Sympathomimetic Overdose With Lisdexamfetamine in a Pediatric Patient Resulting in Stress Cardiomyopathy—A Case Report

Abstract

BACKGROUND:

Sympathomimetic overdoses, as seen in amphetamine ingestions, are known to have cardiac effects ranging from tachycardia and hypertension to coronary vasospasm and myocardial infarction. Stress cardiomyopathy is rare in pediatric patients and has not been reported in association with the extended-release preparation of lisdexamfetamine, indicated for the treatment of attention-deficit hyperactivity disorder.

CASE SUMMARY:

A 17-year-old girl presented with an intentional ingestion of lisdexamfetamine and signs and symptoms of a sympathomimetic toxidrome. She was found to have severe cardiac dysfunction, which worsened within 24 hours of ingestion and required intubation and management of acute heart failure.

CONCLUSIONS:

Stress cardiomyopathy due to extended-release stimulant ingestion is a possible outcome of intentional ingestion. Providers should be vigilant and monitor for signs of cardiac dysfunction.

KEY POINTS.

Question: What are the potential cardiovascular effects and their timing in extended-release amphetamines (e.g., lisdexamfetamine) toxicity?

Findings: A case report of severe pediatric stress cardiomyopathy post-intentional lisdexamfetamine ingestion, which presented with a biphasic response. Contributing factors included extended-release formulation, potential presence of pharmacobezoars, and improved bowel perfusion with acute heart failure treatment.

Meaning: Early echocardiogram and ongoing cardiac monitoring are prudent for patients post-extended-release amphetamine overdoses. Symptoms may worsen for up to 24 hours or more.

Lisdexamfetamine is a pro-drug stimulant widely used in the treatment of attention-deficit hyperactivity disorder (ADHD). It was developed as an extended-release alternative to short-acting amphetamines and is often considered to have lower abuse potential due to rate-limited conversion to dextroamphetamine (1, 2). Toxicity produces a sympathomimetic toxidrome characterized by mydriasis, agitation, hypertension, movement disorders, and seizures (3).

Amphetamine intoxication raises specific concern for cardiovascular complications, ranging from tachycardia and hypertension to aortic dissection, coronary vasospasm, and myocardial infarction (4). While cases of pediatric reversible stress cardiomyopathy have been reported with amphetamine/dextroamphetamine and cocaine ingestions (5, 6), severe cardiac dysfunction following lisdexamfetamine overdose is poorly described. Reported cases mainly highlight agitation and supportive care (7, 8).

We describe a lisdexamfetamine overdose resulting in acute heart failure with global wall motion abnormalities in a 17-year-old girl.

CASE DESCRIPTION

A 17-year-old girl presented to a pediatric tertiary care emergency department 5 hours after an intentional ingestion of approximately 1000 mg of lisdexamfetamine (fifty 20 mg capsules). Her history included major depressive disorder, post-traumatic stress disorder, generalized anxiety disorder, ADHD, and asthma. Medical history was negative for any cardiac conditions, with echocardiogram in 2008 at age 1 (failure to thrive) and 2017 at age 10 (suspicion of bicuspid aortic valve) demonstrating normal function and structure. She denied any recent illness. Family medical history was unknown; patient is adopted. Additional prescribed medications were methylphenidate, sertraline, aripiprazole, and guanfacine, which were all accounted for. She reported chest pain and nausea. Vital signs showed tachycardia (110–130 beats/min), mild hypertension (120–140/90–100 mm Hg), and normothermia (36.5°C). The remainder of her vital signs were within age-appropriate ranges. She was alert, pale, and diaphoretic with brisk capillary refill. Physical examination was otherwise unremarkable with no murmurs, peripheral edema, organomegaly, or findings specific for serotonin syndrome, such as clonus, hyperreflexia, or tremor. Electrocardiogram showed sinus tachycardia, with T-wave inversion (V1) and benign early repolarization (V3). Supportive treatment was initiated with IV fluids, benzodiazepines, and ondansetron.

Blood work revealed lactic acidosis (pH 7.28, Pco₂ 29.7 mm Hg, bicarbonate 14, lactate 10 mmol/L), elevated high-sensitivity cardiac troponin I (hsTnI 268.4 ng/L; Fig. 1), and leukocytosis (WBC 40). Toxicology screens (acetaminophen, salicylate, ethanol, and iron) were negative. Nasopharyngeal swab was positive for enterovirus and rhinovirus. She acutely desaturated (oxygen saturation [Spo₂] 80%), became hypertensive (blood pressure [BP] 140/90 mm Hg), and developed pulmonary rales with diffuse infiltrates on chest radiograph. HsTnI rose to 833.3 ng/L. Point-of-care ultrasound showed reduced left ventricular (LV) function.

Figure 1.

Lactate, troponin, and ejection fraction trend from time of presentation to PICU discharge.

She was treated for pulmonary edema with furosemide, continuous positive airway pressure, and sublingual nitroglycerin. Differential at this time included drug induced cardiac dysfunction, acute respiratory distress syndrome, or aspiration. She was transferred to the PICU (Fig. 2), where echocardiogram demonstrated severely decreased biventricular systolic function, with LV ejection fraction (EF) of ~20%. She was started on a nitroglycerin infusion for ongoing hypertension (with good BP control thereafter) and concern for coronary vasospasm, milrinone for additional afterload reduction and inotropic effect, and benzodiazepines for sympathomimetic toxidrome. Gastrointestinal decontamination would have required endotracheal intubation due to aspiration risk; given the hemodynamic instability, decontamination was deferred.

Figure 2.

Timeline of events from presentation to emergency department to PICU discharge. Numbers denote post-admission day. BiPAP = bilevel positive airway pressure, BP = blood pressure, CPAP = continuous positive airway pressure, EF = ejection fraction, HFNC = high-flow nasal cannula, HR = heart rate, HTN = hypertension, PO = per oral.

On post-admission day (PAD) 1, after ~16 hours of stability, she acutely decompensated with rising hsTnI (Fig. 1), hypoxia (Spo₂ < 90% on 100% oxygen), recurrent hypertension, brief loss of consciousness, and heart rate greater than 170 beats/min. Lactate was improving (4 mmol/L), and she was not acidotic. Nitroglycerin infusion was increased, bilevel positive airway pressure (BiPAP) was added for afterload reduction and oxygenation, and dexmedetomidine was initiated for tachycardia. Repeat echocardiogram demonstrated worsening cardiac function (LV EF < 20%) with septal dyskinesis and a dilated LV. Given persistent instability, she was intubated, with the extracorporeal membrane oxygenation team on standby, which was not ultimately required. Acute heart failure was managed with positive pressure ventilation, milrinone, nitroprusside, inotropes (trials of dobutamine, epinephrine, and dopamine to mitigate tachycardia), nitroglycerin, and therapeutic anticoagulation (unfractionated heparin). Tachycardia remained refractory despite sedation, paralysis, and cooling. Bloodwork showed multiple organ dysfunction: creatinine 101 μmol/L (baseline 58), aspartate aminotransferase 572 U/L, alanine aminotransferase 691 U/L, creatinine kinase 738 U/L, and potassium 5.5 mmol/L. Ceftriaxone was started for presumed aspiration.

On PAD 2, EF improved to the mid-20s. By PAD 3, she weaned off all cardiac infusions except milrinone. She was extubated to BiPAP on PAD 4 (EF of 30%), and anticoagulation was stopped. Lisinopril, intermittent furosemide, spironolactone, and hydralazine were added post-extubation. Respiratory support was discontinued by PAD 7, and milrinone was stopped. She transferred to the pediatric medical unit on PAD 8 and to inpatient psychiatry on PAD 10. She was discharged home on lisinopril on PAD 16, which was stopped 3 weeks later. At the 6-month follow-up, EF normalized to 62%.

Written informed consent was obtained for publication from the patient and her legal guardian.

DISCUSSION

Severe cardiac dysfunction resembling stress cardiomyopathy has not previously been reported with lisdexamfetamine overdose. Severe cases may present with vasospasm or refractory hypotension (4). A literature review (PubMed, MEDLINE, and Embase) identified four cases of lisdexamfetamine overdose and one case series including 7113 exposures. Age ranges included infants to adults. Prominent symptoms were agitation, tachycardia, and hypertension (2, 7–9). Significant cardiac dysfunction, stress cardiomyopathy, or cardiac arrest were not reported; dysrhythmias and hypotension were rare (0.21% and 0.06%, respectively [9]).

No co-ingestants were identified by history or toxicology screening. Lisdexamfetamine levels were unavailable, limiting our ability to definitively attribute causality. However, the temporal relationship and overall clinical course strongly support this association. Drugs that could potentiate the effect of lisdexamfetamine include other stimulants (e.g., cocaine, pseudoephedrine), monoamine oxidase inhibitors, lysergic acid diethylamide, and synthetic cathinones (“bath salts”). Sumatriptan, alcohol, and marijuana have been linked to vasospastic angina in adults (10, 11). While her prescribed medications were accounted for, unreported ingestion of agents such as methylphenidate, sertraline, aripiprazole, or guanfacine cannot be excluded. We cannot exclude methylphenidate as a contributing agent, although the history is that none was ingested. Sertraline is not known to act directly on the myocardium or coronary arteries. There was no prolonged QT interval or torsades de pointes to suggest cardiotoxicity with aripiprazole, and guanfacine causes coronary vasodilation at high concentrations, making co-ingestion with these substances less likely.

Although viral testing was positive for enterovirus/rhinovirus (undifferentiated on nasopharyngeal swab), the clinical trajectory and rapid recovery were inconsistent with myocarditis or sepsis. Advanced cardiac imaging was therefore not pursued.

Takotsubo cardiomyopathy is rare in children (12). Although several proposed pediatric criteria (12) were met—including transient ventricular dysfunction, new electrocardiogram changes, elevated cardiac biomarkers, and no clear evidence of viral myocarditis—the precipitating trigger in this case was toxicologic rather than emotional or physiologic stress. The underlying mechanism is more likely to reflect the toxic and hemodynamic effects of exogenous catecholamine excess rather than the acute endogenous catecholamine surge characteristic of classical Takotsubo cardiomyopathy.

Previously normal echocardiograms and rapid cardiac recovery further support an acute toxic process. No identifiable genetic or metabolic risk factors were present to predispose the patient to a severe course.

The severity of cardiac dysfunction was unexpected for an extended-release amphetamine. Despite a reported time to peak concentration of ~ 4 hours and a half-life of 10–13 hours, the patient experienced secondary deterioration approximately 24 hours post-ingestion. Pharmacokinetics may be altered in overdose due to delayed absorption, impaired metabolism, and excretion. Possible contributors to this clinical picture include large-quantity ingestion of an extended-release drug, which we theorize may have caused delayed and prolonged absorption via pharmacobezoars (13, 14). Bowel hypoperfusion may also have occurred secondary to impaired cardiac function. Afterload reduction and inotropic support may have improved organ perfusion, thereby enhancing drug absorption, as suggested by the recurrent tachycardia and hypertension observed at the time of acute decompensation.

Evaluation of a sympathetic overdose should include assessment of electrolytes, troponin, end-organ function assessment, and electrocardiogram. Early echocardiography is warranted in patients with rising troponin, unexplained lactic acidosis, hemodynamic instability, hypoxia, or signs of cardiogenic shock. Acute heart failure secondary to sympathetic toxicity requires aggressive management, including afterload reduction, strict BP control, and coronary vasodilation to optimize myocardial perfusion. Although nitroglycerin is not typically a first-line agent to achieve these goals, it should be considered if coronary vasospasm is suspected.

Clinicians should remain alert to delayed toxicity with extended-release agents such as lisdexamfetamine. Although intubation for purposes of decontamination is generally avoided in unstable patients, it may be warranted when ongoing drug absorption threatens organ function; this intervention should be discussed with a medical toxicologist. While serial drug levels could identify secondary peaks, this is often unavailable. Instead, we recommend early involvement of local poison centers, vigilant cardiac monitoring, and frequent bloodwork, with particular caution around extended-release formulations.