Drug treatment for arrhythmias has a limited success rate1 and is also associated with significant adverse reactions,2 including proarrhythmias and sudden death.3,4 Because of its high success rate and low incidence of complications, radiofrequency catheter ablation (RFCA) has become a frontline treatment for arrhythmia.5,6 In pediatric patients, general anesthesia is often required to perform these procedures. In addition, according to a consensus on pain control in pediatric patients undergoing cardiac catheterization, remifentanil, a potent, short-acting μ-opioid, has been advocated. Although there have been numerous reports on anesthetic drug interactions and their electrophysiological effect,7–10 the role of opioids on the human cardiac conduction system has not been fully determined.
We have previously demonstrated that in pediatric patients with paroxysmal supraventricular tachycardia (PSVT), the addition of fentanyl to propofol anesthesia increases sinus node recovery time (SNRT), but has no effect on sinoatrial conduction time (SACT).11 Mu-opioid receptor agonists such as fentanyl and remifentanil may alter cardiac function through peripheral opioid receptors12 or by a direct effect of their chemical composition and microstructure.13 Unlike fentanyl, remifentanil has been reported to have a prominent negative chronotropic effect14–16; however, the underlying mechanism of remifentanil-induced bradycardia has yet to be fully elucidated. Thus, the aim of this study was to investigate the effect of remifentanil on the cardiac conduction systems, sinus node function, and atrial-His (AH) interval.
After obtaining approval from the institution's committee on clinical investigation and written parental informed consent, 60 ASA physical status I or II pediatric patients with Wolff-Parkinson-White (WPW) syndrome undergoing RFCA were prospectively enrolled in this study. Exclusion criteria included obesity, food or drug allergy, and history of kidney or liver disease. Patients with severe heart diseases, including cardiomyopathy, valvulopathy, and congenital cardiac disease, were also excluded. The enrolled patients were randomly assigned to 1 of 2 groups that received continuous infusion of remifentanil (Ultiva®; Jannsen Pharmaceutical K.K., Tokyo, Japan) at a rate of either 0.2 μg · kg−1 · min−1 (group M) or 0.4 μg · kg−1 · min−1 (group H).
All antiarrhythmic medications were discontinued 2 days before the RFCA. No patient received premedication for the procedure. During the procedure, all patients were monitored using electrocardiography (ECG), noninvasive and invasive arterial blood pressure, pulse oximetry, capnography, rectal temperature, and bispectral index (BIS). General anesthesia was induced with propofol (2.0 mg · kg−1), and vecuronium (0.1 mg · kg−1) was administered to facilitate tracheal intubation. Propofol (100–167 μg · kg−1 · min−1) was administered by continuous infusion to maintain anesthesia and was titrated to maintain a BIS value of 30 to 40. The lungs were artificially ventilated (fraction of inspired oxygen = 0.4 with air) to maintain an end-tidal CO2 between 35 and 40 mm Hg. For the electrophysiological study (EPS), the catheters were introduced percutaneously into the femoral arteries and veins and the internal jugular vein. Before catheterization, 1% lidocaine (10–20 mL) was administered as a local anesthetic to the multiple catheter insertion sites. A multichannel recording system (EP-WorkMate®; EP MedSystems, Inc., West Berlin, NJ) was used for ECGs obtained via intracardiac catheters.
Ten minutes after completion of catheter insertion, EPS was performed (PRE state). SNRT was first measured by atrial pacing; starting at 10 beats · min−1 faster than the basal sinus rhythm, the pacing was increased to 200 beats · min−1 in 10 beats · min−1 intervals, and each interval lasted 30 seconds. A rest period of 30 seconds was provided between each pacing cycle. After termination of pacing, 10 sinus cycles were analyzed, and SNRT was defined as the longest of these postpacing intervals. P-wave configuration, as observed on both the surface ECG and the intraatrial electrograms, was used to confirm that the first escape beat after termination of pacing was, in fact, sinus in origin. To calculate the corrected SNRT (CSNRT), the mean of 5 consecutive spontaneous sinus node cycles immediately preceding each pacing run was subtracted from the SNRT. Calculated SACT (CSACT) was first determined by atrial pacing for 8 to 10 beats at a rate that was 20% faster than the patient's resting heart rate. CSACT was defined as half of the difference between the P-P interval of the last sinus beat before the onset of pacing and SNRT, or the P-P interval between the last paced beat and the first sinus escape beat. The R-R interval was defined as the time duration between consecutive R waves in the surface ECG. The AH interval was defined as the duration between the atrial and proximal His bundle potential on the His bundle electrogram.
After the first EPS and a subsequent equilibrium period of 10 minutes, remifentanil administration was initiated (1 μg · kg−1 bolus and 0.4 μg · kg−1 · min−1 continuous infusion in group H [high-dose group] or 0.5 μg · kg−1 bolus and 0.2 μg · kg−1 · min−1 continuous infusion in group M [moderate-dose group]). The second EPS study (POST state) began 10 minutes after the continuous infusion of remifentanil was initiated. Changes in propofol dosing were not permitted from the initiation of PRE state EPS until the completion of POST state EPS. The selected infusion dose and rate of remifentanil administration were simulated to result in an effect-site remifentanil concentration ranging from 3.24 to 3.44 ng/mL in group M and from 6.48 to 6.88 ng/mL in group H (Tivatrainer©). The time course of the EPS is illustrated in Figure 1.
All data are presented as the mean (95% confidence interval). For statistical analysis, the paired Student t test, unpaired Student t test, and 2-way repeated-measures analysis of variance were used. All P values are 2-tailed, and P < 0.05 was considered to indicate a significant difference. Based on previously reported data regarding the lengthening of CSACT by pilsicainide17 (from 97.8 ± 21.4 to 111.5 ± 20.9 milliseconds, mean ± SD), it was estimated that a sample size of 15 patients would yield a statistical power of approximately 90% with α = 0.05 (2-tailed). Statistical analysis and sample size determination were performed using SPSS 15.0 for Windows (SPSS Japan, Inc., Tokyo, Japan) and Sample Power® (SPSS, Inc., Chicago, IL). This trial was registered with the UMIN Clinical Trials Registry, number UMIN000004150.
Of the 46 patients recruited for the study, 17 were excluded because of the induction of paroxysmal tachycardia during the first or second EPS. Therefore, 29 patients completed the study, 15 in group H and 14 in group M (Fig. 2). The antiarrhythmic medications discontinued before the study included propranolol, procainamide, flecainide, and/or digoxin. There was no patient taking long-acting drugs such as amiodarone. The groups were similar with regard to age, gender, height, weight, body mass index, duration of surgery, duration of anesthesia, and propofol dose at the beginning of the PRE state EPS (Table 1).
BIS value, R-R interval, CSNRT, CSACT, and AH interval are shown in Figure 3. After the administration of remifentanil, the R-R interval was significantly prolonged from 680 (622–738) milliseconds to 881 (803–958) milliseconds in group H (P < 0.001), and from 737 (677–798) milliseconds to 888 (807–969) milliseconds in group M (P < 0.001). Similarly, CSNRT was significantly elongated in both groups: from 202 (144–260) milliseconds to 307 (232–382) milliseconds in group H (P = 0.019), and from 177 (117–237) milliseconds to 245 (167–322) milliseconds in group M (P = 0.016). CSACT did not differ between the PRE and POST states in group M (56 [38–74] milliseconds and 62 [43–81] milliseconds; P = 0.59), but in group H, CSACT in the POST state (78 [59–96] milliseconds) was significantly elongated compared with that in the PRE state (48 [31–65] milliseconds) (P = 0.038). The AH intervals were not affected in either group. Two-way repeated-measures analysis of variance did not show any significant difference in the effect between the 2 groups, which suggests that the effect of remifentanil on prolongation of the R-R interval and CSNRT is not dose dependent.
The major findings of this study were as follows: (1) a moderate dose of remifentanil (0.2 μg · kg−1 · min−1) elongates CSNRT but not CSACT, (2) high-dose remifentanil (0.4 μg · kg−1 · min−1) elongates CSNRT as well as CSACT but not AH interval, and (3) remifentanil does not show a dose-dependent effect on either CSNRT or R-R interval.
Sinus node function is usually assessed by measuring CSNRT and CSACT. CSNRT reflects sinus node automaticity, whereas CSACT reflects atrio-sinus and sinoatrial conductions.18 It has been reported that selective electrical stimulation of parasympathetic nerve fibers to the human sinus node increases atrial cycle length, but does not affect atrioventricular conduction time.19,20 It has also been reported that in adults, atropine administration can inhibit the prolongation of CSNRT.10 Increased atrial cycle length reflects CSNRT.19,21 Therefore, increased vagal tone has the potential to affect sinus node automaticity (CSNRT) but not atrial conductions (CSACT). In addition, continuous infusion of propofol increases vagal tone.22 Therefore, as observed with the effect of fentanyl, increased vagal tone may be the underlying mechanism for CSNRT prolongation by remifentanil. Moreover, our statistical analysis did not support a dose-dependent effect of remifentanil on CSNRT and R-R interval. Drug-induced receptor-mediated activation responses may be dose dependent; thus, the lack of dose dependency could be evidence for increased vagal tone.
Meanwhile, SACT reflects the conduction of action potential from the sinus node to the surrounding atrial muscle. Sodium channel blockers that are categorized as class I antiarrhythmics have been reported to suppress sinoatrial conduction as a consequence of voltage-gated sodium channel inhibition.23,24 High doses of opioids such as fentanyl and remifentanil have been shown to cause a direct negative chronotropic effect in isolated rat hearts25 and produce significant prolongation of action potential duration in Purkinje fibers.26 Taking into consideration that opioids can block neuronal voltage-gated sodium channels,27 relatively high doses of remifentanil might elongate the SACT via the direct inhibition of voltage-gated sodium channels.
The AH interval partly reveals atrioventricular nodal function. Although few studies have attempted to determine the effect of remifentanil on the cardiac conduction system, Fattorini et al.10 observed that the loss of 1:1 AV conduction during atrial pacing (known as the Wenckebach phenomenon) occurred at a lower pacing rate in the presence of remifentanil than in its absence. In our study, all enrolled patients had an accessory pathway; thus, we could not assess whether the Wenckebach phenomenon was induced via the atrioventricular node or the accessory pathway. However, Zaballos et al.28 reported that in the closed-chest porcine model, a remifentanil dose of 0.5 μg · kg−1 · min−1 prolonged the AH interval. Although it is necessary to carefully consider the results from arrhythmia studies using porcine heart because it is anatomically different from the human heart,29 in our pediatric patients with WPW syndrome, a remifentanil dose of 0.4 μg · kg−1 · min−1 failed to prolong the AH interval.
Our study has 2 limitations. First, for ethical reasons, our study design did not include the effect of naloxone during the EPS. Evidence for an effect in the presence of naloxone might contribute to a clearer understanding of the mechanism by which remifentanil affects the conduction system, specifically whether or not it is μ-opioid receptor mediated. Second, it has been reported that in adults, remifentanil induced severe bradycardia even at low or moderate doses (0.1–0.2 μg · kg−1 · min−1).15,30 Because our results were based on the responses of pediatric patients with WPW syndrome, the findings might not be able to be extrapolated to remifentanil-induced bradyarrhythmia in adults. However, autonomic imbalances during EPS, especially in RFCA, lead to an underestimation of the heart rates during induced PSVT compared with spontaneous PSVT.31,32 Therefore, our results suggest that significant attention should be given when adding remifentanil during general anesthesia for pediatric patients undergoing RFCA.
In conclusion, in pediatric patients with WPW syndrome, remifentanil may inhibit both the intraatrial conduction and SNRT, but it has no effect on the AH interval.
Name: Keisuke Fujii, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Keisuke Fujii has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Hiroshi Iranami, MD.
Contribution: This author helped design the study and write the manuscript.
Attestation: Hiroshi Iranami has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Yoshihide Nakamura, MD.
Contribution: This author helped conduct the study and analyze the data.
Attestation: Yoshihide Nakamura has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Yoshio Hatano, MD.
Contribution: This author helped write the manuscript.
Attestation: Yoshio Hatano has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
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