Anesth Analg 2002;94:1479-1483
© 2002 International Anesthesia Research Society
PEDIATRIC ANESTHESIA
The Hypnotic and Analgesic Effects of Oral Clonidine During Sevoflurane Anesthesia in Children: A Dose-Response Study
Shinichi Inomata, MD*,
Shin-ichi Kihara, MD*,
Masayuki Miyabe, MD*,
Kenji Sumiya, BSPharma
,
Yasuyuki Baba, PhD,
Yukinao Kohda, PhD, and
Hidenori Toyooka, MD*
Departments of *Anesthesiology and Clinical Pharmacy, the University of Tsukuba, Tsukuba City, Ibaraki, Japan
Address correspondence and reprint requests to Shinichi Inomata, MD, Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki 305-8575, Japan. Address e-mail to inomatas{at}md.tsukuba.ac.jp
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Abstract
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Although clonidine has both hypnotic and analgesic actions, the dose relationship for each actions is still unknown in a clinical setting when clonidine is used as a premedication in children. We studied 80 ASA physical status I children (age range, 3–8 yr). Subjects were randomly divided into two groups (minimum alveolar anesthetic concentration [MAC]-Awake group, n = 40; MAC-Tetanus group, n = 40). Each patient received one dose of clonidine from 1 to 5 µg/kg orally, 100 min before arrival at the operating room. Anesthesia was induced and maintained with sevoflurane in oxygen and air. Before tracheal intubation, end-tidal sevoflurane was decreased stepwise by 0.2% at the start of 1.2%, a verbal command was given to the patients, and MAC-awake was determined in each patient. We also investigated MAC-tetanus, determined with transcutaneous electric tetanic stimulations, after tracheal intubation in each patient by observing the motor response to a transcutaneous electric tetanic stimulus to the ulnar nerve at a sevoflurane concentration decreased stepwise by 0.25% at the start of 2.75%. The initial reduction in MAC-tetanus was not as steep as that in MAC-awake. Clonidine reduced MAC-tetanus by 40% at the maximal dose of 5 µg/kg, whereas MAC-awake was already reduced by 50% at 2 µg/kg. We conclude that separate dose-response relationships for oral clonidine are present regarding the hypnotic and analgesic effects in children undergoing sevoflurane anesthesia.
IMPLICATIONS: Separate dose-response relationships for oral clonidine were found regarding the hypnotic and analgesic effects in children undergoing sevoflurane anesthesia.
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Introduction
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2-Adrenergic agonists have both analgesic and hypnotic properties (1). The use of the 
2-agonist clonidine added to general anesthesia with inhaled anesthetics may provide two important functions for clinical anesthesia: loss of consciousness and analgesia. However, only limited clinical investigations about both analgesic and hypnotic actions of this drug are available, and the effects were tested in adult patients, not in children (2,3). Previously we reported that the minimum alveolar anesthetic concentration (MAC)-awake for sevoflurane was markedly reduced by clonidine (at a preanesthetic dose of 2 µg/kg) (4). Furthermore, the reduction in standard MAC for sevoflurane was smaller, even at a larger dose of 4 µg/kg (5). Dose-dependent drug interactions between clonidine and sevoflurane have not been fully elucidated in children. This study was designed to assess the reduction of the MAC-awake and MAC-tetanus of sevoflurane caused by the administration of various doses of clonidine, ranging from 1 µg/kg to a maximum of 5 µg/kg in children.
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Methods
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We studied 80 pediatric patients, ASA physical status I, ranging in age from 3 to 8 years, who were scheduled for general anesthesia for elective inguinal herniorrhaphy. The study protocol was approved by the Clinical Investigation Committee of the University of Tsukuba, and informed consent was obtained from the parent or guardian of each patient.
Patients were randomly allocated, by use of computer-generated numbers, to either the MAC-Awake group or the MAC-Tetanus group (n = 40 each). Each patient received one oral dose of clonidine from 1 to 5 µg/kg mixed with a piece of candy, 100 min before arrival in the operating room. All patients were fasted for a minimum of 5 h before the induction of anesthesia. Venous access was obtained for the infusion of 6 mL · kg-1 · h-1 of lactated Ringer’s solution before surgery. Standard monitoring was used, and body temperature was monitored by a tympanic probe and was kept constant at 36.8°C ± 0.4°C by use of a heating pad. Breath-by-breath inspired/end-tidal sevoflurane and CO2 concentrations were measured with a multigas analyzer (AS/3TM; Datex, Helsinki, Finland) precalibrated with a standard gas mixture. Before tracheal intubation, the end-tidal concentrations were measured at the pharynx via a cannula; after intubation, they were measured from the distal end of tracheal tube by using a tracheal tube with a gas-sampling lumen (Uncuffed Tracheal Tube with Monitoring LumenTM; Mallinckrodt, St. Louis, MO). End-tidal CO2 trace had returned to zero, and there was a good wave formation with a plateau using a total gas inflow of 6 L/min. The end-tidal concentration of CO2 was maintained at 35–40 mm Hg during the study.
Anesthesia was induced and maintained with sevoflurane in oxygen and air (fraction of inspired oxygen, 40%) without IV anesthetics or neuromuscular relaxants throughout the study. Before tracheal intubation, end-tidal sevoflurane was decreased stepwise by 0.2%, a verbal command was played to the patients, and MAC-awake was determined in each patient. Patients received a standardized verbal command to open their eyes, and this command was played from a tape every 5 s via occlusive headphones. No other stimuli were used during the study period. One anesthesiologist, who was blinded to the tested sevoflurane concentration and the dose of clonidine, evaluated their response to verbal stimuli. In the MAC-Tetanus group after tracheal intubation, we investigated the MAC-tetanus in each patient by observing the motor response to a transcutaneous electric tetanic stimulus (a 10-s, 50-Hz, 80-mA stimulus) by use of electric stimulation (NS252TM; Fisher & Paykel Healthcare Division, Auckland, New Zealand) to the ulnar nerve at a sevoflurane concentration decreased stepwise by 0.25%. After electric stimulation, the patients were observed for at least 1 min for gross purposeful muscular movements. Bucking, grimacing, and straining were not considered purposeful. Patients who showed purposeful muscular movements during or after the stimulation were immediately given 4%–5% sevoflurane. Absence of any purposeful movement was determined by one anesthesiologist, who was blinded to the tested sevoflurane concentration and the dose of clonidine.
In each attempt, the end-tidal sevoflurane concentration reached a predetermined value, and then the ratio of predetermined end-tidal to inspiratory concentration was maintained at 0.95–1.00 for at least 15 min. Additionally, when blood pressure or heart rate changed at a stimulus, the next stimulus was applied to the patient after he or she returned to the control values before the stimulus. We chose the end-tidal sevoflurane concentrations and intervals used in the MAC-awake and the MAC-tetanus determination according to a pilot study.
We analyzed the reduction of sevoflurane MAC-awake and MAC-tetanus by using a multiple independent variable logistic regression model (SAS System for Windows, version 6.12; SAS Institute Inc., Cary, NC; and a personal computer) in which P, the probability of no response, was
equation
where X1 is the end-tidal sevoflurane concentration, X2 is the dose of clonidine, ß0 is the regression intercept constant, ß1 is the coefficient for sevoflurane, ß2 is the coefficient for clonidine, and ßl2 is the coefficient for the product of the end-tidal sevoflurane concentration and the dose of clonidine (the interaction coefficient). The main effects components, ß1 andß2, determined whether sevoflurane and clonidine independently affected the response to stimulation. The interaction coefficient, ß12, determined whether sevoflurane and clonidine interacted to affect the response to stimulation. We used the maximum likelihood ratio test to determine which of the independent variables significantly affected the model. To determine the concentration of sevoflurane required to prevent movement in 50% of children, the probability of no response was assigned the value 0.5, and the equation was solved for the sevoflurane concentration as follows:
equation
Likewise, to determine the concentration of sevoflurane required to prevent movement in 5% or 95% of children (95% confidence interval [CI]), the probability of no movement was set at 0.05 or 0.95, and the equation was solved for the sevoflurane concentration.
Patient characteristic data were expressed as mean ± SD, and statistical comparisons were performed with unpaired Student’s t-tests between the two groups (StatView software; SAS Institute Inc.; and a personal computer). P < 0.05 was considered the minimum level of statistical significance.
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Results
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The patient characteristics for children in each group were similar (Table 1). The MAC-awake estimated for the patients who did not receive clonidine was 0.81% (95% CI, 0.70%–0.92%). The MAC-awake was markedly reduced as the dose of clonidine increased. The reduction of MAC-awake was approximately 21%, 53%, or 80% at clonidine doses of 0.5, 2, or 5 µg/kg, respectively (Fig. 1). A 50% reduction in MAC-awake was produced by 1.8 µg/kg of clonidine. A curvilinear relationship was observed, with 3 µg/kg of clonidine providing only an additional 15% reduction in MAC-awake (Fig. 1). The MAC-awake was estimated to be 0% at a clonidine dose of 9.9 µg/kg.
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Figure 1. Minimum alveolar anesthetic concentration (MAC)-awake dose-response relationship for clonidine and sevoflurane in children. Solid line = 50% effective dose (MAC-awake); dotted lines = 95% confidence interval.
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The MAC-tetanus estimated from the patients not receiving clonidine was 2.28% (95% CI, 2.05%–2.52%). The MAC-tetanus was reduced as the dose of clonidine increased. The reduction of MAC-tetanus was approximately 28% or 42% at a clonidine dose of 2 or 5 µg/kg, respectively (Fig. 2). Clonidine reduced MAC-tetanus by 40% at the maximal dose of 5 µg/kg. The calculated MAC-tetanus was reduced by 50% at a clonidine dose of 8.1 µg/kg.
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Figure 2. Minimum alveolar anesthetic concentration (MAC)-tetanus dose-response relationship for clonidine and sevoflurane in children. Solid line = 50% effective dose (MAC-tetanus); dotted lines = 95% confidence interval.
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Discussion
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Knowledge of the dose-dependent effects of an adjuvant premedication with hypnotic and analgesic actions on the MAC-awake and the MAC values of volatile anesthetics is incomplete. Because these drug interactions are important for anesthesiologists to prevent intraoperative movement, awareness, and delayed emergence from anesthesia, we performed this study to assess these drug interactions between clonidine and sevoflurane in a dose-response manner. In this study, we showed that although a steep reduction was observed in the MAC-awake response to sevoflurane by clonidine, such a sharp reduction was not observed in the MAC-tetanus reaction. We conclude that the MAC-awake value of sevoflurane decreases steeply by 50% with even 2 µg/kg of clonidine, and the MAC-tetanus value decreases by only 40% at the maximal dose of 5 µg/kg, suggesting that oral clonidine has more potent hypnotic action than analgesic action during sevoflurane anesthesia in children. Although the reduction curve of MAC-awake was exponential, no obvious ceiling effect was observed at the concentrations administered in this study. Thus, the mode of reduction was different between the hypnotic and analgesic end points. Some observations suggest that motor responses to a noxious stimulus may be primarily mediated by subcortical structures, including the spinal cord (6,7). In contrast, purposeful responsiveness to a verbal command apparently requires intact cortex function. Therefore, clonidine may act at different sites in producing its effect on MAC-awake and MAC-tetanus reductions. The difference in the mode of reduction by clonidine between the MAC-awake and MAC-tetanus values may be caused by a different site, different response, or effect.
In this study, the MAC-awake value for sevoflurane determined in the unpremedicated children at 0.81% was slightly higher than the range previously reported for adults (0.60%–0.67%) (3,8–10). This is in agreement with a previous report that the MAC-awake of volatile anesthetics decreases as the age of the patient increases (8). Additionally, our MAC-awake value in the unpremedicated children agrees well with a previous report that the MAC-awake value of sevoflurane was 0.78% in children (4). Moreover, our MAC-tetanus value (2.28%) in the Control group agrees reasonably well with the MAC (for incision) of sevoflurane (2.03%–2.5%) (11,12). The MAC-awake/MAC (for incision) ratio determined in children was reported to range from 0.31 to 0.39 (0.78%:2.5% to 0.78%:2.03%) (4,11,12), which is very similar to the results obtained in this study (0.35) in unpremedicated children. Although MAC and MAC-awake values change according to the patient’s age, the results of this study and our previous results suggest that the MAC-awake/MAC ratio of sevoflurane is very similar in pediatric (4,11,12) and adult (3,8,10) patients.
The value of MAC is affected by the method of determination, age, body temperature, type of surgery, duration of exposure to a volatile anesthetic, presence or absence of endotracheal tube or laryngeal mask airway, and arterial CO2 tension. Hyperventilation may lead to wider differences between brain and alveolar partial pressures of volatile anesthetics, because of cerebral vasoconstriction, and might decrease the MAC values (13). The patients in this study underwent controlled ventilation so that the end-tidal CO2 tension was maintained between 35 and 40 mm Hg throughout the study, thereby minimizing the effect of cerebral blood flow on the MAC determinations. With spontaneous respiration at the time of emergence from anesthesia, however, MAC values might have been different from these results because clonidine per se possesses a weak respiratory depressant effect, and the combination of clonidine and volatile anesthetics might have caused significant respiratory depression (14). Additionally, pain may have an effect on the results at the end of surgery.
Whereas a current of 60–80 mA is sufficient to cause supramaximal stimulation (15,16), the MAC obtained with tetanic nerve stimulation is generally lower than that obtained with skin incision (17). In addition to skin incision, other noxious stimuli, such as squeezing of the trapezius and tetanic nerve stimulation (17), have been used to assess the potency of anesthetics. Tetanic nerve stimulation is superior to other methods because it is easily performed, repeatable, and easily standardized. Dixon’s up-and-down method (18) assumes that each measurement in a subject is independent and not correlated with any other measurements in that individual. However, the fact that tetanic nerve stimulation was applied at least twice to the same subject in this study is a methodological limitation that could have introduced error into our results because of intrasubject correlations and tolerance or sensitization.
Previous pharmacokinetic studies have shown that the plasma concentration of clonidine increases rapidly after a single oral dose, and it reaches almost 80% of the peak plasma level 1.5 hours after oral intake (19,20). The elimination half-life of clonidine ranges from 6 to 24 hours, with a mean of approximately 12 hours (20). On the basis of these pharmacokinetic data, especially the findings of a long elimination half-life, it is likely that significant plasma clonidine levels were maintained after surgical procedures lasting after the MAC-awake and the MAC-tetanus were determined in this study.
In children who are premedicated with oral clonidine, the MAC-awake/MAC-tetanus ratio decreases as the dose of clonidine increases. Therefore, some patients may have difficulty emerging from anesthesia, even with small doses of clonidine and even when the emergence occurs a long time after the clonidine administration has finished.
In conclusion, we found that an 2-adrenergic agonist, clonidine, has more potent hypnotic action, assessed by MAC-awake, than analgesic action, assessed by MAC-tetanus, during sevoflurane anesthesia in children. We recommend that anesthesiologists consider the need for caution of delayed emergence or a lower sevoflurane level necessary for emergence in the presence of clonidine.
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Acknowledgments
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The authors are very grateful to Dr. Lerman at the University of Toronto for his encouragement and numerous suggestions.
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References
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Accepted for publication January 10, 2002.
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Abstract
Introduction
