Loperamide is an over-the-counter, peripherally-acting, μ-opioid receptor agonist used for the treatment of diarrhea [1]. It undergoes considerable first-pass metabolism, and intestinal absorption is incomplete with poor central nervous system (CNS) penetration related to P-glycoprotein expression limiting abuse potential. However, web-forum analyses over recent years reveal increased discussion of extra-medical uses of loperamide to alleviate opioid-withdrawal symptoms and to achieve euphoria [2]. Further, a series of recentlypublished cases reveals an association with recreational loperamide use (and significantly elevated serum concentrations) with electrocardiographic derangements including QRS complex and QT interval prolongation thought to be related to sodium channel blockade, and potassium channel blockade, respectively, as well as monomorphic ventricular tachycardia and torsades de pointes (TdP) [3-5]. We present a case of high-dose loperamide ingestion leading to bradyarrhythmias, prolongation of the QRS complex and QTc interval, unmasking of Type I Brugada pattern, and episodes of TdP.

A 48 year-old woman, with past medical history significant for alcoholic cirrhosis, depression on sertraline and clonazepam, and polysubstance abuse, was brought into our emergency department by EMS when found appearing somnolent and intoxicated by her daughter. She was noted to be bradycardic with a heart rate of 40-50 beats per minute (BPM) and hypotensive with an initial blood pressure of 70/40 mmHg. Her exam was significant for somnolence without a focal neurological deficit, and a distended abdomen. Laboratory data was significant for serum creatinine of 2.3 mg/dl (0.6 mg/dl baseline), Potassium of 6.2 mmol/l, Magnesium of 1.5 mg/dl, Calcium of 9.9 mg/dl, and ethanol level of 18.0 mg/dl. Her initial electrocardiogram (ECG) was notable for junctional rhythm, junctional premature complexes, and premature ventricular complexes (PVCs) with QRS duration of 120 ms, and QT/QTc of 560/620 ms (Figure 1). Her baseline ECG one year prior was normal sinus rhythm with normal QRS complex and QT interval.

Figure 1: Presenting ECG. Junctional rhythm, PVCs, QRS duration 120 ms, QT/QTc 560/620 ms.

After administration of 2 liters of intravenous normal saline, 45 mEq sodium bicarbonate, 2 g calcium gluconate, insulin, and 2 g magnesium sulfate, her blood pressure and heart rate improved without the need for vasopressor support. Electrolytes normalized, but subsequent ECG revealed sinus bradycardia and competing junctional rhythm, QRS duration of 140 ms, QT/QTc of 600/600 ms, and a Type I

Brugada pattern evident in leads V1-2 (Figure 2). She was admitted to the medical intensive care unit (MICU) for further monitoring and consideration for transvenous pacer insertion for overdrive pacing in case of malignant ventricular tachyarrhythmia. Her transthoracic echocardiogram (TTE) revealed normal bi-ventricular and valvular function. The patient experienced frequent brief runs of polymorphic ventricular tachycardia on overnight monitoring without associated symptoms. After 2 additional boluses of 2 g IV magnesium sulfate and 2 boluses of 45 mEq sodium bicarbonate, events decreased in frequency and fully abated over the next 24 hours. Serial ECGs were significant for ongoing, yet decreasing prolongation of QT and QRS with persistent Brugada pattern. Given the lack of sustained ventricular arrhythmias and decrease in frequency of brief TdP runs, inotrope infusion and overdrive pacing were withheld. Intravenous lipid emulsion, available at bedside, wasnot deemed necessary given the described improvement.

Figure 2: ECG 2 hours later. Sinus bradycardia, junctional rhythm, QRS 140 ms, QT/QTc 600/600, Type I Brugada pattern.

The patient returned to baseline mental status the morning following admission and on further questioning, admitted to taking over 240 mg loperamide over the past few days (maximum daily dose 16 mg) in addition to continued clonazepam and alcohol intake to achieve a high and prevent alcohol and benzodiazepine withdrawal. Toxicology labs the subsequent day reported a loperamide level of 43 ng/ml (reporting limit of 5 ng/ml) while negative for opiates and tricyclic antidepressants. On further questioning, the patient admitted to prior episodes of unheralded syncope over the past years when sober. She was discharged from the MICU after 2 days of monitoring and repeat ECG 3 days later was notable for sinus tachycardia at 114 BPM, QRS duration of 82, QTc of 460, with loss of the Brugada pattern. She was offered an inpatient psychiatric admission and further cardiac evaluation, but left against medical advice prior to additional workup.

We present a case of loperamide-induced QRS and QTc prolongation, bradyarrhythmias, Brugada pattern, and episodes of TdP with resolution of electrocardiographic abnormalities after withdrawal of the offending agent. Despite co-administration of a selective serotonin receptor inhibitor, sertraline, the patient denied abuse and had been on it chronically with an ECG three months prior showing normal sinus rhythm without QRS or QTc prolongation, or Brugada pattern. Further, the patient did not exhibit any signs and symptoms of serotonin syndrome, such as agitation, tachycardia, hypertension, vomiting, or tremor. The patient had a structurally normal heart, and literature review confirmed identical presentations associated with loperamide overdose. While other aforementioned electrocardiographic abnormalities have been described in scant case reports [3-5], to our knowledge, this is the first case report of this agent unmasking a Brugada pattern. Previous reports describe markedly elevated serum loperamide concentrations with presentations including life-threatening ventricular tachyarrhythmias, and varying degrees of QRS and QTc prolongation. Those patients were either managed with isoproterenol infusion, overdrive transvenous pacing in cases of sustained ventricular arrhythmias or cardiac arrest, or observed without intervention in the absence of sustained arrhythmia. Table 1 summarizes previous case reports in terms of presentation and management.

Table 1: Previous Case Reports of Loperamide Toxicity.

The QT interval prolongation related to loperamide has been attributed to inhibition of the human ether-a-go-go-related gene (hERG) responsible for the rapid delayed rectifier potassium current (Ikr); a known mechanism of many QT interval prolonging drugs as well as congenital long QT syndrome type 2 (LQTS2) [3,9-11]. This current mediates cardiac myocyte repolarization and terminates the action potential; hERG inhibition leads to delayed repolarization, predisposes to early after-depolarizations (EADs), heterogeneous myocardial repolarization, and TdP [10]. Drug-mediated slowing of cardiac depolarization (QRS complex prolongation) has also been associated with ventricular arrhythmias particularly with the use of Class IC antiarrhythmic drugs in patients with infarcted or ischemic myocardium [11]. Further, Class IC antiarrhythmic agents are known to cause bradyarrhythmias such as junctional or ventricular escape. Our case, as well as previous reports, demonstrated such effects on both myocardial repolarization as well as depolarization.

The type I Brugada pattern, defined as ≥ 2 mm ST elevation in the right precordial leads with coved appearance and a negative T-wave, is associated with ventricular arrhythmias and sudden cardiac death [12]. Patients may have a normal baseline ECG with induction of the abnormality with drugs or medications with sodium channel blocking properties. The unmasking of the Brugada pattern (often provoked with agents such as cocaine, propofol, tricyclic antidepressants, anesthetics, antiarrhythmic medications, as well as fever or electrolyte imbalance) has been highly-associated with risk for malignant arrhythmias and cardiac arrest [13]. The appearance of a Brugada pattern has been reported in the context of opiate use, such as methadone ingestion and tramadol overdose in previously-published cases [14,15]. The observation of QRS prolongation and Brugada pattern with high serum loperamide concentration suggests potential of sodium channel blockade in a manner similar to Class I antiarrhythmic medications. This finding leads to an opportunity to identify a patient, and potentially relatives, at elevated risk for sudden cardiac death; unfortunately, the patient left against medical advice prior to the initiation of the workup.

The management of high-dose loperamide ingestion is extrapolated from toxidromes related to sodium channel blocker ingestion as well as management of arrhythmias related to QTc prolonging medications. Our approach was based on ECG findings of prolongation of both intervals in consultation with poison control. Hypertonic sodium salts are the treatment of choice in management of sodium channel blocker overdose (e.g. sodium bicarbonate, sodium lactate) and are often administered when the QRS complex is ≥ 120 ms with bolus dosing in the 50-100 mEq range pending normalization of QRS duration or significant alkalemia [16]. The acute management of acquired long QT syndrome and associated TdP involves correction of underlying electrolyte abnormalities, IV magnesium sulfate bolus (2 g) irrespective of the magnesium level, temporary transvenous cardiac pacing at a rate of 90-110 BPM, or Isoproterenol infusion aimed to maintain a heart rate of >90 BPM [16,17]. The latter strategies are often employed with recurrent TdP not responsive to Magnesium administration as a means to prevent pauses, shorten the QTc interval, and enhance repolarization.

Intravenous intralipid, an emulsion in water of soybean oil, glycerin, and egg phospholipid, is considered a reasonable option in the treatment of serious instability related to highly-lipophilic substance ingestion; an option we considered if the patient were to demonstrate worsening cardiotoxic effects. One proposed mechanism is the formation of a “lipid sink”, an intravascular phase that acts to absorb lipophilic free toxin available for myocardial binding. It has been shown to reduce the aqueous plasma concentration of bupivacaine to a much greater extent than expected by hemodilution alone [17,18]. Additional proposed mechanisms of action include the increase of calcium channel current leading to enhanced cardiac function, as well as acting as a direct myocardial energy source [18-20]. Intralipid has been reported effective in cases of local anesthetic, psychotropic drug, beta-blocker, and calcium channel blocker overdoses [18-20]. As our patient had very brief episodes of TdP with improving intervals after sodium bicarbonate and magnesium administration, this therapy was not pursued.

We presented a case describing electrocardiographic conduction abnormalities, TdP, and an unmasked Brugada pattern in the setting of high-dose loperamide ingestion with resolution of aforementioned disturbances by withdrawal of the offending agent, correction of electrolyte abnormalities, and administration of sodium bicarbonate and magnesium sulfate. This case adds to the fairly scant, but growing body of literature describing life-threatening ventricular tachyarrhythmia associated with high-dose loperamide ingestion. Further, this is the first described case of Brugada pattern unmasked in this context. The report adds to the growing awareness of the abuse potential of this over-the-counter medication, and alerts the clinician to recognize associated conduction disturbances and their potential to cause life-threatening arrhythmias.