Anesthesia & Analgesia:
Anesthetic Pharmacology: Research Reports
Sevoflurane Causes Greater QTc Interval Prolongation in Elderly Patients than in Younger Patients
Nakao, Shinichi MD; Hatano, Kiyohiko MD; Sumi, Chisato MD; Masuzawa, Munehiro MD; Sakamoto, Sachiyo MD; Ikeda, Sakahiro MD; Shingu, Koh MD
Section Editor(s): Durieux, Marcel E.; Gin, Tony
From the Department of Anesthesiology, Kansai Medical University, Hirakata, Osaka, Japan.
Accepted for publication November 23, 2009.
Disclosure: The authors report no conflicts of interest.
Address correspondence and reprint requests to Shinichi Nakao, MD, Department of Anesthesiology, Kansai Medical University, 2-3-1 Shinmachi, Hirakata, Osaka 573-1191, Japan. Address e-mail to firstname.lastname@example.org.
BACKGROUND: Sevoflurane and droperidol prolong the QT interval, and advancing age is not only associated with a prolongation of the QT interval but is also a risk factor for drug-induced QT interval prolongation. In this study, we compared the effect of sevoflurane and droperidol on the corrected QT (QTc) interval and the dispersion of ventricular repolarization (time interval from the peak to the end of the T wave [Tp-e]) in elderly patients with those in younger patients.
METHODS: Under sevoflurane anesthesia (1.5%–2.5%) with an antiemetic dose of droperidol (1.25 mg), the QT interval and the Tp-e interval, which indicates transmural dispersion of repolarization across the myocardial wall, were measured in 30 elderly patients (70 years and older) and in 30 younger patients (20–69 years) for 2 hours. The QT interval was normalized for heart rate (QTc) using 3 different formulas: Bazett, Matsunaga, and Van de Water. Data are presented as mean ± sd.
RESULTS: The elderly group was 24.4 years older (P < 0.05) than the younger group. The QTc intervals in the 2 groups before anesthesia were not significantly different. Using all 3 formulas, the QTc interval in the elderly patient group was significantly prolonged by sevoflurane (the QTc intervals at preanesthesia and 60, 75, 90, and 120 minutes after sevoflurane exposure were 0.434 ± 0.028 seconds, 0.450 ± 0.037 seconds, 0.463 ± 0.037 seconds, 0.461 ± 0.037 seconds, and 0.461 ± 0.038 seconds, respectively, with the Bazett formula). The sevoflurane-induced QTc interval prolongation in the elderly patient group was significantly greater than that in the younger patient group (0.450 ± 0.037 seconds vs 0.432 ± 0.034 seconds, 60 minutes after sevoflurane exposure; 0.463 ± 0.037 seconds vs 0.441 ± 0.037 seconds, 75 minutes after sevoflurane exposure; and 0.461 ± 0.038 seconds vs 0.436 ± 0.030 seconds, 120 minutes after sevoflurane exposure with the Bazett formula), but the sevoflurane-induced QTc interval prolongation was neither further enhanced with time nor by droperidol. The Tp-e interval was not affected in either group.
CONCLUSION: Sevoflurane causes greater QTc interval prolongation in elderly patients than in younger patients. Although sevoflurane does not affect the transmural dispersion of repolarization and sevoflurane-induced QTc prolongation does not advance with time and by droperidol administration, QT interval prolongation and its associated arrhythmias should be carefully monitored during sevoflurane anesthesia in elderly patients.
The human heart has been demonstrated to undergo changes in function with advancing age, including increased prevalence of rhythmic abnormalities.1,2 Prolongation of the QT interval in the electrocardiogram (ECG) is associated with torsade de pointes (TdP), a malignant polymorphic ventricular tachyarrhythmia. Several studies have demonstrated that advancing age is associated with a prolongation of the corrected QT (QTc) interval.3,4 Furthermore, Letsas et al.5 recently demonstrated that advanced age (>60 years) was one of the most common identifiable preexisting factors for drug-induced prolonged QT intervals.
It has been reported that sevoflurane inhibits not only hERG (human ether-à-go-go–related gene) currents (IKr) but also long QT (LQT) type 1/minK currents (IKs) and Kv4.3 currents (Ito),6–8 and induces significant QT interval prolongation.9,10 Droperidol is a butyrophenone antipsychotic drug and, at low doses (0.625–1.25 mg), was widely used as an antiemetic drug. Droperidol also blocks the IKr11,12 and causes an increase in action potential duration and QT interval prolongation.13,14
Several studies have revealed that susceptibility to TdP arises from the induction of afterdepolarization and increased dispersion of ventricular repolarization, rather than QT interval prolongation per se.15 Transmural dispersion of repolarization (TDR) across the myocardial wall can be measured on the ECG as the time interval from the peak to the end of the T wave (Tp-e).16
Several authors have already investigated the QT interval and the Tp-e interval changes induced by sevoflurane and/or droperidol administration. However, there have been few investigations of the effect of age difference on the QTc interval and the Tp-e interval changes during anesthesia, especially under sevoflurane anesthesia with droperidol, both of which prolong the QTc interval. We hypothesized that both the QTc interval and the Tp-e interval would be more prolonged by sevoflurane and/or droperidol in elderly than in younger people. In this study, we investigated the QT interval in the elderly population (70 years of age and older) and younger population (20–69 years of age) under sevoflurane anesthesia with droperidol (1.25 mg). Assessment was continued for 2 hours, because the United States Food and Drug Administration recommended that ECG monitoring be continued for 2 to 3 hours after drug administration, and QTc intervals were calculated using 3 different QTc formulas, namely, Bazett, Matsunaga, and Van de Water.17 The TDR was measured simultaneously using the Tp-e interval.
After obtaining institutional approval from the Kansai Medical University (Osaka, Japan) Human Subjects Review Committee and written informed consent, we enrolled 60 patients, 30 elderly patients (70 years and older) and 30 younger patients (20–69 years), classified as ASA physical status I or II. We recruited patients undergoing various kinds of elective surgery, such as abdominal, gynecological, urological, and otorhinolaryngological surgery, with an expected duration of >2 hours. Patients taking medications known to prolong the QT interval and/or with an abnormal QTc prolongation (>450 ms by the Bazett formula) were excluded. An epidural catheter was inserted before anesthesia induction at the doctor's discretion. In all patients, the II lead was recorded throughout the operation. ECG signals were networked to a server storage system, and the ECG recordings were retrieved after the operation. Anesthesia was induced with 2 mg/kg propofol and 100 μg fentanyl, and tracheal intubation was performed after administration of 0.1 mg/kg vecuronium. Anesthesia was maintained with 1.5% to 2.5% sevoflurane with O2 and air and either intermittent fentanyl administration (100 μg just before skin incision followed by 50 μg approximately every 1 hour) for patients without epidural anesthesia or epidural anesthesia with an initial bolus of 4 to 5 mL of 0.375% ropivacaine followed by intermittent 2 to 3 mL of 0.375% ropivacaine approximately every 2 hours. Droperidol was administered 1 hour after the start of sevoflurane exposure. RR intervals, QT intervals (from the onset of the QRS complexes to the end of the T wave), and Tp-e intervals were measured manually by 2 investigators. The QT interval was adjusted for the patient's heart rate using the formulas of Bazett (QTc = QT/[RR/1000]1/2), Matsunaga (QTc = log 600 × QT/log RR), and Van de Water (QTc = QT − 0.087 × [RR − 1000]), where a unit of the RR interval is given in milliseconds.17
Results are presented as mean ± sd. Sample size was calculated with 80% power (α = 0.05 and β = 0.20) to detect a mean difference of 0.02 seconds of the QTc interval between the elderly and younger patients (baseline QTc: 0.420 seconds) and 0.03 seconds of sd with the unpaired t test. This generated an estimate of 28 patients per group. Comparisons of age, and the QTc and the Tp-e intervals at the same time points (before anesthesia induction, just before droperidol administration [60 minutes after the start of sevoflurane exposure], 15 minutes [75 minutes after the start of sevoflurane exposure], 30 minutes [90 minutes after the start of sevoflurane exposure], and 1 hour after droperidol administration [120 minutes after the start of sevoflurane exposure]) between groups were performed using the unpaired t test. The changes in the QTc and the Tp-e intervals within groups were analyzed by 1-way analysis of variance for repeated measures followed by the Bonferroni post hoc test. A P value <0.05 was considered statistically significant.
The elderly group was 24.4 years older (P < 0.05) than the younger group (Table 1). The QTc intervals in the 2 groups before drug administration were not significantly different. No critical arrhythmias occurred, and no electrolyte abnormalities were observed in either group. Using all 3 formulas, the QTc interval in the elderly group was significantly prolonged by sevoflurane, and the sevoflurane-induced prolongation was neither further enhanced with time nor by droperidol. In contrast, in the younger group, the QTc interval was prolonged only after droperidol administration in one instance (Table 2). The QTc intervals in the elderly group were significantly longer than in the younger group after sevoflurane anesthesia (Table 2). A linear regression analysis of age versus the QTc interval (Bazett formula) showed a good correlation only after sevoflurane exposure (Fig. 1); the correlation coefficients between age and the QTc intervals 60, 75, 90, and 120 minutes after sevoflurane exposure were 0.4690 (P = 0.0002), 0.4477 (P = 0.0003), 0.3840 (P = 0.0025), and 0.4070 (P = 0.0012), respectively. The Tp-e interval was not affected in either group (Table 3).
In this study, we demonstrated that sevoflurane significantly prolonged the QTc interval in elderly patients, and the prolongation was significantly greater than in younger patients (Table 2) in all 3 QTc formulas. The results suggest that anesthesiologists should be cautious when using sevoflurane in elderly patients. However, because the Tp-e was unaffected, sevoflurane did not meet the criteria for inducing lethal arrhythmias. It is unclear how much it might increase the risk in patients with a prolonged QT interval or increase Tp-e as seen in patients with congenital LQT syndrome (because of a variety of channel mutations), medicated with drugs that prolong QT interval (certain antiarrhythmics, psychotherapeutics, and antihistamines), or with hypokalemia. On the contrary, because sevoflurane inhibits both cardiac Ca2+ channels and Na+ channels,18,19 it may occasionally contribute as an antiarrhythmic agent.
In 2001, the United States Food and Drug Administration issued a “black box” warning regarding the use of droperidol for the treatment and/or prevention of postoperative nausea and vomiting and the potential for drug-induced QT prolongation and TdP. The warning imposed ECG recording before administration in all patients to determine whether a prolonged QT interval was present, and recommended that ECG monitoring be continued for 2 to 3 hours after drug administration. However, Habib and Gan20 reviewed 10 cases in the Food and Drug Administration database in which serious cardiovascular events were possibly associated with droperidol administration (≤1.25 mg) and found that there were several complicating factors that made it impossible to establish the precise cause of the adverse cardiac events. Furthermore, serious cardiac adverse events or death occurred <20 minutes after droperidol administration in at least 4 of the 10 cases (in 4 of 6 cases in which information of timing before cardiovascular events was available).20 In addition, White et al.21 reported that use of a small dose of droperidol (0.625–1.25 mg) during general anesthesia was not associated with a statistically significant increase in the QTc interval compared with saline. In this study, droperidol did not exacerbate the sevoflurane-induced QTc interval prolongation in the elderly population. Conversely, the QTc interval was not significantly prolonged by sevoflurane in the younger population but was significantly prolonged after droperidol administration (Table 2). This result means that sevoflurane does not affect the QTc interval in younger patients or may have been due to insufficient statistical power, because we found a small, but not statistically significant, increasing trend in the QTc interval after sevoflurane exposure. Previously, we and other groups reported that sevoflurane significantly prolonged the QTc interval in younger patients,9,10,22 but there are some conflicting reports that failed to demonstrate sevoflurane-induced QT interval prolongation.23
There are some explanations for the pronounced prolongation of QTc with advanced age. These include cardiac hypertrophy and a distinct increase in fibrosis in elderly people,1,2 which cause abnormal impulse formation and conduction. Hypertension is likely to cause left ventricular hypertrophy, which is a risk factor for life-threatening ventricular dysrhythmias and sudden cardiac death when the QT is prolonged,24 and is a risk factor that predisposes to drug-induced QT prolongation.5 In this study, more elderly patients were hypotensive than younger patients. Therefore, QTc prolongation with advanced age could be attributed to not only aging but also hypertension, which causes cardiac hypertrophy.
Various correction formulas have been proposed to normalize the QT interval for heart rate (QTc). Use of the Bazett formula is rooted deeply in medical practice, but this equation has been criticized because of its inaccuracy.25 More specifically, it overcorrects the QT interval at rapid heart rates and undercorrects it at slow rates.17 Some investigators recommend that Matsunaga and/or Van de Water formulas would better predict the net repolarization delay.17 We previously found that the Matsunaga and Van de Water formulas were more reliable and sensitive than the Bazett formula at detecting the sevoflurane-induced QTc interval prolongation in patients aged 20 to 70 years, and several patients were already categorized into an abnormal QTc interval group (>450 ms)26 even before sevoflurane exposure (20 of 102) in the operating theater if we used the Bazett formula.22 In this study, the number of patients with a QTc interval >450 ms before anesthesia was 12 of 30 in the elderly patients and 5 of 30 in younger patients as determined by Bazett formula, 0 of 30 and 0 of 30 by Matsunaga formula, and 2 of 30 and 1 of 30 by Van de Water formula. We suggest that this was caused by patient anxiety in the operating room before anesthesia. The patients' heart rates were very rapid, and consequently, the QT interval was overcorrected for heart rate using the Bazett formula.
Several potential limitations of our study should be considered. First, the maximal QTc interval prolongation by droperidol may have been missed, because Charbit et al.14 reported that it occurred at the second minute after droperidol administration although significant QTc prolongation was still observed even 15 minutes after droperidol administration. Second, because we conducted the study in ordinary clinical settings to measure the QT interval for 2 hours, anesthetic methods (e.g., with or without epidural anesthesia) and anesthetic concentrations were not strictly regulated, and the type of surgery was not limited; paradoxically, that is why our results may be important because they apply to various types of anesthesia and surgery. Furthermore, we think that the QTc interval is not likely to be greatly prolonged by stress and pain per se, as long as the patient does not have LQT type 1 syndrome, in which IKs is blocked27 because β-adrenergic stimulation by stress and pain activates not only Ca2+ channels, which increases cation influx, but also IKs,28 which increases cation efflux. Alternatively, IKr is exclusively inhibited in almost all cases of drug-induced QT prolongation. However, both fentanyl at the doses we used and ropivacaine administered epidurally were unlikely to affect the QTc interval and the Tp-e interval directly, because their expected plasma concentrations seem too low to block the IKr.29,30
In conclusion, sevoflurane significantly prolonged the QTc interval in elderly patients, and the prolongation was significantly greater than in younger patients. However, neither sevoflurane nor droperidol affect the TDR, sevoflurane-induced QTc interval prolongation does not advance with time, and droperidol does not enhance the sevoflurane-induced QTc interval prolongation in elderly patients.
1.Lakatta E, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 2003;107:346–54
2.Ocorr K, Akasaka T, Bodmer R. Age-related cardiac disease model of Drosophila. Mech Ageing Dev 2007;128:112–6
3.Taneja T, Mahnert B, Passman R, Goldberger J, Kadish A. Effects of sex and age on electrocardiographic and cardiac electrophysiological properties in adults. Pacing Clin Electrophysiol 2001;24:16–21
4.Mangoni A, Kinirons M, Swift C, Jackson S. Impact of age on QT interval and QT dispersion in healthy subjects: a regression analysis. Age Ageing 2003;32:326–31
5.Letsas K, Efremidis M, Kounas S, Pappas L, Gavrielatos G, Alexanian I, Dimopoulos N, Filippatos G, Sideris A, Kardaras F. Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. Clin Res Cardiol 2009;98:208–12
6.Yamada M, Hatakeyama N, Malykhina A, Yamazaki M, Momose Y, Akbarali H. The effects of sevoflurane and propofol on QT interval and heterologously expressed human ether-a-go-go related gene currents in Xenopus oocytes. Anesth Analg 2006;102:98–103
7.Kang J, Reynolds W, Chen X, Ji J, Wang H, Rampe D. Mechanisms underlying the QT interval-prolonging effects of sevoflurane and its interactions with other QT-prolonging drugs. Anesthesiology 2006;104:1015–22
8.Chae JE, Ahn DS, Kim MH, Lynch C III, Park WK. Electrophysiologic mechanism underlying action potential prolongation by sevoflurane in rat ventricular myocytes. Anesthesiology 2007; 107:67–74
9.Kleinsasser A, Kuenszberg E, Loeckinger A, Keller C, Hoermann C, Lindner K, Puehringer F. Sevoflurane, but not propofol, significantly prolongs the Q-T interval. Anesth Analg 2000;90:25–7
10.Whyte S, Booker P, Buckley D. The effects of propofol and sevoflurane on the QT interval and transmural dispersion of repolarization in children. Anesth Analg 2005;100:71–7
11.Drolet B, Zhang S, Deschκnes D, Rail J, Nadeau S, Zhou Z, January C, Turgeon J. Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol 1999;10:1597–604
12.Schwoerer AP, Blütner C, Brandt S, Binder S, Siebrands CC, Ehmke H, Friederich P. Molecular interaction of droperidol with human ether-a-go-go-related gene channels: prolongation of action potential duration without inducing early afterdepolarization. Anesthesiology 2007;106:967–76
13.Lischke V, Behne M, Doelken P, Schledt U, Probst S, Vettermann J. Droperidol causes a dose-dependent prolongation of the QT interval. Anesth Analg 1994;79:983–6
14.Charbit B, Albaladejo P, Funck-Brentano C, Legrand M, Samain E, Marty J. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology 2005;102:1094–100
15.Belardinelli L, Antzelevitch C, Vos M. Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol Sci 2003;24:619–25
16.Yan G, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation 1998;98:1928–36
17.Takahara A, Sugiyama A, Satoh Y, Hashimoto K. Comparison of four rate-correction algorithms for the ventricular repolarization period in assessing net effects of IKr blockers in dogs. J Pharmacol Sci 2006;102:396–404
18.Park WK, Pancrazio JJ, Suh CK, Lynch C III. Myocardial depressant effects of sevoflurane. Mechanical and electrophysiologic actions in vitro. Anesthesiology 1996;84:1166–76
19.Weigt H, Kwok W, Rehmert G, Turner L, Bosnjak Z. Voltage-dependent effects of volatile anesthetics on cardiac sodium current. Anesth Analg 1997;84:285–93
20.Habib A, Gan T. Food and drug administration black box warning on the perioperative use of droperidol: a review of the cases. Anesth Analg 2003;96:1377–9
21.White P, Song D, Abrao J, Klein K, Navarette B. Effect of low-dose droperidol on the QT interval during and after general anesthesia: a placebo-controlled study. Anesthesiology 2005;102:1101–5
22.Sumi C, Nakao S, Hatano K, Ikeda S, Shingu K. The effect of sevoflurane and propofol with or without droperidol on the QT interval. Anesthesiology 2008;A667
23.Aypar E, Karagoz A, Ozer S, Celiker A, Ocal T. The effects of sevoflurane and desflurane anesthesia on QTc interval and cardiac rhythm in children. Paediatr Anaesth 2007;17:563–7
24.Koren M, Devereux R, Casale P, Savage D, Laragh J. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–52
25.Sagie A, Larson M, Goldberg R, Bengtson J, Levy D. An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study). Am J Cardiol 1992;70:797–801
26.Haddad P, Anderson I. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002; 62:1649–71
27.Roden D. Clinical practice. Long-QT syndrome. N Engl J Med 2008;358:169–76
28.Walsh K, Begenisich T, Kass R. Beta-adrenergic modulation of cardiac ion channels. Differential temperature sensitivity of potassium and calcium currents. J Gen Physiol 1989;93:841–54
29.Katchman A, McGroary K, Kilborn M, Kornick C, Manfredi P, Woosley R, Ebert S. Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. J Pharmacol Exp Ther 2002;303:688–94
30.Friederich P, Solth A, Schillemeit S, Isbrandt D. Local anaesthetic sensitivities of cloned HERG channels from human heart: comparison with HERG/MiRP1 and HERG/MiRP1 T8A. Br J Anaesth 2004;92:93–101
© 2010 International Anesthesia Research Society