Sunday, February 17, 2013

Adjunct antiarrhythmic therapy in refractory ventricular tachycardia: lidocaine versus procainamide

Few management decisions are more controversial at my institution than which antiarrhythmic agent to select in patients with ventricular tachycardia (VT) that remains refractory to first-line therapies (e.g., amiodarone, maximally-tolerated doses of beta blockers) or in whom these therapies are contraindicated.  In many patients with advanced structural heart disease, lidocaine and procainamide are the only two remaining options. While some renewed enthusiasm for procainamide has emerged as of late -- in part a result of its re-appearance in the advanced cardiac life support algorithm for VT [1] -- much of the evidence to support procainamide is derived from studies evaluating its use as monotherapy.  When used alone, procainamide appears to be more effective than lidocaine in a heterogenous patient population [2,3].  However, for a growing number of patients with refractory VT, the challenge facing clinicians is rarely which agent to utilize first (as this is unquestionably amidoarone [4,5]) -- it is which agent to use as adjunct therapy, a scenario where minimal to no data exists to guide clinical decision-making.

Although many clinicians prefer procainamide for this purpose, I hope to make a case for at least attempting a trial of lidocaine, and why I often favor it as the initial adjunct antiarrhythmic to select in patients with advanced structural heart disease and refractory VT.

First, several disadvantages of using procainamide in this patient population are worth highlighting. From a pharmacokinetic standpoint, procainamide has a large volume of distribution, requiring that patients receive a considerable loading dose (i.e., 17 mg/kg) to produce a therapeutic effect. Moreover, procainamide and its active n-acetyl metabolite (NAPA) have a longer half-life than lidocaine -- about 3 and 5-8 hours, respectively, in patients with normal metabolic function.  These times may be prolonged by as much as five-fold in patients with hepatic and/or renal impairment, conditions that are common in patients with end-stage heart failure.  If toxicities (i.e., negative inotropy, hypotension) do emerge following the administration of procainamide, they may persist for extended periods of time, which is especially problematic in patients with compromised baseline hemodynamics. Although monitoring serum concentrations of procainamide and NAPA may ameliorate these risks, few medical centers still perform these tests and the turnaround time for referral assays may take up to a week to produce results. Finally, oral procainamide is no longer available in the US, so in patients for whom a more permanent solution (e.g., cardiac transplantation,  ventricular assist device implantation, VT ablation) is not available, procainamide does not represent a long-term management strategy.

Anecdotally, in the patients with refractory VT that we have treated with procainamide, I have seen at least a third become hemodynamically unstable, many requiring the initiation of inotrope and/or vasopressor therapy and almost all requiring a reduction in their maintenance infusion (often not adequate enough to maintain suppression of the arrhythmia), if not discontinuation of the drug altogether.

Although lidocaine may be less effective as monotherapy, its use in conjunction with amiodarone has not been evaluated in clinical trials, and the combination may actually produce synergistic antiarrhythmic effects. Theoretically, the addition of lidocaine to amiodarone results in more pronounced blockade of sodium channels (given that lidocaine inhibits both open and inactivated channels) as well as prolongation of the effective refractory period. Furthermore, lidocaine demonstrates enhanced activity in depolarized myocardial cells, a characteristic that is common in ischemic tissue. Given the limited hemodynamic reserve in patients with advanced structural heart disease, the increased myocardial oxygen demand that results from prolonged periods of VT is likely to produce transient periods of ischemia where lidocaine may be especially useful.

From a pharmacokinetic standpoint, lidocaine has a smaller volume of distribution than procainamide, so smaller loading doses (i.e., 1-1.5 mg/kg) are required to produce a therapeutic response.  Moreover, the much shorter half-life of lidocaine (1-2 hours in patients with normal hepatic function) means that if a therapeutic effect is not observed soon after initiation (or if toxicities emerge), the drug is essentially eliminated from the body within hours.  While lidocaine may also produce adverse hemodynamic effects, these are more rare at the doses used clinically and are far less pronounced than those observed with procainamide.  Finally, if patients do respond to lidocaine and are not candidates for the advanced therapies mentioned above, the drug may be converted to oral mexiletine for chronic maintenance therapy.

In summary, there is little evidence to guide the management of patients with advanced structural heart disease and refractory VT who are already receiving amiodarone or other antiarrhythmic therapy.  Although procainamide appears to be more effective than lidocaine when used as monotherapy, no data exists to compare their adjunct use with amiodarone, a clinical scenario that is becoming more common in patients who are awaiting advanced therapies (or in whom these therapies are not viable). While the advantages of lidocaine in this scenario are largely theoretical (but reasonable based on existing data), it is the arguably the safer of the two drugs in this population, and the only one for which a long-term oral option exists. As a result, unless a more permanent solution for managing refractory VT is already known and imminent, I think it is reasonable to at least attempt a trial of lidocaine as the adjunct antiarrhythmic in most patients.

References
  1. Neumar RW, Otto CW, Morrison, LJ, et al. 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science: Part 8: Adult Advanced Cardiovascular Life Support. Circulation. 2010;122:S729-S767.
  2. Gorgels AP, van den Dool A, Wellens HJ, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol. 1996 Jul 1;78(1):43-6.
  3. Komura S, Chinushi M, Aizawa Y, et al. Efficacy of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Circ J. 2010 May;74(5):864-9.
  4. Dorian P, Cass D, Barr A, et al. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med. 2002 Mar 21;346(12):884-90.
  5. Somberg JC, Bailin SJ, Molnar J, et al; for the Amio-Aqueous Investigators. Intravenous lidocaine versus intravenous amiodarone (in a new aqueous formulation) for incessant ventricular tachycardia. Am J Cardiol. 2002 Oct 15;90(8):853-9.

2 comments:

Jonathan Farrow said...

A loading dose of 17mg/kg? Isn't this the maximum total dose?

Brent N Reed said...

Yes, procainamide should be administered at 20-50 mg/min until the arrhythmia is suppressed, QRS prolongs (> 50%), or hypotension/hemodynamic instability ensues, up to a maximum loading dose of 17 mg/kg (which is well over 1 g for most patients). After the loading dose, a maintenance infusion should be initiated (usually 2-4 mg/min); there is no maximum cumulative dose for the maintenance infusion, so if serum concentrations of procainamide or NAPA cannot be measured, patients should be monitored for signs/symptoms of procainamide toxicity.