoassay with [3H]-clonidine according to the modified method described previously (13). Linear relationships were obtained from the Scatchard plot against the concentration of labeled plus unlabeled bound ligand. The correlation coefficient was greater than 0.993 for the range of 10 to 1000 pg/mL. The detection limit of clonidine was 10 pg/mL. The coefficient of variation did not exceed 4.3% for any of seven standard determinations performed with five replicates.
Probit analysis was used to define the probability of no response to verbal command. The half-maximal effective concentration (EC50) of the awakening propofol concentration in the three groups was obtained from this analysis. Results are presented as mean ± sd. Analyses of patients’ demographic data or propofol concentration data within each group were performed with one-way or two-way analysis of variance followed by the Scheffé test. The survival functions (distributions of time until recovery) were compared by using the Kaplan-Meier procedure. The correlating coefficients between awakening propofol and clonidine concentrations were analyzed with polynomial regression. A P value of <0.05 was considered to be statistically significant.
There was no significant difference with respect to patient demographic data, rectal temperature, duration of surgery, or duration of propofol administration among the groups (Table 1). Anesthesia induction and maintenance was smooth in all cases, and no patient experienced sustained hypotension or bradycardia requiring vasopressor therapy. Similarly, recovery from anesthesia was uneventful, and none of the patients was able to recall any event during anesthesia.
Propofol and fentanyl consumption in the 5.0 μg/kg Clonidine group was significantly reduced by 25% and 15%, respectively, in comparison with the Control group (P < 0.05;Table 1). There was no significant difference in the serum propofol concentration at discontinuation of anesthesia among the three groups. The time required to respond to a verbal command was 14.9 ± 8.3 min for the 5.0 μg/kg Clonidine group; this was significantly longer than the Control (8.2 ± 5.0 min) or 2.5 μg/kg Clonidine (9.0 ± 3.7 min) groups (P < 0.01;Table 1). Similarly, the serum propofol concentration at awakening in the 5.0 μg/kg Clonidine group was 1.0 ± 0.4 μg/mL, which was significantly smaller than in the Control (1.6 ± 0.4 μg/mL) and the 2.5 μg/kg Clonidine (1.4 ± 0.3 μg/mL) groups (P < 0.01;Table 1). There was a dose-dependent shift to the left in patients receiving clonidine in the propofol concentration/response curves (Fig. 1). The EC50 value in the 5.0 μg/kg Clonidine group was significantly lower than those in the Control and 2.5 μg/kg Clonidine groups (P < 0.001;Table 1). The serum clonidine concentration in the 5.0 μg/kg Clonidine group was significantly larger than that in the 2.5 μg/kg Clonidine group (P < 0.001;Table 1). The survival analysis comparison of the cumulative probability of patients remaining unconscious after discontinuation of propofol in the three groups is shown in Figure 2. Log-rank differences between the 5.0 μg/kg Clonidine group and the Control and 2.5 μg/kg Clonidine groups were statistically significant (P < 0.001). Although there was a significant curvilinear correlation between awakening propofol and clonidine concentrations, the relationship was weak (r = 0.50, P < 0.001;Fig. 3).
Recovery from general anesthesia is governed by pharmacodynamic and pharmacokinetic factors. The awakening propofol concentration is independent of patient age, weight, and type of surgery (14), but it is influenced by the length of propofol infusion when propofol infusion is abruptly discontinued (11). It has been reported that sex is an important variable in recovery from general anesthesia (propofol/alfentanil/nitrous oxide) (15). In this study, only male patients were included, and the length of propofol infusion was similar in the three groups. Therefore, the results of this study indicate that 5 μg/kg oral clonidine premedication reduces the awakening propofol concentration and delays awakening from propofol/fentanyl anesthesia. The blood propofol concentration at awakening or EC50 in the Control group was 1.6 μg/mL, which was equal to that obtained in previous reports (11,16). Schüttler et al. (16) reported that the awakening propofol concentration was 1.59 μg/mL. Kazama et al. (11) reported that the awakening time and the EC50 of the awakening propofol concentration were 9.3 minutes and 1.6 μg/mL, respectively, after 291 minutes of propofol infusion. The slightly shorter awakening time in the Control group of this study compared with that obtained by Kazama et al. (11) might be explained by the slightly shorter duration of propofol in this study.
Our results indicate that the prolongation of recovery by 5 μg/kg oral clonidine premedication is consistent with previous reports, in which the recovery from isoflurane (2) or propofol anesthesia was delayed by clonidine (3,4). Further, the extent of reduction of the awakening propofol concentration by 5 μg/kg oral clonidine premedication in this study was approximately 37%, which is comparable with that obtained by Goyagi et al. (2). They (2) reported that 5 μg/kg oral clonidine premedication reduces the minimum alveolar anesthetic concentration (MAC)-awake of isoflurane by approximately 34%. Our study also demonstrated that that blood clonidine concentration was associated with a decrease in the awakening propofol concentration (Fig. 3). As mentioned previously, contrasting results were reported as to whether oral clonidine premedication delays emergence from anesthesia (2–7). Such confusing results among studies might result from different clonidine doses and the presence or absence of premedication in the control patients (2–7). In the studies in which oral clonidine premedication did not delay recovery from anesthesia, the doses of clonidine were 150–300 μg or 5 μg/kg, and the control patients received flunitrazepam or diazepam (5–7). However, the doses of clonidine were 2.5–5 μg/kg or 600 μg in studies that reported that oral clonidine delays emergence from anesthesia (2–4), and nothing was administered to the Control patients in this study or in those by Goyagi et al. (2,3).
Clonidine has potent analgesic properties that reduce the MAC of volatile anesthetics (17,18). It also decreases the requirement for IV anesthetics and narcotics, as well as the requirement for volatile anesthetics for surgery (19–23). Ghignone et al. (19,20) demonstrated that 5 μg/kg oral clonidine reduced the isoflurane requirement by 40% when assessed by hemodynamic responses (19) and reduced the fentanyl requirement by 45% when assessed by electroencephalogram (20). Imai et al. (21) investigated the effect of 150 μg of oral clonidine on propofol/fentanyl anesthesia and reported a reduction of 40% in the propofol requirement with similar doses of fentanyl by using hemodynamic end points. Fehr et al. (22) reported that 4 μg/kg IV clonidine reduced the requirement of TCI-administered propofol by 20% when anesthetic depth was assessed by bispectral index (BIS). Goyagi et al. (3), however, did not report the maintenance dose of propofol, which was administered by manual infusion by using hemodynamic end points. In our study, 5 μg/kg oral clonidine premedication reduced propofol and fentanyl requirements by 25% and 15%, respectively, when assessed by hemodynamic responses. These confounding results suggest that both computer-assisted TCI and anesthetic depth controlled by monitoring brain function (e.g., with BIS) are required to precisely determine the requirement of IV anesthetics and narcotics.
These results indicate that recovery from propofol anesthesia is delayed by approximately six minutes in patients receiving 5 μg/kg oral clonidine when the same target propofol concentration was maintained in all patients before discontinuation. However, the propofol requirement in patients receiving 5 μg/kg oral clonidine was reduced during surgery compared with the Control group. Therefore, if the propofol concentration had been reduced proportionally during the maintenance of anesthesia in our study, the wake-up time might not have been longer in the 5 μg/kg Clonidine group than in the Control group. Indeed, Fehr et al. (22) reported that clonidine administration did not delay recovery from propofol anesthesia, as clonidine administration resulted in a smaller propofol concentration required to induce a specific level of anesthesia, defined by similar BIS values, which facilitates recovery (23).
Benzodiazepines are standard premedication in clinical practice. They interact synergistically with propofol for the induction of anesthesia (24); however, they do not attenuate the hemodynamic responses to noxious stimuli and do not reduce the dose of propofol required to maintain anesthesia (21). On the other hand, clonidine produces a variety of beneficial perioperative effects, such as sedation, an anesthetic-sparing effect, increased cardiovascular stability, analgesia, and improved outcome (1). In this study, there was no reduction of propofol and fentanyl consumption in the 2.5 μg/kg Clonidine group compared with the Control group (Table 1). On the basis of overall clinical impression, the patients in the 5 μg/kg Clonidine group were more sedated at arrival in the operating room and had greater hemodynamic stability during anesthesia compared with the 2.5 μg/kg Clonidine group. Furthermore, De Deyne et al. (25) were unable to demonstrate that 3 μg/kg IV clonidine reduces the sevoflurane requirement, although anesthetic depth was assessed by BIS. The results of our study, together with the results of the previous studies, indicate that although a large dose of clonidine (4–5 μg/kg) might be required for reduction of the anesthetic requirement, such a large dose might delay recovery from anesthesia unless anesthetic depth is titrated by monitoring brain function (e.g., with BIS).
A possible criticism of this study is that the administration of propofol was discontinued suddenly after the target propofol concentration was maintained at 3.0 μg/mL, without equilibration between blood and the effect site. Although our protocol, using the abrupt discontinuation method, is more clinically relevant, the awakening propofol concentration with this method is likely to be underestimated compared with that using the equilibration method, because of hysteresis (11). In addition, this abrupt discontinuation of propofol might partly explain the weak relationship between the awakening propofol and clonidine concentration (Fig. 3) and the interindividual variability. In this study, the duration of propofol infusions of all patients varied, although the length of propofol infusion was similar in the three groups. This study is also limited in that we did not directly measure blood fentanyl concentrations. The accuracy of fentanyl infusion by the pharmacokinetic data of Shafer et al. (10), which were used in this study, was examined by Nakata et al. (26). According to their studies, the median absolute performance error of this variable is 20% to 30%. Indeed, the EC50 of the awakening propofol concentration in this study was equal to that obtained in the study by Kazama et al. (11), in which the mean fentanyl concentration was 0.88 to 0.91 ng/mL. Without measuring blood fentanyl concentrations, however, we cannot state that because the effect of fentanyl on awakening concentration was equivalent across all groups, it was not responsible for any difference among the three groups. A final and critical limitation of our study is that anesthetic depth was assessed only by hemodynamic responses. The accuracy of assessing anesthetic depth by hemodynamic responses after the administration of clonidine, which depresses autonomic nervous responses, is questionable (22,25). As mentioned previously, anesthetic depth-monitored brain function, such as BIS, is required to precisely evaluate the anesthetic-sparing effect of clonidine.
In summary, we investigated the awakening propofol concentrations with or without 2.5 or 5 μg/kg oral clonidine premedication in surgical patients. Oral clonidine premedication at a dose of 5 μg/kg decreased the awakening propofol concentration and delayed recovery from propofol anesthesia. The blood clonidine concentration was associated with the decrease in the awakening propofol concentration.
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