Methadone Induced Torsades

The Case

A 49 year old male with a reported history of seizures, as well as opiate dependence on methadone, presents the day after a so called “seizure.” He states that he has been feeling out of sorts ever since he had a breakthrough seizure last night while lying in bed. He has no other complaints.

He endorses intermittent adherence to his scheduled home benzodiazepine as well as his valproic acid. Bam, problem solved! You practically know the ICD-10 code by heart. Recurrent seizures in the face of sub-therapeutic anti-epileptic!

Does this feel like his regular seizure prodrome and post seizure event? Yes, he says, entirely like his previous seizures...with the exception that he usually does NOT feel lightheaded and sweaty before his seizures. This time he did.

An ECG is obtained:

The computer calculated the following:

Ventricular rate: 66 bpm
PR interval: 160 ms
QRS duration: 85 ms
QTc: 720 ms

On further history, the patient notes he takes 550 mg of methadone daily, considerably higher than a typical standard dose.

Right in front of you, he experiences the following electrical episode, all the while remaining asymptomatic.

Your diagnosis… Torsades.

Torsades de Pointe (TdP)

TdP is a polymorphic ventricular tachycardia (PVT) in the setting of a prolonged QTc. First described in 1966 by Dessertenne. It is thought to be due to multiple ventricular foci with resulting complexes that vary in axis, duration, and amplitude, usually at a rate of 200-250 [1].

PVT without a prolonged QTc is decidedly not TdP, but simply polymorphic ventricular tachycardia, which has a whole host of other causes. In essence, PVT of any sort usually has three main causes [2]:

Structural heart disease, specifically ischemic heart disease
Molecular or genetic abnormalities in ion channel function (i.e. channelopathies)
Drug interactions or electrolyte abnormalities (electrolytes mainly being magnesium and potassium)
Rarely, it is caused by intracranial hemorrhage

The Fate Of A TdP Rhythm

The actual rhythm of TdP is usually self-limited, and will more often than not spontaneously convert to sinus rhythm, which explains our patient’s reversible syncopal event yesterday. It may also lead to transient cerebral hypo-perfusion which may manifest as seizure-like activity [2]. More concerning, it has a high risk to degenerate into frank ventricular fibrillation and thus sudden cardiac death.

A Little Bit About Prolonged QT Intervals

A prolonged QTc (typically > 440ms in males, > 460ms in females, but for all intents and purposes > 480ms in the emergency department) means prolonged repolarization. Prolonged repolarization means more time for an early depolarization to occur during the repolarization (so called R-on-T phenomenon), triggering the polymorphic electrical storm that is torsades. This risk is higher in bradycardia which allows even more repolarization time in the cardiac cycle for the depolarization to occur [2].

Here’s a mnemonic from First Aid for the Emergency Medicine Clerkship to help remember some of the different causes of torsades [3]:

POINTES

Phenothiazines
Other medications (a long list, methadone is included)
Intracranial bleed
No known cause (idiopathic)
Type I anti-arrhythmics (quinidine, procainamide, dispyramide)
Electrolyte abnormalities (specifically hypomagnesemia and hypokalemia)
Syndrome of prolonged QT (aka Long QT Syndrome)

How To Measure QTc

You can always look at what the computer spits out however often this is incorrect. One quick way is to measure the QT in relation to the R-R interval. It should be less than half.

If you’re feeling fancy or if there is any doubt, use Bazett's formula (QTC = QT / √ RR) for a heart rate of 60-100 and use either Fridericia (QTC = QT / RR 1/3) or Framingham (QTC = QT + 0.154 (1 – RR)) for a heart rate of < 60 or > 100 [4]. There are now multiple i-phone apps that will calculate QTc for you (e.g. MedCalc), and the website MDCalc.com has a quick and easy QTc calculator that is free to use.

ECG Factors That May Imply Impending Torsades

It is interesting that there are a few patterns of ECG findings that may imply impending torsades besides QTc prolongation.

Bigeminy [2]
Progressively prolonged TU waves [5]
Changes in the height or polarity of QRS complexes [6]
Short runs of PVT (these may be confused for monomorphic ventricular tachycardia especially when viewed in isolated leads [2])

A Little Bit About Methadone-Induced Torsades:

Methadone is one of a laundry list of medications known for prolonging the QTc. It predisposes patients to torsades in two key ways [7]:

Prolongs the QTc by blocking the rapid component of potassium ion current
Provides a negative chronotropic effect that slows down the heart rate (methadone is chemically similar to verapamil)

Does The Dose Of Methadone Matter?

Methadone and QTc prolongation has been thought to be dose dependent, but no such established risk between torsades and levels of methadone has been identified. However, the risk of all cause sudden death is raised in anyone who takes the drug, even at “regular” dosing levels [8]. The case literature is littered with examples of methadone-induced torsades. More interesting than this are the multiple case examples of methadone-induced torsades that mimic seizures, even in clinical presentation with witnessed generalized shaking [9].

How should you treat these patients?

Magnesium!
- Dose: 1-2g IV over 30-60 seconds. This can be repeated in 5-15 minutes.
If your patient is bradycardic and intermittently going into TdP in spite of magnesium therapy, isoproterenol can be used to keep the heart rate above 90 bpm. This will accelerate AV conduction and decrease the QT interval. Note that this is contraindicated in the congenital form of long QT as this form is adrenergic-dependent.
Correct any electrolyte derangements, specifically hypomagnesemia or hypokalemia.
Specifically with methadone-induced TdP, consider calling poison control. If the ingestion was recent enough, you may consider GI decontamination and other such therapies.

The Magnesium Went In...But The Patient Is Now In Sustained TdP?

Defibrillate, unsynchronized, even if they miraculously have a pulse.
Never cardiovert! The variability of the QRS waveform makes synchronization impossible [11]
Dose: Defibrillationat 200J biphasic, or 360J monophasic
If defibrillation doesn’t work, consider giving more magnesium.
If still refractory, consider overdrive pacing. As discussed earlier with regards to isoproterenol, increasing the heart rate shortens the QT interval. Therefore pacing, whether transcutaneous or transvenous, can be instituted to increase the heart rate until the QT normalizes and TdP is terminated.

Take Home Points

Intermittent ventricular tachycardia can present as a seizure, always obtain an ECG even if it is a witnessed “seizure.”
While TdP is usually self limited, it has the potential to degenerate to ventricular fibrillation and sudden cardiac death therefore its recognition and treatment is of upmost importance.
Don’t always rely on the ECG computer to interpret correctly, always self check the QTc if there is any concern for prolongation.
Give Magnesium! 1-2 grams over 30-60 seconds and repeat in 5-15 minutes if necessary.
Consider early consultation with cardiology if a patient continues to experiences episodes of TdP is spite of magnesium therapy as they will be more familiar with advanced therapies.

Expert Commentary

My congratulations to Dr. Caffrey for an outstanding review of methadone-induced Torsades de Pointes (TdP). This is an entity that we see in our emergency department (ED) here in Baltimore at least a few times per year, given our ED population’s relatively high use of methadone. I only learned about the sodium channel blocking effects of methadone approximately 10 years ago and often wonder how many cases of this I missed during my prior 10 years of practice in Baltimore! I can’t add much to the excellent discussion of methadone above, so I’ll add just a few comments related to TdP and also syncope vs. seizures.

Prolonged QT and Torsades de Pointes

“Torsades de Pointes” is a term that is often used synonymously with “polymorphic ventricular tachycardia” (PVT) but it is important to understand the difference. TdP is a specific type of PVT that is associated with a prolonged QT interval. This difference between the two determines the therapy: patients with TdP should never be treated with Type I medications such as amiodarone or procainamide because they may further prolong the QT and induce intractable TdP (unfortunately I’ve seen this happen). On the other hand, generic PVT with a normal QT can be treated with these medications if needed.

If the patient is in the midst of persistent TdP, the best therapy is electricity. If shocks don’t work, magnesium can be added. If shocks do work, a post-conversion bolus and infusion of magnesium should be initiated. If the TdP is intermittent, on the other hand, and the patient is relatively stable, then magnesium may be used initially instead of shocks. Overdrive pacing may also be initiated in order to increase the underlying heart rate. Accelerating the heart rate will produce a relative decrease in the QT interval and termination of the arrhythmia. Overdrive pacing may be performed chemically with isoproterenol or by electrical pacing. Regardless of how the TdP is terminated, immediate efforts should be made to identify and reverse the underlying cause of the prolonged QT.

Syncope and Seizures

The case presented is a classic example of how arrhythmias can mimic seizures. In fact it is not at all uncommon for patients to have syncope due to an arrhythmia and then have some myoclonic jerking for 10-15 seconds and be misdiagnosed by bystanders or health care providers as having a seizure. A major difference between a true seizure vs. syncope is that the patient with syncope should have a minimal period, or absence, of confusion after the “spell” and typically the shaking lasts for no more than 20-30 seconds. In addition, patients with true seizures are more likely to have tongue biting. A prior history of coronary disease or congestive heart failure favors syncope, whereas a prior history of seizures favors a recurrent seizure. Prolonged sitting or standing before the “spell,” or nausea or diaphoresis immediately afterwards favors syncope. An aura prior to the spell favors a seizure.

Because syncope can so easily be misdiagnosed as a seizure, it is critically important to always obtain an electrocardiogram (ECG) in any patient with a first-time seizure. The ECG should then be scrutinized for signs of arrhythmia, such as AV block, hypertrophic cardiomyopathy, Brugada Syndrome, arrhythmogenic right ventricular dysplasia, pre-excitation, and of course prolonged QT.

Congratulations again to Dr. Caffrey and the creators of the NUEM Blog for their valuable work!

References

Dessertenne, F., [Ventricular tachycardia with 2 variable opposing foci]. Arch Mal Coeur Vaiss, 1966. 59(2): p. 263-72.
Choudhuri, I., et al., Polymorphic ventricular tachycardia-part I: structural heart disease and acquired causes. Curr Probl Cardiol, 2013. 38(11): p. 463-96.
Stead, L.G., S.M. Stead, and M.S. Kaufman, Torsade, in First Aid for the Emergency Medicine Clerkship. 2006, McGraw-Hill Medical Pub. Division: New York. p. vii, 484 p.
Viskin, S., The QT interval: too long, too short or just right. Heart Rhythm, 2009. 6(5): p. 711-5.
Kirchhof, P., et al., Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation. J Am Coll Cardiol, 2009. 54(2): p. 143-9.
Buchanan Keller, K. and L. Lemberg, Torsade. Am J Crit Care, 2008. 17(1): p. 77-81.
Ashwath, M.L., M. Ajjan, and T. Culclasure, Methadone-induced bradycardia. J Emerg Med, 2005. 29(1): p. 73-5.
Khalesi, S., H. Shemirani, and F. Dehghani-Tafti, Methadone induced torsades de pointes and ventricular fibrillation: A case review. ARYA Atheroscler, 2014. 10(6): p. 339-42.
Hasnain, M., et al., Methadone and torsade de pointes: how can we better understand the association? Am J Med, 2013. 126(9): p. 757-8.
Foley, P., P. Kalra, and N. Andrews, Amiodarone--avoid the danger of torsade de pointes. Resuscitation, 2008. 76(1): p. 137-41.
Marill, K.A., Tachydysrhythmias, in Emergency medicine : clinical essentials, J. Adams and E.D. Barton, Editors. 2013, Elsevier Saunders: Philadelphia, PA. p. xxviii, 1859 pages.