Background

Clonidine, which is known to have analgesic and sedative properties, has recently been shown to be an effective preanesthetic medication in children. The drug may cause side effects, including bradycardia and hypotension. This study was conducted to evaluate the ability of intravenous atropine to increase the heart rate (HR) in awake children receiving clonidine preanesthetic medication.

Methods

We studied 96 otherwise healthy children, 8-13 yr old, undergoing minor surgery. They received, at random, oral clonidine 2 or 4 micrograms.kg-1 or placebo 105 min before scheduled induction of anesthesia. Part I (n = 48, 16 per group): When hemodynamic parameters after insertion of a venous catheter had been confirmed to be stable, atropine was administered in incremental doses of 2.5, 2.5, and 5 micrograms.kg-1 every 2 min. The HR and blood pressure were recorded at 1-min intervals. Part II (n = 48, 16 per group): After the recording of baseline hemodynamic values, successive doses of atropine (5 micrograms.kg-1 every 2 min, to 40 micrograms.kg-1), were administered until HR increased by 20 beats.min-1. The HR and blood pressure were recorded at 1-min intervals.

Results

Part I: The increases in HR in response to a cumulative dose of atropine 10 micrograms.kg-1 were 33 +/- 3%, 16 +/- 3%, and 8 +/- 2% (mean +/- SEM) in children receiving placebo, clonidine 2 micrograms.kg-1, and clonidine 4 micrograms.kg-1, respectively (P < 0.05). Part II: The HR in the control group increased by more than 20 beats.min-1 in response to atropine 20 micrograms.kg-1 or less. In two patients in the clonidine 4 micrograms.kg-1 group, HR did not increase by 20 beats.min-1 even after 40 micrograms.kg-1 of atropine.

Conclusions

Oral clonidine premedication (4 micrograms.kg-1) blunted the increase in HR after intravenous atropine in awake children, although clonidine 2 micrograms.kg-1 did not. A larger dose of atropine was required to increase the HR by 20 beats.min-1 in children receiving the premedicant in the larger dose.

Key words: Anesthesia: pediatric. Parasympathetic nervous system, antagonist: atropine. Sympathetic nervous system, alpha2- adrenergic agonist: clonidine.

CLONIDINE has been demonstrated to be a useful preanesthetic medication in adults because of its sedative [1–3] and analgesic [4,5] properties. We have recently shown that oral clonidine 4 micro gram *symbol* kg sup -1 given preoperatively provided preoperative anxiolysis and cooperation in children. [6] Untoward side effects after clonidine premedication may include severe bradycardia or altered atrioventricular conduction. [7] Clonidine has been reported to decrease the heart rate (HR) response to intravenous atropine in awake adult patients. [8] Although repeated doses of atropine have successfully treated bradycardia resulting from clonidine overdose in children, [9–13] the relation between the dose of atropine and the increase in HR in children receiving clonidine has not been firmly established. Therefore, we conducted the current study in awake children to evaluate the effect of clonidine preanesthetic medication on the response of HR to intravenous atropine.

Materials and Methods

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.

Part I

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.

Part II

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.

Statistical Analysis

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.

Results

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).

Part I

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.

Figure 1. Changes in heart rate after cumulative doses of atropine. Data are expressed as means plus/minus SEM. #P < 0.05 versus baseline values;*P < 0.05 versus placebo.

Figure 1. Changes in heart rate after cumulative doses of atropine. Data are expressed as means plus/minus SEM. #P < 0.05 versus baseline values;*P < 0.05 versus placebo.

Figure 2. Changes in systolic (open symbols) and diastolic (solid symbols) blood pressure after cumulative doses of atropine. Data are expressed as means plus/minus SEM. P > 0.05 for all variables.

Figure 2. Changes in systolic (open symbols) and diastolic (solid symbols) blood pressure after cumulative doses of atropine. Data are expressed as means plus/minus SEM. P > 0.05 for all variables.

Part II

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.

Figure 3. Cumulative percentages of patients showing an increase in heart rate of more than 20 beats *symbol* min sup -1 compared with baseline values.

Figure 3. Cumulative percentages of patients showing an increase in heart rate of more than 20 beats *symbol* min sup -1 compared with baseline values.

Discussion

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.

REFERENCES

REFERENCES
1.
Segal IS, Jarvis DJ, Duncan SR, White PF, Maze M: Clinical efficacy of oral-transdermal clonidine combinations during the perioperative period. ANESTHESIOLOGY 74:220-225, 1995.
2.
Wright PMC, Carabine UA, McClune S, Orr DA, Moore J: Preanaesthetic medication with clonidine. Br J Anaesth 65:628-632, 1990.
3.
Ghignone M, Noe C, Calvillo O, Quintin L: Anesthesia for ophthalmic surgery in the elderly: The effects of clonidine on intraocular pressure, perioperative hemodynamics, and isoflurane requirements. ANESTHESIOLOGY 68:707-716, 1988.
4.
Ghignone M, Quintin L, Duke PC, Kehler CH, Calvillo O: Effects of clonidine on narcotic requirements and demodynamic response during induction of fentanyl anesthesia and endotracheal intubation. ANESTHESIOLOGY 64:36-42, 1986.
5.
Flacke JW, Bloor BC, Flacke WE, Wong D, Dazza S, Stead SW, Laks II: Reduced narcotic requirement by clonidine hemodynamics and adrenergic stability in patients undergoing coronary bypass surgery. ANESTHESIOLOGY 67:11-19, 1987.
6.
Mikawa K, Maekawa N, Nishina K, Takao Y, Yaku H, Obara H: Efficacy of oral clonidine premedication in children. ANESTHESIOLOGY 79:926-931, 1993.
7.
Byrd BF II, Collins HW, Primm R: Risk factors for during severe bradycardia oral clonidine therapy for hypertension. Arch Intern Med 148:729-733, 1988.
8.
Nishikawa T, Dohi S: Oral clonidine blunts the heart rate response to intravenous atropine in humans. ANESTHESIOLOGY 73:217-222, 1991.
9.
Fiser DH, Moss MM, Walker W: Critical care for clonidine poisoning in toddlers. Crit Care Med 18:1124-1128, 1990.
10.
Wiley JF, Weiley CC, Torrey SB, Henretig F: Clonidine poisoning in young children. J Pediatr 116:654-658, 1990.
11.
Anderson RJ, Hart GR, Crumpler CP, Lerman M: Clonidine overdose: Report of six cases and review of the literature. Ann Emerg Med 10:107-112, 1981.
12.
Pai GS, Lipsitz DJ: Clonidine poisoning. Pediatrics 58:749-750, 1975.
13.
Olsson JM, Pruitt AW: Management of clonidine ingestion in children. J Pediatr 103:646-650, 1983.
14.
Ghignone M, Calvillo O, Quintin L: Anesthesia sion effect of clonidine and hypertension: The perioperative hemodynamics and isoflurane requirements. ANESTHESIOLOGY 67:3-10, 1987.
15.
Nishikawa T, Kimura T, Taguchi N, Dohi S: Oral clonidine preanesthetic medication augments the pressor responses to intravenous ephedrine in awake or anesthetized patients. ANESTHESIOLOGY 74:705-710, 1991.
16.
Waite R: Inhibition of sympathetic nerve activity resulting from central alpha-adrenoceptor stimulation. Recent Advances in Hypertension. Volume II. Edited by Milliez P. Safar M. Reims Cedex. Allinea Society, 1975, pp 27-35.
17.
Svensson TH, BS, Aghajanian K: Inhibition adrenergic and scrotonergic neurons in brain by the agonist clonidine. Brain Res 92:291-306, 1975.
18.
Kobinger W, Walland A: Evidence for a central activation of a vagal cadiodepressor reflex by clonidine. Eur J Pharmacol 19:203- 209, 1972.
19.
Martin PR, Ebert MH, Gordon EK, Linnoila M, Kopin IJ: Effects of clonidine on central and peripheral catecholamine metabolism. Clin Pharmacol Ther 35:322-327, 1984.
20.
De Jonge A, Timmermans PBMWM, van Zwieten PA: Participation of cardiac presynaptic alpha sub 2 -adrenoceptors in the bradycardic effects of clonidine and analogues. Naunyn Schmiedebergs Arch Pharmacol 317:8-12, 1981.
21.
Clementy J, Catagne D, Dallocchio M, Bricaud H: Study of the electrophysiologic properties of clonidine administration intravenously. J Cardiovasc Pharmacol 8:S24-S29, 1986.
22.
Firestone L, editor: Clinical Anesthesia Procedures of the Massachusetts General Hospital, 3rd edition. Boston, Little, Brown, 1988, p 594.
23.
Primm RK, Urthaler F, James TS: Selective effects of clnidine on the canine sinus node. J Pharmacol Exp Ther 214:223-228, 1980.
24.
Dundee JW: Barbiturates, Intravenous Anaesthesia, 2nd edition. Edited by Dundee JW, New York, Churchill Livingstone, 1988, pp 137-154.
25.
Marshall BE, Longnecker DE: General anesthetics. The pharmacological Basis of Therapeutics. 8th edition. Edited by Gilman AG, Rall TW, Nies AS, Palmer T. New York, Pergamon Press, 1990 pp 285-310.
26.
Dubois MC, Piat V, Murat I: Induction of anaesthesia with sevoflurane in children: haemodynamic effects (abstract). Br J Anaesth 72:A189, 1994.
27.
Miller BR, Friesen RH: Oral atropine premedication in infants attenuates cardiovascular depression during halothane anesthesia. Anesth Analg 67:180-185, 1988.
28.
Weldon BC, Watcha MF, White PF: Oral midazolam in children: Effect of time and adjunctive therapy. Anesth Analg 75:51-55, 1992.