Occurrence Of Torsade De Pointes Research Articles

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit

Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. ClinicalTrials.gov Identifier: NCT01211522.

Chloroquine and hydroxychloroquine provoke arrhythmias at concentrations higher than those clinically used to treat COVID-19: A simulation study.

The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID‐19), but the reported number of life‐threatening arrhythmic events or deaths is relatively small. The objective of this study was to assess the arrhythmogenic risk of these two drugs using a multiscale heart simulation, which allows testing even at high concentrations, including those that cause fatal arrhythmias. We measured the inhibitory action of CQ, HCQ, and HCQ with 30 μM azithromycin (AZ) on six ion currents (fast [INa] and late [INa,L] components of the sodium current, L‐type calcium current [ICa,L], rapid [IKr/hERG], and slow [IKs] components of delayed rectifier potassium, and inward rectifier potassium [IK1]) over a wide range of concentrations using the automated patch‐clamp system. Using the concentration–inhibition relationship that was thus obtained, we simulated the drug effects while increasing the concentration until the life‐threatening arrhythmia, torsade de pointes (TdP), was observed. The obtained threshold concentrations for TdP were 12.5, 35, and 22.5 μM for CQ, HCQ, and HCQ with AZ, respectively. Adding therapeutic concentrations of mexiletine or verapamil successfully prevented the occurrence of TdP, and verapamil was more effective. CQ, HCQ, and HCQ with AZ thresholds for TdP were larger than both antiviral concentrations that were reported by in vitro experiments and free plasma concentrations that were attained by the clinically used dosage. The current simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Despite the potent in vitro antiviral effect, clinical trials have failed to show the therapeutic effects of chloroquine (CQ) and hydroxychloroquine (HCQ)/azithromycin (AZ) to treat coronavirus disease 2019. Torsadogenic potentials may limit the dosage of these drugs, but the reported incidence of fatal arrhythmias is rare. WHAT QUESTION DID THIS STUDY ADDRESS? Our objective was to assess the arrhythmogenicity of CQ and HCQ/AZ over a wide range of drug concentrations using a multiscale heart simulation. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study showed that CQ and HCQ/AZ do not induce fatal arrhythmias even at concentrations much higher than in vitro antiviral half‐maximal effective concentration (EC50) values at which QT prolongation exceeds 150 ms. We also found that estimated free plasma concentrations of CQ and HCQ/AZ achieved by currently used dosing protocols are lower than the antiviral EC50 for these drugs. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Our simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ.

Dexmedetomidine reduces ventricular arrhythmias in a model of drug-induced QT-prolongation

Abstract Background Dexmedetomidine is increasingly employed for conscious sedation during electrophysiological procedures. Recent experimental data have suggested direct effects of dexmedetomidine on cardiac electrophysiology. The aim of the present study was to assess the effects of dexmedetomidin on drug-induced QT-prolongation. Methods and results In 12 isolated rabbit hearts the macrolide antibiotic erythromycin (300μM) was infused as a potent Ikr blocker after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant prolongation of QT-interval (+25ms, p<0.05) accompanied by a moderate increase of action potential duration (APD, +5ms, p=ns) after infusion of erythromycin as compared with baseline. Effective refractory period (ERP) was also elevated (+33ms, p<0.05). Erythromycin (+26ms, p<0.05) also significantly increased spatial dispersion of repolarisation. Additional infusion of dexmedetomidine (3μM) resulted in a rather stable QT-interval (+7ms, p=ns) and APD (+7ms, p=ns) as compared with sole erythromycin treatment. Of note, a significant decrease of spatial dispersion (−24ms, p<0.05) was observed while ERP was moderately increased (+13ms, p=ns). Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) and drug induced proarrhythmia with torsade de pointes in 6 of 12 erythromycin-treated hearts (40 episodes). Additional infusion of dexmedetomidine reduced the occurrence of torsade de pointes (4 of 12 hearts, 9 episodes). Conclusion Infusion of dexmedetomidine resulted in a reduction of spatial dispersion of repolarization in the presence of a prolonged repolarization period. This resulted in a reduction of torsade de pointes with dexmedetomidine. Furthermore, an increase of ventricular refractory periods reduced inducibility of ventricular arrhythmias. Thus, in an experimental setting dexmedetomidine shows significant antiarrhythmic effects, which may influence electrophysiologic findings during clinical electrophysiologic studies. This needs to be studied in the clinical setting. Funding Acknowledgement Type of funding source: None

Drug use and torsades de pointes cardiac arrhythmias in Sweden: a nationwide register-based cohort study

ObjectiveTo study the occurrence of torsades de pointes (TdP) ventricular tachycardia in relation to use of drugs labelled with TdP risk, using two nationwide Swedish registers.DesignProspective register-based cohort study.SettingEntire Sweden.ParticipantsPersons...

QTc Prolongation Associated With Psychiatric Medications: A Retrospective Cross-Sectional Study of Adult Inpatients.

The aim of our study was to assess the impact of psychiatric medications and concomitant risk factors on the prevalence of QTc prolongation and torsades de pointes (TdP) in hospitalized subjects. We examined the association between individual risk scores and QTc prolongation and proposed an evidence-based protocol for electrocardiogram monitoring on psychotropic medications. Electrocardiograms (ECGs) of subjects hospitalized over a 1-year period were analyzed for QTc prolongation, associated risk factors, and use of medications. Analysis was performed using logistic regression to identify independent predictors of QTc prolongation, and the Pearson χ test was used for risk score assessment. A total of 1249 ECGs of 517 subjects were included in this study. Eighty-seven subjects had QTcB intervals greater than 470 milliseconds for females and greater than 450 milliseconds for males. Twelve (2.3%) subjects had QTcB of 500 milliseconds or greater, or greater than 60 milliseconds of change from baseline. Of these subjects, only 1 case of QTc interval change was related to routine use of psychiatric medications. There were no incidents of TdP. Age, diabetes, hypokalemia, overdose, diphenhydramine, and haloperidol were significant independent predictors of QTc prolongation. Risk scores were significantly correlated with QTc prolongation (P = 0.001). Our retrospective review study found that the occurrence of TdP and QTc prolongation was low in this subject population. QT abnormalities were associated with known risk factors, and risk scores correlated well with QTc prolongation. Providers can use the protocol proposed in this study, which incorporates risk scores and the CredibleMeds classification system to determine the need for ECG monitoring and to guide treatment.

Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin

Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at ×10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical “safe space” for post-approval risk management to identify high-risk clinical scenarios.

PK/PD Modelling of the QT Interval: a Step Towards Defining the Translational Relationship Between In Vitro, Awake Beagle Dogs, and Humans.

Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.

Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms.

Drug-induced ventricular tachyarrhythmias can be caused by cardiovascular drugs, noncardiovascular drugs, and even nonprescription agents. They can result in arrhythmic emergencies and sudden cardiac death. If a new arrhythmia or aggravation of an existing arrhythmia develops during therapy with a drug at a concentration usually considered not to be toxic, the situation can be defined as proarrhythmia. Various cardiovascular and noncardiovascular drugs can increase the occurrence of polymorphic ventricular tachycardia of the 'torsade de pointes' type. Antiarrhythmic drugs, antimicrobial agents, and antipsychotic and antidepressant drugs are the most important groups. Age, female sex, and structural heart disease are important risk factors for the occurrence of torsade de pointes. Genetic predisposition and individual pharmacodynamic and pharmacokinetic sensitivity also have important roles in the generation of arrhythmias. An increase in spatial or temporal dispersion of repolarization and a triangular action-potential configuration have been identified as crucial predictors of proarrhythmia in experimental models. These studies emphasized that sole consideration of the QT interval is not sufficient to assess the proarrhythmic risk. In this Review, we focus on important triggers of proarrhythmia and the underlying electrophysiological mechanisms that can enhance or prevent the development of torsade de pointes.

The correlation between prolonged corrected QT interval with the frequency of respiratory arrest, endotracheal intubation, and mortality in acute methadone overdose.

Corrected QT interval (QTc) prolongation is long considered as a predisposing factor for the occurrence of torsade de pointes (TdP) and sudden cardiac arrest in methadone maintenance treatment. We aimed to elucidate the correlation between QTc prolongation and in-hospital death, respiratory arrest, and endotracheal intubation in acute methadone-intoxicated patients presenting to the emergency department and to assess the value of QTc in predicting these outcomes. A prospective cross-sectional study with a convenience sample of patients with acute methadone overdose was done. Participants were 152 patients aged 15-65 with negative urinary dipstick test for cyclic antidepressants, no history of other QTc-prolonging conditions and co-ingestions, no severe comorbidities affecting the outcomes, and positive urinary dipstick results for methadone. QTc intervals were measured and calculated in triage-time electrocardiogram (ECG). Death was correlated with QTc (P=0.014) and length of ICU admission (P<0.001). In multivariable analysis, death was independently associated only with length of ICU admission [odds ratio (OR) 95% confidence intervals (95% CI) 1.36 (1.14-1.61)]. Intubation and respiratory arrest were independently associated with QTc interval [OR (95% CI) 1.03 (1.02-1.04) and 1.02 (1.01-1.03), respectively]. The receiver operating characteristics curves drawn to show the ability of QTc to predict death, intubation, and respiratory arrest showed thresholds of 470, 447.5, and 450ms with sensitivity (95% CI) and specificity (95% CI) of 87.5 (47.3-99.7), 86.8 (74.7-94.5), and 77.3 (62.2-88.5), respectively. Our study showed that QTc is a potential predictor for adverse outcomes related to acute methadone intoxication. The correlations shown in this study between triage-time QTc and in-hospital respiratory arrest or intubation in methadone overdose may be of clinical value, whether these outcomes are hypothesized to be a reflection of background TdP or intoxication severity.

QT prolongation and torsades de pointes during emergency treatment with nifekalant for refractory ventricular tachyarrhythmias: Post-hoc analysis from a large-scale multicenter post-marketing survey in Japan

BackgroundNifekalant, a first-line drug for the treatment of ventricular tachycardia/ventricular fibrillation (VT/VF) in Japan, has been known to prolong the QT interval; however, the incidence of excess QT/QTc prolongation and subsequent torsades de pointes (TdP) has not yet been reported. MethodsThe QT/QTc interval and occurrence of TdP during nifekalant therapy were evaluated in 1402 emergency patients with VT/VF. ResultsThirty-five cases (2.5%) of QT/QTc prolongation and 54 cases (3.9%) of TdP were reported. High nifekalant doses and long QTc intervals were associated with frequent TdP. The incidence of TdP was 1.4% for QTc intervals <0.43, 3.9% for those 0.44–0.49, 5.3% for those 0.50–0.55, 7.3% for those 0.56–0.61, 11.1% for those 0.62–0.67, and 12.5% for those ≥0.68. The odds ratio for TdP was elevated in women (2.48); in patients with any heart disease (4.68), New York Heart Association (NYHA) III or IV (1.81), Forrester subset 2 or worse (2.13), depressed cardiac function (1.86), or liver dysfunction (2.06); and in patients who were receiving concomitant drugs (2.67). In 42 patients (77.8%), TdP required treatment with direct current shock or a second drug. ConclusionNifekalant was effective for refractory VT/VF, although careful observation of the QT/QTc interval and possible occurrence of TdP is required, especially in high-risk patients.

Risk Factors Need to Be Considered

No information is provided by merely listing the occurrence of QT prolongation for different drugs without considering known risk factors, because in this way it is not possible to distinguish between the effects of either. The authors correctly state that QT prolongation is almost always affected by risk factors such as hypokalemia (30%) or hypomagnesemia. But these electrolyte imbalances still do not receive anywhere near enough attention. Magnesium, the second most common intracellular cation after potassium, is not usually included in the electrolyte status. Potassium deficiency, however, almost always goes hand in hand with magnesium deficiency and can be balanced only by administering magnesium simultaneously. In conclusion: if the intention is to administer drugs with repolarizing or depolarizing effects, for example in potential QT prolongation, any existing hypokalemia and hypomagnesemia needs to be treated first. In acute cases, magnesium sulfate should be administered intravenously, in all other cases, oral administration of magnesium aspartate will suffice. What remains of interest subsequently is only the occurrence of Torsade de pointes in patients with balanced electrolytes, but this has to be investigated when testing a drug.

KCNH2 Channel Activators Increase Ikr in Hl-1 Cardiomyocytes and May Prevent the Occurrence of Torsades De Pointes in Long QT Syndrome

Introduction: Several KCNH2 channel activators may provide a novel pharmacological approach for the treatment of long QT syndrome (LQTS). We therefore investigated the effects of the activators on IKr and action potential of cardiac myocytes.Methods: We characterized the actions of three KCNH2 channel activators, mallotoxin (MTX), PD-118057 (PD), and NS1643 (NS) on IKr of HL-1 cardiomyocytes, using the whole cell patch clamp technique. With a mathematical model of human ventricular myocytes, we further evaluated the impact of activator-induced changes in IKr kinetics on the action potential configuration in normal and LQTS.Results: The maximum tail currents of IKr were 23.4±3.5 nA/pF with 10 μM MTX (n=12), 22.1±2.7 nA/pF with 10 μM PD (n=13), and 23.3±2.7 nA/pF with 10 μM NS (n=16), which were significantly greater than 12.8±1.0 nA/pF in control (n=38). The half-maximal activation voltage was significantly shifted from −1.8±2.7 (n=38) to −13.0±2.3 (n=11), −8.3±2.1 (n=13), and −14.7±3.2 (n=14) mV by MTX, PD, and NS, respectively. Deactivation during the repolarization to −40 mV was significantly slowed by MTX, but not by PD or NS. The half-maximal inactivation voltage was significantly shifted from −6.6±2.2 (n=28) to −29.9±2.9 (n=15) mV by MTX, but not by PD, and NS. Simulation study showed that the activator-induced changes of IKr increased the amplitude of IKr during phase 2 of action potentials and consequently shortened the action potential duration by 19.7-23.6% in LQT1 and LQT3 models. A reduction of IKr in the LQT3 model evoked early afterdepolarization, which was abolished by the activator-induced enhancement of IKr.Conclusion: KCNH2 channel activators, mallotoxin, PD-118057, and NS1643 increases IKr through distinct kinetic mechanisms and can be utilized for potential therapy of LQTS and torsades de pointes.

A sympathetic model of L-type Ca2+ channel-triggered arrhythmias

A sympathetic model of L-type Ca²⁺ channel-triggered arrhythmias

Antitorsadogenic Effects of (±)-N-(2,6-Dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (Ranolazine) in Anesthetized Rabbits

Ranolazine [Ranexa; (+/-)-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine] is novel anti-ischemic agent that has been shown to inhibit late I(Na) and I(Kr) and to have antiarrhythmic effects in various preclinical in vitro models. This study was undertaken to investigate the effects of ranolazine on drug-induced Torsade de Pointes (TdP) in vivo. TdP was induced by an I(Kr) blocker, clofilium, in anesthetized, alpha(1)-agonist-sensitized rabbits. Clofilium prolonged QT interval corrected for heart rate (QTc) (52 +/- 9%) and monophasic action potential duration (MAPD)(90) (56 +/- 9%) and caused TdP in eight of eight rabbits. Pretreatment with ranolazine (480 microg/kg/min) or lidocaine (200 microg/kg/min) reduced the clofilium-induced prolongation of QTc (15 +/- 3 and 19 +/- 3%, respectively, p < 0.001 versus vehicle) and MAPD(90) (21 +/- 4 and 20 +/- 2%, respectively, p < 0.001 versus vehicle) and prevented the occurrence of TdP (zero of eight and zero of eight, respectively). Administration of ranolazine after the first episode of TdP terminated TdP and prevented its recurrence (zero of four versus vehicle, four of four). To rule out an alpha(1)-adrenoceptor antagonistic activity of ranolazine, we compared the effects of ranolazine on blood pressure with those of the alpha(1)-antagonist, prazosin. Although prazosin (10 microg/kg/min) markedly shifted the phenylephrine (alpha(1)-agonist) dose-response curve to the right, it did not have any effect on clofilium-induced prolongation of QTc and MAPD(90) (43 +/- 7 and 53 +/- 9%, respectively) or the occurrence of TdP (seven of eight). In contrast, ranolazine completely suppressed TdP but did not cause any shift in the phenylephrine dose-response curve at the highest dose tested (480 microg/kg/min). We conclude that ranolazine antagonizes the ventricular repolarization changes caused by clofilium and suppresses clofilium-induced TdP in rabbits.

Human Atrial Natriuretic Peptide Suppresses Torsades de Pointes in Rabbits

The increase in inward current, primarily L-type Ca2+ current, facilitates torsades de pointes (TdP). Because human atrial natriuretic peptide (ANP) moderates the L-type Ca2+ current, in our study it was hypothesized that ANP counteracts TdP. We tested the effect of ANP, guanosine 3', 5'-cyclic monophosphate analogue (8-bromo cGMP) and hydralazine on the occurrence of TdP in a rabbit model. In control rabbits, administration of methoxamine and nifekalant almost invariably caused TdP (14/15). In contrast, ANP (10 microg . kg(-1) . min(-1)) markedly abolished TdP (2/15), whereas hydralazine failed to show a comparable anti-arrhythmic action (10/15). TdP occurred only in 1 of 15 rabbits treated with 8-bromo cGMP. Presence of early afterdepolarization-like hump in the ventricular monophasic action potential was associated with the occurrence of TdP. Results suggest that ANP affects TdP in the rabbit model, and that this anti-arrhythmic effect of ANP is not necessarily shared by other vasodilating agents.

Potentiation of E‐4031‐induced torsade de pointes by HMR1556 or ATX‐II is not predicted by action potential short‐term variability or triangulation

Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP. Experiments were performed in open-chest, pentobarbital-anaesthetized, alpha 1-adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg(-1) min(-1)), the IKs blocker HMR1556 (25, 75 and 250 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg(-1)) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded. HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred. Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP.

Biventricular Pacing and QT Interval Prolongation

The purpose of this study was to examine BiV pacing-dependent changes in QT interval and the related potential for proarrhythmia. Biventricular (BiV) pacing has emerged as a promising therapy for patients with advanced congestive heart failure (CHF) and bundle branch block (BBB). One hundred and seventy-six consecutive patients (123 men and 53 women; mean age 67 +/- 16 years) with ischemic (n = 128) or nonischemic (n = 48) cardiomyopathy in New York Heart Association Class II (8%) or III (92%) CHF (ejection fraction 24 +/- 9%) underwent atrial synchronous BiV pacing. The QRS, QT, and JT intervals were measured at 30 minutes after initiation of BiV pacing, at 24 hours, and at 1 month postimplant. QT interval was defined as the time interval between the initial deflection of the QRS complex and the point at which the T wave crossed the isoelectric line. At baseline, the average QRS duration was 178 +/- 10 ms, attributable to left BBB (n = 158) or intraventricular conduction delay (n = 18). BiV pacing resulted in a small but statistically significant reduction in QRS duration (148 +/- 9 ms during BiV pacing vs 178 +/- 10 ms at baseline [P < 0.0001]), yet the QT increased to 470 +/- 34 ms with BiV pacing versus 445 +/- 32 ms at baseline [P < 0.0001]). The JTc interval during BiV pacing was significantly shorter than during LV pacing (290 +/- 9 ms vs 320 +/- 20 ms, P < 0.0001). During a mean follow-up of 24 +/- 6 months, one patient developed recurrent torsade de pointes. That was eliminated once left ventricular pacing was discontinued. Biventricular pacing prolongs QT interval. However, the occurrence of torsade de pointes is uncommon.

Development of torsade de pointes caused by exacerbation of QT prolongation during clipping of cerebral artery aneurysm in a patient with subarachnoid haemorrhage

We report the case of a 79-yr-old woman with subarachnoid haemorrhage (SAH) in whom torsade de pointes (TdP) caused by worsening the QT prolongation occurred during clipping of cerebral artery aneurysm. This patient shows a potential risk of occurrence of life-threatening tachyarrhythmia, TdP by prolonging the QT interval during surgery in patients with SAH even with no additional factors that predispose to TdP. Therefore, a proper monitoring of the QT interval is necessary as a predictor of TdP. When ventricular tachyarrhythmia occurs, recognition of TdP is important because antiarrhythmic drug therapy for TdP is different from that for ventricular tachyarrhythmias that is not TdP.

QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system

Recent case series have associated the synthetic opioid, methadone, with QT prolongation and torsades de pointes (TdP) ventricular arrhythmia. To review and analyze adverse events (QT prolongation and TdP) reported to the Food and Drug Administration (FDA) to determine the patient characteristics, dosages of methadone, and outcomes of methadone-treated patients. The study design was a retrieval and retrospective analysis of reports of adverse events associated with methadone voluntarily reported to the FDA MedWatch program from 1969 to October 2002. Reports were accessed via QSCAN (DrugLogic, Reston, VA), a commercially available software interface. In a total of 5,503 reports of adverse events associated with methadone, 43 (0.78%) noted the occurrence of TdP and 16 (0.29%) QT prolongation. Doses were reported in 42/59 (71%) of cases; mean dose was 410 +/- 349 mg/day (median 345, range 29-1680). The dosages for 10 of the 42 cases (29%) were within the recommended range for methadone maintenance treatment, 60-100 mg/day. Female gender, interacting medications, hypokalemia, hypomagnesemia, and structural heart disease, risk factors previously identified with other drugs known to cause TdP, were found in 44 (75%) cases. Most adverse events required hospitalization or resulted in prolonged hospitalization (28/59, 47%) and 5/59 (8%) were fatal. Cases of TdP associated with methadone have been reported to the FDA MedWatch system. Analysis of the cases provides evidence that prolonged QT and TdP can occur over a wide range of dosages including those usually recommended for addiction treatment.

QT Interval Prolongation and Torsades de Pointes Due to a Coadministration of Metronidazole and Amiodarone

This report documents the occurrence of torsades de pointes (TdP) caused by marked QT interval prolongation in the case of a 71-year-old woman receiving both metronidazole and amiodarone for the treatment of pseudomembranous colitis and paroxysmal atrial fibrillation. The case highlights a previously unknown drug interaction. The role of inhibition of cytochrome P-450 CYP3A4 is discussed.