Torsades De Pointes In Patients Research Articles

Treatment of a Paradoxical Reaction to Midazolam with Haloperidol

Treatment of a Paradoxical Reaction to Midazolam with Haloperidol

Time- and Rate-Dependent Alterations of the QT Interval Precede the Onset of Torsade de Pointes in Patients With Acquired QT Prolongation

Objectives. The purpose of this study was to determine whether the QT interval dynamics that precede torsade de pointes are consistent with the initiation of this arrhythmia by early afterdepolarization-induced triggered activity.Background. Early afterdepolarization-induced triggered activity has been suggested as an electrophysiologic mechanism for torsade de pointes. Consequently, the initiation of torsade de pointes should involve time- and rate-dependent alterations of ventricular repolarization similar to those known to modulate the development of early afterdepolarizations.Methods. RR and QT intervals were measured in digitized 24-h ambulatory electrocardiographic recordings obtained from seven patients with acquired prolongation of ventricular repolarization. Each patient had one or more episodes of torsade de pointes. The relation between RR and QT intervals was determined before, during and after multiple episodes of torsade de pointes.Results. In patients with multiple episodes of ventricular arrhythmias, the onset of the arrhythmias was associated with a critical prolongation of the QT interval. In some episodes, prolongation of the QT interval was associated with sudden prolongation of the sinus cycle length, whereas in other episodes, the QT interval prolonged progressively at a constant cycle length.Conclusions. The association between a critically prolonged QT interval and the onset of ventricular arrhythmias suggests that the initial complex of torsade de pointes is an early afterdepolarization-induced triggered response. However, prolongation of the QT interval itself was not sufficient to account for the initiation of torsade de pointes, suggesting that other, as yet unidentified factors are required.(J Am Coll Cardiol 1997;30:209–17)

Efficacy and proarrhythmia with the use of d,l-sotalol for sustained ventricular tachyarrhythmias.

This study prospectively evaluated the clinical efficacy, the incidence of torsades de pointes, and the presumable risk factors for torsades de pointes in patients treated with d,l-sotalol for sustained ventricular tachyarrhythmias. Eighty-one consecutive patients (54 with coronary artery disease, and 20 with dilated cardiomyopathy) with inducible sustained ventricular tachycardia or ventricular fibrillation received oral d,l-sotalol to prevent induction of the ventricular tachyarrhythmia. During oral loading with d,l-sotalol, continuous electrocardiographic (ECG) monitoring was performed. Those patients in whom d,l-sotalol prevented induction of ventricular tachycardia or ventricular fibrillation were discharged with the drug and followed up on an outpatient basis for 21 +/- 18 months. Induction of the ventricular tachyarrhythmia was prevented by oral d,l-sotalol in 35 (43%) patients; the ventricular tachyarrhythmia remained inducible in 40 (49%) patients; and two (2.5%) patients did not tolerate even 40 mg of d,l-sotalol once daily. Four (5%) patients had from torsades de pointes during the initial oral treatment with d,l-sotalol. Neither ECG [sinus-cycle length (SCL), QT or QTc interval, or U wave] nor clinical parameters identified patients at risk for torsades de pointes. However, the oral dose of d,l-sotalol was significantly lower in patients with torsades de pointes (200 +/- 46 vs. 328 +/- 53 mg/day; p = 0.0017). Risk factors associated with the development of torsades de pointes were the appearance of an U wave (p = 0.049), female gender (p = 0.015), and significant dose-corrected changes of SCL, QT interval, and QTc interval (p < 0.05). During follow-up, seven (20%) patients had a nonfatal ventricular tachycardia recurrence, and two (6%) patients died suddenly. One female patient with stable cardiac disease had recurrent torsades de pointes after 2 years of successful treatment with d,l-sotalol. Torsades de pointes occurred early during treatment even with low doses of oral d,l-sotalol. Pronounced changes in the surface ECG (cycle length, QT, and QTc) in relation to the dose of oral d,l-sotalol might identify a subgroup of patients with an increased risk for torsades de pointes. Other ECG parameters before the application of d,l-sotalol did not identify patients at increased risk for torsades de pointes. Recurrence rates of ventricular tachyarrhythmias are high despite complete suppression of the arrhythmia during programmed stimulation. Therefore programmed electrical stimulation in the case of d,l-sotalol seems to be of limited prognostic value.

Torsade de pointes as a complication of subarachnoid hemorrhage: A critical reappraisal

Subarachnoid hemorrhage is widely accepted as a potential cause of torsade de pointes (TdP), yet this putative etiologic relationship has never been systematically evaluated. We therefore undertook a MEDLINE search from 1966 through 1993, with relevant back referencing, and identified 20 cases of TdP in the setting of subarachnoid hemorrhage. It was impossible in any of these cases (usually because of insufficient data) to completely exclude one or more alternative explanations for TdP, including congenital long QT syndrome, hypokalemia, hypomagnesemia, or drug-induced QT prolongation. Furthermore, of a total of 1,139 patients in 16 prospective series of subarachnoid hemorrhage with electrographic analyses, there were only five reported cases of TdP, all in patients with hypokalemia. Thus, extremely limited scientific data exist to support the notion that subarachnoid hemorrhage can be a distinct cause of TdP. Until more definitive evidence is available, the development of TdP in patients with subarachnoid hemorrhage is probably better characterized as a multifactorial phenomenon occurring in an acute, typically intensive care, setting.

Spontaneous sequences of onset of torsade de pointes in patients with acquired prolonged repolarization: Quantitative analysis of Holter recordings

Objectives. This study investigated the cycle length changes preceding the spontaneous onset of torsade de pointes in patients with acquired prolonged ventricular repolarization.Background. Torsade de pointes is a polymorphic ventricular tachycardia generally associated with prolonged ventricular repolarization. Because torsade de pointes is not inducible by programmed electrical stimulation, quantitative analysis of Holter recordings of spontaneous episodes may clarify the mechanisms favoring the onset of torsade de pointes in actual clinical conditions.Methods. The digitized Holter recordings of 12 patients were analyzed by a computerized Holter system (ATREC). All arrhythmias were grouped according to three classes: 1) isolated premature ventricular beats (n = 47,147, mean/patient [±SD] 3,929 ± 11,571); 2) salvos of 2 to 4 consecutive beats (n = 2,003, mean/patient 167 ± 359); 3) torsade de pointes ≥5 beats (n = 105, mean/patient 9 ± 11). For each patient and class of arrhythmias, six variables were computed from the 10 min and the 10 cycles preceding the event onset.Results. A significant heart rate increase in the last minute (p < 0.01) and typical oscillatory short-long-short cycle length sequences preceded the onset of arrhythmias, with greater oscillation preceding torsade de pointes than salvos and premature ventricular beats. The cycle lengths preceding the onset were highly correlated with the class of arrhythmias (r = 0.65, p < 0.005) and allowed the correct classification of 69% of events by discriminant analysis (p < 0.0001). A significant negative correlation was observed between the duration of torsade de pointes and the mean length of the initial cycles (r = −0.62, p < 0.001), indicating that longer torsade de pointes had a faster rate than that at onset.Conclusions. In patients with acquired prolonged repolarization, the spontaneous onset of ventricular arrhythmias was preceded by an increasing heart rate in the last minute and escalating oscillatory “short-long-short” cycle length patterns, with greater oscillations preceding torsade de pointes than salvos and isolated ventricular beats. These findings suggest that adrenergic- and pause-dependent mechanisms (possibly inducing afterdepolarizations and triggered activity) may have a synergetic role in the genesis of complex ventricular arrhythmias associated with delayed ventricular repolarization.

Cycle-length effects on the initiation of simulated torsade de pointes

The sequence of a short and long cycle length has been observed frequently to precede the onset of torsade de pointes in patients. The purpose of this study was to determine the mechanism of that relation by means of a computer model of propagated excitation. The model included cycle length-dependent refractoriness and slow propagation during incomplete recovery and has been used previously to document that changing QRS waveform and limited duration of torsade de pointes episodes can be explained by moving sites of reentrant excitation. In this study, a short-long cycle-length sequence due to a ventricular premature response and compensatory pause was shown to prolong the period during which simulated torsade de pointes could be initiated. A premature response that failed to initiate the arrhythmia in the absence of that sequence did so after the sequence. Both the premature ventricular response and compensatory pause of the short-long cycle-length sequence contributed to prolongation of the torsade period, but by different mechanisms. The compensatory pause prolonged refractory periods and increased their disparity by a direct effect of cycle length. The ventricular premature response had similar effects, but these were indirect and due to the activation sequence of the response. When such a response was followed by a supraventricular response, the ventricular cycle length included atrioventricular conduction time and was longer than that with a series of responses of either supraventricular or ventricular origin. In addition to elucidating the mechanism of the short-long cycle sequence relation to torsade de pointes, the findings suggest that long cycles of whatever nature or the sequence of ventricular and supraventricular responses of whatever cycle length may facilitate initiation of the arrhythmia.

Understanding Consequences of Concurrent Therapies

In 1989, the occurrence of a rare, life-threatening ventricular arrhythmia (torsades de pointes) in an otherwise healthy young woman led alert clinicians at the Naval Hospital in Bethesda, Md, to consider the possibility that the patient's near-fatal arrhythmia was triggered by a drug-drug interaction involving her antihistamine (terfenadine) and her antifungal (ketoconazole) medications. 1 Consulting clinical pharmacologists from the Uniformed Services University of the Health Sciences and the US Food and Drug Administration (FDA) suggested that ketoconazole inhibited the oxidative metabolism of terfenadine. Analysis of blood samples revealed that the patient had high levels of unmetabolized terfenadine, a compound not usually detectable in blood because it is metabolized so quickly. Review of reports to the FDA's spontaneous reporting system revealed that among additional cases of torsades de pointes in patients receiving terfenadine, many were also receiving ketoconazole. This evidence led the FDA to ask Marion Merrill Dow, Kansas City, Mo,

Safety of bepridil: From review of the European data

In France, bepridil has been available since 1981 for treatment of angina. Reports of arrhythmogenic effects (torsades de pointes) related to bepridil led to the assembly of a task force of physicians from France and the Netherlands. The task force found that the risk of torsades de pointes was indeed increased in elderly patients, especially women >70 years old, as well as in those taking diuretics, which can precipitate hypokalemia. Postmarketing surveillance data developed from 1981 to 1989 have revealed 108 validated episodes of torsades de pointes in patients treated with bepridil. Improved patient selection has dramatically decreased the incidence of this complication. Several comparative clinical trials assessing the safety of bepridil have concluded that the drug may prolong the QT interval in certain patients; however, no occurrence of torsades de pointes was documented in these safety studies. The 9-year French experience suggests that bepridil is a safe and effective agent for treatment of angina pectoris in properly selected patients.

Nicorandil suppresses early afterdepolarisation and ventricular arrhythmias induced by caesium chloride in rabbits in vivo

Outward K current of cardiac membrane has been shown to be suppressed by caesium chloride (Cs) and enhanced by nicorandil, a coronary vasodilator. The aim of this study was to assess the effects of nicorandil on the Cs induced early afterdepolarisations and associated ventricular arrhythmias in the rabbit heart in vivo. Intravenous bolus injections of Cs (1 mmol.kg-1) were given three times at 20 min intervals. Monophasic action potentials of the left ventricular endocardium and the ECG (lead II) were recorded simultaneously over 60 min, under the intrinsic (sinus node) cardiac rhythm. Eight rabbits were treated with Cs alone (control group); seven other rabbits were first treated with an intravenous infusion of nicorandil (0.2 mg.kg-1) (nicorandil treated group) and the effects of Cs were then examined. In the control group, Cs produced early afterdepolarisations, premature ventricular beats and ventricular tachycardias. The ventricular tachycardias included two different types: (1) non-sustained polymorphic ventricular tachycardia mimicking the torsade de pointes in patients with long QT syndrome; (2) sustained monomorphic ventricular tachycardia. In the nicorandil treated group, the amplitude of the early afterdepolarisations and the incidence of ventricular tachycardias were significantly less than in the control group. Nicorandil suppresses the early afterdepolarisations and ventricular tachyarrhythmias induced by Cs, possibly by increasing the membrane K conductance.

Treatment of Torsade de pointes with intravenous magnesium in idiopathic long QT syndrome.

A middle aged woman with idiopathic long QT syndrome was found to have repetitive ventricular tachycardia of the "torsade de pointes" type. The arrhythmia was resistant to mexiletine and lidocaine, but was controlled by intravenous magnesium sulfate (MgSO4). The recurrent attacks were abolished by a bolus of 2.0 g MgSO4, and extremely prolonged QTU interval was reduced by intravenous infusion of 5 mg/min MgSO4 for 36 h. This case shows the effectiveness of intravenous magnesium in controlling the attack of torsade de pointes in patients with idiopathic long QT syndrome.

Pentamidine-Induced Torsades de Pointes in a Renal Transplant Recipient With Pneumocystis carinii Pneumonia

Pentamidine isethionate, an important agent used to treat Pneumocystis carinii pneumonia, has been shown to be associated with the development of torsades de pointes in patients with AIDS. We have described a case of pentamidine-induced polymorphous ventricular tachycardia in a renal transplant recipient whose renal insufficiency may have prolonged the duration of arrhythmias. Careful ECG monitoring should be done during pentamidine administration, especially in patients with renal insufficiency. Physicians should be aware that this variety of polymorphous ventricular tachycardia can occur well within the recommended dose of pentamidine. More data are needed to define the relationship between renal dysfunction, plasma levels, and pentamidine cardiotoxicity.