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.
1. Luedtke SA, Kuhn RJ, McCaffrey FM. Pharmacologic management of supraventricular tachycardias in children. Part 1. Wolff-Parkinson-White and atrioventricular nodal reentry. Ann Pharmacother 1997;31:1227–43
2. Ratnasamy C, Rossique-Gonzalez M, Young ML. Pharmacological therapy in children with atrioventricular reentry: which drug? Curr Pharm Des 2008;14:753–61
3. Prystowsky EN. Proarrhythmia during drug treatment of supraventricular tachycardia: paradoxical risk of sinus rhythm for sudden death. Am J Cardiol 1996;78:35–41
4. Brendorp B, Pedersen O, Torp-Pedersen C, Sahebzadah N, Køber L. A benefit-risk assessment of class III antiarrhythmic agents. Drug Saf 2002;25:847–65
5. Spector P, Reynolds MR, Calkins H, Sondhi M, Xu Y, Martin A, Williams CJ, Sledge I. Meta-analysis of ablation of atrial flutter and supraventricular tachycardia. Am J Cardiol 2009;104:671–7
6. Joung B, Lee M, Sung JH, Kim JY, Ahn S, Kim S. Pediatric radiofrequency catheter ablation: sedation methods and success, complication and recurrence rates. Circ J 2006;70:278–84
7. Lavoie J, Walsh EP, Burrows FA, Laussen P, Lulu JA, Hansen DD. Effects of propofol or isoflurane anesthesia on cardiac conduction in children undergoing radiofrequency catheter ablation for tachydysrhythmias. Anesthesiology 1995;82:884–7
8. Ikeno S, Akazawa S, Shimizu R, Nakaigawa Y, Ishii R, Inoue S, Satoh M. Propofol does not affect the canine cardiac conduction system under autonomic blockade. Can J Anaesth 1999;46:148–53
9. Sharpe MD, Dobkowski WB, Murkin JM, Klein G, Yee R. Propofol has no direct effect on sinoatrial node function or on normal atrioventricular and accessory pathway conduction in Wolff-Parkinson-White syndrome during alfentanil/midazolam anesthesia. Anesthesiology 1995;82:888–95
10. Fattorini F, Romano R, Ciccaglioni A, Pascarella MA, Rocco A, Mariani V, Pietropaoli P. Effects of remifentanil on human heart electrical system: a transesophageal pacing electrophysiological study. Minerva Anestesiol 2003;69:673–7
11. Fujii K, Iranami H, Nakamura Y, Hatano Y. Fentanyl added to propofol anesthesia elongates sinus node recovery time in pediatric patients with paroxysmal supraventricular tachycardia. Anesth Analg 2009;108:456–60
12. Shinohara K, Aono H, Unruh GK, Kindscher JD, Goto H. Suppressive effects of remifentanil on hemodynamics in baro-denervated rabbits. Can J Anaesth 2000;47:361–6
13. Kanaya N, Zakhary DR, Murray PA, Damron DS. Differential effects of fentanyl and morphine on intracellular Ca2+ transients and contraction in rat ventricular myocytes. Anesthesiology 1998;89:1532–42
14. Altermatt FR, Muñoz HR. Asystole with propofol and remifentanil. Br J Anaesth 2000;84:696–7
15. DeSouza G, Lewis MC, TerRiet MF. Severe bradycardia after remifentanil. Anesthesiology 1997;87:1019–20
16. Reid JE, Mirakhur RK. Bradycardia after administration of remifentanil. Br J Anaesth 2000;84:422–3
17. Ino T, Atarashi H, Kuruma A, Onodera T, Saitoh H, Hayakawa H. Electrophysiologic and hemodynamic effects of a single oral dose of pilsicainide hydrochloride, a new class 1c antiarrhythmic agent. J Cardiovasc Pharmacol 1998;31:157–64
18. Gomes JA, Kang PS, El-Sherif N. The sinus node electrogram in patients with and without sick sinus syndrome: techniques and correlation between directly measured and indirectly estimated sinoatrial conduction time. Circulation 1982;66:864–73
19. Prystowsky EN, Jackman WM, Rinkenberger RL, Heger JJ, Zipes DP. Effect of autonomic blockade on ventricular refractoriness and atrioventricular nodal conduction in humans: evidence supporting a direct cholinergic action on ventricular muscle refractoriness. Circ Res 1981;49:511–8
20. Carlson MD, Geha AS, Hsu J, Martin PJ, Levy MN, Jacobs G, Waldo AL. Selective stimulation of parasympathetic nerve fibers to the human sinoatrial node. Circulation 1992;85:1311–7
21. Narula OS, Samet P, Javier RP. Significance of the sinus-node recovery time. Circulation 1972;45:140–58
22. Win NN, Fukayama H, Kohase H, Umino M. The different effects of intravenous propofol and midazolam sedation on hemodynamic and heart rate variability. Anesth Analg 2005;101:97–102
23. Kobayashi M, Shimotori M, Ogiwara Y, Chiba S. Effects of calcium channel blockers on sinoatrial conduction in the isolated and blood-perfused dog atrium. Arch Int Pharmacodyn Ther 1986;279:72–82
24. Lei M, Goddard C, Liu J, Léoni AL, Royer A, Fung SS, Xiao G, Ma A, Zhang H, Charpentier F, Vandenberg JI, Colledge WH, Grace AA, Huang CL. Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a. J Physiol 2005;567:387–400
25. Gürkan A, Birgül Y, Ziya K. Direct cardiac effects in isolated perfused rat hearts of fentanyl and remifentanil. Ann Card Anaesth 2005;8:140–4
26. Blair JR, Pruett JK, Introna RP, Adams RJ, Balser JS. Cardiac electrophysiologic effects of fentanyl and sufentanil in canine cardiac Purkinje fibers. Anesthesiology 1989;71:565–70
27. Haeseler G, Foadi N, Ahrens J, Dengler R, Hecker H, Leuwer M. Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels. Pain 2006;126:234–44
28. Zaballos M, Jimeno C, Almendral J, Atienza F, Patiño D, Valdes E, Navia J, Anadón MJ. Cardiac electrophysiological effects of remifentanil: study in a closed-chest porcine model. Br J Anaesth 2009;103:191–8
29. Bharati S, Levine M, Huang SK, Handler B, Parr GV, Bauernfeind R, Lev M. The conduction system of the swine heart. Chest 1991;100:207–12
30. Elliott P, O'Hare R, Bill KM, Phillips AS, Gibson FM, Mirakhur RK. Severe cardiovascular depression with remifentanil. Anesth Analg 2000;91:58–61
31. Waxman MB, Wald RW, Sharma AD, Huerta F, Cameron DA. Vagal techniques for termination of paroxysmal supraventricular tachycardia. Am J Cardiol 1980;46:655–64
32. Hamer ME, Wilkinson WE, McCarthy EA, Page RL, Pritchett EL. Heart rate during spontaneous and induced paroxysmal supraventricular tachycardia. Pacing Clin Electrophysiol 1995;18:2155–7