Oral Clonidine Premedication Blunts the Heart Rate Response to Intravenous Atropine in Awake Children 

After obtaining the approval of Kobe University Hospital and informed consent from the parents of all children, we studied 96 children (American Society of Anesthesiologists physical status 1 inpatients), 8–13 yr old. The study was carried out in two parts.

In each part, 48 children were randomly divided into three groups (16 children per group) according to their premedication: oral clonidine (Catapres, Boehringer Ingelheim) in a dose of 2 or 4 micro gram *symbol* kg sup -1 or placebo. These medications were given 105 min before the scheduled induction of anesthesia. This timing of administration was the same as described in our previous report. [6].

HR and blood pressure (BP) were measured before premedication and 30 min before induction of anesthesia. All children were pretreated with a local anesthetic cream 60 min before anesthesia (lidocaine and prilocaine mixture) to alleviate pain during venous cannulation.

In the operating room, a 22-G intravenous catheter was inserted into a vein of the dorsum of the hand. Patients whose fear of venous cannulation was not allayed or in whom venous cannulation was difficult to perform were excluded from the study. Lead II of the electrocardiogram and noninvasive BP were monitored (Pulsemate BX-5, Nippon Colin, Tokyo, Japan). The HR was determined as an average of every 15-s interval from the electrocardiogram monitor. After HR and BP were stable, hemodynamic baseline values were recorded.

These 48 patients received incremental doses of atropine, 2.5, 2.5, and 5 micro gram *symbol* kg sup -1 over a 5-s period at 2- min intervals while spontaneously breathing room air. The HR and BP were measured at 1′-min intervals until 2 min after the last dose of atropine.

This part of the study was designed to determine the dose of atropine needed to increase HR by 20 beats *symbol* min sup -1.

After a stable hemodynamic state was obtained, all patients received incremental doses of atropine 5 micro gram *symbol* kg sup -1 over a 5-s period at 2-min intervals until HR increased by 20 beats *symbol* min sup -1 from the baseline value. If HR increased by more than 20 beats *symbol* min sup -1 from the baseline value, no additional atropine was administered. The maximum dose of atropine was restricted to 40 micro gram *symbol* kg sup -1. The number of patients whose HR increased by more than 20 beats *symbol* min sup -1 with each atropine dose was recorded.

Data were expressed as mean plus/minus SD or SEM as appropriate. Statistical comparisons among the three groups were performed by the analysis of variance followed by the Newman-Keuls test for continuous variables. Repeated-measures analysis of variance followed by the Student's t test was used for analyzing HR and BP responses within each group in part I. Comparisons of the incidence of positive HR response to administration of atropine among the three groups were made by using the Kruskal-Wallis test in part II. P < 0.05 was considered statistically significant.

The mean (SD) age, weight, height, and premedication time of the six groups were 10.8 (1.6) yr, 38 (14) kg, 145 (11) cm, and 106 (8) min, respectively. They did not differ among the groups. Mean values for hemodynamic parameters (HR [beats per minute], systolic BP [millimeters mercury], and diastolic BP [millimeters mercury]) were 82, 109, and 67; 81, 110, and 64; and 83, 110, and 67 before premedication and 82, 105, and 67; 82, 110, and 65; and 81, 108, and 63, respectively, 30 min before induction of anesthesia in the control, clonidine 2 micro gram *symbol* kg sup -1, and clonidine 4 micro gram *symbol* kg sup -1 groups, respectively. Preanesthetic HR and BP were not significantly different among the three groups nor between, before, or after premedication within each group. Preoperative sedation was assessed on arrival to the operating room with a three-point scale (1 = fearful or tense; 2 = alert or aware; and 3 = drowsy or sleeping). The sedation score was significantly higher in the clonidine 4 micro gram *symbol* kg sup -1 group (numbers of patients with sedation scores of 1, 2, and 3 were 12, 20, and 0; 7, 17, and 8; and 2, 8, and 22, respectively, in the control, clonidine 2 micro gram *symbol* kg sup -1, and 4 micro gram *symbol* kg sup -1 groups, respectively).

The HR was decreased by a smaller dose of atropine but was increased by incrementally larger doses of the drug in the control and 2 micro gram *symbol* kg sup -1 clonidine groups (Figure 1). The increase in HR after 10 micro gram *symbol* kg sup -1 atropine was blunted in the 4-micro gram *symbol* kg sup -1 clonidine group but not in 2-micro gram *symbol* kg sup -1 clonidine group (vs. the control group). The BP changes were significant neither within each group nor between groups (Figure 2). Side effects (bradycardia [HR < 60 beats *symbol* min sup -1] or hypotension [systolic BP < 80 mmHg or decrease by > 20 mmHg]) were not observed in any patient during the study period.

Atropine in a cumulative dose of 20 micro gram *symbol* kg sup -1 increased HR by 20 beats *symbol* min sup -1 in every patient in the control group, whereas as much as 30 micro gram *symbol* kg sup -1 atropine was necessary to increase HR by 20 beats *symbol* min sup -1 in patients receiving 2 micro gram *symbol* kg sup -1 clonidine (P < 0.05 vs. control). However, 40 micro gram *symbol* kg sup -1 of atropine was not effective in increasing HR by 20 beats *symbol* min sup -1 in two children in the clonidine 4-micro gram *symbol* kg sup -1 group (Figure 3). No adverse effects related to large doses of atropine were observed.

Clonidine has gained interest because of its anxiolytic, [1–3] analgesic, [4,5] and anesthetic-sparing properties. [1,14] The drug in doses currently used for preanesthetic medication has been reported to cause bradycardia or hypotension in some patients. [8,15] Case reports have occasionally described accidental clonidine overdose (to 3 mg) in children. [9–13] Successful pharmacologic treatments for clonidine poisoning include repeated administration of atropine, naloxone, and dopamine with volume expansion. [7,9].

The current study has shown that oral clonidine 4 micro gram *symbol* kg sup -1 pretreatment attenuated the increase in HR produced by intravenous atropine in children. A larger dose of atropine was required to counteract the HR effect of clonidine. It has been reported that clonidine diminishes the HR increase in response to intravenous atropine in awake adult patients [8]; our observations in children are consistent with that finding.

Some mechanisms by which clonidine slows HR have been suggested. Inhibition of central sympathetic outflow, [16,17] enhancement of vagal activity, [18] reduction of catecholamine release at cardiac postganglionic sympathetic nerve endings, [19,20] and a direct negative dromotropic effect on the cardiac conduction system [21] are among possible explanations.

Attopine increases HR through M²receptors on the sinoatrial nodal pacemaker. The increase in HR response to atropine is larger in persons in whom vagal tone is considerable. Thus, in infants, even large doses of atropine may fail to increase the HR. A sufficient dose of atropine abolishes reflex vagal cardiac slowing or asystole induced by stimulation of the carotid sinus, pressure on the eyeballs, or peritoneal traction. However, a large dose of atropine (1 mg *symbol* kg sup -1) has no effect on the sinus slowing produced by clonidine in dogs with the sinus node selectively perfused. [22] The enhancement of vagal activity may not be the sole mechanism whereby the HR is decreased by clonidine pretreatment.

The protocol for the current study was based on the following concept. Intravenous atropine 10 micro gram *symbol* kg sup -1 is routinely used in our clinical setting of pediatric anesthesia and has been recommended for bradycardia in children. [23] Thus, a total dose of 10 micro gram *symbol* kg sup -1 was used in part I of the current study. Because the HR response to 10 micro gram *symbol* kg sup -1 of atropine was different among the three groups in part I of study, an attempt was made to determine the dose of atropine required to overcome the effect of clonidine. The results of part I showed that atropine 10 micro gram *symbol* kg sup -1 increased HR by 24 plus/minus 7 beats *symbol* min sup -1 in the control group. Thus, we chose an increase in HR by 20 beats *symbol* min sup -1, which was observed in 50% of the patients in the control group, as an end point of part II of the study.

Because anesthetics per se have some effects on hemodynamics, we studied awake children in the current investigation. Thiopental, halothane, and sevoflurane, which are commonly used as induction agents in pediatric anesthesia, have been reported to influence cardiac function. Thiopental slightly increases HR. [24] Halothane slows HR through reduction of cardiac sympathetic activity with a consequent vagal predominance (atropine-sensitive) and direct slowing of sinoatrial nodal discharge (atropine-insensitive). [25] Slow induction of anesthesia using sevoflurane has been reported to increase HR in children. [26] Further studies would be required to clarify whether anesthetic agents modulate the clonidine-induced decrease in HR response to intravenous atropine.

Most younger children cry or move if not given any sedative drugs or anesthetics. This behavior also changes HR and BP. Thus, because of the difficulty in accurately assessing the responses of hemodynamic variables in awake younger children, we included only older children (greater or equal to 8 yr old) in the current study. The autonomic innervation of the heart is incomplete in the newborn, with a relative lack of sympathetic elements, and develops during infancy and young childhood. To the best of our knowledge, no data are available to date to ascertain as to whether infants or younger children are more susceptible to bradycardia by clonidine. The cardiac output depends to a considerable extent on the HR during infancy. Oral clonidine may not be suitable for sedatives in infants because of its potential bradycardic effect. Because the drug may be an effective and useful premedicant in younger children, the effect of clonidine on the HR response to atropine deserves further studies involving subjects of this age group. Anesthetized children should be enrolled in those studies.

In infants (1–6 months old), oral atropine has been reported to be effective in attenuating the cardiovascular depressant effects of halothane [27]; therefore, atropine has often been given for preanesthetic medication to children. However, in 1–8-yr-old children, oral atropine premedication did not affect the incidence of perioperative bradycardia after halothane anesthesia. [28] Recently, the frequency with which atropine is used as a premedicant for pediatric anesthesia has been decreasing; however, this trend probably cannot be extrapolated to children given clonidine as a premedicant. Although in our previous study in children aged 4–12 yr⁶atropine was orally administered 30 min before induction of anesthesia to ensure safety, in the current study atropine was not given as a premedicant even to the children receiving clonidine. However, there were no significant differences in HR and BP just before the induction of anesthesia between the control (placebo) and clonidine groups. Oral atropine should preferably be avoided because of its bitter taste. Routine preanesthetic medication with oral atropine may be unnecessary even for all children receiving clonidine.

In none of the children receiving oral clonidine at either dose did bradycardia develop as a result of the stimulation of intubation. A curved blade was used for laryngoscopy, and the trachea was intubated immediately after intravenous administration of atropine; these maneuvers may have contributed to the success in the prevention of bradycardia. The combination of oral clonidine and intravenous atropine never enhanced the bradycardic response to tracheal intubation. However, this phenomenon cannot be extrapolated to the general population because of the small number of patients enrolled in this study.

In conclusion, oral clonidine premedication (4 micro gram *symbol* kg sup -1) suppressed the response of HR to intravenous atropine 10 micro gram *symbol* kg sup -1 in awake children, although 2 micro gram *symbol* kg sup -1 of clonidine did not. A larger dose of atropine was needed to increase the HR by 20 beats *symbol* min sup -1 in patients given the larger dose of clonidine.