A 42-year-old comatose man is brought to the emergency department (ED) by ambulance. He had recently been hospitalized for decompensated hepatitis C virus (HCV) liver cirrhosis at another hospital, from which he left against medical advice. In the hours before admission to the ED, the patient experienced 2 witnessed episodes of loss of consciousness associated with urinary incontinence and myoclonic jerks.
The patient's prescribed medications include abacavir, lamivudine, and zidovudine daily for HIV infection. He also takes furosemide 50 mg, potassium canrenoate (an aldosterone antagonist), lorazepam, and methadone 90 mg (the latter for the management of heroin addiction).
On physical examination, the patient is lethargic, and his Glasgow Coma Scale (GCS) score is 6 (Eye Opening Response, 1; Verbal Response, 1; Motor Response; 4). His pupils are normal in size and bilaterally reactive to light. He has a temperature of 96.8°F (36.5°C), a blood pressure of 90/54 mm Hg, and a pulse rate of 86 bpm. His respiratory rate is 18 breaths/min, and he has an oxygen saturation of 98% while breathing room air. On auscultation, the lung fields are clear bilaterally, and normal heart sounds are heard. His peripheral pulses are palpable; however, bilateral lower extremity pitting edema is present. The abdomen is distended, tense, and with ascites. His sclerae are noted to be icteric.
Laboratory tests are ordered, with pertinent findings that include a hemoglobin level of 11.1 g/dL (111 g/L) and a platelet count of 24 × 103/μL (24 × 109/L). A chemistry panel reveals a sodium level of 134 mEq/L (134 mmol/L), a potassium level of 3.2 mEq/L (3.2 mmol/L), a creatinine level of 0.6 mg/dL (53.04 µmol/L), a glucose level of 148 mg/dL (8.21 mmol/L), a bilirubin level of 4.7 mg/dL (80.37 µmol/L), a magnesium level of 1.3 mg/dL (0.53 mmol/L; normal range, 1.5-2.5 mg/dL), an ammonium level of 153.3 µg/dL (90 μmol/L; normal range, 11-79 µg/dL), and an ionized calcium level of 3.96 mg/dL (0.99 mmol/L; normal range 4.6-5.6 mg/dL). The troponin level is 0.07 ng/mL (0.07 μg/L; normal value is < 0.12 ng/mL). Serum alcohol testing results negative, and a urine toxicology screen is negative for cannabinoids, cocaine, and opiates (note that methadone usage may not cause a positive opiate result). A computed tomography (CT) scan of the brain is negative for acute abnormalities.
The patient is initially thought to have had a seizure and is cautiously given benzodiazepines to prevent a recurrence.
An electrocardiogram (ECG) is then performed (see Figure 1). Soon afterwards, an abnormal tracing is seen on the cardiac monitor (see Figure 2), and the patient becomes pulseless and apneic and requires cardiopulmonary resuscitation.The cardiac rhythm strip (Figure 2) demonstrated torsade de pointes, otherwise known as simply "torsades" or polymorphic ventricular tachycardia. The initial ECG (Figure 1), which was obtained before the development of the torsades, revealed a prolonged QT interval (544 msec), with a QT interval corrected for the heart rate (QTc) of 647 msec. Moreover, notched T waves were noted in leads II, III, aVF, and V1-V6. A prolonged QT interval is often noted incidentally on an ECG in an asymptomatic patient; however, in a patient who presents with palpitations, presyncope, syncope, or cardiac arrest, the presence of a prolonged QT interval should raise particular concern for torsade de pointes.
QT prolongation can be either acquired or congenital. A thorough clinical history-taking and knowledge of the patient's current medications is very important for this differentiation. Congenital long QT syndrome (LQTS) is a disorder characterized by abnormal QT-interval prolongation on the ECG caused by cardiac myocyte ion channel gene mutations, with a propensity to ventricular tachyarrhythmias. Patients are typically young and may present with syncope or sudden death.[1,13]
Acquired QT interval prolongation may be drug-induced or it may be caused by certain electrolyte derangements, such as hypomagnesemia, hypokalemia, and hypocalcemia. Many drugs have been implicated, including class 1A antiarrhythmic drugs such as quinidine and procainamide and class III antiarrhythmics such as amiodarone and sotalol. Others drugs that have been implicated include antihistamines (terfenadine, astemizole), macrolide antibiotics (erythromycin, clarithromycin, clindamycin), pentamidine, serotonin receptor antagonists (ketanserin), diuretics (indapamide), certain fluoroquinolone antibiotics, tricyclic antidepressants, antipsychotics (phenothiazines, haloperidol, mesoridazine, pimozide, thioridazine, ziprasidone), gastrointestinal motility enhancers (cisapride, domperidone), inotropes (amrinone, milrinone), toxins (organophosphates, arsenic), protease inhibitors, and methadone. A number of internet resources are available that feature databases of drugs that can induce QT prolongation (http://www.azcert.org, www.torsades.org, www.qtdrugs.org, www.longqt.org, www.sads.org, etc.).[2-8,10]
Drug-induced prolongation of the QT interval is directly linked to a modification in myocardial cell repolarization, which is mediated by the efflux of potassium ions. The shape of the action potential depends on the balance between sodium and calcium inflow and potassium outflow. Two subtypes of the delayed rectifier K+ current, IKr (rapid) and IKs (slow) are responsible for repolarization. The Human Ether-a-go-go Related Gene (hERG; also termed KCNH2) codes for a protein known as the Kv 11.1 potassium ion channel, which mediates the repolarizing potassium current IKr. Blockage of the hERG-encoded potassium channels has been implicated as a cause of drug-induced QT prolongation. There is a strong correlation between IKr blockade and ventricular arrhythmia or sudden death. Drugs that block the IKr channel increase the QT interval and allow inward current, particularly calcium, to reactivate, leading to early after-depolarizations (EAD) in cardiac tissue that may result in torsades. Other drugs implicated in QT prolongation have no effect on the potassium channels; therefore, additional cardiac mechanisms can play a significant role
Some medications prolong the QT interval at specific doses, while others may act at any dose. Several agents are metabolized by the hepatic cytochrome P450 3A4 (CYP3A4) system, and drug-drug interactions and consequent QT prolongation can causes torsades. Drug interactions in this setting are primarily pharmacokinetic. When administering a drug that potentially prolongs the QT interval, a number of predisposing factors for torsades development must be considered, including advanced age, obesity, poor nutrition (anorexia nervosa, starvation diets, alcoholism), bradycardia
Torsade de pointes is characterized by QRS complexes that vary in axis and amplitude over the isoelectric line ("twisting around the points", as the name implies). Other associated characteristics include the presence of long and short RR interval onset after an early premature ventricular contraction. A relationship exists between the degree of QT interval prolongation and the development of torsades. The QT interval varies directly with heart rate, and a correction is required in order to compensate for heart rate. A commonly used correction (QTc) is the Bazett correction (QTc=QT/√RR), wherein QT is the longest QT interval measured on the ECG and RR is an average RR interval. QT measurement should be made manually from a 12-lead ECG, and it is calculated from the beginning of the QRS complex to the end of the T wave and averaged over 3-5 beats in a single lead. Prominent U waves should be included in the measurement if they merge into the T wave. It is advisable to assess QT during peak plasma concentration of any ingested QT-prolonging substances, and to correct it for heart rate while looking for other warning signs, including the appearance of prominent U waves, extrasystoles, and U wave augmentation after extrasystole. Corrected QT is considered to be prolonged if it is beyond 440 ms for adult males, 460 ms for adult females, and 500 ms in the presence of ventricular depolarization abnormalities (ie, bundle branch blocks or intraventricular conduction delay greater than 120 ms). The uncorrected QT interval should also be considered, however, as a very long QT (> 600 ms) after drug exposure is a marker of an increased risk for torsades.
The patient in this case was initially treated with 2 g intravenous magnesium sulfate and 1 g of calcium chloride. Despite this, he developed recurrent torsade de pointes. He underwent repeated defibrillation followed by irregular rhythms, including premature atrial complexes and ventricular bigeminy. The recurrent episodes of torsade de pointes were then treated with an intravenous bolus of lidocaine followed by a 2 mg/min infusion. Normal sinus rhythm then returned and the patient slowly improved and regained consciousness.
In this case, the cause of the patient's QT prolongation was likely multifactorial and probably included the chronic use of methadone and electrolyte derangement. Slight hypomagnesemia, hypocalcemia, and hypokalemia were noted. These mild electrolyte abnormalities alone would not be sufficient to result in torsade de pointes, as evidenced by the persistence of episodic torsade de pointes despite electrolyte replacement. Once the methadone was withdrawn, however, no further episodes of torsade de pointes occurred, and the QT interval normalized.
Immediate treatment for patients who develop torsades can be categorized into pharmacologic and nonpharmacologic approaches. Intravenous magnesium sulfate (2 g bolus followed by an infusion of 2-4 mg/min) is the initial therapy, regardless of the serum levels of magnesium. If the patient is hemodynamically unstable and the torsades persists, or if ventricular fibrillation develops, immediate unsynchronized defibrillation is indicated. Serum potassium levels should be maintained in the high-normal range (4.5-5 mmol/L). Overdrive transvenous pacing shortens the QT interval and is highly effective in preventing recurrences, especially in the setting of bradycardia. Maintaining a heart rate greater than 70 bpm protects against drug-induced torsades.
Isoproterenol is useful if temporary pacing is unavailable or while preparing for transvenous catheter insertion. It is contraindicated in patients with congenital LQTS and in ischemic heart disease. Additional treatments include discontinuation of any drug known to cause QT prolongation, correction of electrolyte disturbances, and monitoring the cardiac rhythm until the patient is considered out of risk. Beta-blockers can help prevent symptoms in most people with long QT syndrome, but they do not substantially shorten the QT interval. This class of drugs slows the heart rate and helps prevent tachyarrhythmia. Long-acting preparations such as nadolol and atenolol are usually used. The use of implantable cardioverter-defibrillators (ICDs) is widely considered in patients at high risk of sudden death.
This case illustrates an incident of likely drug-induced torsades de pointes resulting from methadone usage in the setting of electrolyte abnormalities. The case highlights the need for an evaluation for potential cardiogenic causes of syncope in patients who present with an abnormal ECG.A patient presents to the emergency department after a syncopal episode and is found to have a prolonged QT interval; subsequently, the patient develops torsade de pointes. Which of the following clinical scenarios is most likely to result in this condition?
sinus infection
A 45-year-old diabetic woman with a blood glucose of 458 mg/dL (25.4 mmol/L) and no urine.
A number of medical conditions and medications have been shown to result in a prolonged QT interval. A single condition or medication alone is unlikely to result in torsade unless an underlying congenital QT prolongation exists; however, interaction between medications, such as the use of macrolide antibiotics concomitantly with antipsychotics (as in this example), significantly raises the potential for complications such as torsade de pointes.
Which of the following choices would be the best initial therapy for recurrent torsades de pointes without hemodynamic instability for the same patient described in the above question?
Intravenous magnesium sulphate
