Arrhythmogenic Antitussive: A Case of Pediatric Benzonatate Overdose With Torsades de Pointes, Cardiac Arrest, and Complete Recovery Without Neurologic Deficits

Abstract

Benzonatate is a commonly prescribed antitussive with rapid and deadly effects in overdose. We report a 14-year-old female who ingested 14 capsules containing 200 mg benzonatate. Her case represents the only reported benzonatate overdose with torsades de pointes, as well as the only reported pediatric benzonatate ingestion complicated by cardiac arrest with full recovery.

Introduction

Coughing is disproportionately distressing to patients relative to the innocuous nature of most etiologies. Suppressant therapeutics act centrally via opioid receptors¹ or peripherally. Benzonatate is thought to primarily act peripherally via anesthetization of respiratory tree and pulmonary vagal stretch receptors.² It has a structure similar to local anesthetics, and thus has sodium channel blocking properties. Current literature suggests that benzonatate toxicity is rapid in onset and may present with ventricular tachycardia and cardiac arrest.^2–6

As a prescription, benzonatate is available in 100-mg and 200-mg liquid-filled capsules² with paraben preservatives.⁵ It is favored by medical providers as the solitary non-narcotic, prescription antitussive, although it is not approved for children younger than 10 years of age.¹ In fact, a black box warning was assigned to benzonatate in 2010 due to its resemblance to candy and potential for morbid toxicity to children, even in low doses.¹

Strikingly, benzonatate prescriptions increased by 53% from 2004–2009.² Given this dramatic rise in prescriptions, the 2013 analysis of benzonatate overdoses among adults and children from 1969–2010 (a US Department of Agriculture review of the AERS, Adverse Event Reporting System, and NEISS-CADES, National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project, databases and the IMS commercial data vendor) is of great interest. This report implicates benzonatate in association with seizures, cardiac arrest, coma, brain edema or anoxic encephalopathy, apnea, tachycardia, and respiratory arrest. In some fulminant cases, rapidity of death was noted, even including within 15 minutes of ingestion. This report also noted that a solitary capsule could be fatally toxic in young children.⁴ A 2011 brief³ adds that chewing or sucking the capsules can release the liquid and cause laryngospasm, bronchospasm, and circulatory collapse.

We present the only reported benzonatate overdose with torsades de pointes as the presenting ventricular dysrhythmia, and the only reported pediatric ingestion that resulted in cardiac arrest and complete recovery without residual neurologic deficits.

Case

A 14-year-old female (55 kg) with no medical problems presented to an emergency department approximately 15 minutes after ingesting a “handful” of tablets (later discovered to be 14 capsules of 200 mg benzonatate, 50.9 mg/kg). Her mother drove her to this local emergency department after the patient had lost consciousness while getting into their car to go to school. On arrival to the hospital, the patient was pulseless and cyanotic, so cardiopulmonary resuscitation (CPR) was initiated. The initial cardiac rhythm strip showed polymorphic ventricular tachycardia in a torsades de pointes morphology. After defibrillation at 200 J, return of spontaneous circulation (ROSC) was achieved 5 minutes after the initiation of CPR. No other adjuvant medications were administered during this brief administration of CPR. After CPR, 20 mg (0.36 mg/kg) of etomidate and 100 mg (1.8 mg/kg) of succinylcholine were administered to allow intubation for airway protection. A 2-mg naloxone administration was trialed with minimal response. A propofol drip was initiated at a dose of 20 mcg/kg/min and titrated to a rate of 40 mcg/kg/min. A nasogastric tube was placed. Magnesium sulfate (1 g) was administered, as well as 10 mg (0.2 mg/kg) of vecuronium and 50 g of activated charcoal with sorbitol and 1 L of normal saline. The patient was transferred to a children's hospital. Initial laboratory results are given as in Tables 1 and 2. A non-contrast CT scan of the head revealed no acute intracranial pathology.

Table 1.

Diagnostic Laboratory Results

Parameter	Value	Reference Range
Na, mEq/dL	139	135–144
K, mEq/dL	3.9	3.6–5.1
Cl, mEq/dL	107	101–111
Bicarbonate, mEq/dL	18.0	22.0–32.0
BUN, mg/dL	17	6–20
SCr, mg/dL	0.77	0.40–1.00
AST, units/L	91	15–41
ALT, units/L	83	5–30
Anion gap, mEq/dL	14.0	8.0–16.0
Acetaminophen, mg/L	<10	<30
Salicylate, mg/dL	<4.0	4.0–30.0
Ethanol, mg/dL	<10.0	<10
UDS	Negative	Negative

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; SCr, serum creatinine; UDS, urine drug screen

Table 2.

Arterial Blood Gas Values

Parameter	Initial in ED	At Children’s Hospital
pH	7.25	7.4
pCO2, mm Hg	37.0	38
pO2, mm Hg	219.0	66
Bicarbonate, mmol/L	16.2	23

Within hours of arrival at the children's hospital, she was extubated and was subsequently awake and alert with no focal neurologic deficits. A repeat non-contrast CT scan of the head was again normal. Her laboratory work remained unremarkable. A cardiac echo was unrevealing. MRI of the brain 3 days after cardiac arrest was normal. The patient's first rhythm strip and postdefibrillation strip are given as Figure 1.

Figure 1.

Initial (top) and postdefibrillation (bottom) cardiac rhythm strips.

Serial 12 lead ECGs were performed, with findings given per Table 3. The initial presence of QRS prolongation, consistent with sodium channel blockade physiology, is clearly evident. Rapid resolution of this electrophysical abnormality is additionally well exemplified. QTc prolongation is additionally present, with delayed normalization. Most significant prolongation was noted in the time period close to arrest. QTc prolongation is a known risk factor for torsades de pointes. The patient was initially tachycardic, with resolution of tachycardia by approximately 7 hours after presentation.

Table 3.

Electrocardiogram Trend

Day	Time	QRS	QTc	Heart Rate
1	7:36 am	Torsades de pointes	Torsades de pointes	N/A
	7:44 am	111	467	113
	10:05 am	83	553	94
	10:22 am	92	516	104
	10:39 am	86	483	97
	1:46 pm	89	458	138
	1:49 pm	93	455	118
	2:42 pm	91	469	98
2	6:05 am	94	426	64
3	6:06 am	91	439	87

N/A, not applicable

Discussion

Benzonatate is the generic name for the commonly prescribed antitussive Tessalon Perles (Pfizer Inc, Madison, NJ). It has been available in the United States since 1958³ and mechanistically anesthetizes the peripheral respiratory tree vagal stretch receptors. Chemically, benzonatate is a 4-butylamino benzoic acid,² a polyglycol derivative structure.³ In fact, benzonatate is actually an admixture of structurally related molecules that vary by number of side chain (OCH₂CH₂) groups.⁵ Structurally, it is similar to the local anesthetics, and in particular, tetracaine⁷ and procaine (Figure 2).⁵

Figure 2.

Structural chemistry of benzonatate and local anesthetics.

Not surprisingly given its structural similarity to the local anesthetics, benzonatate is a potent voltage-gated sodium channel blocker. It is rapidly metabolized via plasma butyrylcholinesterase to the major metabolite 4-(butylamino) benzoic acid and polyethylene glycol monomethyl ethers.¹

Solitary reports in the literature are consistent with the general findings of this report. A search of the PubMed database using the keywords “benzonatate” and “ingestion” identified 5 additional publications regarding the toxicity of ingested benzonatate. Both pediatric and adult overdose cases were reported.

Of the adult cases, Crouch et al⁵ describe a 39-year-old male who presented in ventricular tachycardia and required one 100-J defibrillation to achieve ROSC. The patient survived neurologically intact.

Of the pediatric cases reported, toxicity ranged and included isolated seizures without cardiac arrest⁷; seizures with arrest, ROSC, and persistent short-term memory deficits²; seizures and asystole followed by pulseless ventricular tachycardia resolving to ROSC but with residual blindness and generalized confabulations;⁶ and death.5 The patient in the case reported by Cohen et al⁶ demonstrated an MRI with diffuse bilateral basal ganglia and occipital lobe infarcts, as well as white matter findings consistent with anoxic injury. Additionally, this publication reviewed published case reports from 1986–2003, none of which reported torsades de pointes as a presenting rhythm, and none of which reported pediatric cardiac arrest without residual neurologic deficit.

Appropriate therapy for benzonatate toxicity mimics that of local anesthetics. Given the risk of seizures and rapid onset of toxicity, activated charcoal should not be administered, given the potential risk of aspiration pneumonia.⁹ In our case, activated charcoal was empirically administered by the preliminary treatment facility because the exact identity of the ingested medication was initially unknown. Due to the sodium-channel blocking effects of benzonatate, it is reasonable to consider sodium bicarbonate administration to overcome sodium channel blockade.^2,6

Lipid emulsion therapy (LET) is a pharmacologic curiosity with indications not yet well defined outside of local anesthetic toxicity. It is proposed to function as a “lipid sink” for lipid-soluble medications, buffering the site of action by sequestering the drug in lipid. The role of LET as an antidote in cardiac arrest secondary to a local-anesthetic conduction blockade is generally considered appropriate; extrapolation of this benefit to benzonatate toxicity is postulated secondary to the similarity of chemical structures and the clinical effects in toxicity.^2,6,7 One case report described narrowing of QRS on ECG after receiving LET for benzonatate toxicity; however, the case did not give specific interval values or clear time association data.²

Our case represents the first report of a pediatric benzonatate toxicity presenting in torsades de pointes and achieving full recovery. Because benzonatate was the only ingested agent, this avoids obfuscation of the clinical manifestations. The patient underwent an extensive workup to rule out other etiologies for her clinical manifestations. Additionally, her cardiac parameters were meticulously monitored, adding important characterization to the timeline of the cardiac conduction manifestations of her toxic exposure. This report adds benzonatate to the consideration of agents causing ventricular dysrhythmias and further characterizes the dramatic toxicity, rapid effects, and low therapeutic index of this commonly prescribed agent.

This case report is limited by the lack of a confirmatory serum level of benzonatate, although, given the rapidity of resolution of clinical toxicity, it is unclear how long a benzonatate level would persist. In literature, serum concentration analysis is limited by its rapid metabolism. Additionally, the fact that benzonatate itself is a heterogenous admixture of structural variants poses a unique analytic laboratory challenge. Nonetheless, liquid chromatography with tandem mass spectrometry has qualitatively identified benzonatate in some cases.¹ However, the patient's history, in conjunction with the appropriately matching clinical symptoms, is quite convincing in identifying benzonatate as the exposure. Additionally, given her negative cardiac workup, it is unlikely this was a native structure or electrical cardiac aberration.

Our report illustrates the need for awareness amongst healthcare providers regarding the dramatic toxicity, rapid effects, and small number of pills required for toxic effect, of this commonly prescribed medication. This information has important potential implications in regards to appropriate prescribing habits, patient education, and emergent assessment of patients presenting with toxicity. Benzonatate should also be in the medical professional's diagnostic differential for a range of ventricular dysrhythmias, including torsades de pointes. We aim to encourage safe prescribing habits and effective patient education regarding the risks and benefits of cough treatment.

ABBREVIATIONS

ALT

alanine aminotransferase

AST

aspartate aminotransferase

BUN

blood urea nitrogen

CPR

cardiopulmonary resuscitation

CT

computed tomography

ECG

electrocardiogram

ED

emergency department

LET

lipid emulsion therapy

MRI

magnetic resonance imaging

ROSC

return of spontaneous circulation

SCr

serum creatinine

UDS

urine drug screen