Therapeutics

Termination of drug-induced Torsades de pointes with overdrive pacing

Nathan P. Charlton MD, David T. Lawrence DO, William J. Brady MD, Mark A. Kirk MD, Christopher P. Holstege MD?

Department of Emergency Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

Received 27 August 2008; revised 17 September 2008; accepted 19 September 2008

Abstract Drug-induced prolongation of the QT interval is frequently encountered after medication overdose. Such toxicity can result in degeneration to torsades de pointes (TdP) and require overdrive pacing. We present 3 cases in which intentional medication overdose resulted in QTc prolongation with subsequent degeneration to TdP. Despite appropriate care, including magnesium therapy, each case required overdrive pacing for resolution of TdP. Although rarely encountered, patients with drug- induced TdP can be successfully managed with overdrive pacing.

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case presentations”>Introduction

There is an ever-growing list of prescribed medications that have been shown to possess QT interval prolonging effects when taken both in therapeutic dosing and in overdose (Table 1). QT prolongation may be more pronounced when 2 or more of these medications are prescribed concomitantly or when suicidal patients acutely overdose on these medications. This QT interval prolonga- tion can degenerate into the ventricular dysrhythmia torsades de pointes (TdP). Treatment consists of implementing measures to stabilize the myocardium to prevent this reentrant rhythm. The purpose of this report is to present a case series of drug-induced TdP requiring overdrive pacing and to clarify specific treatment strategies of QTc prolonga- tion and TdP.

* Corresponding author. Division of Medical Toxicology, University of Virginia School of Medicine, PO Box 800774, Charlottesville, VA 22908- 0774, USA. Fax: +1 434 971 8657.

E-mail address: [email protected] (C.P. Holstege).

Case presentations

Case 1

A 53-year-old woman presented with altered mental status after an acute overdose of verapamil, citalopram, and alprazolam. The time of ingestion was unknown. Her initial blood pressure was 110/70 mm Hg with a pulse rate in the 40s. The initial electrocardiogram (ECG) was significant for a bradycardia with a QTc of 558 milliseconds (Fig. 1). Within 6 hours of arrival, the patient sustained 2 brief seizures and then developed multiple runs of TdP (Fig. 2). A transvenous pacemaker was inserted, and the generator was set at a rate of 100 beats per minute (bpm) (Fig. 3). The patient’s initial laboratory values were significant for a serum potassium of 4.2 mmol/L and a magnesium of 2.2 mmol/L. On day 5 of hospitalization, pacing was discontinued; and the patient was noted to be in normal sinus rhythm with a heart rate of 84 bpm and with a QTc interval of 590 milliseconds. On day 6, the patient experienced another episode of TdP, at which point pacing was resumed. By day 10 of hospitalization, the patient had again stabilized with a

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override ventricular ectopy. The patient required pacing for approximately 24 hours. The patient required prolonged ventilatory support for aspiration pneumonitis and was extubated on day 8 of hospitalization and transferred to a psychiatric facility on day 9.

Antihistamines Astemizole Clarithromycin Diphenhydramine Loratidine Terfenadine Antipsychotics Chlorpromazine Droperidol Haloperidol Mesoridazine Pimozide Quetiapine Risperidone Thioridazine Ziprasidone Arsenic trioxide Bepridil Chloroquine Cisapride Citalopram Clarithromycin

Class IA antiarrhythmics Disopyramide Quinidine Procainamide

Class IC antiarrhythmics Encainide

Flecainide Moricizine Propafenone

Class III antiarrhythmics Amiodarone

Dofetilide Ibutilide Sotalol

Cyclic antidepressants Amitriptyline Amoxapine Desipramine Doxepin

Imipramine Nortriptyline Maprotiline Erythromycin Fluoroquinolones Ciprofloxacin Gatifloxacin Levofloxacin Moxifloxacin Sparfloxacin Hydroxychloroquine Levomethadyl Methadone Pentamidine Quinine

Tacrolimus Venlafaxine

Table 1 K⁺ efflux channel blocking drugs

2.3. Case 3

normal sinus rhythm and QTc interval of 400 milliseconds. The patient experienced no further episodes of TdP.

Case 2

A 49-year-old woman presented with a toxic ingestion of 10 g of diphenhydramine. The patient also had access to ziprasidone, lithium, and clonazepam, but denied that she took these medications in overdose. Her mental status declined soon after arrival, and she was intubated for airway protection. Her initial vitals were significant for a systolic blood pressure of 80 mm Hg and a wide complex sinus tachycardia with a rate of 140 bpm. Her ECG revealed a QTc of 480 milliseconds. The laboratory values on arrival, including serum potassium and magnesium, were within normal limits. On the second hospital day, the patient’s ECG was significant for a QTc of 647 milliseconds along with short runs of hemodynamically stable polymorphic ventri- cular tachycardia (VT) (Fig. 4). Later that day, the patient experienced multiple episodes of TdP (Fig. 5). Multiple doses of magnesium sulfate and sodium bicarbonate were administered, and a transvenous pacemaker was inserted in the patient. The initial paced rate was set at 110 bpm to

A 36-year-old man presented to an outside hospital after an overdose of sotalol, olanzapine, and beer. The patient’s medical history included Surgical repair for transposition of the great vessels. The patient was drowsy with slurred speech on presentation. Initial vital signs included a blood pressure of 104/46 mm Hg and heart rate of 54 bpm. On ECG, the QTc was 421 milliseconds and QRS was 112 milliseconds. The patient was intubated approximately 2 hours after presentation secondary to declining mental status. During intubation, the patient’s blood pressure fell to 93/48 mm Hg, heart rate fell to 46 bpm, and he had 2 runs of nonsustained VT. The patient received 5 mg of intravenous (IV) glucagon. The blood pressure rose to 110 mm Hg systolic soon after glucagon infusion.

During transport to a tertiary care center, the patient’s blood pressure decreased to 87/42 mm Hg with a heart rate of 38 bpm. The ECG (Fig. 6) revealed a rate of 38 bpm with a QTc of 528 milliseconds and a QRS of 108 milliseconds. The patient received an additional 5 mg of glucagon and 2 g of magnesium sulfate IV. A glucagon infusion was initiated at 5 mg/h. The patient’s blood pressure continued to fall, and 50 mEq of Calcium gluconate was administered IV. The blood pressure subsequently rose to 116/66 mm Hg with a pulse of

41 bpm. However, the patient began to have frequent episodes of TdP (Fig. 7). Because of surgical correction of his transposition during childhood (Fontan procedure), he was not considered a candidate for transvenous pacing. Therefore, an isoproterenol infusion was initiated, raising his heart rate to 70 to 80 bpm. He had no further episodes of TdP.

Discussion

Physiology

In its resting state, the myocardial cell membrane is impermeable to sodium. During this phase, the Na⁺-K⁺ ATPase is actively working to maintain an electrochemical gradient across the cell membrane, pumping out 3 Na⁺ ions in exchange for 2 K⁺ ions. Depolarization of the cardiac cell occurs secondarily to the opening of voltage-sensitive Na⁺ channels and the subsequent influx of Na⁺ (phase 0). This Na⁺ influx results in ventricular depolarization correspond- ing with the QRS interval of the ECG (Fig. 8). At the peak of the action potential, the activation of K⁺ efflux channels occurs along with the closure of Na⁺ channels (Phase 1). Calcium channels then open, causing calcium to enter the

Fig. 1 Case 1 presenting ECG demonstrating Sinus bradycardia with a QTc of 558 milliseconds.

myocytes and resulting in the plateau phase (Phase 2). The entry of calcium into the myocardial cell triggers release of calcium from the Sarcoplasmic reticulum, resulting in muscle contraction. As more K⁺ efflux channels open, cellular potential again becomes more negative to approach the resting potential of -90 mV (phase 3). It is the inhibition of

the K⁺ efflux channels that results in QT prolongation and creates a risk for the development of TdP.

Normal QT intervals are generally described as less than 440 milliseconds in men and less than 460 milliseconds in women [1,2]. QTc intervals greater than 500 milliseconds appear to correspond with an increasing risk of dysrhythmia;

Fig. 2 Case 1 rhythm strips demonstrating TdP.

Fig. 3 Case 1 rhythm strips demonstrating a transvenous paced rhythm at a rate of 100 bpm.

however, this correlation is variable because dysrhythmias have occurred at lengths less than 500 milliseconds and patients have remained dysrhythmia free at intervals greater than 500 milliseconds [3,4]. Consequently, it appears that variations (dispersion) in repolarization may be more important in the production of TdP than actual length of QT interval [3,5,6].

The QT interval is measured from the beginning of the Q wave of the QRS complex to the end of the T wave. Although lead II may be the most commonly used lead from calculation, a recent study showed that leads V₃ and V₄ may best approximate the longest QT interval [3,7]. There are 2 primary formulations for calculating the QT interval. The most common is the Bazett formula (QTc = QT/RR^1/2), although this formula may be inaccurate in patients with tachycardia and bradycardia [8]. In these instances, the

Fridericia formula may be more appropriate (QTc = QT/ RR^1/3) [3]. In addition to these calculations, a nomogram has been proposed by Chan et al [9] for predicting the risk of TdP for patients with QT prolongation (Fig. 9). The potential benefit of this nomogram is that it takes into account the relative protective effect of tachycardia and the relative arrhythmogenic effect of bradycardia in the setting of QT prolongation [9]. However, this nomogram has not yet received rigorous validation.

The blockade of potassium efflux from the cell increases the amount of positive ions in the cell and, therefore, raises the membrane potential. As calcium is continuing to enter the myocyte, the cell is maintained at an elevated polarity, which may trigger an additional inward sodium current resulting in a subsequent depolarization, termed early after-depolariza- tion (EAD) [3]. If the depolarization is large enough to reach

Fig. 4 Case 2 ECG on day 2 demonstrating a QTc of 647 milliseconds with short runs of polymorphic VT.

Fig. 5 Case 2 rhythm strip demonstrating a run of TdP.

the threshold, myocyte firing may occur. An EAD that occurs in a vulnerable period during ventricular repolarization may initiate a reentrant rhythm [1].

QT interval prolongation may be either congenital or acquired. Congenital forms are acquired by inherited gene mutations encoding ion channels involved in cardiac action potential repolarization [4,10,11]. These genes encode either sodium or potassium channels depending on the specific mutation [4,12]. Acquired QT prolongation may be obtained by several different mechanisms. Medications/toxins and electrolyte imbalances are the 2 most common means; however, myocardial infarction, cerebral vascular accidents, hypothyroidism, and hypothermia have also been reported to cause QT prolongation [4,12,13]. Medication-induced QT prolongation is most commonly generated by potassium efflux channel blockade [1,2]. There is an extensive list of these medications (Table 1).

Variation appears to exist in the sensitivity of myocardial cells to K⁺ channel blockade. Research shows that this heterogeneity may be greatest in either the Purkinje fibers or

M cells of the myocardium [1,5,11,14]. This heterogeneity in repolarization predisposes to reentrant rhythms [12,14]. The onset of TdP in both congenital and acquired forms appears to be precipitated by a “short-long-short” pattern of ventricular beats. In this pattern, a premature ventricular contraction with a corresponding compensatory pause is followed by sinus beat, followed by another ventricular beat during repolarization, triggering TdP [3,4,11].

Management

Initially, repletion of potassium, calcium, and magnesium is essential when hypokalemia, hypocalcemia, or hypomag- nesemia is present, respectively, as any of these electrolyte abnormalities may contribute to a prolonged QT interval and TdP. Although supplementing these electrolytes back into normal range is likely sufficient, the optimal range in dysrhythmia is truly unknown. Many experts recommend that Potassium levels be supplemented to the high normal range (4.5-5.0 mmol/L) [8,12].

Fig. 6 Case 3 presenting ECG demonstrating sinus bradycardia with a QTc of 528 milliseconds and a QRS of 108 milliseconds.

Fig. 7 Case 3 rhythm strip demonstrating TdP.

After Electrolyte replacement, intravenous magnesium sulfate is the first line therapy for both the prevention and treatment of medication-induced TdP, even in the setting of a normal serum magnesium level. Although magnesium’s mechanism of action has not been fully determined, magnesium appears to stabilize the myocardium by suppressing EADs. Likely mechanisms of magnesium’s antidysrhythmic properties include blockade of membrane L-type calcium channels, stabilization of the membrane gradient through activation of the Na⁺-K⁺ ATPase with subsequent reduction of the Na⁺-Ca²⁺ exchanger, and activation of the magnesium-dependent Ca²⁺ ATPase [2,15-18]. Magnesium infusion, however, is not expected

to change the heart rate or the QT interval on the ECG [12,15,17]. An intravenous dose of 2 g (16 mEq) of magnesium sulfate in adults (25-50 mg/kg up to 2 g in children) may be given to patients with QTc intervals greater than 500 milliseconds after a known or possible toxic ingestion because this interval appears to correlate with the development of TdP [4]. Although there is no consensus on repetitive dosing, it is reasonable to repeat this dose every 6 hours if the QTc remains greater than 500 milliseconds.

In the treatment of TdP, 2 g of magnesium sulfate in adults (25-50 mg/kg up to 2 g in children) is given IV over 60 seconds [18,19]. This dose may be repeated in 5 to 15 minutes for refractory dysrhythmias [4,12]. Continuous infusion of up to 3 to 10 mg/min in adults may also be started for persistently refractory dysrhythmias [12,18]. One small study demonstrated the optimum continuous infusion

Fig. 8 Myocardial action potential with relationship to ECG and

ion channel opening. Fig. 9 QT interval nomogram. Adapted from Chan et al [9].

rate in children to be 0.5 to 1.0 mg/(kg h) [20]. When starting a continuous infusion, care must be taken to avoid magnesium toxicity, which is signified by hyporeflexia, central nervous system depression, respiratory depression, and hypotension. In most instances, toxicity is not seen unless serum levels reach 3.5 to 4.0 mEq/L; recall that toxicity likely will develop before a clinician’s ability to monitor results of serum level testing.

Refractory TdP may be amenable to cardiac pacing, either chemical or electrical. In either treatment instance, increasing the baseline heart rate is the therapeutic goal, whether it be via electrical pacing or “chemical” pacing. Pacing can be used prophylactically to suppress frequent, self-limited runs of TdP that the clinician is worried may progress to unstable or refractory TdP. It also may be used to override refractory, persistent TdP before degeneration to ventricular fibrillation. Patients with Cardiovascular collapse must be treated with direct current cardioversion and standard Resuscitation protocols.

Transcutaneous cardiac pacing can be initiated as a temporary treatment, but transvenous pacing is the preferred method of pacing because the incidence of cardiac capture is higher and sedation is generally not necessary. With transcutaneous pacing, the clinician cannot rely on the ECG to determine electrical capture; in fact, such a determination is not possible in most such situations-the applied voltage from transcutaneous pacing “overwhelms” any spontaneous voltage from the heart, rendering the ECG incapable of assessing whether or not there is adequate capture. Rather, the clinician should palpate the patient’s pulse to determine if both mechanical capture and electrical capture have occurred. Success rates in transcutaneous pacing are rather low.

If access to transvenous pacing is readily available, it is also preferable over chemical pacing because electrical means carry less risk in patients with congenital long QT syndrome (LQTS) [12]. Transvenous pacing is best, and most successfully, applied under fluoroscopic guidance, which is often difficult to obtain in the ED. After proper catheter placement and cardiac capture, the ventricular rate should be adjusted to suppress ectopic ventricular beats. An asynchronous (fixed rate) mode must be used to overcome the patient’s intrinsic rhythm. Although ventricular rates of 90 to 110 bpm are usually sufficient to eliminate ventricular ectopy, rates of up to 140 may be needed in some patients [4,8,12]. Once control of the dysrhythmia has been obtained, the pacing rate can be gradually diminished to the lowest paced rate that adequately suppresses further ectopy and dysrhythmia [1].

Isoproterenol is a nonselective ?-adrenergic agonist agent that has been used for overdrive pacing-in essence, a “chemical” attempt at increasing the heart rate and thus shortening the QT interval. ?1-Adrenergic receptors function to increase inotropy and chronotropy in the heart, whereas ?2-adrenergic receptors cause peripheral vasodilation. Per- ipheral vasodilation may result in a subsequent decrease in

blood pressure. For refractory TdP, initial dosing of isoproterenol is 0.5 to 1.0 ug/min in an adult and 0.1 ug/ (kg min) in a child. Upper limit of dosing is 20 ug/min in an adult and 1.5 ug/(kg min) in a child. The end point of treatment is similar to that of mechanical cardiac pacing: suppression of ectopic ventricular beats and TdP. Doses of 2 to 10 ug/min are typically sufficient to raise the heart rate to greater than 90 bpm to begin appropriate overdrive [10]. After suppression of dysrhythmia, the infusion can be titrated to a rate that adequately suppresses aberrant rhythms. Use of isoproterenol increases cardiac demand; so caution should be used in patients with preexisting cardiovascular disease, particularly ischemic heart disease [4,10]. Of course, a risk- benefit analysis is best performed by the treating clinician in situations where relative contraindications to isoproterenol exist. Isoproterenol may also increase the risk of dysrhythmia in patients with congenital LQTs and therefore should be reserved for those patients with acquired LQTS [8,12].

Conclusion

As the use of drugs with potential to cause QT prolongation is on the rise, the number of patient’s presenting with TdP is likely to increase. Both magnesium sulfate and overdrive pacing can be used to suppress this aberrant rhythm. Overdrive pacing is a relatively simple lifesaving procedure that can provide a bridge until metabolism of the compound and return of normal repolarization can be achieved. It should be recognized by treating physicians as a useful tool in the treatment of TdP.

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