Oral Clonidine Premedication Does Not Change Efficacy of Simulated Epidural Test Dose in Sevoflurane-anesthetized Children

One hundred twenty children, aged 18–90 months (American Society of Anesthesiologists status I), with a normal sinus rhythm assessed by preoperative electrocardiography were enrolled in the current study after obtaining institutional approval and informed parental consent. The patients, who were scheduled to undergo minor surgery, were randomly assigned to one of six groups (n = 20 each) according to a combination of their premedicants and catecholamine for simulation of epidural test dose as follows: control–saline, children did not receive any premedicant but received intravenous saline; clonidine–saline, children received oral clonidine premedication followed by intravenous saline; control–epinephrine, children did not receive any premedicant but received an intravascular test dose of lidocaine containing epinephrine; clonidine–epinephrine, children received oral clonidine premedication followed by an intravascular test dose of lidocaine containing epinephrine; control–isoproterenol, children did not receive any premedicant but received an intravascular test dose of lidocaine containing isoproterenol; and clonidine–isoproterenol, children received oral clonidine premedication followed by an intravascular test dose of lidocaine containing isoproterenol.

In the three clonidine groups, children received clonidine 4 mg/kg 90–110 min before induction of anesthesia with a small amount of water. All children were prohibited from eating solid food or drinking milk products after midnight, but were instructed to ingest clear fluid 3 h before induction of anesthesia. Table 1shows the demographic data of the six groups. Monitoring included pulse oximetry, respiratory gas analysis, automated noninvasive oscillometric BP device, and electrocardiography. Anesthesia was induced with sevoflurane and nitrous oxide (70%) in oxygen using a semiclosed circle system. After loss of consciousness, venous access was obtained on a forearm peripheral vein for injection of study drugs and intraoperative infusion. Atropine 0.01 mg/kg was intravenously given to all patients 10 min after induction of anesthesia. End-tidal concentration of sevoflurane for anesthetic maintenance was 3.0% (in control groups) 8or 1.6% (in clonidine groups) 9measured with AS/3 (Datex-Ohmeda, Helsinki, Finland), corresponding to 1.2 minimum alveolar concentration (MAC). Ventilation of the lungs was first assisted and thereafter controlled to obtain end-tidal carbon dioxide tensions of 32–39 mmHg.

We confirmed that hemodynamics in each patient were stable for 10 min after injection of atropine, then the control–epinephrine or clonidine–epinephrine group received an intravenous test dose consisting of 1% lidocaine with 1:200,000 epinephrine solution 0.1 ml/kg (= lidocaine 1 mg/kg plus epinephrine 0.5 mg/kg), the control–isoproterenol or clonidine–isoproterenol group received that consisting of 1% lidocaine with 3:4000,000 isoproterenol solution 0.1 ml/kg (= lidocaine 1 mg/kg plus isoproterenol 75 ng/kg), and the control–saline or clonidine–saline group received saline 0.1 ml/kg. The test solutions were prepared by the second author (K.N.) and injected by a blind observer (M.S.) over 5 s. The data were recorded and analyzed by the observer who was blinded to the group assignment. HR and BP were recorded before premedication at the hospital ward, immediately before induction of anesthesia, 10 min after induction of anesthesia and immediately before intravenous atropine, 10 min after intravenous atropine and immediately before injection of the test solutions or saline (time 0 in figures), and subsequently at 15-s (for HR continuously monitored) and 30-s (for BP) intervals for 5 min.

Morphologic changes of T wave continuously recorded in a strip chart were analyzed at preinduction, postinduction, and pretest dose points by the blinded observer (K.M.). Furthermore, the maximal values of HR, BP, and T-wave amplitude after the test dose or saline were recorded. Time to measured HR increase of 10 beats/min greater than pretest dose value, time to maximal increases in HR and T-wave amplitude from injection of the test solutions, and duration of time for increased HR ≥ 10 beats/min were obtained. All measurements were completed before surgical skin incision. Oxygen saturation assessed by pulse oximeter was ≥ 97% in all children during the study. No children had arrhythmia during the study.

Criteria for definition of positive hemodynamic responses included HR increase ≥ 20 beats/min and systolic BP (SBP) increase ≥ 15 mmHg, occurring within 2 min after administration (conventional criteria). 10These criteria were determined from data in unmedicated, awake adult volunteers. 10Thus, a new HR criterion for positive test dose in anesthetized children was advocated: positive if ≥ 10 beats/min HR increase. 11–13Furthermore, a T-wave criterion was proposed: positive if ≥ 25% increase in amplitude. 12,13Use of the new HR and T-wave criteria has been shown to provide better sensitivity. 12,13In the current study, sensitivity (true positive/[true positives + false negatives]) and specificity (true negatives/[true negatives + false positives]) were calculated on the basis of these traditional and new criteria.

Data are expressed as mean values ± SD. Data were statistically analyzed by two-way analysis of variance to compare changes in hemodynamics and T-wave amplitude between groups. When a significant difference was identified, this was followed by an unpaired Student t  test. Changes in hemodynamics and T-wave amplitude over time within each group were analyzed using repeated-measures analysis of variance, followed by a paired Student t  test. Statistical significance of nonparametric data (e.g. , sensitivity, specificity) was determined using the Fisher exact probability test. For all comparisons, P < 0.05 was considered significant. The sample size of the current study is sufficient to detect large differences (effect size = (mean¹− mean²)/SD = 0.7–1.0) in variables at a significance level of 0.05 and a power of 0.7–0.85. 14 

Mean (± SD) age, weight, and height were 53 ± 25 months, 18 ± 7.0 kg, and 105 ± 18 cm, respectively, and were comparable in the six groups. Table 1shows that there was no significant difference in hemodynamics at the hospital ward and HR increased before induction of anesthesia in the control groups. However, BP and HR at postinduction and pretest dose (time 0) points did not differ between the clonidine and control groups. The T-wave amplitude was similar at any point among the groups (table 1).

There were no significant difference in timing, duration, or degree of HR increase produced by epinephrine or isoproterenol between the control and clonidine groups (fig. 1). Oral clonidine premedication had no effect on maximal increase in SBP induced by epinephrine or isoproterenol (fig. 1and table 1). T-wave amplitude was increased in all children receiving epinephrine or isoproterenol, although the degrees were different. Clonidine did not modify the maximal increase T-wave morphologic changes or time to the peak value from injection of these catecholamines (table 1).

In the saline groups, intravenous injection of saline did not essentially change HR, SBP, or T-wave amplitude (data not shown). Thus, specificities of epinephrine or isoproterenol based on four types of criteria were all 100% (table 2). Sensitivities of epinephrine or isoproterenol according to the new HR criterion were all 100% (table 2). However, sensitivities of epinephrine or isoproterenol were 75–85% based on the conventional HR criterion. Sensitivities of epinephrine based on SBP criterion were 100% in the two epinephrine groups (table 2). Sensitivities of epinephrine based on T-wave criterion were 90% in both of the groups. However, sensitivities of isoproterenol based on SBP and T-wave criteria were lower than those of epinephrine (table 2). Oral clonidine premedication did not alter the sensitivities of epinephrine or isoproterenol based on these hemodynamic and T-wave criteria (table 2).

Much has been shown about modulation of clonidine on hemodynamic responses to exogenously administered drugs acting on the cardiovascular system. 6,15,16Oral clonidine attenuates the bradycardia-reversing effect of intravenous atropine in awake children. 17In adults, oral clonidine enhances the pressor response to ephedrine 15and phenylephrine. 16On the other hand, oral clonidine does not alter the efficacy of a simulated intravenous test dose containing epinephrine in awake adults. 18Another study found that the same dose of clonidine enhances the hemodynamic responses to epinephrine-containing test solutions. 18,19 

In agreement with previous reports, 12,13the epinephrine-containing test dose did not provide 100% sensitivity on the basis of conventional HR criteria. In sevoflurane-anesthetized children, the new HR criterion would be useful. T-wave amplitude is advocated as a novel reliable guide for detecting intravascular injection of a test dose containing epinephrine in sevoflurane-anesthetized children with 100% sensitivity and specificity. 12,13However, shortcomings of this indicator include age limit for successful application. Elevation of T-wave amplitude to epinephrine is inversely proportional to age, and the upper age limit where this increase is detectable is estimated at 92 months as calculated from extrapolation of linear fitted line to zero of T-wave morphologic change. 13Another drawback of this marker is that T-wave positive response to intravenous epinephrine requires atropine pretreatment. 20We were unable to confirm completeness of this marker: sensitivity was 90% despite the use of atropine pretreatment. Our failure may be a result of the use of some older children (aged 85–90 months) in the current study. Furthermore, intravenous treatment with atropine before epinephrine prolongs duration of the HR positive response and augments SBP increase sufficiently to ameliorate sensitivity for detection of intravascular injection of test dose. 11Atropine may be used in children scheduled to undergo epidural anesthesia to improve efficacy of simulated epidural test dose containing epinephrine.

Hemodynamic responses to epinephrine or isoproterenol vary from several clinical situations, including inhalational anesthetics. Sevoflurane inhibits pressor and tachycardic responses to epinephrine in children. 11–13Although sevoflurane at concentrations of 1–2 MAC has no effect on HR and causes dose-dependent reduction of BP in adults, 21the effects of the volatile anesthetic on HR and BP in infants and children vary from age. 22Inhalation of sevoflurane at 1 MAC has no effect on HR in neonates, infants, and children aged less than 3 yr, whereas the anesthetic (1 MAC) increases HR in children older than 3 yr. 22In children aged 1–3 yr or 5–12 yr, SBP is not changed by inhalation of 1 MAC sevoflurane. However, SBP decreases in children aged 3–5 yr receiving sevoflurane. 22Halothane is also known to suppress hemodynamic responses to epinephrine. 23Halothane per se slows HR through reduction of cardiac sympathetic activity with a consequent vagal predominance and direct slowing of sinoatrial nodal discharge. 24A decreased chronotropic responses to isoproterenol was found in sevoflurane-anesthetized children compared with halothane-anesthetized children at 1 MAC. 4Thus, our data obtained in 1.2 MAC sevoflurane-anesthetized children cannot be extrapolated to pediatric patients receiving halothane or other concentrations of sevoflurane.

We have found that isoproterenol caused SBP increase and T-wave morphologic change in all of the children. However, because we have also observed a great individual variation in degree of increases in these guides, sensitivities based on SBP and T-wave criteria were as low as 30–55%. Thus, when isoproterenol-containing test solution is used in children, a new HR criterion rather than conventional HR, SBP, or T-wave criteria is a useful indicator with 100% sensitivity. In this point, isoproterenol may be inferior to epinephrine as a marker for detection of accidental intravascular injection of epidural test dose.

In conclusion, we have shown that oral clonidine did not change the efficacy of a simulated epidural test dose containing epinephrine or isoproterenol in sevoflurane-anesthetized children as assessed by a new HR criterion. Conventional HR and T-wave criteria may be limited to application of epinephrine–isoproterenol-containing test solution. Epinephrine was also reliable based on SBP criterion.