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Anesth Analg 2007;104:277-282
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000252417.23986.6e

PEDIATRIC ANESTHESIA

A Comparison of the Effect on Dispersion of Repolarization of Age-Adjusted MAC Values of Sevoflurane in Children

Simon D. Whyte, MBBS, FRCA*{ddagger}, Shubhayan Sanatani, MD, BSc, FRCPC{dagger}§, Joanne Lim, MASc*{ddagger}, and Peter D. Booker, MBBS, MD, FRCA¶#

From the Departments of *Pediatric Anesthesia and {dagger}Pediatric Cardiology, British Columbia Children's Hospital; {ddagger}Department of Anesthesiology, Pharmacology and Therapeutics, and §Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; ¶Jackson-Rees Department of Anesthesia, Royal Liverpool Children's Hospital and #Department of Anesthesia, Liverpool University, Liverpool, United Kingdom.

Address correspondence and reprint requests to Simon D. Whyte, MBBS, FRCA, Department of Pediatric Anesthesia, Room 1L7, British Columbia Children's Hospital, 4480 Oak St., Vancouver, BC, V6H 3V4, Canada. Address e-mail to swhyte{at}cw.bc.ca


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: QT interval prolongation is associated with torsades des pointes (TdP), but is a poor predictor of drug torsadogenicity. Susceptibility to TdP arises from increased transmural dispersion of repolarization (TDR) across the myocardial wall, rather than QT interval prolongation per se. TDR can be measured on the electrocardiogram as the time interval between the peak and end of the T-wave (Tp-e). Thus Tp-e is a readily measured assay of drug torsadogenicity. Several anesthetic drugs prolong the QT interval, but their effect on TDR is largely unknown.

METHODS: We investigated the effects of sevoflurane on corrected QT (QTc) and Tp-e intervals in 54 unpremedicated ASA I-II children, aged 3–10 yr, who were randomized to receive sevoflurane 1, 1.25, or 1.5 MAC, age-adjusted. Twelve-lead electrocardiograms were recorded before and after sevoflurane exposure. QTc and Tp-e were compared within and among groups using 2-way analysis of variance. Change in Tp-e after sevoflurane exposure was the primary outcome measure.

RESULTS: Sevoflurane significantly prolonged preoperative QTc at all doses (P < 0.005), with no dose-response relationship, but had no effect on preoperative Tp-e.

CONCLUSION: Sevoflurane markedly prolongs the QTc in healthy children, but does not increase dispersion of repolarization as measured by the Tp-e interval, indicating low or no torsadogenicity, and making it unlikely to increase predisposition to TdP.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ventricular repolarization is represented on the surface 12-lead electrocardiogram (ECG) by the QT interval, measured from the start of the QRS complex to the end of the T-wave, and standardized by correction for heart rate. There are several formulae for correcting the QT interval for heart rate (QTc) and, although there is debate about which is the best, the most commonly used is Bazett's formula (1), in which QTc = QT/{surd}RR. Using this formula, the accepted upper limit of normal for the duration of repolarization is 440 ms (2).

Prolongation of ventricular repolarization beyond 440 ms is associated with an increased risk of torsades des pointes (TdP). However, there is convincing evidence that this risk is not solely related to the presence of QT interval prolongation (3–5). A more reliable indicator of the true risk of TdP would be extremely useful. The interval from the peak to the end of the T-wave (Tp-e) is a candidate, as it is a measure of transmural dispersion of repolarization (TDR). The electrophysiological substrate for TdP is increased TDR (6–9). TdP only occurs when TDR is increased; QT interval prolongation per se is neither necessary nor sufficient to predispose to TdP (7,9). We have previously summarized the electrophysiology of TDR in detail (10). In brief, the cellular composition of the myocardium is not homogenous, and its component cells repolarize at different rates. Repolarization, therefore, occurs asynchronously across the myocardial wall, producing a physiological TDR. The intrinsic differential time course of repolarization across the myocardial wall is responsible for the morphology of the ECG T-wave (6,11). Epicardial cells repolarize first, and the peak of the T-wave corresponds with the completion of epicardial repolarization. Midmyocardial (M) cells, which repolarize last, determine the total duration of the action potential; the end of the T-wave corresponds with the full recovery of these cells (6). It follows that the Tp-e interval may be used as a measure of TDR. The M cell is characterized by the capacity for its action potential to lengthen disproportionately, compared with those in other areas of the myocardial wall, in response to various stimuli. In this milieu, early after-depolarizations (the R-on-T phenomenon) can initiate re-entrant circuits between areas of myocardium in variable states of refractoriness, i.e., exaggeration of TDR is arrhythmogenic (12).

QT interval prolongation is frequently drug-induced, resulting in an acquired long QT syndrome (LQTS) that is almost exclusively caused by drugs that block iKr channels, which are partly responsible for conducting the potassium efflux that effects repolarization. However, as previously mentioned, not all QTc-prolonging drugs are torsadogenic. It is logical to hypothesize that drugs actually associated with TdP are capable of increasing TDR through a preferential effect on M cell repolarization dynamics. As TDR can be measured as Tp-e, the latter may provide a readily available, noninvasive assay of drug torsadogenicity.

Volatile anesthetics are iKr channel blockers; the QTc is prolonged in healthy patients undergoing anesthesia with halothane, enflurane, isoflurane, or sevoflurane (10,13–20). Sevoflurane is widely used in pediatric anesthesia and most patients with symptomatic QT prolongation are children and young adults with an inherited mutation in one of the genes encoding the constituent proteins of channels involved in conducting repolarizing currents. There is little evidence to guide the rational selection of anesthetic drugs in these patients, where the aim is clearly to avoid anything that may increase the already elevated risk of TdP. However, only one study has investigated the effect of these anesthetic drugs on TDR, which is more relevant to the attendant risk of TdP (10). In that preliminary study, sevoflurane was investigated at only one dose, which was not adjusted for age, across an age range of 1–16 yr. Data from studies published since have better defined the change in Tp-e that would be clinically relevant. The aims of this study were to examine in greater depth the effects of sevoflurane on repolarization dynamics in a pediatric population by adjusting MAC values for age, by investigating the concentration-response relationship between sevoflurane and indices of myocardial repolarization, and by seeking any true differences in Tp-e with maximum power.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
With the approval of the institutional and university research and ethics boards, we recruited 54 unpremedicated ASA I-II children, aged between 3 and 10 yr, undergoing elective surgery under general anesthesia. We excluded patients receiving medications known to prolong the QT interval or with a family history of LQTS. After obtaining written informed consent from parents, and the written assent of older children where appropriate, we randomized enrolled patients to receive one of three age-adjusted MAC concentrations of sevoflurane: 1 MAC, 1.25 MAC, or 1.5 MAC. The statistician advising the study prepared the computer-generated randomization schedule. Adjustment of MAC values for age was achieved using the formula of Nickalls and Mapleson (21):



Formula 1

where k is the MAC multiple required and MAC40 is the ETsevo value in oxygen at 40 yr of age that is equivalent to 1 MAC (=1.8).

On arrival in the anesthetic room, and before induction of anesthesia, we placed ECG electrodes at standardized locations for acquisition of a preoperative 12-lead ECG. An intraoperative ECG was taken 15 min after induction of anesthesia, using the same electrode positions. The subject's involvement in the study was then complete, and conduct of anesthesia continued at the discretion of the supervising anesthesiologist. All ECGs were recorded in duplicate on a Hewlett Packard Pagewriter Xli Model 1700A (Philips Medical Systems, Bothell, WA), at a paper speed of 50 mm/s. No identifying data or automated analysis were printed on the recorded traces. Each ECG was given a random number three-figure code to allow identification of paired pre- and intraoperative traces after analysis.

Anesthesia was induced and maintained for 15 min with the drug allocated by randomization. Each child received sevoflurane 8% in oxygen for induction. After induction, we diluted the inspired oxygen concentration to 40% with air and titrated sevoflurane to the end-tidal concentration determined by the age-adjusted MAC value to which the child had been randomized. We maintained the airway by facemask or laryngeal mask airway. In an attempt to minimize sympathetic stimulation, laryngoscopy was not permitted during the study period. No other drugs were administered and no local anesthetic blocks were conducted during the study period. Throughout the study period, all children breathed spontaneously and received routine monitoring, including capnography. End-tidal carbon dioxide values ranged between 35–43 mm Hg.

Two authors (SS and PDB) independently analyzed all the ECG traces in accordance with predetermined criteria. Both were blinded to the concentration of anesthetic used and to the status of the ECG recording (pre- or intraoperative). Neither was involved in recruitment or randomization of patients, or in conduct of anesthesia or acquisition of ECG recordings, all of which were performed by the other two authors (SDW and JL).

We measured the QT, RR, and Tp-e intervals in leads II and V5. We measured the QT interval from the start of the QRS complex to the end of the T-wave and the Tp-e interval from the peak of the T-wave to the end of the T-wave, defined as the point of return to the T-P baseline (22). If U-waves were present, we defined the end of the T-wave as the nadir of the curve between the T and U-waves. We calculated QT and Tp-e intervals for all complete P-QRS-T cycles in each lead and averaged them to give a mean QT interval and Tp-e interval for that lead. QT intervals were corrected according to the formula of Bazett (1), where QTc = QT/{surd}RR. We used Bland-Altman plots to compare the ECG data from the two independent reviewers. Where we found an inter-observer difference of >10 ms in an RR interval or of >20 ms in a QT or Tp-e interval, we reanalyzed the recordings, still coded, and reached a consensus if possible. Thus, for leads II and V5 in each trace, we eventually obtained two values for the mean RR interval, the mean QTc interval and the mean Tp-e interval, one from each independent reviewer. Each pair of values was then averaged to give an overall mean value for use in further statistical analysis.

We performed within-group and between-group comparisons of pre- and intraoperative ECG indices using two-way analysis of variance with a priori Bonferroni correction for multiple pairwise testing. Statistical analysis was conducted with Analyse-It® software (Analyze-It Software, Leeds, England). Using published data (10,23,24), interpretation of an effect in either direction, and the criterion for significance ({alpha}) set at <0.003 (<0.05 before a priori Bonferroni correction), we had calculated that a sample size of 14 per group would detect a difference of 25 ms in Tp-e between the intraoperative means of the three groups with a power of >99%.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We recruited 54 patients to the study. There were no significant demographic differences among the three groups generated by randomization (Table 1). ECG data were unavailable for one child in Group 1.25 MAC.


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  		Table 1. Demographic Characteristics

 

We found very close agreement between the reviewers in measured RR intervals in both leads (lead II mean bias 7 ms; mean error –1.9% to +1.7%; lead V5 mean bias 3 ms; mean error –2.2% to +1.7%). The interobserver bias (95% limits of agreement) for the measurement of QTc was 5 ms (–11 to +22 ms) both in lead II and V5. For the measurement of Tp-e, the values were –4.5 ms (–18.7 to +9.7 ms) in lead II and –3.8 ms (–16.7 to +9.1 ms) in lead V5. These figures mean that, between the reviewers, the difference in measured QTc and Tp-e intervals averaged less than one small ECG square either way.

Table 2 shows the results of the within-group analyses of pre- and intraoperative QTc measurements in groups 1, 1.25, and 1.5 MAC. The QTc interval was normal preoperatively in all three groups, with no significant differences among groups (ANOVA, P = 0.07 and 0.22 for leads II and V5, respectively). Sevoflurane markedly prolonged the QTc in both leads II and V5, in all three groups, by 28–55 ms. After 15 min of sevoflurane anesthesia, the absolute QTc exceeded the upper limit of normal in both leads in all three groups. These differences were statistically significant in all groups. Between-group analysis of the QTc values after sevoflurane confirmed the absence of a dose-response relationship (ANOVA, P = 0.69 and 0.95 for leads II and V5, respectively).


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  		Table 2. Comparison of Preoperative and Intraoperative QTc (ms) within Groups

 

Table 3 shows the results of the within-group analysis of pre- and intraoperative Tp-e measurements in Groups 1, 1.25, and 1.5 MAC. The Tp-e interval was normal preoperatively in all three groups, with no significant differences among the groups (ANOVA, P = 0.68 and 0.85 for leads II and V5, respectively). There were no significant increases in Tp-e in either lead II or V5 after sevoflurane exposure and no dose-response relationship between sevoflurane concentration and Tp-e (ANOVA, P = 0.66 and 0.5 for leads II and V5, respectively).


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  		Table 3. Comparison of Preoperative and Intraoperative Tp-e (ms) within Groups

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The effects on QTc of several commonly used anesthetic drugs have been investigated in healthy adults and children. Sevoflurane, isoflurane, and thiopental have been reported to prolong QTc, but the clinical significance of this has been unclear; it is usually concluded that anesthesiologists should be aware of a potential increased risk of TdP with these drugs. Droperidol has been extensively used in anesthetic practice for many years, and has long been known to prolong the QTc. Controversy over the relabeling of droperidol in the face of seven case reports of TdP, some or all of which may be attributable to other associated risk factors, indicates in very practical terms how an unsatisfactory assay for a rare, but potentially fatal complication can adversely affect the use of a valuable drug with proven efficacy, and supports the need for a better way of predicting drug torsadogenicity. Very few of these previous studies have examined the effect of a single drug in unpremedicated patients and in the absence of confounding adrenergic stimulation from airway manipulation or surgery. None has investigated the effect of anesthetics on TDR. The aim of this study was to rigorously investigate the effect of sevoflurane on QTc, and on Tp-e as a marker of TDR.

Our results indicate that clinically relevant doses of sevoflurane do not exaggerate Tp-e, despite prolonging the QTc. This leads us to suggest that sevoflurane has extremely low torsadogenicity or none at all. This assertion is based on the assumptions that the risk of TdP is directly attributable to increases in TDR, and that Tp-e is a valid and reliable surrogate marker of TDR.

QTc prolongation is a poor predictor of the risk of TdP actually occurring: up to 40% of patients with congenital QT prolongation are asymptomatic at the time of diagnosis (3); not all drugs that are capable of prolonging the QT interval are torsadogenic (4); 6% of patients with symptomatic LQTS, i.e., having episodes of TdP, have a baseline QTc interval that is not absolutely prolonged (5). In arterially perfused canine heart wedge models, it has been demonstrated that QTc prolongation per se does not predispose to TdP, but exaggeration of physiological TDR does (7,9,11). Preclinical drug testing for torsadogenicity includes assessment of the effect of drugs on TDR, although considerable debate continues about the best indices for measuring it (25).

The observation, in the arterially perfused wedge model, that conclusion of epicardial repolarization coincides with the peak of the T-wave and completion of M cell repolarization coincides with the end of the T-wave, led to the proposition of the Tp-e interval as a surface ECG marker of TDR (6). Evidence for the validity of this parameter in clinical practice continues to accumulate. In patients with acquired LQTS, Tp-e was found by logistic regression analysis to be the best predictor of which patients developed TdP (26). Tp-e is prolonged in symptomatic congenital LQTS patients (24). In assessing the risk of arrhythmias in LQT1 and LQT2, Tp-e appears to be a useful index of TDR (27,28). Tp-e is increased in premature neonates receiving the torsadogenic drug cisapride (23).

Our finding that sevoflurane does not prolong Tp-e is consistent with the apparent absence of TdP associated with extensive sevoflurane usage around the world, despite the drug's ability to dramatically prolong QTc. Although a recent case report attributed episodes of intraoperative TdP to the use of sevoflurane (29), several more probable causative factors were present (Whyte SD, Sanatani S, Booker PD. Torsades de points with sevoflurane. Pediatr Anaesth 2006;16:1199–1200). We are unaware of any reports that convincingly attribute an intraoperative or postoperative complication to cardiac repolarization abnormalities after sevoflurane anesthesia in pediatric patients. Interestingly, thiopental, which also prolongs QTc but appears not to be torsadogenic, reduced TDR in an in vivo animal model (30). Conversely, although there are contradictory reports on the ability of halothane to prolong QTc (13–15,31,32), it exaggerates TDR in dogs (33), and was the anesthetic in use in three case reports of perioperative TdP in patients with previously undiagnosed LQTS (34–36). All these observations are compatible with the evolving hypothesis that it is possible to have a prolonged QT interval without exaggerated TDR; the risk of TdP in these instances is very low, whereas increased TDR increases the risk of arrhythmias, even if the absolute QT interval is normal.

Our second finding, that sevoflurane significantly prolongs the QTc, is in keeping with previous studies in adults and children, which have consistently shown a marked propensity for sevoflurane to prolong the QTc (16–20). In addition, we have shown that there is no concentration-response phenomenon in the 1–1.5 MAC range. QT prolongation by sevoflurane is a predictable side effect. In guinea pig cardiac myocytes, sevoflurane inhibits iKr channels, which contribute significantly to the repolarizing current in phase 3 of the cardiac cycle action potential in many species (37). Mutations in iKr channel proteins cause LQTS 2 and 6 in humans (38,39) and most drug-induced LQTS is caused by iKr channel blockade (40). However, sevoflurane had no significant effect on the Tp-e interval in this study, suggesting that it does not increase the risk of TdP, despite its propensity to prolong the QTc. One explanation to account for this discrepancy is that sevoflurane has an equal effect on repolarization in epicardial, endocardial, and M cells, such that there is prolongation in the overall duration of repolarization (reflected in QTc prolongation), but no increase in TDR.

QTc is conventionally measured in lead II. The best lead for measuring Tp-e has not been defined, but it has been suggested that the left precordial lead values may best reflect true TDR (30). We have previously examined interobserver variability in all 12 leads (10) and found it to be least in leads I, II, and V5. Hence, we thought that leads II and V5 were the most appropriate from which to report our results. Xia et al. (41) have reported that maximal Tp-e correlates with TDR in pigs, while Tp-e in leads II and V5 may under-estimate TDR. Conversely, a computer simulation study suggests that Tp-e may over-estimate TDR (42). Further studies of the correlation between TDR and surface ECG T-wave morphology in humans are needed to refine the relationship between TDR and Tp-e.

We used published criteria to define the end of the T-wave (22). U-waves were commonly present in precordial leads, but did not complicate definition of the T-wave end. There are objective criteria for defining the peak of T-waves with complex morphology, but not for normal, monophasic T-waves, whose peaks are typically discrete and readily identified. Nevertheless, the subjective defining of T-wave peak introduces a potential source of inaccuracy in measuring Tp-e.

The normal range (and hence the upper limit of normal) for Tp-e has not been defined. We found a mean Tp-e of 76.0 (sd 11.6) ms in our sample of 53 preoperative ECG traces from healthy children. This is similar to the value of 72.2 (sd 10.9) ms in our pilot study, on which we based our power calculations. Preliminary studies in neonates on cisapride, and in treated LQTS patients, suggest that an increase of 20–35 ms in Tp-e is clinically significant. Our study gave us 99% power to detect a 25 ms difference.

The major limitation in this study is that we did not study children with overt long QT syndrome, which inevitably makes speculative our conclusions regarding the effects of sevoflurane on dispersion of repolarization in such patients. For this reason, we must emphasize caution in the extrapolation of our findings to these patients. Nevertheless, we defend the clinical relevance of our findings, as there is a hidden population of phenotypically normal patients, with subclinical genetic mutations in iKr, iKs, and iNa cardiac ion channels that result in reduced repolarization reserve (43,44); such patients are at risk of unmasking of their genotype when exposed to additional impairment of their repolarization mechanisms, such as pharmacological iKr blockade (45,46).

In conclusion, sevoflurane 1–1.5 MAC non-dose-dependently prolongs the QTc interval in healthy children, but does not appear to exaggerate physiological TDR, as measured by the Tp-e interval. These results suggest that sevoflurane has low or no intrinsic torsadogenicity and does not increase the risk of TdP.


   Footnotes
 
Accepted for publication October 16, 2006.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353–70.[Web of Science]
  2. Davignon A, Rautahaju P, Boiselle E, et al. Normal ECG standards for infants and children. Pediatr Cardiol 1979;1:123–31.[Web of Science]
  3. Ackerman MJ. The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc 1998;73:250–69.[Abstract]
  4. www.torsades.org.
  5. Garson A Jr, Dick M II, Fournier A, et al. The long QT syndrome in children. An international study of 287 patients. Circulation 1993;87:1866–72.[Abstract/Free Full Text]
  6. Yan GX, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation 1998;98:1928–36.[Abstract/Free Full Text]
  7. Shimizu W, Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade des pointes in LQT2 and LQT3 models of the long-QT syndrome. Circulation 1997;96:2038–47.[Abstract/Free Full Text]
  8. Shimizu W, Antzelevitch C. Differential effects of ß-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J Am Coll Cardiol 2000;35:778–86.[Abstract/Free Full Text]
  9. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of ß-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 1998;98:2314–22.[Abstract/Free Full Text]
  10. Whyte SD, Booker PD, Buckley DG. The effects of propofol and sevoflurane on the QT interval and transmural dispersion of repolarization in children. Anesth Analg 2005;100:71–7.[Abstract/Free Full Text]
  11. Antzelevitch C, Shimizu W, Yan GX, Sicouri S. Cellular basis for QT dispersion. J Electrocardiol 1998;30(Suppl):168–75.[Web of Science][Medline]
  12. Antzelevitch C, Shimizu W, Yan GX, et al. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 1999;10:1124–52.[Web of Science][Medline]
  13. Schmeling WT, Warltier DC, McDonald DJ, et al. Prolongation of the QT interval by enflurane, isoflurane, and halothane in humans. Anesth Analg 1991;72:137–44.[Web of Science][Medline]
  14. Michaloudis D, Fraidakis O, Lefaki T, et al. Anaesthesia and the QT interval in humans. The effects of isoflurane and halothane. Anaesthesia 1996;51:219–24.[Web of Science][Medline]
  15. Michaloudis D, Fraidakis O, Lefaki T, Kanakoudis F, Askitopoulou H. Anaesthesia and the QT interval in humans: effects of halothane and isoflurane in premedicated children. Eur J Anaesthesiol 1998;15:623–8.[Web of Science][Medline]
  16. Kuenszberg E, Loeckinger A, Kleinsasser A, et al. Sevoflurane progressively prolongs the QT interval in unpremedicated female adults. Eur J Anaesthesiol 2000;17:662–4.[Web of Science][Medline]
  17. Loeckinger A, Kleinsasser A, Maier S, et al. Sustained prolongation of the QTc interval after anesthesia with sevoflurane in infants during the first 6 months of life. Anesthesiology 2003;98:639–42.[Web of Science][Medline]
  18. Kleinsasser A, Kuenszberg E, Loeckinger A, et al. Sevoflurane, but not propofol, significantly prolongs the Q-T interval. Anesth Analg 2000;90:25–7.[Abstract/Free Full Text]
  19. Kleinsasser A, Loeckinger A, Lindner KH, et al. Reversing sevoflurane-associated Q-Tc prolongation by changing to propofol. Anaesthesia 2001;56:248–50.[Web of Science][Medline]
  20. Gallagher JD, Weindling SN, Anderson G, Fillinger MP. Effects of sevoflurane on QT interval in a patient with congenital long QT syndrome. Anesthesiology 1998;89:1569–73.[Web of Science][Medline]
  21. Nickalls RW, Mapelson WW. Age-related iso-MAC charts for isoflurane, sevoflurane and desflurane in man. Br J Anaesth 2003;91:170–4.[Abstract/Free Full Text]
  22. Lepeschkin E, Surawicz B. The measurement of the Q-T interval of the electrocardiogram. Circulation 1952;6:378–88.[Web of Science][Medline]
  23. Benatar A, Cools F, Decraene T, et al. The T wave as a marker of dispersion of ventricular repolarization in premature infants before and while on treatment with the I(Kr) channel blocker cisapride. Cardiol Young 2002;12:32–6.[Web of Science][Medline]
  24. Lubinski A, Lewicka-Nowak E, Kempa M, et al. New insight into repolarization abnormalities in patients with congenital long QT syndrome: the increased transmural dispersion of repolarization. Pacing Clin Electrophysiol 1998;21:172–5.[Medline]
  25. Lawrence CL, Pollard CE, Hammond TG, Valentin JP. Nonclinical proarrhythmia models: predicting Torsades de Pointes. J Pharmacol Toxicol Methods 2005;52:46–59.[Medline]
  26. Yamaguchi M, Shimizu M, Ino H, et al. T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin Sci (Lond) 2003;105:671–6.[Medline]
  27. Tanabe Y, Inagaki M, Kurita T, et al. Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome. J Am Coll Cardiol 2001;37:911–19.[Abstract/Free Full Text]
  28. Shimizu W, Tanabe Y, Aiba T, et al. Differential effects of ß-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the LQT1 and LQT2 forms of congenital long QT syndrome. J Am Coll Cardiol 2002;39:1984–91.[Abstract/Free Full Text]
  29. 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;16:63–5.[Medline]
  30. Antzelevitch C, Fish J. Electrical heterogeneity within the ventricular wall. Basic Res Cardiol 2001;96:517–27.[Web of Science][Medline]
  31. Gallagher JD. Effects of halothane and quinidine on intracardiac conduction and QTc interval in pentobarbital-anesthetized dogs. Anesth Analg 1992;75:688–95.[Abstract/Free Full Text]
  32. Lindgren L. ECG changes during halothane and enflurane anaesthesia for ENT surgery in children. Br J Anaesth 1981;53:653–62.[Abstract/Free Full Text]
  33. Weissenburger J, Nesterenko VV, Antzelevitch C. Transmural heterogeneity of ventricular repolarization under baseline and long QT conditions in the canine heart in vivo: torsades de pointes develops with halothane but not pentobarbital anesthesia. J Cardiovasc Electrophysiol 2000;11:290–304.[Web of Science][Medline]
  34. Adu-Gyamfi Y, Said A, Chowdhary UM, et al. Anaesthetic-induced ventricular tachyarrhythmia in Jervell and Lange- Nielsen syndrome. Can J Anaesth 1991;38:345–6.[Web of Science][Medline]
  35. Holland JJ. Cardiac arrest under anaesthesia in a child with previously undiagnosed Jervell and Lange-Nielsen syndrome. Anaesthesia 1993;48:149–51.[Web of Science][Medline]
  36. Wig J, Bali IM, Singh RG, et al. Prolonged Q-T interval syndrome. Sudden cardiac arrest during anaesthesia. Anaesthesia 1979;34:37–40.[Web of Science][Medline]
  37. 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.[Web of Science][Medline]
  38. Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795–803.[Web of Science][Medline]
  39. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175–87.[Web of Science][Medline]
  40. Escande D. Pharmacogenetics of cardiac K(+) channels. Eur J Pharmacol 2000;410:281–7.[Web of Science][Medline]
  41. Xia Y, Liang Y, Kongstad O, et al. T(peak)-T(end) interval as an index of global dispersion of ventricular repolarization: evaluations using monophasic action potential mapping of the epi- and endocardium in swine. J Interv Card Electrophysiol 2005;14:79–87.[Web of Science][Medline]
  42. Van Huysduynen BH, Swenne CA, Draisma HH, et al. Validation of ECG indices of ventricular repolarization heterogeneity: a computer simulation study. J Cardiovasc Electrophysiol 2005;16:1097–103.[Web of Science][Medline]
  43. Chevalier P, Rodriguez C, Bontemps L, et al. Non-invasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates. Cardiovasc Res 2001;50:386–98.[Abstract/Free Full Text]
  44. Yang P, Kanki H, Drolet B, et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002;105:1943–8.[Abstract/Free Full Text]
  45. Kannankeril PJ, Roden DM, Norris KJ, et al. Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives. Heart Rhythm 2005;2:134–40.[Web of Science][Medline]
  46. Aiba T, Shimizu W, Inagaki M, et al. Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil. J Am Coll Cardiol 2005;45:300–7.[Abstract/Free Full Text]



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