Long QT Syndrome, Amiodarone Use, and the Mechanism Underlying Lidocaine Toxicity

To the Editor Nathan et al.1 describe management of a neonate with long QT syndrome (LQTS) associated with a compound mutation, refractory ventricular tachycardia necessitating multimodal pharmacotherapy with lidocaine, esmolol, and amiodarone along with ventricular pacing. In addition, they report a presumed neurotoxicity due to lidocaine despite normal serum concentrations. LQTS is a disorder of myocardial repolarization characterized by a prolonged QT interval and is associated with a high risk of life-threatening arrhythmias.2,3 Amiodarone is a class III antiarrhythmic agent that blocks the Ikr current, prolongs repolarization and cardiac refractoriness, and finally predisposes to torsade de pointes (TdP).4 The risk for amiodarone-induced TdP is increased in the presence of electrolyte imbalance and/or concomitant drugs delaying ventricular repolarization. Therefore, avoiding amiodarone in patients with LQTS2–5 is recommended and we suggest that the refractory ventricular tachycardia and episodic TdP were caused by its use. Nathan et al. suggested immature end organ function of the liver, kidney, and brain affecting pharmacokinetic mechanisms of drug distribution and excretion, lower levels of α1-acid glycoprotein resulting in an increased free fraction of lidocaine, and reduction in lidocaine clearance by competitive inhibition of CYP 3A4 by amiodarone as explanations for the lidocaine toxicity despite normal lidocaine concentrations. We disagree with this explanation because each of these hypotheses should have led to increased serum lidocaine concentrations. Therefore, we suggest an alternative hypothesis concerning altered pharmacodynamics rather than pharmacokinetics: that lidocaine neurotoxicity could result from inhibition of ATP-binding cassette transporters (especially P-glycoprotein) by phenytoin, leading to an intracellular accumulation of lidocaine in the brain.6 Because phenytoin was used by Nathan et al., this cellular mechanism might also be implicated in their clinical case and could explain the refractory ventricular tachycardia and the subsequent TdP.7 Nathan et al. rightly point out that aggressive anticipatory clinical management with b-blockers is required for a good outcome, especially in the symptomatic neonate. However, it is also important to stress that avoidance of drugs prolonging QT interval or reducing serum potassium and/or magnesium concentrations remains the cornerstone of the management of patients with long QT syndrome. Of note, the website www.qtdrugs.org provides useful information to check drugs that increase QT interval and may promote TdP. Clément Hoffmann, MD Elisabeth Falzone, MD Department of Anesthesiology and Intensive Care Percy Military Teaching Hospital Clamart Cedex, France [email protected] Marion Augé, MD Sylvie Dinanian, MD Frédéric Jean Mercier, MD, PhD Department of Anesthesiology and Intensive Care Antoine Béclère Hospital–Assistance Publique des Hôpitaux de Paris (APHP)