Eur J Anaesthesiol 2015; 32:330–335
ORIGINAL ARTICLE
Effect of ramosetron on the QT interval during sevoflurane anaesthesia in children A prospective observational study Ji-Hyun Lee, Eun-Kyung Yoo, In-Kyung Song, Jin-Tae Kim and Hee-Soo Kim BACKGROUND We investigated the effects of concomitant administration of sevoflurane and ramosetron on the QT interval, the interval between the peak and end of the T wave (Tpe) and Tpe/QT ratio in children.
MAIN OUTCOME MEASURES The heart rate corrected interval with Bazett’s formula (QTc), Tpe interval and Tpe/ QT ratio were calculated and the changes were analysed using repeated-measures analysis of variance (ANOVA).
OBJECTIVES To compare the effects of concomitant administration of ramosetron and sevoflurane on heart rate corrected interval with Bazett’s formula (QTc), Tpe interval and Tpe/QT ratio.
RESULTS The QTc interval at BASE was 388.5 29.3 ms. It increased with sevoflurane anaesthesia to 414.9 21.4 ms and did not change with the administration of ramosetron (418.2 23.0 ms). The Tpe interval and Tpe/QT ratio did not differ between measurements. No ventricular arrhythmias occurred during the study.
DESIGN A prospective observational study. SETTING Elective orthopaedic surgery with patient-controlled analgesia. PATIENTS Forty children aged between 3 and 12 years. INTERVENTION ECG recordings were collected before induction (BASE), before sevoflurane administration (SEVO) and after the administration of ramosetron (SEVO and R).
CONCLUSION Ramosetron was not associated with prolongation of the QTc interval when it was given concomitantly with sevoflurane in children. No ventricular arrhythmias or other adverse effects occurred during the study. Published online 5 December 2014
Introduction Following general anaesthesia, patients often experience postoperative nausea and vomiting (PONV) despite prophylactic antiemetics. Postoperative use of patient-controlled analgesia (PCA) with opioids can also exacerbate PONV. 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are frequently used to control PONV. Ondansetron is commonly used to prevent PONV, but it prolongs the QTc interval by affecting the human ether-a-go-gorelated gene (hERG) Kþ channel, which is also the case for some other drugs.1,2 Previously, we found that sevoflurane prolongs the QTc interval and, in combination with ondansetron, prolongation of the QTc interval is further aggravated in children.3 Prolongation of the QTc interval is a known risk factor for torsades de pointes
(TdP) arrhythmias; hence, it is important to anaesthesiologists.4 Ramosetron is a new selective 5-HT3 receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists in small doses. It has significantly greater binding affinity to 5HT3 receptors, with a slower dissociation rate, resulting in more potent and longer receptor-antagonising effects than older 5-HT3 receptor antagonists.5,6 A recent study7 concluded that ramosetron is more effective than ondansetron in children during the first 24-h postoperative period after general anaesthesia. In the present study, we investigated the effects of concomitant administration of ramosetron and sevoflurane on the QTc interval, the Tpe interval and the Tpe/ QT ratio in a paediatric population.
From the Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Korea Correspondence to Hee-Soo Kim, #101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: +82 2 2072 3659; e-mail: [email protected] 0265-0215 ß 2015 Copyright European Society of Anaesthesiology
DOI:10.1097/EJA.0000000000000200
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Effects of ramosetron on QT interval 331
Materials and methods This prospective observational study was approved by the Institutional Review Board of Seoul National University Hospital (H-1306-100-499, Seoul, Korea) and registered at cris.nih.go.kr (KCT0000923). After obtaining informed consent from the parents or guardians of children scheduled for postoperative intravenous PCA, we enrolled 45 children (3 to 12 years of age) who were categorised as either status 1 or 2 in the American Society of Anesthesiologists’ physical status classification system. Exclusion criteria were a history of hypersensitivity to opioids or NSAIDs, hypothyroidism, electrolyte imbalance and an increased QT interval (>450 ms) in the preoperative ECG. We also excluded children who were given medications known to affect QTc, such as antiarrhythmics, b-blockers, calcium channel blockers and tricyclic antidepressants. Children arrived at the reception area without premedication. In the operating room, children were monitored using lead II of the three-lead ECG. We also monitored noninvasive blood pressure (NIBP) at 1-min intervals, peripheral pulse oximetry (SpO2) and end-tidal carbon dioxide concentration (ETCO2; Solar 8000, GE Medical, Milwaukee, Wisconsin, USA). A standardised anaesthesia method was followed. General anaesthesia was induced with thiopental 6 mg kg1, followed by inhalation of sevoflurane 6 to 8% in 100% oxygen. Artificial ventilation of the lungs was started if respiration became shallow. Following tracheal intubation and after full relaxation with rocuronium 0.6 mg kg1, inhalational anaesthesia was maintained with sevoflurane 2 to 3% in 35% oxygen based on the blood pressure and heart rate. Ramosetron (6 mg kg1, maximum 200 mg) was administered intravenously about 30 min before the end of surgery for prophylaxis of PONV induced by opioid in the postoperative PCA system. After surgery, patients were transferred to the postanaesthesia care unit (PACU) and stayed at least 30 min before discharge to the ward. ECG, NIBP and sevoflurane concentration were collected from the beginning of monitoring to the end of the study (data for 3 min during the resting period before anaesthesia and from 5 min before administering ramosetron until 20 min after the ramosetron injection). Data were transferred to a computer using an analogue-to-digital converter (DA 149; DATAQ Instruments, Akron, Ohio, USA) at 1000 Hz. The data were divided into three segments: data collected before induction (BASE), data collected when the patient was receiving only sevoflurane (SEVO) and data collected when the patient was receiving sevoflurane and had been given ramosetron (SEVO and R). The ECG data (BASE, SEVO and SEVO as well as R) were analysed using LabChart ver. 7 (AD Instruments, Colorado Springs, Colorado, USA) after manual removal of artefact. The QT interval was calculated as the time from the start of the QRS complex to the end of the T
wave. It was corrected for the heart rate (QTc) using Bazett’s formula. Parameters were averaged for four successive beats. Tpe interval (the interval between the peak and end of the T wave) was measured and the Tpe/QT ratio was calculated. The QTc interval, the Tpe interval and the Tpe/QT ratio in each segment were averaged. The JT interval (from S wave end to T wave end) was also measured. Artefacts generated by electrocautery or movement of the ECG cable were excluded by offline inspection. The primary study outcome measure was the change in QTc after ramosetron administration compared with administration of sevoflurane alone. The secondary outcomes were the changes in the Tpe and the Tpe/QT ratio between the segments. Sample size was calculated on the basis of unpublished pilot data. A minimum of 39 patients was estimated to show a clinically significant difference with ramosetron administration, with a ¼ 0.05 and b ¼ 0.2. Therefore, it was planned to recruit 46 patients, with a 20% expected loss. We used the Power Analysis and Sample Size software PASS 2008 (NCSS, Utah, USA). Data are expressed as mean SD. We analysed the changes in the QTc interval, the Tpe interval and the Tpe/QT ratio in each segment using repeated measures analysis of variance (ANOVA). The end-expiratory concentrations of sevoflurane during the SEVO and SEVO and R periods were compared using the paired t-test. Simple linear regression analysis was used to examine the relationship between the sevoflurane concentration and changes in QTc. Blood pressure and heart rate in each segment were compared using repeated measures ANOVA. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) ver. 19.0 (SPSS, Chicago, Illinois, USA). A P value less than 0.05 was considered statistically significant.
Results Forty-five patients were enrolled and 40 children completed the study (Table 1). Five patients were excluded because of errors in transferring data from the monitor. The SBP and mean blood pressure during sevoflurane anaesthesia were lower than baseline, but there were no changes following administration of ramosetron (Table 2). DBP did not change in the three measured segments. The heart rate did not change during stable sevoflurane Table 1
Baseline characteristics of the patients
Age (years) Sex (M:F) Height (cm) Weight (kg) Type of surgery Mean operating time (min) Mean anaesthetic time (min)
9.3 3.9 22 : 18 135.3 45.9 34.2 4.9 All orthopaedic 142.6 68.2 176.1 72.4
Data are presented as mean SD, or numbers.
Eur J Anaesthesiol 2015; 32:330–335 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
332 Lee et al.
The preoperative QTc interval was 396.2 33.7 ms, which was not significantly different from the baseline QTc in the operating room (388.5 29 ms). Seven patients had a QTc interval more than 440 ms preoperatively with no evidence of long QT syndrome [M:F ¼ 3 : 4, median (range) age 9 (3 to 12) years] and their baseline QTc did not exceed 440 ms in the operating room before anaesthesia. The QTc interval increased with 2.5% sevoflurane anaesthesia (414.9 21.4 ms) and the value did not change significantly after administration of ramosetron (418.2 23.0 ms). Figure 1 shows the changes in QTc before and after administration of ramosetron. There were no ventricular arrhythmias during the study. The mean Tpe intervals are summarised in Table 3. Compared with 57.9 13.4 ms at BASE, the mean intervals at 2.5% of SEVO and 2.5% of SEVO and R were 56.4 13.2 and 57.8 13.6 ms, respectively. The Tpe interval did not increase in either intraoperative segment. The mean Tpe/QT ratio during the three stages were 0.18 0.03, 0.18 0.04 and 0.18 0.03, respectively. The averaged changes of QTc, Tpe interval and Tpe/QT ratio in the study periods are shown in Fig. 2. In the multivariate linear regression analysis, no significant relationships were found. We further analysed the data in two groups. One group included seven patients with QTc more than 440 ms preoperatively and the other group encompassed the rest of the patients. The former group had a mean preoperative QTc interval of 445.4 8.6 ms preoperatively, but the two groups showed no differences during sevoflurane anaesthesia. We reanalysed the data for sex according to a previous study.8 The preoperative Tpe/JT ratio was relatively larger in boys than in girls, but the difference was not significant (Table 3). The Tpe/JT ratio decreased during sevoflurane anaesthesia in boys compared with girls without reaching a statistically significant level.
Discussion The QTc interval reflects the action potential of cardiac cells, and changes in the QTc interval can cause Table 2
Fig. 1
QTc 385
Corrected QT interval (ms)
anaesthesia with an inspired concentration of 2.5% in comparison with the baseline values. The sevoflurane concentration was similar before and after administration of ramosetron (2.45 vs. 2.43%).
380
375
370
365 0
5
10
15
20
Time (min) Changes in QTc before and after ramosetron administration. The arrow indicates the point of ramosetron administration.
homogeneous or heterogeneous changes in the duration of the action potential.4 The T wave is the ECG manifestation of ventricular repolarisation. Recent experimental evidence has suggested that the interval from the peak to the end of the T wave (Tpe interval) corresponds to the dispersion of ventricular repolarisation.9,10 Transmural dispersion of repolarisation (TDR) is the interval between the peak and end of the T wave (Tpe), and the Tpe/QT ratio has been proposed as an arrhythmogenic index.11,12 These repolarisation disorders are responsible for life-threatening arrhythmias such as TdP.13 Previous studies have reported that sevoflurane prolongs the QTc interval. Volatile anaesthetics inhibit the cardiac potassium channels by blocking the potential of hERG or the rapidly activating delayed rectifier Kþ current (IKr), which is the mechanism of QTc prolongation.14 This is a side effect of sevoflurane, but it is the most commonly used volatile anaesthetic in children with no reported ventricular arrhythmias. Paediatric anaesthesiologists should keep this side effect in mind because children with long QT syndrome might be missed if there is no preoperative ECG screening or family history of dysrhythmias compatible with long QT syndrome. Currently, intravenous PCA is the standard postoperative pain management treatment that is used to provide
The mean end-expiratory concentration of sevoflurane, blood pressure and heart rate
End-expiratory sevoflurane concentration (%) HR (beats per min) SBP (mmHg) MBP (mmHg) DBP (mmHg)
Before induction
Sevoflurane
Sevoflurane and ramosetron
107.4 20.1 118.6 22.5 82.8 12.4 62.8 9.5
2.45 0.48 101.6 16.9 106.5 11.6M 72.6 11.5M 60.7 17.5
2.43 0.48 100.0 15.9 106.4 13.6M 71.7 11.5M 59.3 18.8
Data are presented as mean SD. DPB, diastolic blood pressure; HR, heart rate; MPB, mean blood pressure; SPB, systolic blood pressure. before induction.
M
P < 0.05 compared with
Eur J Anaesthesiol 2015; 32:330–335 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Effects of ramosetron on QT interval 333
Table 3
Corrected QT interval, Tpe interval, Tpe/QT ratio and Tpe/
Fig. 2
JT ratio
414.9 21.4M 56.4 13.2 0.18 0.04 0.18 0.04 0.17 0.04 0.23 0.06 0.23 0.06 0.22 0.06
418.2 23.0M 57.8 13.6 0.18 0.03 0.18 0.04 0.18 0.04 0.22 0.06 0.23 0.06 0.22 0.07
Data are presented as mean SD.
M
P < 0.05 compared with before induction.
opioid analgesics to children when moderate to severe pain is expected. PCA with opioids is effective and well tolerated in children15,16 despite the relatively high incidence of PONV.17 Prophylactic antiemetics have become popular along with the increasing incidence of PONV associated with PCA.18 Traditionally, ondansetron is used as a prophylactic antiemetic, but some side effects have been reported.19,20 Ramosetron is more effective than ondansetron in preventing moderate to severe nausea and vomiting in adults undergoing spinal surgery due to its longer duration of action and receptor selectivity.21–23 Therefore, the new 5HT3 receptor antagonist, ramosetron, might be a suitable alternative to ondansetron in children.5,24 Previously, we showed that the QTc interval is prolonged when ondansetron is administered concomitantly with sevoflurane in children.3 There were no serious cardiac complications in that study. Preoperative ECG screening is mandatory at our institution to avoid a disaster with an unidentified long QT syndrome patient. However, some hospitals do not obtain a preoperative ECG in children, which makes missing children with an asymptomatic QT syndrome very likely. Because long QT syndrome is relatively more common in children who present for anaesthesia and surgery such as cochlear implantation with sensorineural hearing loss than in adults,25,26 paediatric anaesthesiologists should stay alert to the possibility of QTc prolongation during the coadministration of ondansetron and sevoflurane. Although ondansetron and sevoflurane are risk factors for ventricular arrhythmias in congenital long QT syndrome,27,28 previous studies concluded that they do not affect the TDR in healthy patients.29,30 TDR is more accurate in predicting arrhythmias than QT prolongation.31 However, the Tpe/QT ratio is more sensitive than the Tpe interval, which has confounding effects on heart rate variability and eliminates the influence of variation in the QT interval.12 In our previous study, ondansetron increased the Tpe interval by 3 ms. The Tpe interval was also increased with ramosetron by 1.4 ms, but the difference was not significant. This value was similar to that during BASE in our study. The Tpe/QT ratio was 0.18 in the three measured segments. Therefore, sevoflurane and ramosetron did not affect the Tpe/QT ratio.
Corrected QT interval (ms)
388.5 29.3 57.9 13.4 0.18 0.03 0.18 0.03 0.17 0.03 0.26 0.06 0.27 0.06 0.23 0.06
QTc 500
450
*
*
400
350
300 Base
Sevo
Sevo+R
Tpe 100
Tpe interval (ms)
Sevoflurane
Sevoflurane and ramosetron
80
60
40
20 Base
Sevo
Sevo+R
Tpe/QT 0.3
Tpe/QT ratio
Corrected QT interval Tpe interval (ms) Tpe/QT ratio male female Tpe/JT ratio male female
Before induction
0.2
0.1
Base
Sevo
Sevo+R
The averaged changes in QTc, Tpe interval and Tpe/QT ratio before induction, with sevoflurane and with sevoflurane and ramosetron (mean, standard deviation bar). The QTc interval was significantly prolonged during sevoflurane anaesthesia, but there were no differences after ramosetron administration. P < 0.05 compared with baseline.
The difference between the effects of ondansetron and ramosetron on the QTc interval might stem from the dose that is routinely used for antiemesis. The recommended dose of ondansetron is 100 mg kg1 for nausea and vomiting in children, although the dose of ramosetron is 6 mg kg1 with a similar prophylactic antiemetic effect.
Eur J Anaesthesiol 2015; 32:330–335 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
334 Lee et al.
Consequently, the relative clinical dose of ondansetron is much higher than that of ramosetron. A previous study reported that prolongation of the QTc interval is related to ondansetron dosage.32 Therefore, a higher dose of ondansetron than ramosetron is one possible explanation for the difference in their QTc effects. We analysed separately the seven patients who had a preoperative QTc more than 440 ms. However, these patients had a normal baseline QTc (390.9 30.1 ms). The probable explanation for this difference is the duration of ECG recording and the ECG analysis methods. The preoperative screening ECG is recorded for 30 s and the QT interval is measured from the earliest detection of depolarisation in any lead to the latest detection of repolarisation in any lead. The QTc interval was corrected using the Bazett formula. However, we obtained the baseline ECG for 3 min just before anaesthesia and QTc was calculated with the Bazett formula and averaged. Our study has several limitations. First, we did not check the antiemetic effect of ramosetron postoperatively. We focused on the effects of ramosetron on the QTc interval during anaesthesia and did not design the study to compare the antiemetic effects of ondansetron and ramosetron. However, a previous study has shown that ramosetron has a better antiemetic effects than ondansetron. Although we did not record PONV in this study, a routine check of PONV in the ward found a similar or lower incidence of PONV than ondansetron. The second limitation is that there are differences in the Tpe intervals based on the recorded ECG lead, especially precordial leads, in normal children, which stems from uneven distribution of M cells.8 This might also have affected the results. Lastly, sevoflurane may not be potent enough to be used alone for orthopaedic surgery in children and sometimes needs adjuvant opioids. However, opioids do not affect the QTc,33 so the use of opioids for balanced anaesthesia should not change the results of this study. In conclusion, ramosetron was not associated with adverse effects in this study. Ramosetron might be a suitable alternative to ondansetron from the perspective of the QTc interval.
Acknowledgements relating to this article Assistance with the study: none.
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9 10 11
12 13 14
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18 19
20 21
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Conflicts of interest: none. Financial sponsorship and support: none. Presentation: none.
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Lee JH, Park YH, Kim JT, et al. The effect of sevoflurane and ondansetron on QT interval and transmural dispersion of repolarization in children. Paediatr Anaesth 2013; 24:421–425. Malik M, Camm AJ. Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. Drug Saf 2001; 24:323–351. Rabasseda X. Ramosetron, a 5-HT3 receptor antagonist for the control of nausea and vomiting. Drugs Today (Barc) 2002; 38:75–89. Akuzawa S, Ito H, Yamaguchi T. Comparative study of [3H]ramosetron and [3H]granisetron binding in the cloned human 5-hydroxytryptamine3 receptors. Jpn J Pharmacol 1998; 78:381–384. Park YH, Jang YE, Byon HJ, et al. Comparison of the efficacy of ramosetron and ondansetron in the prophylaxis of postoperative vomiting in children receiving fentanyl by patient-controlled analgesia after orthopedic surgery: a randomized controlled trial. Paediatr Anaesth 2013; 23:360–364. Bieganowska K, Sawicka-Parobczyk M, Bieganowski M, Piskorski J. TpeakTend interval in 12-lead electrocardiogram of healthy children and adolescents Tpeak-Tend interval in childhood. Ann Noninvasive Electrocardiol 2013; 18:344–351. Antzelevitch C. T peak-Tend interval as an index of transmural dispersion of repolarization. Eur J Clin Invest 2001; 31:555–557. Antzelevitch C. Heterogeneity and cardiac arrhythmias: an overview. Heart Rhythm 2007; 4:964–972. Barbhaiya C, Po JR, Hanon S, Schweitzer P. Tpeak - Tend and Tpeak Tend/QT ratio as markers of ventricular arrhythmia risk in cardiac resynchronization therapy patients. Pacing Clin Electrophysiol 2013; 36:103–108. Gupta P, Patel C, Patel H, et al. T(p-e)/QT ratio as an index of arrhythmogenesis. J Electrocardiol 2008; 41:567–574. Roden DM. A practical approach to torsade de pointes. Clin Cardiol 1997; 20:285–290. Yamada M, Hatakeyama N, Shibuya N, et al. Mechanism of QT interval prolongation induced by sevoflurane in guinea-pig ventricular myocyte. Masui 2003; 52:482–488. Butkovic D, Kralik S, Matolic M, et al. Postoperative analgesia with intravenous fentanyl PCA vs epidural block after thoracoscopic pectus excavatum repair in children. Br J Anaesth 2007; 98:677–681. Chiaretti A, Genovese O, Antonelli A, et al. Patient-controlled analgesia with fentanil and midazolam in children with postoperative neurosurgical pain. Childs Nerv Syst 2008; 24:119–124. Kokinsky E, Thornberg E, Nilsson K, Larsson LE. Postoperative nausea and vomiting in children using patient-controlled analgesia: the effect of prophylactic intravenous dixyrazine. Acta Anaesthesiol Scand 1999; 43:191–195. Allen D, Jorgensen C, Sims C. Effect of tropisetron on vomiting during patient-controlled analgesia in children. Br J Anaesth 1999; 83:608–610. Chandrakala R, Vijayashankara CN, Kumar KK, Sarala N. Ondansetron induced fatal ventricular tachycardia. Indian J Pharmacol 2008; 40:186– 187. Patel A, Mittal S, Manchanda S, Puliyel JM. Ondansetron-induced dystonia, hypoglycemia, and seizures in a child. Ann Pharmacother 2011; 45:e7. Endo T, Minami M, Kitamura N, et al. Effects of various 5-HT3 receptor antagonists, granisetron, ondansetron, ramosetron and azasetron on serotonin (5-HT) release from the ferret isolated ileum. Res Commun Mol Pathol Pharmacol 1999; 104:145–155. Shi Y, He X, Yang S, et al. Ramosetron versus ondansetron in the prevention of chemotherapy-induced gastrointestinal side effects: a prospective randomized controlled study. Chemotherapy 2007; 53:44–50. Choi YS, Shim JK, Yoon DH, et al. Effect of ramosetron on patientcontrolled analgesia related nausea and vomiting after spine surgery in highly susceptible patients: comparison with ondansetron. Spine 2008; 33:E602–E606. Fujii Y. Current review of ramosetron in the prevention of postoperative nausea and vomiting. Curr Drug Saf 2011; 6:122–127. Yanmei F, Yaqin W, Haibo S, et al. Cochlear implantation in patients with Jervell and Lange-Nielsen syndrome, and a review of literature. Int J Pediatr Otorhinolaryngol 2008; 72:1723–1729. Chinagudi S, Patted SM, Herur A. A study of electrocardiographic changes in congenital deaf school children. Indian J Otolaryngol Head Neck Surg 2010; 62:44–48. McKechnie K, Froese A. Ventricular tachycardia after ondansetron administration in a child with undiagnosed long QT syndrome. Can J Anaesth 2010; 57:453–457. Saussine M, Massad I, Raczka F, et al. Torsade de pointes during sevoflurane anesthesia in a child with congenital long QT syndrome. Paediatr Anaesth 2006; 16:63–65. Nakao S, Hatano K, Sumi C, et al. Sevoflurane causes greater QTc interval prolongation in elderly patients than in younger patients. Anesth Analg 2010; 110:775–779.
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Eur J Anaesthesiol 2015; 32:330–335 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
ORIGINAL ARTICLE
Effect of ramosetron on the QT interval during sevoflurane anaesthesia in children A prospective observational study Ji-Hyun Lee, Eun-Kyung Yoo, In-Kyung Song, Jin-Tae Kim and Hee-Soo Kim BACKGROUND We investigated the effects of concomitant administration of sevoflurane and ramosetron on the QT interval, the interval between the peak and end of the T wave (Tpe) and Tpe/QT ratio in children.
MAIN OUTCOME MEASURES The heart rate corrected interval with Bazett’s formula (QTc), Tpe interval and Tpe/ QT ratio were calculated and the changes were analysed using repeated-measures analysis of variance (ANOVA).
OBJECTIVES To compare the effects of concomitant administration of ramosetron and sevoflurane on heart rate corrected interval with Bazett’s formula (QTc), Tpe interval and Tpe/QT ratio.
RESULTS The QTc interval at BASE was 388.5 29.3 ms. It increased with sevoflurane anaesthesia to 414.9 21.4 ms and did not change with the administration of ramosetron (418.2 23.0 ms). The Tpe interval and Tpe/QT ratio did not differ between measurements. No ventricular arrhythmias occurred during the study.
DESIGN A prospective observational study. SETTING Elective orthopaedic surgery with patient-controlled analgesia. PATIENTS Forty children aged between 3 and 12 years. INTERVENTION ECG recordings were collected before induction (BASE), before sevoflurane administration (SEVO) and after the administration of ramosetron (SEVO and R).
CONCLUSION Ramosetron was not associated with prolongation of the QTc interval when it was given concomitantly with sevoflurane in children. No ventricular arrhythmias or other adverse effects occurred during the study. Published online 5 December 2014
Introduction Following general anaesthesia, patients often experience postoperative nausea and vomiting (PONV) despite prophylactic antiemetics. Postoperative use of patient-controlled analgesia (PCA) with opioids can also exacerbate PONV. 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are frequently used to control PONV. Ondansetron is commonly used to prevent PONV, but it prolongs the QTc interval by affecting the human ether-a-go-gorelated gene (hERG) Kþ channel, which is also the case for some other drugs.1,2 Previously, we found that sevoflurane prolongs the QTc interval and, in combination with ondansetron, prolongation of the QTc interval is further aggravated in children.3 Prolongation of the QTc interval is a known risk factor for torsades de pointes
(TdP) arrhythmias; hence, it is important to anaesthesiologists.4 Ramosetron is a new selective 5-HT3 receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists in small doses. It has significantly greater binding affinity to 5HT3 receptors, with a slower dissociation rate, resulting in more potent and longer receptor-antagonising effects than older 5-HT3 receptor antagonists.5,6 A recent study7 concluded that ramosetron is more effective than ondansetron in children during the first 24-h postoperative period after general anaesthesia. In the present study, we investigated the effects of concomitant administration of ramosetron and sevoflurane on the QTc interval, the Tpe interval and the Tpe/ QT ratio in a paediatric population.
From the Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Korea Correspondence to Hee-Soo Kim, #101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: +82 2 2072 3659; e-mail: [email protected] 0265-0215 ß 2015 Copyright European Society of Anaesthesiology
DOI:10.1097/EJA.0000000000000200
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Effects of ramosetron on QT interval 331
Materials and methods This prospective observational study was approved by the Institutional Review Board of Seoul National University Hospital (H-1306-100-499, Seoul, Korea) and registered at cris.nih.go.kr (KCT0000923). After obtaining informed consent from the parents or guardians of children scheduled for postoperative intravenous PCA, we enrolled 45 children (3 to 12 years of age) who were categorised as either status 1 or 2 in the American Society of Anesthesiologists’ physical status classification system. Exclusion criteria were a history of hypersensitivity to opioids or NSAIDs, hypothyroidism, electrolyte imbalance and an increased QT interval (>450 ms) in the preoperative ECG. We also excluded children who were given medications known to affect QTc, such as antiarrhythmics, b-blockers, calcium channel blockers and tricyclic antidepressants. Children arrived at the reception area without premedication. In the operating room, children were monitored using lead II of the three-lead ECG. We also monitored noninvasive blood pressure (NIBP) at 1-min intervals, peripheral pulse oximetry (SpO2) and end-tidal carbon dioxide concentration (ETCO2; Solar 8000, GE Medical, Milwaukee, Wisconsin, USA). A standardised anaesthesia method was followed. General anaesthesia was induced with thiopental 6 mg kg1, followed by inhalation of sevoflurane 6 to 8% in 100% oxygen. Artificial ventilation of the lungs was started if respiration became shallow. Following tracheal intubation and after full relaxation with rocuronium 0.6 mg kg1, inhalational anaesthesia was maintained with sevoflurane 2 to 3% in 35% oxygen based on the blood pressure and heart rate. Ramosetron (6 mg kg1, maximum 200 mg) was administered intravenously about 30 min before the end of surgery for prophylaxis of PONV induced by opioid in the postoperative PCA system. After surgery, patients were transferred to the postanaesthesia care unit (PACU) and stayed at least 30 min before discharge to the ward. ECG, NIBP and sevoflurane concentration were collected from the beginning of monitoring to the end of the study (data for 3 min during the resting period before anaesthesia and from 5 min before administering ramosetron until 20 min after the ramosetron injection). Data were transferred to a computer using an analogue-to-digital converter (DA 149; DATAQ Instruments, Akron, Ohio, USA) at 1000 Hz. The data were divided into three segments: data collected before induction (BASE), data collected when the patient was receiving only sevoflurane (SEVO) and data collected when the patient was receiving sevoflurane and had been given ramosetron (SEVO and R). The ECG data (BASE, SEVO and SEVO as well as R) were analysed using LabChart ver. 7 (AD Instruments, Colorado Springs, Colorado, USA) after manual removal of artefact. The QT interval was calculated as the time from the start of the QRS complex to the end of the T
wave. It was corrected for the heart rate (QTc) using Bazett’s formula. Parameters were averaged for four successive beats. Tpe interval (the interval between the peak and end of the T wave) was measured and the Tpe/QT ratio was calculated. The QTc interval, the Tpe interval and the Tpe/QT ratio in each segment were averaged. The JT interval (from S wave end to T wave end) was also measured. Artefacts generated by electrocautery or movement of the ECG cable were excluded by offline inspection. The primary study outcome measure was the change in QTc after ramosetron administration compared with administration of sevoflurane alone. The secondary outcomes were the changes in the Tpe and the Tpe/QT ratio between the segments. Sample size was calculated on the basis of unpublished pilot data. A minimum of 39 patients was estimated to show a clinically significant difference with ramosetron administration, with a ¼ 0.05 and b ¼ 0.2. Therefore, it was planned to recruit 46 patients, with a 20% expected loss. We used the Power Analysis and Sample Size software PASS 2008 (NCSS, Utah, USA). Data are expressed as mean SD. We analysed the changes in the QTc interval, the Tpe interval and the Tpe/QT ratio in each segment using repeated measures analysis of variance (ANOVA). The end-expiratory concentrations of sevoflurane during the SEVO and SEVO and R periods were compared using the paired t-test. Simple linear regression analysis was used to examine the relationship between the sevoflurane concentration and changes in QTc. Blood pressure and heart rate in each segment were compared using repeated measures ANOVA. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) ver. 19.0 (SPSS, Chicago, Illinois, USA). A P value less than 0.05 was considered statistically significant.
Results Forty-five patients were enrolled and 40 children completed the study (Table 1). Five patients were excluded because of errors in transferring data from the monitor. The SBP and mean blood pressure during sevoflurane anaesthesia were lower than baseline, but there were no changes following administration of ramosetron (Table 2). DBP did not change in the three measured segments. The heart rate did not change during stable sevoflurane Table 1
Baseline characteristics of the patients
Age (years) Sex (M:F) Height (cm) Weight (kg) Type of surgery Mean operating time (min) Mean anaesthetic time (min)
9.3 3.9 22 : 18 135.3 45.9 34.2 4.9 All orthopaedic 142.6 68.2 176.1 72.4
Data are presented as mean SD, or numbers.
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332 Lee et al.
The preoperative QTc interval was 396.2 33.7 ms, which was not significantly different from the baseline QTc in the operating room (388.5 29 ms). Seven patients had a QTc interval more than 440 ms preoperatively with no evidence of long QT syndrome [M:F ¼ 3 : 4, median (range) age 9 (3 to 12) years] and their baseline QTc did not exceed 440 ms in the operating room before anaesthesia. The QTc interval increased with 2.5% sevoflurane anaesthesia (414.9 21.4 ms) and the value did not change significantly after administration of ramosetron (418.2 23.0 ms). Figure 1 shows the changes in QTc before and after administration of ramosetron. There were no ventricular arrhythmias during the study. The mean Tpe intervals are summarised in Table 3. Compared with 57.9 13.4 ms at BASE, the mean intervals at 2.5% of SEVO and 2.5% of SEVO and R were 56.4 13.2 and 57.8 13.6 ms, respectively. The Tpe interval did not increase in either intraoperative segment. The mean Tpe/QT ratio during the three stages were 0.18 0.03, 0.18 0.04 and 0.18 0.03, respectively. The averaged changes of QTc, Tpe interval and Tpe/QT ratio in the study periods are shown in Fig. 2. In the multivariate linear regression analysis, no significant relationships were found. We further analysed the data in two groups. One group included seven patients with QTc more than 440 ms preoperatively and the other group encompassed the rest of the patients. The former group had a mean preoperative QTc interval of 445.4 8.6 ms preoperatively, but the two groups showed no differences during sevoflurane anaesthesia. We reanalysed the data for sex according to a previous study.8 The preoperative Tpe/JT ratio was relatively larger in boys than in girls, but the difference was not significant (Table 3). The Tpe/JT ratio decreased during sevoflurane anaesthesia in boys compared with girls without reaching a statistically significant level.
Discussion The QTc interval reflects the action potential of cardiac cells, and changes in the QTc interval can cause Table 2
Fig. 1
QTc 385
Corrected QT interval (ms)
anaesthesia with an inspired concentration of 2.5% in comparison with the baseline values. The sevoflurane concentration was similar before and after administration of ramosetron (2.45 vs. 2.43%).
380
375
370
365 0
5
10
15
20
Time (min) Changes in QTc before and after ramosetron administration. The arrow indicates the point of ramosetron administration.
homogeneous or heterogeneous changes in the duration of the action potential.4 The T wave is the ECG manifestation of ventricular repolarisation. Recent experimental evidence has suggested that the interval from the peak to the end of the T wave (Tpe interval) corresponds to the dispersion of ventricular repolarisation.9,10 Transmural dispersion of repolarisation (TDR) is the interval between the peak and end of the T wave (Tpe), and the Tpe/QT ratio has been proposed as an arrhythmogenic index.11,12 These repolarisation disorders are responsible for life-threatening arrhythmias such as TdP.13 Previous studies have reported that sevoflurane prolongs the QTc interval. Volatile anaesthetics inhibit the cardiac potassium channels by blocking the potential of hERG or the rapidly activating delayed rectifier Kþ current (IKr), which is the mechanism of QTc prolongation.14 This is a side effect of sevoflurane, but it is the most commonly used volatile anaesthetic in children with no reported ventricular arrhythmias. Paediatric anaesthesiologists should keep this side effect in mind because children with long QT syndrome might be missed if there is no preoperative ECG screening or family history of dysrhythmias compatible with long QT syndrome. Currently, intravenous PCA is the standard postoperative pain management treatment that is used to provide
The mean end-expiratory concentration of sevoflurane, blood pressure and heart rate
End-expiratory sevoflurane concentration (%) HR (beats per min) SBP (mmHg) MBP (mmHg) DBP (mmHg)
Before induction
Sevoflurane
Sevoflurane and ramosetron
107.4 20.1 118.6 22.5 82.8 12.4 62.8 9.5
2.45 0.48 101.6 16.9 106.5 11.6M 72.6 11.5M 60.7 17.5
2.43 0.48 100.0 15.9 106.4 13.6M 71.7 11.5M 59.3 18.8
Data are presented as mean SD. DPB, diastolic blood pressure; HR, heart rate; MPB, mean blood pressure; SPB, systolic blood pressure. before induction.
M
P < 0.05 compared with
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Effects of ramosetron on QT interval 333
Table 3
Corrected QT interval, Tpe interval, Tpe/QT ratio and Tpe/
Fig. 2
JT ratio
414.9 21.4M 56.4 13.2 0.18 0.04 0.18 0.04 0.17 0.04 0.23 0.06 0.23 0.06 0.22 0.06
418.2 23.0M 57.8 13.6 0.18 0.03 0.18 0.04 0.18 0.04 0.22 0.06 0.23 0.06 0.22 0.07
Data are presented as mean SD.
M
P < 0.05 compared with before induction.
opioid analgesics to children when moderate to severe pain is expected. PCA with opioids is effective and well tolerated in children15,16 despite the relatively high incidence of PONV.17 Prophylactic antiemetics have become popular along with the increasing incidence of PONV associated with PCA.18 Traditionally, ondansetron is used as a prophylactic antiemetic, but some side effects have been reported.19,20 Ramosetron is more effective than ondansetron in preventing moderate to severe nausea and vomiting in adults undergoing spinal surgery due to its longer duration of action and receptor selectivity.21–23 Therefore, the new 5HT3 receptor antagonist, ramosetron, might be a suitable alternative to ondansetron in children.5,24 Previously, we showed that the QTc interval is prolonged when ondansetron is administered concomitantly with sevoflurane in children.3 There were no serious cardiac complications in that study. Preoperative ECG screening is mandatory at our institution to avoid a disaster with an unidentified long QT syndrome patient. However, some hospitals do not obtain a preoperative ECG in children, which makes missing children with an asymptomatic QT syndrome very likely. Because long QT syndrome is relatively more common in children who present for anaesthesia and surgery such as cochlear implantation with sensorineural hearing loss than in adults,25,26 paediatric anaesthesiologists should stay alert to the possibility of QTc prolongation during the coadministration of ondansetron and sevoflurane. Although ondansetron and sevoflurane are risk factors for ventricular arrhythmias in congenital long QT syndrome,27,28 previous studies concluded that they do not affect the TDR in healthy patients.29,30 TDR is more accurate in predicting arrhythmias than QT prolongation.31 However, the Tpe/QT ratio is more sensitive than the Tpe interval, which has confounding effects on heart rate variability and eliminates the influence of variation in the QT interval.12 In our previous study, ondansetron increased the Tpe interval by 3 ms. The Tpe interval was also increased with ramosetron by 1.4 ms, but the difference was not significant. This value was similar to that during BASE in our study. The Tpe/QT ratio was 0.18 in the three measured segments. Therefore, sevoflurane and ramosetron did not affect the Tpe/QT ratio.
Corrected QT interval (ms)
388.5 29.3 57.9 13.4 0.18 0.03 0.18 0.03 0.17 0.03 0.26 0.06 0.27 0.06 0.23 0.06
QTc 500
450
*
*
400
350
300 Base
Sevo
Sevo+R
Tpe 100
Tpe interval (ms)
Sevoflurane
Sevoflurane and ramosetron
80
60
40
20 Base
Sevo
Sevo+R
Tpe/QT 0.3
Tpe/QT ratio
Corrected QT interval Tpe interval (ms) Tpe/QT ratio male female Tpe/JT ratio male female
Before induction
0.2
0.1
Base
Sevo
Sevo+R
The averaged changes in QTc, Tpe interval and Tpe/QT ratio before induction, with sevoflurane and with sevoflurane and ramosetron (mean, standard deviation bar). The QTc interval was significantly prolonged during sevoflurane anaesthesia, but there were no differences after ramosetron administration. P < 0.05 compared with baseline.
The difference between the effects of ondansetron and ramosetron on the QTc interval might stem from the dose that is routinely used for antiemesis. The recommended dose of ondansetron is 100 mg kg1 for nausea and vomiting in children, although the dose of ramosetron is 6 mg kg1 with a similar prophylactic antiemetic effect.
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334 Lee et al.
Consequently, the relative clinical dose of ondansetron is much higher than that of ramosetron. A previous study reported that prolongation of the QTc interval is related to ondansetron dosage.32 Therefore, a higher dose of ondansetron than ramosetron is one possible explanation for the difference in their QTc effects. We analysed separately the seven patients who had a preoperative QTc more than 440 ms. However, these patients had a normal baseline QTc (390.9 30.1 ms). The probable explanation for this difference is the duration of ECG recording and the ECG analysis methods. The preoperative screening ECG is recorded for 30 s and the QT interval is measured from the earliest detection of depolarisation in any lead to the latest detection of repolarisation in any lead. The QTc interval was corrected using the Bazett formula. However, we obtained the baseline ECG for 3 min just before anaesthesia and QTc was calculated with the Bazett formula and averaged. Our study has several limitations. First, we did not check the antiemetic effect of ramosetron postoperatively. We focused on the effects of ramosetron on the QTc interval during anaesthesia and did not design the study to compare the antiemetic effects of ondansetron and ramosetron. However, a previous study has shown that ramosetron has a better antiemetic effects than ondansetron. Although we did not record PONV in this study, a routine check of PONV in the ward found a similar or lower incidence of PONV than ondansetron. The second limitation is that there are differences in the Tpe intervals based on the recorded ECG lead, especially precordial leads, in normal children, which stems from uneven distribution of M cells.8 This might also have affected the results. Lastly, sevoflurane may not be potent enough to be used alone for orthopaedic surgery in children and sometimes needs adjuvant opioids. However, opioids do not affect the QTc,33 so the use of opioids for balanced anaesthesia should not change the results of this study. In conclusion, ramosetron was not associated with adverse effects in this study. Ramosetron might be a suitable alternative to ondansetron from the perspective of the QTc interval.
Acknowledgements relating to this article Assistance with the study: none.
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9 10 11
12 13 14
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20 21
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Conflicts of interest: none. Financial sponsorship and support: none. Presentation: none.
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