Long QT Syndrome and Perioperative Torsades de Pointes: What the Anesthesiologist Should Know

TORSADES DE pointes (TdP or "twisting of the points") is a rare but potentially fatal polymorphic ventricular tachycardia characterized by rapid, wide QRS complexes of gradually varying amplitude that appear to "twist" around the isoelectric baseline on the electrocardiogram (ECG) (Fig. 1). Although TdP frequently terminates spontaneously, it has the potential to degenerate into ventricular fibrillation and lead to cardiac arrest. Due to the transient nature of TdP, its incidence is largely unknown, but it has been reported to occur with a frequency of anywhere from 0.004% to 0.343% per year.1Saraganas G. Garbe E. Kimpel A. et al.Epidemiology of symptomatic drug-induced long QT syndrome and Torsade de Pointes in Germany.Europace. 2014; 16: 101-108Crossref PubMed Scopus (0) Google Scholar, 2Molokhia M. Pathak A. Lapeyre-Mestre M. et al.Case ascertainment and estimated incidence of drug-induced long-QT syndrome: Study in Southwest France.Br J Clin Pharmacol. 2008; 66: 386-395Crossref PubMed Scopus (43) Google Scholar, 3Vandael E. Vandenberk B. Vandenberghe J. et al.Incidence of Torsade de Pointes in a tertiary hospital population.Int J Cardiol. 2017; 243: 511-515Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar It is widely accepted that TdP is associated with lengthening of the corrected QT interval (QTc). QTc prolongation may be congenital (ie, inherited channelopathies) or acquired as in the setting of drug administration, electrolyte disturbances, hypothermia, cardiac disease, cerebrovascular injury, thyroid dysfunction, and other factors. The perioperative period is a unique time frame during which patients are exposed to a number of factors that are known to induce QTc prolongation. Surgical stress can trigger proinflammatory responses, fluid shifts, and electrolyte abnormalities, as well as myocardial injury. In addition, the patient is exposed to a number of drugs, including anesthetics, many of which may cause QTc prolongation. In one study, roughly 80% of patients undergoing noncardiac surgery under general anesthesia developed postoperative QTc prolongation.4Nagele P. Pal S. Brown F. et al.Postoperative QT interval prolongation in patients undergoing noncardiac surgery under general anesthesia.Anesthesiology. 2012; 117: 321-328Crossref PubMed Scopus (47) Google Scholar It is, therefore, critical that anesthesia providers understand the factors that contribute to this potentially fatal arrhythmia and its specific treatment strategies. In this review, the authors present the current knowledge of perioperative TdP, as well as its known mechanisms and risk factors, including an overview of the numerous medications commonly used in the perioperative period. The cardiac conduction system is comprised of specialized "pacemaker" cells that spontaneously generate electric activity and conduction pathways that propagate it throughout the heart in a coordinated fashion, generating action potentials (APs) in individual cardiac myocytes.5Amin A.S. Tan H.L. Wilde A.A. Cardiac ion channels in health and disease.Heart Rhythm. 2010; 7: 117-126Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar The AP relies on a number of ion channels within the sarcolemma and is divided into five phases—Phase 0 to Phase 4 (Fig. 2). Phase 0 (rapid depolarization), corresponding to the start of systole, is triggered by the depolarization of neighboring cells via current leakage through gap junctions. Once a threshold potential is reached, the cardiac myocyte rapidly depolarizes due to an influx of sodium (INa) via fast, time-dependent sodium channels.6Schmitt N. Grunnet M. Olesen S.P. Cardiac potassium channel subtypes: New roles in repolarization and arrhythmia.Physiol Rev. 2014; 94: 609-653Crossref PubMed Scopus (137) Google Scholar This depolarization initiates the opening of a long-opening (L-type) calcium channel, allowing calcium to begin to flow into the cell.6Schmitt N. Grunnet M. Olesen S.P. Cardiac potassium channel subtypes: New roles in repolarization and arrhythmia.Physiol Rev. 2014; 94: 609-653Crossref PubMed Scopus (137) Google Scholar Phase 1 is the transient repolarization phase. This brief repolarization is associated with inactivation of the sodium channels and activation of transient outward potassium current, IKto.6Schmitt N. Grunnet M. Olesen S.P. Cardiac potassium channel subtypes: New roles in repolarization and arrhythmia.Physiol Rev. 2014; 94: 609-653Crossref PubMed Scopus (137) Google Scholar Phase 2 (plateau phase) is characterized by a constant, small inward current of calcium (ICa,L) that is electrically balanced by an outward potassium current through three delayed rectifier potassium channels (IKur, IKr, and IKs).5Amin A.S. Tan H.L. Wilde A.A. Cardiac ion channels in health and disease.Heart Rhythm. 2010; 7: 117-126Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar,6Schmitt N. Grunnet M. Olesen S.P. Cardiac potassium channel subtypes: New roles in repolarization and arrhythmia.Physiol Rev. 2014; 94: 609-653Crossref PubMed Scopus (137) Google Scholar It is during this phase that excitation-contraction coupling occurs. Repolarization occurs in Phase 3 wherein calcium channels are inactivated and increased conductance of rapid potassium current (IKr) completes repolarization, together with contributions from slow potassium current (IKs) and inward rectifying current (IK1).5Amin A.S. Tan H.L. Wilde A.A. Cardiac ion channels in health and disease.Heart Rhythm. 2010; 7: 117-126Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar,6Schmitt N. Grunnet M. Olesen S.P. Cardiac potassium channel subtypes: New roles in repolarization and arrhythmia.Physiol Rev. 2014; 94: 609-653Crossref PubMed Scopus (137) Google Scholar When there is a decrease in the outward potassium current or an increase in the inward calcium or sodium currents during this phase, QT prolongation may occur. Finally, Phase 4 represents the cell's resting potential.6Schmitt N. Grunnet M. Olesen S.P. Cardiac potassium channel subtypes: New roles in repolarization and arrhythmia.Physiol Rev. 2014; 94: 609-653Crossref PubMed Scopus (137) Google Scholar Quantitative or qualitative defects in ion channels lead to the generation of abnormal APs and have the potential to result in arrhythmias.5Amin A.S. Tan H.L. Wilde A.A. Cardiac ion channels in health and disease.Heart Rhythm. 2010; 7: 117-126Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar TdP has been associated with the occurrence of delayed repolarization with early afterdepolarization, delayed afterdepolarization, and functional re-entry in the setting of unidirectional conduction block and increased transmural dispersion of repolarization (TDR, a measure of the intrinsic electrical heterogeneity of the ventricular myocardium).7Surawicz B. 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This increase in cytosolic calcium level then translates into new sodium inward current via calcium-sodium exchanger for afterdepolarization,14Neira V. Enriquez A. Simpson C. et al.Update on long QT syndrome.J Cardiovasc Electrophysiol. 2019; 30: 3068-3078Crossref PubMed Scopus (0) Google Scholar which leads to the generation of a premature ventricular complex. On ECG, the QT interval represents the sum of ventricular depolarization and repolarization.15Locati E.T. Bagliani G. Padeletti L. Normal ventricular repolarization and QT interval: Ionic background, modifiers, and measurements.Card Electrophysiol Clin. 2017; 9: 487-513Abstract Full Text Full Text PDF PubMed Google Scholar It is measured from the start of the earliest Q wave to the end of the latest in the lead showing the longest interval16Lepeschkin E. Surawicz B. The measurement of the Q-T interval of the electrocardiogram.Circulation. 1952; 6: 378-388Crossref PubMed Google Scholar (Fig. 3). Although some authors recommend that the measurement should include large, fused U waves (when present), the most recent American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society (AHA/ACCF/HRS) Recommendations for the Standardization and Interpretation of the Electrocardiogram recommend that when fused U waves are present, the QT interval should be measured in a lead without U waves or that the end of the T wave should be determined by drawing a tangent to the steepest proportion of the downslope until it crosses the TP segment17Goldenberg I. Moss A.J. Zareba W. QT interval: How to measure it and what is "normal".J Cardiovasc Electrophysiol. 2006; 17: 333-336Crossref PubMed Scopus (360) Google Scholar,18Rautaharju P.M. Surawicz B. Gettes L.S. et al.AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: The ST segment, T and U waves, and the QT interval: A scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: Endorsed by the International Society for Computerized Electrocardiology.Circulation. 2009; 119: e241-e250Crossref PubMed Scopus (253) Google Scholar (Fig. 3). The QT interval is inversely proportional to heart rate, and as such is often corrected to a standardized heart rate of 60 beats/min in order to improve diagnostic utility. The most common method of calculating QTc is the Bazett formula19Bazett H.C. An analysis of the time-relations of electrocardiograms.Heart. 1920; 7: 353-370Google Scholar:QTc=QT/(RR)1/2where QT is the measured QT interval and RR is the RR interval. Other formulae for calculation for QTc are listed in Table 1. What constitutes a normal QT value depends on both age and sex.20Alimurung M.M. Joseph L.G. Craige E. et al.The Q-T interval in normal infants and children.Circulation. 1950; 1: 1329-1337Crossref PubMed Scopus (0) Google Scholar,21Mason J.W. Ramseth D.J. Chanter D.O. et al.Electrocardiographic reference ranges derived from 79,743 ambulatory subjects.J Electrocardiol. 2007; 40: 228-234Crossref PubMed Scopus (213) Google Scholar According to the AHA/ACCF/HRS recommendations, QTc prolongation is defined as ≥450 ms in men, and ≥460 ms in women.18Rautaharju P.M. Surawicz B. Gettes L.S. et al.AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: The ST segment, T and U waves, and the QT interval: A scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: Endorsed by the International Society for Computerized Electrocardiology.Circulation. 2009; 119: e241-e250Crossref PubMed Scopus (253) Google Scholar A QTc greater than 470 ms generally is considered to be prolonged regardless of age and sex; however, in an otherwise asymptomatic individual without any family history, QTc >500 ms is needed to demonstrate a meaningful predictability of Long QT Syndrome (LQTS). Normal QTc values are depicted in Table 2.Table 1Formula for QTc CalculationNameFormulaBazett FormulaQTc = QT/(RR)1/2Fredericia FormulaQTc = QT/(RR)1/3Framingham FormulaQTc = QT+0.154(1-RR)Hodges FormulaQTc = QT+1.75(heart rate-60)Rautaharju FormulaQTc = QT−0.185(RR−1)+k(k = +0.006 for men and +0 for women)Abbreviations: QTc, corrected QT interval; RR, . Open table in a new tab Table 2Normal QTc ValuesQTc (ms)1-12 yWomen (>12 y)Men (>12 y)Short<390<390Normal390-460390-450Prolonged≧450≧460≧450Abbreviation: QTc, corrected QT interval. Open table in a new tab Abbreviations: QTc, corrected QT interval; RR, . Abbreviation: QTc, corrected QT interval. Although QT prolongation is a risk factor for TdP, the QT interval is not its sole electrophysiologic marker of risk.22Zareba W. Moss A.J. Schwartz P.J. et al.Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group.N Engl J Med. 1998; 339: 960-965Crossref PubMed Scopus (639) Google Scholar, 23Moss A.J. Measurement of the QT interval and the risk associated with QTc interval prolongation: A review.Am J Cardiol. 1993; 72: 23B-25BAbstract Full Text PDF PubMed Scopus (403) Google Scholar, 24Malfatto G. Beria G. Sala S. et al.Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome.J Am Coll Cardiol. 1994; 23: 296-301Crossref PubMed Scopus (149) Google Scholar, 25Topilski I. Rogowski O. Rosso R. et al.The morphology of the QT interval predicts torsade de pointes during acquired bradyarrhythmias.J Am Coll Cardiol. 2007; 49: 320-328Crossref PubMed Scopus (166) Google Scholar In fact, in studies of drug-induced QT prolongation, QT prolongation in the absence of increased TDR has been shown not to provoke TdP.13Antzelevitch C. Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes.Heart Rhythm. 2005; 2: S9-15Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,26Shimizu 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: 2038-2047Crossref PubMed Google Scholar, 27Shimizu W. Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: Effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes.Circulation. 1998; 98: 2314-2322Crossref PubMed Scopus (448) Google Scholar, 28Shimizu W. Antzelevitch C. Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome.J Am Coll Cardiol. 2000; 35: 778-786Crossref PubMed Scopus (340) Google Scholar On ECG, the morphology of the T wave is representative of the intrinsic differential time course of regional repolarization (ie, TDR) across the myocardium.10Yan G.X. Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome.Circulation. 1998; 98: 1928-1936Crossref PubMed Google Scholar TDR can be measured as the interval from the peak of the T wave to the end of the T wave (TPE) (Fig. 3).26Shimizu 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: 2038-2047Crossref PubMed Google Scholar, 27Shimizu W. Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: Effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes.Circulation. 1998; 98: 2314-2322Crossref PubMed Scopus (448) Google Scholar, 28Shimizu W. Antzelevitch C. Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome.J Am Coll Cardiol. 2000; 35: 778-786Crossref PubMed Scopus (340) Google Scholar Patients with LQTS have been found to have abnormal T-wave morphology (eg, biphasic or notched T waves, T wave alternans, U waves) as well as greater median and maximum TPE, indicating abnormal TDR.29Viitasalo M. Oikarinen L. Väänänen H. et al.Differentiation between LQT1 and LQT2 patients and unaffected subjects using 24-hour electrocardiographic recordings.Am J Cardiol. 2002; 89: 679-685Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 30Viitasalo M. Oikarinen L. Swan H. et al.Ambulatory electrocardiographic evidence of transmural dispersion of repolarization in patients with long-QT syndrome type 1 and 2.Circulation. 2002; 106: 2473-2478Crossref PubMed Scopus (0) Google Scholar, 31Porta-Sánchez A. Spillane D.R. Harris L. et al.T-wave morphology analysis in congenital long QT syndrome discriminates patients from healthy individuals.JACC Clin Electrophysiol. 2017; 3: 374-381Crossref PubMed Scopus (16) Google Scholar The cut-off value of TPE associated with increased arrhythmogenicity has yet to be conclusively defined. A meta-analysis by Tse et al. concluded that the cut-off point of TPE prolongation for a significant elevation in arrhythmic risk in the general population is 113.6 ms, with lower values in certain disease states such as Brugada syndrome (95.8 ms) or heart failure (106.3 ms), but cautioned that the TPE alone should not be used to estimate arrhythmia risk.32Tse G. Gong M. Wong W.T. et al.The Tpeak - Tend interval as an electrocardiographic risk marker of arrhythmic and mortality outcomes: A systematic review and meta-analysis.Heart Rhythm. 2017; 14: 1131-1137Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar QTc is automatically calculated in some of the currently available intraoperative monitoring devices, and TPE is not. Availability of automatic TPE calculation might be helpful as an adjunct to intraoperative monitoring. In patients with a prolonged QRS interval (QRS ≧120 ms), the JT interval (QTc – QRS) (Fig. 3) may be more indicative of a mortality risk than the QTc interval. Zulqarnain et al. (Third National Health and Nutrition Examination Survey) demonstrated that a prolonged JT interval (>362 ms) was a stronger risk factor for all-cause mortality than a prolonged QT interval in patients with QRS≧120 ms; however, Crow et al. (Atherosclerosis Risk In Communities Study) found this only to be true in men.33Zulqarnain M.A. Qureshi W.T. O'Neal W.T. et al.Risk of mortality associated with QT and JT intervals at different levels of QRS duration (from the Third National Health and Nutrition Examination Survey).Am J Cardiol. 2015; 116: 74-78Abstract Full Text Full Text PDF PubMed Google Scholar,34Crow R.S. Hannan P.J. Folsom A.R. Prognostic significance of corrected QT and corrected JT interval for incident coronary heart disease in a general population sample stratified by presence or absence of wide QRS complex: The ARIC Study with 13 years of follow-up.Circulation. 2003; 108: 1985-1989Crossref PubMed Scopus (125) Google Scholar The AHA/ACCF/HRS guidelines make no specific recommendations of the use of JT interval over QTc interval, but note that if used, normal standards specific to the JT interval should be used.18Rautaharju P.M. Surawicz B. Gettes L.S. et al.AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: The ST segment, T and U waves, and the QT interval: A scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: Endorsed by the International Society for Computerized Electrocardiology.Circulation. 2009; 119: e241-e250Crossref PubMed Scopus (253) Google Scholar In 1957, Anton Jervell and Fred Lang-Nielsen described a syndrome in four siblings consisting of prolonged QT interval, congenital deafness, functional heart disease, and sudden death.35Jervell A. Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death.Am Heart J. 1957; 54: 59-68Crossref PubMed Google Scholar Since that time, several other named syndromes (Romano-Ward, Timothy, Andersen-Tawil) involving QT prolongation have been described and enormous strides have been made in the understanding of the genetics and molecular biology underpinning inherited channelopathies. LQTS is the most common genetic arrhythmogenic disease , with an estimated prevalence of 1/2,000.36Schwartz P.J. Stramba-Badiale M. Crotti L. et al.Prevalence of the congenital long-QT syndrome.Circulation. 2009; 120: 1761-1767Crossref PubMed Scopus (625) Google Scholar To date, 17 LQTS susceptibility genes have been identified with varying levels of evidence to support disease causation37Adler A. Novelli V. Amin A.S. et al.An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome.Circulation. 2020; 141: 418-428Crossref PubMed Scopus (72) Google Scholar (Table 3). LQTS1, LQTS2, and LQTS3 are the common genotypes of LQTS, accounting for 40%-55%, 30%-45%, and 5%-10% of LQTS, respectively.38Schwartz P.J. Crotti L. Insolia R. Long-QT syndrome: From genetics to management.Circ Electrophysiol. 2012; PubMed Scopus Google Scholar LQTS may lead to cardiac or sudden The mortality of LQTS is to per due to fatal In patients with symptomatic LQTS, there is a mortality rate within one and within P.J. long QT syndrome: and Heart J. PubMed Scopus Google S. et statement on the of genetic for the and This was developed as a between the Heart Rhythm Society and the Heart Rhythm Association PubMed Scopus Google Scholar patients with the most common on LQTS in the have with estimated cardiac and mortality of and A. et in patients with long QT syndrome.J Am Coll Cardiol. 2017; PubMed Scopus Google Scholar Patients with including the Jervell and Lange-Nielsen Syndrome and Syndrome to be to and a risk of P.J. Crotti L. Insolia R. Long-QT syndrome: From genetics to management.Circ Electrophysiol. 2012; PubMed Scopus Google of a and T are often triggered by to have cardiac in can cause or notched T wave that is and are often triggered by (eg, an from or of to have risk of cardiac in of delayed T Cardiac to occur in and be more Cardiac are associated with (eg, at and during to wide of (ie, polymorphic ventricular conduction dysfunction, and can cause syndrome. may lead the to as syndrome. by ventricular and susceptibility to ventricular in A. P. Clinical and genetic of long QT Cardiol. 2007; PubMed Scopus (0) Google risk of sudden cardiac with as characterized by cardiac including and prolonged A. P. Clinical and genetic of long QT Cardiol. 2007; PubMed Scopus (0) Google the of sodium channel to A. P. Clinical and genetic of long QT Cardiol. 2007; PubMed Scopus (0) Google with QTc ms, and A. P. Clinical and genetic of long QT Cardiol. 2007; PubMed Scopus (0) Google drug-induced long QT ECG, LQTS, Long QT Open table in a new tab Abbreviations: drug-induced long QT ECG, LQTS, Long QT According to the Heart Rhythm Heart Rhythm Society statement on the and of patients with inherited arrhythmia LQTS is in the presence of a LQTS risk in the absence of a secondary cause for QT prolongation in the presence of an in one of the LQTS genes or in the presence of a corrected QT interval for heart rate using ms in and in the absence of a secondary cause for QT A. et in patients with long QT syndrome.J Am Coll Cardiol. 2017; PubMed Scopus Google Scholar In a patient with and without a secondary cause for QT prolongation or a LQTS can be in the presence of a QTc between and ms in Wilde A.A. M. et statement on the and of patients with inherited arrhythmia PubMed Google Scholar The Schwartz (Table is a of diagnostic that is widely used to estimate the of P.J. Crotti L. QTc during and genetic for the long-QT syndrome.Circulation. PubMed Scopus Google Scholar This system family history, clinical history, and electrocardiographic into is as point = of LQTS, = of LQTS, = of P.J. Crotti L. QTc during and genetic for the long-QT syndrome.Circulation. PubMed Scopus Google Scholar of TDR (eg, TPE, JT interval, and QRS are not in this as it the of the the of TDR on risk Risk QTc QTc QTc ms in QTc ms in of from Torsade de pointes from T-wave in 3 T-wave for Congenital with sudden in a family LQTS, Long QT QTc, corrected QT interval. Open table in a new tab Abbreviations: LQTS, Long QT QTc, corrected QT interval. is by a of channel, that causes a decrease in outward potassium current during Phase