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Abstract
A young man presented to the emergency department with seizures and recurrent episodes of polymorphic ventricular tachycardia (PMVT)/torsades de pointes (TdP) requiring cardioversion and administration of intravenous magnesium. A battery of tests performed to identify a cause for his arrhythmias and seizures were all normal. A revisit of history with family revealed he had consumed over 100 tablets/day of loperamide for the past 1 year. A prolonged QT interval on his ECG raised concerns for long QT syndrome (LQTS) (congenital or acquired). Our patient was suspected to have loperamide-induced cardiotoxicity. TdP is a specific PMVT that occurs with a prolonged QT interval and is usually drug-induced. Less frequently, congenital LQTS may be implicated. With supportive care, including mechanical ventilation, vasopressors and temporary transvenous overdrive pacing, our patient recovered completely. We describe the importance of a systematic and time-sensitive approach to diagnosing critical illness. Loperamide overdose may cause QT prolongation, life-threatening arrhythmias/cardiogenic shock, or cardiac arrest. Seizures/epilepsy may also be a manifestation in young patients. There is a substantial need to revisit the safety of over-the-counter medications and increasing awareness of manifestations of drug overdose.
- arrhythmias
- pacing and electrophysiology
- adult intensive care
- drug misuse (including addiction)
- toxicology
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- arrhythmias
- pacing and electrophysiology
- adult intensive care
- drug misuse (including addiction)
- toxicology
Background
Polymorphic ventricular tachycardia (PMVT) is an uncommon cardiac arrhythmia with multiple causes. Torsades de pointes (TdP), a specific subtype of PMVT, is associated with prolonged QT interval (congenital or acquired). Several medications can cause QT prolongation (acquired), including loperamide, an over-the-counter (OTC) antidiarrhoeal agent. As a synthetic opioid, loperamide acts via the μ-opioid receptors in the gastrointestinal tract (GIT), to inhibit gut peristalsis and reduce intestinal fluid/electrolyte losses. Over time, loperamide has found off-label use in the self-treatment of opiate withdrawal, particularly in higher than recommended doses, to produce ‘opioid-like’ euphoria.1 Loperamide can cause fatal cardiotoxicity by inhibition of the delayed-rectifying human ether-à-go-go related gene (hERG) potassium ion (K+) current channels, prolonged cardiac repolarisation (QT prolongation) and life-threatening dysrhythmias (TdP/PMVT) or sudden cardiac death (SCD).2 The high addictive/abuse potential of loperamide, coupled with its risks of cardiotoxicity, have raised concern regarding its OTC use in recent years.3
With these considerations, we describe the case of a young man who presented with recurrent TdP/PMVT, and subsequent cardiovascular collapse. With timely acquisition of an accurate health history and an understanding of the complex clinical presentation of long QT syndromes (LQTS), we were able to diagnose and treat a patient with lethal arrhythmias induced by loperamide. We highlight the essential steps in the challenge of caring for patients with complex cardiovascular illness and life-threatening arrhythmias.
Case presentation
A 27-year-old man with a history of epilepsy (for last 5 years, not on antiepileptic medications) presented to our emergency room (ER) with sudden-onset generalised tonic-clonic seizures. On arrival, his blood pressure was 106/64 mm Hg, pulse was 87 beats/min, respiratory rate was 21 breaths/min, pulse oximetry (SpO2) measured 99% on room air. Within minutes of arrival in the ER, he developed runs of PMVT/TdP followed by pulseless electrical activity (PEA). He received immediate advanced cardiac life support (ACLS) and intubation. With brief periods of stabilisation, he was noted to develop recurrent PMVT/TdP that required repetitive cardioversions and administration of intravenous magnesium (figures 1 and 2). He was then transferred to the intensive care unit (ICU) where he soon required high vasopressor support (norepinephrine) for cardiogenic shock. Laboratory and neurological workup (complete blood count, blood chemistry including urea, creatinine, electrolytes, thyroid profile, arterial blood gas measurements, brain MRI and cerebrospinal fluid studies were performed. A transthoracic echocardiogram showed normal-sized cardiac chambers but moderate-to-severely reduced left ventricular systolic function (ejection fraction 30%). ER and ICU 12-lead ECGs revealed QT prolongation (537 ms) (figures 3 and 4). An electroencephalogram (EEG) showed slowing and intermittent spikes coincident with documented dysrhythmias. Family history was significant for SCD (sister died at age 15 years).
Rhythm strip showing recurrent polymorphic ventricular tachycardia.
Rhythm strip showing resolution of polymorphic ventricular tachycardia (cardioversion); white arrow shows return to normal sinus rhythm.
Initial ECG on presentation showing a prolonged QT interval.
Prolonged QTc interval during hospital stay.
Differential diagnosis
With a clinical presentation of seizures and previous history of epilepsy our initial diagnostic workup targeted the central nervous system (CNS) (infection, stroke or an occult brain tumour) with possible secondary cardiovascular effects (stress-induced cardiomyopathy). However, a thorough laboratory and neurological workup were all unremarkable.
Given recurrent PMVT/TdP requiring ACLS followed by cardiovascular collapse within 12–24 hours of ICU admission, we moved away from suspecting a primary CNS pathology to revisiting his cardiovascular findings. ECGs were reviewed carefully, with emphasis on TdP/PMVT as the predominant and recurrent tachyarrhythmia and a prolonged QT interval. Following a systematic deductive process, we revisited history with family and found the patient had consumed excessive amounts of loperamide. His family reported he took loperamide for diarrhoea as prescribed by a local general practitioner (GP) over the last 5 years. However, he had increased his daily intake of loperamide over the last 1 year. We derived he maybe addicted to the drug’s ‘euphoric’ effects. We did not find evidence of any other opiate addiction in our patient. However, urine drug screening was not performed. With these details, our diagnostic differentials narrowed to a possible congenital versus drug-induced LQTS.
Treatment
Following discovery of a prolonged QT and recurrent PMVT, we decided to proceed with the insertion of a temporary transvenous pacemaker for overdrive pacing. Electrolytes were corrected. Figure 3 shows a 12-lead ECG just prior to pacing with a QTc measurement of 537 msec. Following transvenous pacing, the patient had no further episodes of tachyarrhythmia and EEG spikes resolved. Norepinephrine was weaned off. He was started on a low dose of bisoprolol for left ventricular dysfunction. Antibiotics and antiepileptic agents were gradually de-escalated.
Outcome and follow-up
Temporary pacing removed after 72 hours. His QTc interval normalised (540–440 ms). The patient was successfully extubated. After recovery, the patient confirmed he had been taking loperamide for diarrhoea over the last 5 years, but had increased his intake to over 100 tablets/day (with soda) for the last 1 year due to addiction. He did not report taking other concomitant medications that could contribute to a prolonged QT interval. He did not endorse suicidal intent.
A transthoracic echocardiogram 5 days later revealed improvement of left ventricular systolic function to 55%. At 1-month follow-up, studies showed a normal QT interval (figure 5). Due to family history of SCD, workup for congenital LQTS was performed to exclude the possibility of a concealed congenital LQTS exacerbated with loperamide. A family pedigree chart is shown (figure 6). Exercise tolerance test revealed a normal QT both during exercise and in recovery phase. Genetic workup revealed a variant of uncertain significance in FLNC gene. Both the patient and family were counselled regarding potential QT prolonging medications and the patient was also referred to gastroenterology for workup of his altered bowel habits (no specific cause identified). Overall, the patient is now well, withdrawn off bisoprolol 6 months post discharge and with a QT interval within normal limits.
Resolution of prolonged QTc on follow-up.
Family pedigree.
Discussion
PMVT is a rapid ventricular tachycardia (faster than 100 beats/min) in which the QRS complexes vary in coupling interval, morphology and axis on a beat-to-beat basis. PMVT has two distinct forms: PMVT without QT prolongation or with QT prolongation. PMVT with QT prolongation is known as TdP and is usually caused by electrolyte imbalances (hypomagnesaemia or hypokalaemia) or drugs (Class Ia, Ic, III antiarrhythmics, tricyclic antidepressants, antipsychotics, phenothiazines, antihistamines, opioids, macrolides and antifungals). VT storm is a lethal syndrome defined as three or more sustained episodes of VT, or appropriate implantable cardioverter defibrilator shocks during a 24-hour period.4
Our case highlights key aspects in caring for the critically ill. First, ‘time’ means ‘life’. To this end, teams must obtain an accurate historical account from distressed caregivers at the initial point of contact since this significantly impacts outcomes. Various sociocultural stigma associated with recreational drug abuse may prevent caregivers from divulging accurate information, as in our case. For the first 24 hours of his hospitalisation, the patient underwent shotgun diagnostic testing and treatment for instability as it arose (ie, repeated cardioversion for recurrent arrhythmias, escalating antiepileptics for seizures, escalating vasopressors for cardiovascular collapse and a battery of tests to identify a potential CNS source of infection to explain seizures), with little clarity as to the pathophysiology of illness. Once history was revisited and a drug overdose found, we were able to prevent escalation of futile therapies (adding more antiepileptics for seizures) and de-escalate unnecessary therapies (antibiotics for possible meningitis) and focus on consulting the correct teams (electrophysiology) and managing the observed QT prolongation and associated cardiovascular collapse.
Second, critical cognitive skills help analyse key data in dissecting patterns that appear ‘amiss’ for a particular disease course. For instance, profound cardiovascular depression (although possible) would be unusual for a primary CNS event. TdP/PMVT as a predominant arrhythmia should always prompt review for an ominously prolonged QT. Identification of a prolonged QT would then alert an astute physician to look for both congenital or acquired causes and review medications and family history. Unexplained epilepsy without an observed structural CNS lesion should also raise concern of the possibility of seizures provoked by ventricular arrhythmias (transient loss of blood supply to CNS), as LQTS may be asymptomatic (40%) or cause seizures as it degenerates into a lethal dysrhythmias (10%).5 Having a clear understanding of the pathophysiology behind clinical manifestations is central to taking care of any patient, particularly a critically ill one.
Third, it is vital to be aware of the critical side effect profile of seemingly benign OTC medications. Loperamide (or Imodium) is a readily available and exerts its antidiarrheal effects via μ-opioid receptors in the GIT, inhibiting smooth muscle peristalsis and limiting fluid/electrolyte losses from the large intestine. In recommended doses (maximum adult dose; 16 mg/day) systemic absorption is extremely low and curtailed by efflux by intestinal P-glycoprotein (P-gp) and first-pass metabolism (liver; cytochrome P-450 (CYP450)). In doses recommended for diarrhoea (4–16 mg/day), loperamide is rarely associated with side effects and does not penetrate the blood–brain barrier, lacking the euphoric effects of opiates. It is when either recommended doses of loperamide are used with a P-gp or CYP450 inhibitors or in supratherapeutic doses (higher than 60 mg daily for ‘off-label’ management of opiate withdrawal) that efflux and first-pass metabolism is overwhelmed, allowing drug entry into CNS, driving psychoactive and serious cardiovascular events.6 Benzodiazepines, opiates and antidepressants (mostly selective serotonin reuptake inhibitors (SSRIs)) are commonly reported to be used in combination with loperamide. SSRIs are P-gp inhibitors and increase loperamide bioavailability. Since loperamide is metabolised via the cytochrome P450 (CYP450), CYP2C8 and CYP3A4 isozymes, its concomitant use with CYP3A4 (ie, cimetidine, omeprazole, grapefruit juice, tonic water and itraconazole); and CYP2C8 (ie, gemfibrozil) inhibitors can also increase loperamide plasma levels, and toxicity.7 hERG channel are major portion of proteins that conduct K+ out of myocardial and Purkinje cells and allow membrane repolarisation . In the ventricles, loss-of-function mutations in genes encoding K+ channels (mainly hERG channels) cause hereditary LQTS—placing these patients at risk for SCD. Mutations in the genes for KvLQT1 (IKs) and hERG (IKr) account for 80%–90% of all hereditary LQTS. hERG is also susceptible to low extracellular K+ levels and drug binding, both of which decrease channel function (drug‐induced LQTS), resulting in risk for PMVT/ventricular fibrillation and SCD.8
Loperamide prolongs cardiac repolarisation by inhibiting delayed-rectifying hERG K+ current channels (slow potassium rectifying current, IKr). Once repolarisation is delayed, early depolarisation in the form of premature ventricular contraction can trigger life-threatening dysrhythmias, that is, TdP/PMVT. Cells become refractory, allowing action potentials to re-enter and continue the lethal cycle of TdP. QT prolongation reflects the delay in repolarisation (ie, potassium channel blockade) while QRS prolongation is related to a delay in depolarisation (ie, sodium channel blockade). Currently, the exact cellular mechanisms underlying loperamide-induced cardiotoxicity are not completely understood. For instance, hERG channel blockers with comparable potencies, but different binding and unbinding kinetics pose different levels of proarrhythmia risk, and there is currently no information regarding the dynamics of loperamide and hERG channel interaction. In addition, loperamide’s block of both outward hERG current and inward fast Na current may vary with systemic free drug levels.9–11 Our case is limited in that free drug levels of loperamide were not checked (due to unavailability).
And finally, although initially approved as a ‘controlled-substance’ in the USA, loperamide was ‘decontrolled’ in 1982 due to its safety and low physical dependance risk. Cheap and readily available, loperamide has gained alarming popularity in the off-label, self-management of opiate-withdrawal (‘poor-man’s methadone’). Since 2015, loperamide associated adverse drug reactions (ADRs) have risen dramatically. LQTS, TdP/PMVT, cardiac arrest and cardiomyopathy are reported, particularly with chronic use of doses ranging from 70–1600 mg/daily (4–100 times recommended dose).12–14
Physicians can play a crucial role in detecting and reporting cases of loperamide abuse and toxicity. Being aware of local drug use patterns and being well-versed in clinical signs and symptoms of potential toxicity from drugs, will help reduce mortality. We recommend that healthcare providers report such adverse events to local regulatory authorities. A range of other important strategies have been suggested, including registering cases in an online ADRs database. In addition, pharmacists can discourage use by storing products with high abuse potential out of sight and referring patients to GPs, who can then take a close view and consider referral to special addiction services (for appropriate treatment).7
Patient’s perspective
I was very satisfied with the treatment and thankful to the whole team for taking care of me in the best possible way.
Learning points
Emergency department/intensive care unit teams caring for critically ill patients should focus on obtaining an accurate historical account from caregivers at initial point of contact. Physicians should also frequently revisit history; particularly where the patient’s clinical presentation is not fully explained by reported events.
Evaluation of critically ill patients must follow a systematic approach with a critical analysis of available data and a sense of pattern recognition (or lack thereof) that fits disease trajectory. Attention to detail helps clinicians find ‘what does not fit’ within a presumed diagnosis.
Long QT syndrome (LQTS; acquired or congenital) can present with central nervous system symptoms (seizures).
Torsades de pointes/polymorphic ventricular tachycardia often occurs in the pretext of drug-induced LQTS and should prompt search for causative agents.
Loperamide is a cheap and readily available antidiarrhoeal. While caution has been exercised by regulatory bodies in curtailing open access to QT prolonging medications, a growing number of reports of near-fatal cardiac events secondary to drug misuse, should prompt a review of these guidelines.
Physicians can play a key role in being familiar with the local drug abuse patterns, familiar with the clinical presentations of drug overdoses, as well as in the timely reporting of such cases to local authorities.
Ethics statements
Footnotes
SI and SMF are joint first authors.
Twitter @MasoomaAqeel2
Contributors SI wrote the manuscript with input from SMF. SI collected the data from the medical records and took consent from the patient for the publication of the case report. All the authors contributed in planning and designing of the manuscript. YS and MA reviewed and supervised the case report.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer-reviewed.