Loperamide-induced cardiogenic syncope: a case report of a life-threatening presentation of an over-the-counter drug

Abstract

Background

Loperamide at supratherapeutic doses can cause cardiac toxicity, presenting as cardiogenic shock, prolonged QT, malignant arrhythmias, or in severe cases sudden cardiac death. Surreptitious loperamide use is difficult to diagnose. We present an interesting case of loperamide use presenting with polymorphic ventricular tachycardia, cardiogenic shock.

Case summary

A 25-year-old female presented with multiple syncopal episodes for 12 months with an electrocardiogram showing a Brugada-like pattern for which she underwent implantable cardioverter-defibrillator placement. One day following the procedure, she developed cardiogenic shock and was transferred to our tertiary care centre. Extensive workup was unrevealing. She responded well to supportive management, recovering from shock and was transferred to the floor. Unfortunately, she again developed cardiogenic shock, ultimately leading to cardiac arrest. Given the unclear cause for her cardiovascular symptoms, futher medication history was obtained. It was revealed that she was taking 100–150 tablets of loperamide per day. The decision was made to treat with intralipid emulsion therapy empirically given the strong suspicion for loperamide toxicity. The patient recovered well with supportive care. Loperamide levels returned elevated at 190 ng/mL. Repeated studies showed improvement of the conduction block, resolution of arrhythmias, and recovery of right and left ventricular function.

Discussion

Acute loperamide toxicity can present as biventricular failure, with difficult-to-control arrhythmias. It requires a high index of suspicion. Treatment for loperamide toxicity is mainly supportive, lipid emulsion therapy can be considered in severe or refractory cases.

Learning points.

• Loperamide is an over-the-counter anti-diarrhoeal medication that has the potential for abuse. Loperamide toxicity may be present with a wide variety of arrhythmias including conduction block, Brugada-like pattern, ventricular tachycardia, Torsades de Pointes accompanied by cardiogenic shock.

• Loperamide should be kept in the differential diagnosis pathway, especially for young patients presenting with syncope, ventricular arrhythmia, or cardiogenic shock of unclear aetiology.

Introduction

Loperamide is an insoluble piperidine analogue that is used commonly as an over-the-counter anti-diarrhoea medication. It exerts its effects by acting on mu-opioid receptors, inhibiting peristalsis.¹ At therapeutic doses, it lacks central opioid effects due to the action of the P-glycoprotein; however, this may be overcome by ingesting large quantities of the drug or by taking it with an inhibitor of P-glycoprotein. Loperamide at supratherapeutic doses can cause cardiac toxicity, presenting as cardiogenic shock, prolonged QT, malignant arrhythmias, or in severe cases sudden cardiac death.² Surreptitious loperamide use is difficult to diagnose. We present an interesting case of young female showing polymorphic ventricular tachycardia (VT) and cardiogenic shock secondary to loperamide use.

Timeline

Three months prior to admission	Patient presents to an outside cardiology clinic with complaints of weakness, light-headedness, and syncope. Electrocardiogram with new first-degree block, right bundle branch block. Echocardiogram within normal limits. An event monitor is ordered.
Two months prior to admission	Brugada-like morphology was seen on the event monitor. Cardiac magnetic resonance imaging revealed a mildly dilated right ventricular outflow tract (RVOT) but otherwise normal and no apparent scar
Two days prior to admission	Patient presents for scheduled electrophysiology (EP) testing, which reveals isoproterenol induced non-sustained ventricular tachycardia. Implantable cardioverter-defibrillator is placed.
One day prior to admission	Patient experiences syncopal episodes. Device interrogation shows slow ventricular tachycardia (VT). Patient subsequently deteriorates and develops cardiogenic shock.
Transfer to tertiary care hospital	Admission echocardiogram, right heart catheterization consistent with right heart failure. Stabilized in the intensive care unit. Amiodarone initiated; pacemaker settings adjusted. Patient quickly recovers and is transferred to the floor.
Day 7	Re-development of cardiogenic shock. Two episodes of cardiac arrest. Emergent right and left heart catheterization with coronary angiography performed with myocardial biopsy.
Day 8	Discovered the history of loperamide abuse and suspected loperamide-induced cardiotoxicity. Started on intralipid emulsion therapy empirically. Supportive care with aggressive treatment of arrhythmias.
Day 10	Recovery from cardiogenic shock. Marked improvement in ventricular function noted.

Case presentation

A 25-year-old female presented to an outside cardiology clinic with complaints of multiple syncopal episodes with subjective weakness. The syncopal episodes started 12 months prior, occurring at different times of the day, and were triggered by minimal physical activity.

The patient’s past medical history included anxiety, psychogenic seizures, and migraines. She drank socially but did not smoke or report the use of illicit drugs. Her family history was non-contributory.

Electrocardiogram (ECG) in the outside hospital clinic showed sinus rhythm with first-degree atrioventricular (AV) block, atypical right bundle block, and Brugada-like pattern (Figure 1). Echocardiography performed at the time showed normal left and right ventricular size and function with no significant valvular abnormalities. Due to recurrent syncopal episodes, an event monitor was ordered. It revealed episodes of first-degree AV block with junctional escape, right bundle branch block. No high-grade AV block was noted. Further workup included cardiac magnetic resonance imaging, which showed right ventricular outflow tract dilation but was otherwise unremarkable. Given the Brugada-like pattern seen on the ECG, an electrophysiology study was conducted with isoproterenol. By pacing with a drive train of 600 ms and one extra stimulus, VT with a left bundle branch morphology was induced. During the study, there were difficulties mapping VT to a specific position, and the decision was made to place a transvenous implantable cardioverter-defibrillator. In addition, during the procedure, there was difficulty with device capture despite high threshold voltages.

Figure 1.

Electrocardiogram showing sinus rhythm with atypical right bundle branch block, prolonged QRS of 180 ms, and prolonged QTc of 657 ms.

On the day after the procedure, the patient began complaining of light-headedness and shortly afterward became hypotensive. Device interrogation during the episode showed VT with a slow ventricular rate for which sotalol was started. Echocardiography showed biventricular failure with a left ventricular ejection fraction of 40%, severely reduced right ventricular function, and no pericardial effusion. Computerized tomography with pulmonary embolism protocol did not show evidence of a clot. Repeat device interrogation after treatment initiation did not show VT. Despite aggressive resuscitative efforts, she continued to deteriorate requiring pressor support. She was intubated and transferred to our tertiary care cardiac intensive care unit for further management.

Labs on admission to our hospital are mentioned in Table 1. Right heart catheterization showed elevated right-sided filling pressures and reduced cardiac indices consistent with cardiogenic shock (Table 2). Initial differential diagnoses included autoimmune/infiltrative cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, other considerations included ischaemic disease, Lev-Lenegeres disease, sodium channelopathies, and cardiomyopathy secondary to toxic/metabolic causes.

Table 1.

Laboratory parameters at baseline, following cardiac arrest and on discharge

Parameters	On admission	Following cardiac arrest	On discharge	Reference ranges
Haemoglobin (g/dL)	10.4	10.0	7.9	12.0–15.0
Haematocrit %	30.1	30.9	22.0	36–45
Platelet count (per μL)	219 000	68 000	279	150–400
White blood cells (per μL)	9400	15 000	12 000	4.5–11.0
Procalcitonin (ng/mL)	0.14			<0.25
Troponin I (ng/mL)	0.10	0.05		0.00–0.05
B natriuretic peptide (pg/mL)	990			0–100
TSH (mIU/mL)	0.54			0.35–5.00
ESR (mm/hr)	3			0–20
CRP (mg/dL)	3.88			<1.0
Sodium (mmol/L)	136	139	143	137–147
Potassium (mmol/L)	3.8	4.4	4.0	3.5–5.1
Chloride (mmol/L)	104	95	102	98–110
Bicarbonate (mmol/L)	21	34	30	21–30
Magnesium (mg/dL)	2.7	1.9	1.7	1.6–2.6
Creatinine (mg/dL)	0.65	3.04	4.25	0.4–1.00
BUN (mg/dL)	10	32	25	7–25
Lactate (g/dL)	0.5	8.5	0.9	0.5–2.0
Total bilirubin	0.5	1.8	0.6	<0.4
AST	86	3817	18	7–40
ALT	77	1646	6	7–56

Specialty labs
Parameters	Result	Reference ranges
ESR (mm/hr)	3	0–20
CRP (mg/dL)	3.88	<1.0
TSH (mIU/mL)	0.54	0.35–5.00
Antinuclear antigen (ANA) titre	<80	<80
Respiratory viral panel	No viruses detected
Trypanosoma cruzi enzyme immunoassay	Negative
Borrelia burgdorferi enzyme immunoassay	Negative

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TAH, thyroid stimulating hormone.

Table 2.

Cardiac indices on admission and following cardiac arrest

Parameters	On admission	Following cardiac arrest
Right atrial pressure (mmHg)	13	35
Right ventricular pressure (mmHg)	31/11	42/35
Pulmonary artery pressure (mmHg)	32/23, mean 26	40/32, mean 26
Pulmonary capillary wedge pressure (mmHg)	16	32
Pulmonary vascular resistance (Woods units)	2.9	< 1
Cardiac output (L/min)	3.4	4.7
Cardiac index (L/min/m2)	1.8	2.6

Dobutamine was initiated for cardiogenic shock. The electrophysiology team was consulted. Device interrogation showed Torsades (Figure 2) when the device basal rate was dropped to 70/min from 90/min.

Figure 2.

Telemetry rhythm strip showing Torsades de Pointes.

Figure 3.

Cardiac magnetic resonance imaging showing no delayed gadolinium enhancement. Normal right and left ventricular morphology.

Sotalol was discontinued, intravenous amiodarone (150 mg followed by 1 mg/min) and magnesium (2 g over 15 min) were initiated for arrhythmia control. The basal pacing rate was increased, and the detection thresholds were widened. The patient recovered well with supportive measures and was weaned off the dobutamine on Day 2. She was transferred to the telemetry floor for cardiomyopathy workup. Treadmill testing was ordered to investigate exercise-induced changes; however, the patient was unable to complete the test due to pre-syncopal symptoms.

On the 6th day of admission, her clinical condition worsened, and she developed shock requiring pressors, inotropic medication, followed by cardiac arrest. The initial rhythm was pulseless electrical activity which then culminated in monomorphic VT requiring synchronized cardioversion. Return of spontaneous circulation was achieved. Labs following cardiac arrest are mentioned in Table 1. Urgent left and right heart catheterization with endomyocardial biopsy (EMB) were performed (Table 2). This showed elevated right and left filling pressures, and severe cardiogenic shock. The EMB showed normal myocardium with no myocarditis or morphological abnormalities.

Given the unclear cause for her collapse, upon further questioning family revealed that she had been taking at least 100–150 tablets of 2 mg loperamide (maximum recommended dose is 16 mg/8 tablets) per day. Loperamide levels were elevated at 190 ng/mL, and its metabolite, desmethyl-loperamide was 520 ng/mL. Repeatedly, she had been using loperamide since 2019 after gastric ulcer surgery for chronic diarrhoea.

Management involved the prompt treatment of both ventricular arrhythmias and cardiogenic shock. Torsades as mentioned above were treated with intravenous magnesium, and amiodarone, and her basal rate pacing rate was increased to 90/min. She required multiple pressors and inotrope medications for haemodynamic support, filling pressures were optimized with diuresis. Intravenous lidocaine was loaded at 1.5 mg/kg for ventricular arrhythmias. The decision was made to treat empirically with intralipid emulsion therapy given the severity of her presentation and strong suspicion for loperamide toxicity. Her pressors, inotropic support was weaned over 72 h. Repeated studies showed improvement of the first-degree AV block, resolution of arrhythmias, and recovery of right and left ventricular function within 72 h of treatment. Anti-arrhythmic medications were stopped. Loperamide was undetectable in repeat labs 6 days after lipid emulsion therapy. Unfortunately, during counselling regarding loperamide cessation patient left against medical advice and was lost to follow-up.

Discussion

Loperamide toxicity may present with a wide variety of arrhythmias including severe bradycardia, widened QRS intervals, prolonged QTc, polymorphic VT, and cardiac arrest in the setting of overdose.¹ Loperamide-induced cardiotoxicity has been related to inhibition of the delayed rectifier current (IKr) channels, and NaV1.5 sodium channels that lead to increased QRS duration, QTc prolongation, Brugada pattern, delayed repolarization, increased pacemaker capture thresholds, and increased risk of ventricular arrhythmia.^1–3

Of note, biventricular dysfunction may also be associated with loperamide toxidrome. Case reports have noted depressed global ventricular function with a normal coronary angiography study, a takotsubo-like presentation, and left ventricular anterior wall motion abnormality in the setting of loperamide overdose.⁴ While the mechanism remains unclear, the ventricular dysfunction is usually transient, with recovery in ejection fraction with cessation of the drug.

In our case, the abnormalities noted in the EP study, arrhythmias, and ventricular dysfunction were likely related to loperamide toxicity. The strong temporal relationship between the onset of her symptoms and surreptitious use, improvement with removal of loperamide, extensive workup being unremarkable favours this explanation. The patient's clinical worsening 1 week after presentation would not be typical of acute loperamide toxicity, however, she continued to use loperamide during the hospital stay without the knowledge of the medical care team contributing to her unique presentation. The rhythm and pacing threshold all normalized with close observation and no further ingestion of loperamide, therefore, genetic testing or assessment for channelopathies was not pursued.

Loperamide does not appear on regular drug screens and surreptitious use requires a high degree of suspicion to diagnose.⁵ Management of loperamide toxicity is challenging. It includes decontamination, supportive measures, and intralipid emulsion therapy.⁶ Supportive care includes management according to advanced cardiac life support protocols, optimization of electrolytes, and use of medications for haemodynamic stability. Magnesium, overdrive pacing had been utilized in managing Torsades, and sodium bicarbonate for widened QRS complex in these patients. Intralipid emulsion therapy has not been utilized in most of the previously published cases. One theory is that it acts as a ‘lipid sink’ absorbing lipophilic toxins like loperamide in the intravascular phase and, hence preventing myocardial binding.⁶ Intralipid emulsion therapy was successfully used in our case with the patient making a rapid clinical recovery with normalization of echocardiographic parameters, and resolution of arrhythmias.

In summary, acute loperamide toxicity can present with a wide variety of malignant arrhythmias and requires a high index of suspicion to diagnose. Treatment for loperamide toxicity is mainly supportive, and lipid emulsion therapy can be utilized in selected cases.

Lead author biography

Vishwajit Hegde is an Internal Medicine Resident at the University of Kansas. He is interested in clinical education and critical care.

Supplementary material

Supplementary material is available at European Heart Journal—Case Reports.