Larry Mellick, MD, MS, FAAP, FACEP
Professor of Emergency Medicine
Medical College of Georgia

Sean Arbuckle, DO
Resident Physician, Department of Emergency Medicine
Medical College of Georgia

Pearl: Doxylamine succinate overdose can cause prolongation of the QT interval and can be associated with wide complex tachycardias. Amiodarone also can cause widening of the QT interval and should not be used to treat wide complex tachycardia when the offending drug already has caused prolongation of the QT interval.

Presentation: A 31-year-old man was found by power company workers face down and unresponsive in the mud along a local canal bank. The EMS crew indicated that the patient was immobile and unresponsive until they turned him on his back. At that time, he became agitated, made incoherent verbalizations, and any physical stimulation caused him to begin shaking and thrashing his upper extremities.On the cardiac monitor, he was noted to have a wide complex tachycardia.

On presentation to the emergency department, the patient appeared to have an anticholinergic toxidrome. His initial vital signs were temperature 43.5 degrees (39.8 degrees 20 minutes later), blood pressure 144/78, heart rate 144 /minute, respirations 23/minute. He was febrile, incoherent, agitated with any stimulation, his skin was flushed, his pupils were widely dilated (see Figure 1), and the cardiac monitor demonstrated a wide complex tachycardia. The patient's clothing was covered with canal bank grass and debris, and his front teeth had a coating of mud. (See Figure 2.)

The wide complex tachycardia was diagnosed as ventricular tachycardia. (See Figure 3.) Intravenous lines were placed, and normal saline infusion was started. Amiodarone 150 mg IV over 10 minutes was administered without any apparent improvement. One ampule of sodium bicarbonate subsequently was administered. The patient's QRS narrowed and demonstrated a "Brugada pattern." (See Figure 4.) Further review of the ECG demonstrated a prolonged QTc to 512. A second dose of amiodarone (150 mg) was discontinued, and magnesium sulfate, 1 gram, was given intravenously as well as an additional bolus of sodium bicarbonate. An additional gram of magnesium sulfate and at least 3 more ampules of sodium bicarbonate were administered as the improvement with QRS narrowing eventually would wane. A lidocaine bolus and infusion were started just prior to the patient being transferred to the intensive care unit.

The patient had an overdose with a sleeping medication several weeks prior to this overdose event. Following recovery, the patient admitted to having again ingested the same brand of sleeping medication and described an orange box color that was consistent with the doxylamine-containing formulation.

Discussion: The learning points from this case are important. Overdoses of diphenhydramine or doxylamine can cause a drug-induced sodium channel blockade and medication-induced long QT interval, wide complex tachycardias, and a Brugada-like pattern on the electrocardiogram.^1,2,4 While our usual reflex response is to order amiodarone for wide complex tachycardias, this therapeutic option is the wrong choice in this setting. In fact, amiodarone actually may exacerbate the condition and cause further deterioration of the patient's condition. Instead, just as for tricyclic antidepressant overdoses, sodium bicarbonate is the treatment of choice.^3,4

There are six structural classes of antihistamines, and doxylamine and diphenhydramine are in the same structural class (ethanolamines). Overdoses with doxylamine are reported less frequently, but there is evidence that fatalities occur commonly after large overdoses.^5,6 In addition to being reversible competitive inhibitors of histamine receptors and competitive inhibitors of muscarinic receptors, first-generation H1-receptor blockers disrupt cortical neurotransmission and block fast sodium channels. Consequently, seizure activity and cardiac conduction delays (widening of the QRS interval) are seen with toxic amounts of the drug. QT interval prolongation occurs with diphenhydramine, and the ECG changes are identical to those that occur with tricyclic antidepressants. TCA-induced cardiac toxicity² and torsades de pointes have been described.⁷ As seen in our patient who overdosed on doxylamine, the Brugada sign also has been reported with diphenhydramine overdose.¹ And, just as in TCA overdose, intravenous sodium bicarbonate improves impaired sodium conduction that may result from overdoses of these antihistamines.^3,4

To make matters worse for the unsuspecting clinician, amiodarone, the ACLS recommended therapy for wide complex tachycardia, also prolongs the QT interval. Amiodarone exerts its electrophysiologic effects by prolonging the action potential duration and consequently prolongs repolarization, which is manifest on the ECG as a prolonging of the QT interval.⁸ Consequently, amiodarone actually can worsen the patient's condition and should not be administered. An impressive number of other drugs can cause QT prolongation and when these drugs are used in suicide attempts, the patient may present with a widened QRS, and amiodarone may be considered as a therapeutic option with potentially tragic consequences.^9,10

References:

1. López-Barbeito B, Lluis M, Delgado V, et al. Diphenhydramine overdose and Brugada sign. Pacing Clin Electrophysiol2005;28:730-732.
2. Zareba W, Moss AJ, Rosero SZ, et al. Electrocardiographic findings in patients with diphenhydramine overdose. Am J Cardiol 1977;80:1168-1173.
3. Sharma AN, Hexdall AH, Chang EK, et ak. Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. Am J Emerg Med 2004;22:496.
4. Clark RF, Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: Successful treatment with sodium bicarbonate. Ann Emerg Med 1992;21:318-321.
5. Köppel C, Tenczer J, Ibe K. Poisoning with over-the-counter doxylamine preparations: An evaluation of 109 cases.Hum Toxicol 1987;6:355-359.
6. Bockholdt B, Klug E, Schneider V. Suicide through doxylamine poisoning.Forensic Sci Int 2001;119:138-140.
7. Joshi AK, Sljapic T, Borghei H, et al. Case of polymorphic ventricular tachycardia in diphenhydramine poisoning. J Cardiovasc Electrophysiol 2004;15:591-593.
8. Nkomo VT, Shen WK. Amiodarone-induced long QT and polymorphic ventricular tachycardia. Am J Emerg Med 2001;19:246-248.
9. Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: Clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J 2000;21:1216-1231.
10. Letsas KP, Efremidis M, Filippatos GS, et al. Drug-induced long QT syndrome.Hellenic J Cardiol 2007;48:296-299.

Online Resources:

1. http://emedicine.medscape.com/article/812828-overview
2. http://www.cvpharmacology.com/antiarrhy/sodium-blockers.htm
3. http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm

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