A Canine Model of Torsades de Pointes

Although quinidine has been reported to induce QT interval prolongation and torsades de pointes clinically, the only experimental model currently available for quinidine-induced torsades de pointes requires the concurrent use of ischemia, reperfusion and cardiac pacing of the isolated, perfused heart. Our purpose in this study was to determine the circumstances under which quinidine might elicit torsades de pointes consistently in the intact dog. We found that maintenance of therapeutic plasma quinidine concentrations, alone, did not induce the arrhythmia. Rather, arrhythmia induction required the additional application of aconitine, which induces early afterdepolarizations and triggered activity. When aconitine was applied to two epicardial sites in dogs having quinidine-induced QT interval prolongation greater than 10%, torsades de pointes occurred in 80% of instances. When QT prolongation was less than 10%, aconitine-induced torsades de pointes was seen in only 21% of animals. Our results suggest that in a previously healthy heart quinidine-induced QT prolongation is, itself, insufficient to induce torsades de pointes consistently, and two independent sites of ectopic activity are needed as well. The ectopic foci appear to modulate one another's impulse initiation or activation sequence, thereby giving rise to the classical "twisting of the points" associated with the arrhythmia.     

Azithromycin-induced torsade de pointes

Although erythromycin frequently induces long QT interval and torsade de pointes, the newer drug, azithromycin, has rarely been reported to be associated with torsade de pointes. We report here the occurrence of a significant typical QT prolongation within a few hours after taking azithromycin which lead to torsade de pointes.     

Risk of Torsades de Pointes From Oral Erythromycin with Concomitant Carbimazole (Methimazole) Administration

There are many reports of intravenous erythromycin causing QT prolongation and torsades de pointes, but this complication is seldom ascribed to orally administered erythromycin, which is by far the most commonly prescribed route. This report describes a case of torsades de pointes associated with oral erythromycin as a result of a previously undescribed interaction with carbimazole, an antithyroid drug that is metabolized to the active drug methimazole, and the potential pharmacokinetic and pharmacodynamic mechanisms are highlighted.     

QT Interval Prolongation and Torsades de Pointes Unmasked by Intracoronary Acetylcholine Administration

Intracoronary acetylcholine administration, which was performed to exclude vasospasms, unmasked an abnormal QT interval prolongation and initiated torsades de pointes in a patient with normal QT interval at rest.     

Amiodarone Induced Torsades de Pointes with Excessive QT Dispersion Following Quinidine Induced Polymorphic Ventricular Tachycardia

We report a case of amiodarone induced torsades de pointes (TdP) associated with increase QT dispersion in a patient with a history of quinidine induced TdP. An increase in QT dispersion of > 100% was noted on the 12 lead surface ECG postamiodarone therapy. In summary, amiodarone has a potential to induce TdP in patients with a previous history of quinidine induced TdP. QT dispersion could be a potential marker of TdP in these patients.     

Levofloxacin induced polymorphic ventricular tachycardia with normal QT interval

Polymorphic ventricular tachycardia (PVT) is a form of ventricular tachycardia characterized by QRS complexes that seem to change direction during the tachycardia. If associated with a prolonged QT interval, it is called torsades de pointes. In the absence of a congenital long QT syndrome, torsades is seen with certain drugs such as antiarrhythmic agents (Class IA, IC, III), psychotropic medications, antidepressants, antihistamines, and electrolyte disturbances. We report the first case of polymorphic ventricular tachycardia with normal QT interval associated with the oral use of levofloxacin in the absence of other etiologies known to cause these arrhythmias.     

Mechanisms in Adrenergic Dependent Onset of Torsades de Pointes

Pause dependent onset of torsades de pointes is characteristic in acquired long QT syndromes, and the probable mechanism is reentry facilitated by increased disparity of refractoriness following a long cycle. Adrenergic dependent onset is usual in familial long QT syndromes, and the mechanism is uncertain. In this study with a computer simulation of torsades de pointes, possible mechanisms of adrenergic dependent onset have been identified. Decreased refractory periods facilitated the initiation of torsades de pointes by permitting earlier premature excitation and allowing reentry in the presence of the shorter refractory period that had been further shortened by the earlier excitation. In addition, accelerating rate resulted in responses occurring in the presence of refractory periods set by the prior response so each response was premature with respect to the preceding one. The difference between cycle lengths and refractory period decreased with increasing rate leading to the functional block required for initiation of simulated torsades de pointes. Findings define possible mechanisms in which the adrenergic effects of reduced refractory period duration and increased rate may lead to the initiation of torsades de pointes.     

Adenosine Induced Torsades de Pointes in a Child with Congenital Long QT Syndrome

Torsades de pointes is a rare arrhythmia characterized by its bradycardia dependence and increased adrenergic discharge, whether it occurs as a congenital anomaly or as an acquired problem resuiting from drug intoxication or other conditions. There are no reliable tests to assess the propensity toward torsades de pointes or evaluate the efficacy of treatment in these patients. Adenosine can result in marked slowing of sinus and ventricular rate and leads to increased sympathic discharge when given intravenously. We induced torsades de pointes in a child with congenital long QT syndrome (Jervell-Lange-Nielsen syndrome) using 200 μg/kg IV adenosine bolus. Higher dosage of adenosine (600 μg/kg) did not lead to torsades de pointes after β blockade. Adenosine may induce torsades de pointes in patients with the long QT syndrome and may be used as a test to reproduce the clinical arrhythmia. Whether adenosine proves to be useful for assessing the efficacy of treatment will require extensive investigation in larger series of patients.     

Medikamentös induzierte Verlängerung des QT-Intervalls

Prolongation of the ventricular repolarisation manifests itself as a prolongation of the QT intervall on the surface ECG and represents a major risk for a special form of ventricular tachycardia called "torsades de pointes". Torsades de pointes are often self limited and are associated with palpitations, dizziness or syncope. Degeneration into ventricular fibrillation and sudden cardiac death can occur. In addition to the various forms of the congenital long QT syndrome many drugs, such as antiarrhythmic drugs class IA and III, antibiotics, antihistamines, antidepressants, and methadone are known to prolong the QT interval. Most of these drugs block a specific potassium channel substantially involved in the ventricular repolarisation. In addition, drug interaction or disturbances of drug metabolism may play a major role in the acquired form of the long QT syndrome. The individual risk and the potential of a pharmacologic substance to prolong the QT interval are not predictable. Certain risk factors identify patients at higher risk for drug-induced prolongation of the QT interval. Correctable factors include electrolyte disorders (e.g. hypokalemia) and concomitant administration of different QT prolonging drugs. External defibrillation is the therapy of choice in the hemodynamic unstable patient presenting torsades de pointes. In hemodynamic more stable patients application of intravenous magnesium can terminate torsades de pointes (membrane stabilizing properties). Temporary external or transvenous pacing at high heart rate might terminate incessant torsades de pointes by decreasing QT interval. Repeated ECG controls during therapy with QT prolonging drugs are mandatory, especially when drug doses are changed, additional drugs are prescribed, or in case of vomiting and diarrhea. QT prolongation in individual medical therapy is not always predictable. Therefore, updated lists of drugs with the potential of QT prolongation are available on the Internet (e.g. www.qtdrugs.org ).     

New-onset QT prolongation and torsades de pointes accompanied by left ventricular dysfunction secondary to acute pancreatitis

A 70-year-old woman presented with acute pancreatitis and new-onset QT prolongation with subsequent torsades de pointes. Coronary catheterization was performed and was unremarkable. After persistent QT prolongation, despite temporary atrial pacing, a permanent dual chamber cardioverter defibrillator was implanted. In addition to the QT prolongation, significant depression in the left ventricular function was noted. Both resolved once the pancreatitis abated.     

QT Interval prolongation and torsades de pointes due to a coadministration of ciprofloxacin and azimilide in a patient with implantable cardioverter-defibrillator

The presented case report describes a male patient with an implanted cardioverter-defibrillator (ICD) in whom a coadministration of ciprofloxacin and azimilide caused QT interval prolongation and multiple episodes of torsades de pointes (TdP) followed by ICD shocks (arrhythmic storm). The case highlights a not described drug interaction between azimilide and ciprofloxacin, which is believed to be the safest member of fluoroquinolones class.     

Torsades de pointes ventricular tachycardia induced by mosapride and flecainide in the presence of hypokalemia

We report a 68-year-old man who developed torsades de pointes ventricular tachycardia induced by combined use of mosapride and flecainide. He had a permanent pacemaker (DDD mode) implanted because of sick sinus syndrome (bradytachy syndrome) 6 years earlier. The patient had started taking mosapride for upper abdominal discomfort 2 weeks earlier. On admission, ECG showed prolongation of the QTc interval from 0.48 to 0.56 seconds and self-terminating torsades de pointes occurred. We considered that this proarrhythmia was induced by mosapride in combination with antiarrhythmic agents.     

Medical toxicologists’ practice patterns regarding drug-induced QT prolongation in overdose patients: A survey in the United States of America,Europe, and Asia Pacific region

Abstract

Objective. To describe practice patterns of medical toxicologists in the United States of America (USA), Europe, and Asia Pacific Region regarding management of drug induced QT prolongation and torsades de pointes in overdose. Methods. A survey was developed to assess current practice patterns and consistency with guidelines published by the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). It was reviewed by our department research committee and the American College of Medical Toxicology (ACMT). The ACMT, European Association of Poisons Centres and Clinical Toxicologists, and Asia Pacific Association of Medical Toxicology electronically disseminated the survey to their physician members in the USA, Europe and Asia Pacific Region. Results. The overall response rate was 37% (229/617) (36% USA; 32% Europe; 52% Asia Pacific Region). Twelve toxicologists from Asia Pacific Region and Europe used the QT nomogram (Australia-5, New Zealand-1, United Kingdom-1) or QT alone (France-1, Russia-1, Romania-1, Germany-1, Philippines-1), in lieu of the corrected QT (QTc) to determine risks of developing torsades de pointes. Because only those who used QTc could proceed through the remainder of the survey, only 217 could do so. Approximately half of the respondents (52%) did not calculate QTc manually and based decisions on the electrocardiogram machines automated measurement. For those who corrected the QT interval themselves, the most common formula used was Bazett's (40%). There is great variation in the QTc value considered prolonged. Most responders considered QTc greater than 450 ms in men (28%) and 460 ms in women (25%) to be prolonged. Interestingly, approximately 15% of participants did not consider the QTc prolonged until it exceeded 500 ms in both men and women. Given an overdose scenario of a male patient with a QTc of 560 ms, heart rate of 90 beats/minute, 59% would not recommend administering intravenous magnesium sulfate. Forty-five percent and 36% believed magnesium could shorten QTc and prevent torsades de pointes, respectively. In addition, almost 90% believed administering 1–2 boluses of intravenous magnesium is safe, even when serum magnesium is not available. In regards to cardiac pacing of patients with QT prolongation and torsades de pointes, only 38% of the participating toxicologists’ responses agreed with AHA/ACC/ESC recommendations. Furthermore, 21% would not pace a patient who developed torsades de pointes regardless of the scenario. Discussion and conclusions. The results indicate that medical toxicologists have considerable heterogeneity in terms of management practices for overdose patients with QT prolongation and torsades de pointes. Medical toxicologists may benefit from developing evidence-based consensus guidelines for the management of this relatively common finding in overdose of QT-prolonging drugs.     

Long QTc and Torsades de Pointes in Human Immunodeficiency Virus Disease

Three patients with human immunodeficiency virus (HIV) infection presented with QT_c prolongation (> 440 ms) and torsades de pointes. We sought to evaluate the etiology of the long QT syndrome in these patients without previously identified causes for QT_c prolongation, and determine the prevalence among patients with HIV infection. The three index patients underwent: (1) left stellate ganglion block; (2) β-blocker challenge; and (3) electrocardiographic stress testing. QT_c interval was measured before and after intervention. We undertook a retrospective analysis of prevalence of QT_c prolongation among all patients with computerized ECGs over a 6-month period at one institution and compared it to the prevalence in hospitalized patients with HIV disease. Thirty-four thousand one hundred eighty-one patients with computerized ECGs were screened for QT_c prolongation. Forty-two hospitalized patients with HIV disease had computerized ECG during the same 6-month period. In the three index patients, the QT_c failed to shorten with left stellate ganglion blockade, β-blocker challenge, or stress testing, suggesting an acquired form of the long QT syndrome in these patients with HIV disease. None had previously recognized acquired causes of QT_c prolongation. Mexiletine hydrochloride was useful in preventing recurrences of torsades de pointes. We observed a 7.0% prevalence of QT_c prolongation among all patients screened. Hospitalized patients with HIV disease (n = 42) during this same period, demonstrated an increased prevalence of QT_c prolongation (28.6%, P = 0.002). Patients with HIV disease have a significantly higher prevalence of QT_c prolongation than a general hospital-based population, may have an unrecognized acquired form of the long QT syndrome, and are at risk for torsades de pointes.     

Marked QT prolongation and ventricular tachycardia of a transient nature in young children with cardiomyopathy

Significant prolongation of the QT interval in pediatric patients with cardiomyopathy is rare. We report two cases of dilated myopathy with transient and dramatic QT prolongation. Both had associated ventricular arrhythmias, with one having torsade de pointes, and the other nonsustained ventricular tachycardia. Normalization of their QTc occurred as their ventricular function improved.     

QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs

A long QT interval due to prolonged repolarization may be associated with a polymorphic ventricular tachycardia known as torsades de pointes. During marked prolongation of the action potential (long QT) early after depolarizations may occur, which when propagated may trigger an arrhythmia. The duration of QTc interval is the major determinant of the risk of drug-induced torsades. Congenital long QT syndrome, female gender, hypokalemia and use of sympathomimetics increase the risk of torsades, and potentiate the QT prolonging effects of drugs. Antiarrhythmics that block the potassium channel prolong the QT and increase the risk for torsades (amiodarone, sotalol, quinidine, procainamide, ibutilide, disopyramide). Additionally, some macrolide and fluoroquinolone antibiotics, antipsychotic and antidepressant drugs, serotonin agonists of the triptan class, cisapride, dolasetron and others have been reported to be associated with QT prolongation or cases of torsades. Drug-induced effects on the QT interval with the associated possibility of inducing fatal arrhythmias have become a new challenge for the practitioner, the drug development process and the regulatory agencies.     

Chronic methadone therapy complicated by torsades de pointes: a case report

Methadone is commonly used by patients presenting to the Emergency Department (ED). The common, acute side effects of central nervous system depression and respiratory depression are easily recognizable by treating physicians as attributable to methadone; however, the cardiac toxicity of chronic methadone use recently has only been recognized. Both chronic use of large doses and a recent increase in the daily dose of methadone have been associated with QT prolongation and subsequent development of torsades de pointes. We describe the case of a 40-year-old woman whose methadone dose recently had been increased to 135 mg per day. She then presented to the ED with symptomatic torsades de pointes. She was stabilized in the ED by cardioversion and infusions of magnesium sulfate and lidocaine. The markedly prolonged corrected QT interval significantly shortened after discontinuing methadone. Inpatient cardiology evaluation found no other cause for the dysrhythmia. She was definitively treated with reduction of the daily methadone dose and an implanted cardioverter-defibrillator.     

Marked QT prolongation and torsades de pointes secondary to acute ischemia in an elderly man taking dofetilide for atrial fibrillation: a cautionary tale

Dofetilide has been shown to be effective and safe in maintaining sinus rhythm in patients with persistent atrial fibrillation and congestive heart failure. Because of serious side effects of an increase in the QT interval causing torsades de pointes, dofetilide must be initiated with close monitoring of the QT interval in an inpatient setting. However, little has been reported about conditions surrounding the change in QT interval after the steady state is achieved that may have implications in the safety and efficacy of the drug. We report marked QT prolongation and torsades de pointes in a setting of flash pulmonary edema resulting from acute myocardial ischemia in a patient who was being treated with dofetilide for atrial fibrillation. Our case reminds the clinicians that the adverse and proarrhythmic effects of dofetilide can occur due to changes in the arrhythmic substrate during acute severe ischemia.     

Changes in Repolarization Dynamicity and the Assessment of the Arrhythmic Risk

At the present time, the assessment of the arrhythmic risk from surface ECG recordings is built on time-domain and frequenct-domain analysis of high resolution ECG acquisition together with in-terlead variability of QT interval duration (QT dispersion). The corresponding raw ECG tracings are obtained in resting conditions. However, the dynamic aspects of the EGG signal is a rapidly evolving matter of interest. In addition to the beat-to-beat oscillations of the ventricular repolarization amplitude (QT ai-ternans), there is growing evidence that the patterns of QT interval shortening with increasing heart rate are linked to suceptibility to ventricular arhythmias. In this report, we will mailnly address the association between QT dynamicity and the risk of developing torsades de pointes.