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Fentanyl Added to Propofol Anesthesia Elongates Sinus Node Recovery Time in Pediatric Patients with Paroxysmal Supraventricular Tachycardia

Fujii, Keisuke MD*; Iranami, Hiroshi MD, PhD*†; Nakamura, Yoshihide MD, PhD; Hatano, Yoshio MD, PhD§

doi: 10.1213/ane.0b013e31819002d4
Pediatric Anesthesiology: Research Reports

BACKGROUND: In some types of pediatric supraventricular tachycardia, reentrant mechanisms are sensitive to enhanced vagal tone. Propofol is a feasible anesthetic for pediatric electrophysiological study and radiofrequency catheter ablation. Although fentanyl and propofol infusions both enhance cardiac vagal tone, it is unclear whether the combination of propofol and fentanyl has a potential to enhance it. In this study, we evaluated the hypothesis that fentanyl combined with propofol could alter cardiac electrophysiological activities in pediatric patients undergoing electrophysiological study and radiofrequency catheter ablation.

METHODS: Twenty-seven pediatric patients (9 Wolff-Parkinson-White syndrome, 7 concealed accessory pathway and 11 atrioventricular nodal reentry tachycardia) were enrolled in this study. Anesthesia was induced with propofol 2.0 mg/kg and was maintained with a continuous infusion of propofol at a rate of 100–167 μg · kg−1 · min−1. During a stable anesthetic state, the calculated sinoatrial conduction time and corrected sinus node recovery time (CSNRT) were measured before and after fentanyl administration. The fentanyl dose consisted of an initial 2.0 μg/kg IV bolus and subsequent continuous infusion of 0.075 μg · kg−1 · min−1.

RESULTS: Bispectral Index scores and systemic blood pressure remained unchanged throughout the examinations. Fentanyl administration significantly prolonged CSNRT (P = 0.005) but not calculated sinoatrial conduction time (P = 0.35).

CONCLUSION: Since an enhanced cardiac vagal tone is one of the causative factors for prolonged CSNRT, our findings greatly support the hypothesis that fentanyl combined with propofol has a potential to enhance cardiac vagal tone.

IMPLICATIONS: This study showed that fentanyl combined with propofol caused a propranolol-like effect on sinus node function tests and suggests that this anesthetic method has a potential of enhancing cardiac vagal tone.

From the *Department of Anesthesiology, Japanese Red Cross Society Wakayama Medical Center, Wakayama City, Wakayama, Japan; †Department of Anesthesiology, Wakayama Medical University, Wakayama City, Wakayama, Japan; ‡Department of Pediatric Cardiology, Japanese Red Cross Society Wakayama Medical Center, Wakayama City, Wakayama, Japan; and §Department of Anesthesiology, Wakayama Medical University, Wakayama City, Wakayama, Japan.

Accepted for publication September 25, 2008.

Address correspondence and reprint requests to Keisuke Fujii, MD, 4-20 Komatsubara-dori, Wakayama City, Wakayama 640-8558, Japan. Address e-mail to

Radiofrequency catheter ablation (RFCA) is a nonpharmacologic intervention for treatment of tachyarrhythmia. It works by controlled trauma to cardiac tissue and thereby modifies reentrant circuits.1–3 Before the actual ablation, an electrophysiological study (EPS) as well as mapping are performed in order to identify the origins of the tachyarrhythmias. During routine EPSs, a variety of electrophysiological variables of the sinus node, intraatrial, atrioventricular (AV) node, and His-Purkinje system are measured. After baseline studies, IV therapeutic drugs are often administered to determine drug efficacy, facilitate the induction of tachycardias, induce sinus node dysfunction, and produce AV block. Sinus node function is usually assessed indirectly by EPS, and indirect measurements used in EPS include sinus node recovery time (SNRT) as a measure of sinus node automaticity and the sinoatrial conduction time (SACT) as an estimate of conduction through sinoatrial tissue.4,5

RFCA for pediatric patients often requires general anesthesia. Since postoperative emesis is common after RFCA in children,6 propofol anesthesia with or without opioids is frequently used. Although the effects of anesthetics with regard to drug interactions and cardiac monitoring have been reported,7–12 sinus node functions, including calculated SACT (CSACT) and corrected SNRT (CSNRT), do not seem to be affected by the use of halothane, desflurane, sevoflurane, isoflurane or propofol.7–12 In addition, propofol, when combined with nitrous oxide, alfentanil and midazolam has also been shown to maintain sinoatrial function.12 However, μ opioids (e.g., fentanyl) enhance vagal tone and cause bradycardia.13

Increased cardiac vagal tone, but not sympathetic, is involved in prolongation of CSNRT.14–16 Therefore, this study was designed to evaluate the effects of fentanyl on sinoatrial function in pediatric patients anesthetized with propofol who were undergoing RFCA.

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After obtaining approval from the institution’s committee on clinical investigation and written informed consent from the parents, 27 (21 males and 6 females) ASA physical status two pediatric patients with paroxysmal supraventricular tachycardia (PSVT) who were scheduled to undergo RFCA were prospectively enrolled in this study. Excluded criteria included obesity, allergy to foods and drugs, and history of kidney and/or liver disease. Patients with severe heart disease, including cardiomyopathy, valvulopathy, and congenital cardiac diseases, were also excluded. All antiarrythmic medicines were discontinued at 18:00 before surgery. No patients were premedicated for the procedure. During the procedure, all patients were monitored with electrocardiography (ECG), noninvasive and invasive arterial blood pressure, pulse oximetry, capnography, rectal temperature, and Bispectral Index (BIS). Anesthetic induction was started approximately 15 h after the discontinuation of the antiarrhythmic medications. In all patients, anesthesia was induced with propofol 2.0 mg/kg and vecuronium (0.1 mg/kg) was administered to facilitate tracheal intubation. Anesthesia was maintained with a continuous infusion of propofol (100–167 μg · kg−1 · min−1), which was titrated to maintain BIS between 30 and 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 EPS portion of the RFCA procedure, catheters were introduced percutaneously into the femoral arteries and veins and/or the internal jugular vein. Before the catheterization, topical anesthesia with 1% lidocaine 10–20 mL was performed at multiple catheter insertion sites. ECGs derived from the intracardiac catheters were recorded on a multichannel recording system (EPWorkMate; EPMedSystems, West Berlin, NJ).

Ten minutes after insertion of the catheters, EPS was performed. No changes in propofol dosing were allowed until the studies were completed. SNRT was measured first by atrial pacing with an increasing rate of up to 200 bpm, starting from 10 beats faster than the basal sinus rhythm, with each pacing interval increased by 10 bpm and lasting for 30 s at each level. A 30-s rest was provided between each length of the pacing cycle. Ten sinus cycles were analyzed after termination of pacing, and SNRT was defined as the longest of these postpacing intervals. P-wave configuration, as observed on the surface ECG, in conjunction with the intraarterial electrograms, was used to verify that the first escape beat after termination of pacing was indeed sinus in origin. The CSNRT was calculated by subtracting the mean of five consecutive spontaneous sinus node cycles immediately preceding each pacing run from measured SNRT.

CSACT was determined first by atrial pacing at a rate 20% more than the patient’s resting heart rate for 8–10 beats. One-half the differences between the PP intervals of the last sinus beat before onset of pacing and SNRT or the PP interval between the last paced beat and the first sinus escape beat was defined as CSACT.

After the subsequent equilibrium period for 20 min following the first EPS, fentanyl administration was begun (2 μg/kg bolus and 0.075 μg · kg−1 · min−1 continuous infusion). Ten minutes after the start of the continuous infusion of fentanyl, the second EPS study (POST state) was started. The selected infusion dose and rate of fentanyl administration was simulated to result in an effect-site fentanyl concentration ranging from 2.49 to 2.46 ng/mL (Tivatrainer©). The time course of EPSs is illustrated in Figure 1.

Figure 1

Figure 1

BIS scores and systemic blood pressures were recorded at the following times in all patients: A: just before the first EPS, B: just before the end of the first EPS, C: just before fentanyl administration, D: 5 min after fentanyl administration, E: just before the second EPS, F: just before the end of the second EPS, and G: 15 min after the second EPS study. Continuous data were presented as mean (SD), and data were evaluated parametrically. The paired Student’s t-test, unpaired Student’s t-test, and Friedman test were used for statistical analysis. P value <0.05 was considered to be significantly different.

There has been no available information regarding to what extent fentanyl at its effect-site concentration of 2.5 ng/mL should elongate CSNRT, although, based on the previously reported data regarding the effects of remifentanil on CSNRT,17 a sample size of 27 patients was estimated to yield statistical power of approximately 90% with α = 0.05 (2-tailed). Statistical analysis and sample size determination were aided by SPSS 13.0 for Windows (SPSS Japan, Tokyo, Japan) and Sample Power® (SPSS, Chicago, IL).

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Of 27 patients, 16 patients had accessory pathways (9 Wolff-Parkinson-White syndrome [WPW], 7 concealed accessory pathway [CAP]), and 11 patients had atrioventricular nodal reentry tachycardia (AVNRT). The demographic data are shown in Table 1.

Table 1

Table 1

EPSs were successfully performed before and after the administration of fentanyl in all enrolled patients. CSACTs and CSNRTs are shown in Table 2. CSACTs did not differ significantly between PRE and POST states (P = 0.35), but CSNRT of POST state was significantly elongated compared with PRE state (P = 0.005). The BIS scores at the seven time points were not significantly different from one another. During the measurement periods, systemic blood pressure of all patients was within 10% of baseline (Data were not shown).

Table 2

Table 2

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Baseline sinus node function tends to remain stable throughout life, but that variation in autonomic tone, whether natural or drug-induced, can affect sinus node function.18 This study examined CSNRTs and CSACTs before and after fentanyl administration in pediatric patients anesthetized with propofol. Our patients had different diagnoses of PSVT, including WPW, CAP, and AVNRT. The characteristics of WPW, CAP, and AVNRT are an accessory pathway between the atrium and ventricle and a reentrant circuit in AV node. There were no reports that these diseases show any abnormalities in sinus node, therefore, these different diagnoses (WPW, CAP, and AVNRT) in this study were considered not to affect sinus node function studies. Our results showed that fentanyl significantly elongated CSNRT but not CSACT. The function of the sinus node is not only to generate the normal heart beat but also to respond to physiologic influences. Sinus node function is usually assessed by measuring CSNRT and CSACT. CSNRT reflects sinus node automaticity, whereas CSACT reflects atriosinus and sinoatrial conductions.19 Selective electrical stimulation of parasympathetic nerve fibers to the human sinus node has been shown to increase atrial cycle length (increased CSNRT) without affecting AV conduction time.20,21 Increased atrial cycle length reflects CSNRT.5,20 Therefore, increased vagal tone has a potential to affect atrial automaticity (CSNRT) but not conductions (CSACT). Previous pediatric EPSs have shown that propranolol prolongs CSNRT, but not CSACT,22 and that digitalis prolongs CSACT but not CSNRT.23 Fentanyl’s effect on sinus node function tests seems similar to propranolol (i.e., affects sinus node automaticity not sinoatrial conduction). Although we did not obtain any data regarding the background sympathetic activity, these results greatly support our hypothesis that fentanyl added to propofol anesthesia influences cardiac vagal tone.

Riznyk et al.24 have shown that IV bolus propofol used for the induction of anesthesia reduces cardiac vagal tone rather than sympathetic tone and increased heart rate. However, others have shown that in power spectral analysis of heart rate variability (PSHRV), propofol has a biphasic response of an initial reduction and then subsequent increase in cardiac vagal tone.25,26 Continuous propofol infusion enhances cardiac vagal tone in PSHRV, whereas, midazolam increases cardiac sympathetic tone.27 It has also been shown that the combination of propofol and remifentanil anesthesia affords higher cardiac vagal activity compared with sevoflurane-remifentanil anesthesia.28

Although in adults cardiac vagal tone correlates positively to the depth of hypnosis,29 it has been shown that there is a positive correlation of cardiac vagal tone inhibition with propofol depth of hypnosis in both adults and children.26,27 These findings may lead to complexity in our understanding of the effects of fentanyl administration during propofol anesthesia on CSNRTs. In this study, the patients’ systemic blood pressure measurements were within 10% of their baseline, and their BIS values during the first and the second EPSs were stable (ranging from 30 to 40). Thus, we believe the effect of fentanyl on CSNRT occurred during a stable hypnotic state.

The clinical implication from our findings suggests that in some patients enhanced cardiac vagal tone facilitates induction of PSVT through its effect on refractoriness of slow and fast nodal conduction pathway.30–33 The autonomic nervous system may have a role in triggering or terminating PSVT confined to the AV node or accessory pathway.30,34,35 In addition, because autonomic imbalances during EPS lead to under-estimation of PSVT’s heart rates compared with spontaneous PSVT,35,36 any alterations in autonomic imbalance caused by anesthetics may affect accurate mapping study. Also, sinus node remodeling has been known to occur with sinoatrial dysfunction observed in tachyarrhythmic patients.37–39 In some patients with deteriorated sinus node function, there is a caudal shift of pacemaker function as well as abnormal and circuitous conduction pathways around areas of conduction block.40 Therefore, during general anesthesia for pediatric patients undergoing RFCA, fentanyl added to propofol anesthesia may cause further inhibition of their sinus node function, which results in the occurrence of abnormal circuitous conduction with hemodynamic disturbances.

This study has a few limitations: a lack of information regarding fentanyl’s dose-response effect and a lack of information regarding the duration of fentanyl’s effect. In most cases, RFCA is usually conducted successfully with propofol anesthesia combined with topical anesthesia at multiple catheter insertion sites. Although RFCA, unlike cryoablation, sometimes causes pain,41–43 the addition of fentanyl should be made cautiously in patients with AV nodal reentrant tachycardia because the addition of fentanyl to propofol can inhibit sinoatrial function.

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