A description of the clinical course of severe benzonatate poisonings reported in the literature and to NPDS: A systematic review supplemented with NPDS cases

Abstract

Background:

Benzonatate is a commonly prescribed medication that can be lethal in acute overdose of a small number of capsules.

Objective:

This was a systematic review to describe the course of severe poisoning and deaths from benzonatate supplemented with the National Poison Data System (NPDS) fatalities module.

Methods:

The NPDS was queried from 2000 to 2018 for benzonatate fatalities. Pubmed, Cochrane, Embase, and Google Scholar were searched for combinations of benzonatate and “poisoning,” “overdose,” and “toxicity.” References of relevant articles were searched for additional publications. Articles were included if they described the clinical course of at least one patient suffering from benzonatate poisoning and available in English. Dual independent review and extraction were performed.

Results:

Seventeen cases from NPDS and 19 published reports met the inclusion criteria resulting in 36 cases, mostly (28/36) self-harm ingestions. Most patients were young [17 (11–29), median (IQR)] and female (22). Onset of toxicity was rapid at <5 min (9). Most common symptoms included cardiac arrest (29), seizures (24), and dysrhythmias (24). Treatments included intubation (26), cardiopulmonary resuscitation (28), vasopressors (20) and others. Return of spontaneous circulation was achieved in 23/28 patients, but most had significant neurologic deficits or other end organ damage and 5 survived with a good neurologic outcome.

Conclusion and relevance:

Overdose ingestions of benzonatate can cause significant toxicity with a rapid onset. Interventions performed were generally supportive in nature. Duration of directly toxic effects is short, but dramatic with neurologic devastation and resuscitated patients often still have a poor outcome.

Keywords

Clinical toxicology topical anesthetics toxicity critical care emergency medicine

Introduction

Benzonatate is a commonly prescribed cough suppressant with over 3 million prescriptions per year in the US in 2016. Benzonatate shares structural similarities with other local anesthetics such as benzocaine and tetracaine, and alleviates cough through numbing the peripheral stretch receptors in the respiratory system.¹ Calls to poison centers about benzonatate exposures have risen drastically (doubling since the 2012 FDA warning) with a concomitant increase in the number of severe poisonings from approximately 120 in 2012 to 240 in 2019.² Sporadic cases of severe benzonatate poisoning are reported in the literature.^3–5

This was a descriptive study using the National Poison Data System (NPDS) fatalities module in combination with a systematic review to describe the course of severe poisoning and deaths from benzonatate.

Methods

Two independent authors performed searches of Pubmed, Cochrane, Embase, and Google scholar for combinations of benzonatate and “poisoning,” “overdose,” and “toxicity” from database inception until November 2019 (benzonatate AND (poisoning OR overdose OR toxicity)). Additionally, references of relevant articles were searched for additional papers. The only exclusion on the type of article was English language. Articles were included if they described the clinical course of at least one patient poisoned from benzonatate. Studies and articles that provided only coded data were excluded from analysis unless they described individual severe cases. Cases identified in both NPDS and published literature were only presented once. Severe cases were defined by a case that had life-threatening symptoms or symptoms that resulted in significant residual disability or disfigurement. Abstracts were included as long as the clinical course was described. Due to the descriptive nature, no meta-analysis was planned. The review was not pre-registered. We used Covidence systematic review software (Version v2553 b219db6b, Veritas Health Innovation, Melbourne, Australia) to manage the systematic review and followed the PRISMA guidelines for reporting systematic reviews (see supplemental material)⁶

Both authors independently reviewed titles, abstracts, and full-text of each article. After a decision of which articles met inclusion, both authors extracted data from each article. Discrepancies were resolved through discussion.

Poison Centers in the United States submit cases to the NPDS. In cases that result in fatalities, the poison center submits a fatality abstract providing further information surrounding the case. The fatality review team assigns a Relative Contribution to Fatality (RCF) on a rank of one to six: 1—undoubtedly responsible, 2—probably responsible, 3—contributory, 4—probably not responsible, 5—clearly not responsible, 6—unknown. Benzonatate fatality abstracts were requested from the NPDS from 2000 to 2018 (pre-2000 data is archived and more difficult to obtain). Cases were included if the RCF was 1—undoubtedly responsible or 2—probably responsible for the death.

Data were dually extracted from each case included age, sex, dose, onset of symptoms, specific symptoms during acute toxicity, therapies, duration of effect, and sequelae of the poisoning. Missing data were not imputed. Any discrepancies in data extracted were resolved through discussion.

Results

The literature searches yielded 169 articles of which 107 were removed as duplicates. One additional article was found from searching of the citations. After screening for eligibility, 18 abstracts or full-text manuscripts were included and yielded 19 cases (Figure 1). From the NPDS, 52 cases included benzonatate as a substance listed. Of these 52 cases, 17 were included for a total of 36 cases between the two data sources. No cases were duplicated in the published literature and NPDS deaths. The majority patients were young [17 (11–29), median (IQR)], female (22), and mostly intentional self-harm exposures (28) (Table 1). Onset of symptoms was <5 min in 9/16 patients where a time of onset was known. Most commonly reported symptoms included cardiac arrest (29), seizures (24), and dysrhythmias (24). Specific dysrhythmias included asystole, pulseless electrical activity, ventricular tachycardia, and ventricular fibrillation. Case descriptions are available in Table 2.

Figure 1.

Included studies.

Table 1.

Clinical effects and treatments of benzonatate poisonings.

	All patients (n = 36)	Lived (n = 13)	Died (n = 23)
Age, median (IQR)	17 (11–29)	20 (15–53)	16 (11–26)
Age, mean (SD)	20 (13)	22 (15)	17 (12)
Intentional	25 (73.5)	10 (76.9)	15 (65.2)
Male, n (%)	N = 34	N = 11
Male, n (%)	12 (35.3)	6 (54.5)	6 (26.1)
Time to onset	N = 16	N = 7	N = 9
<5 min	9 (56.3)	3 (42.9)	6 (66.7)
≤30 min	3 (18.8)	3 (42.8)	—
>30 min	4 (25.0)	1 (14.3)	3 (33.3)
Clinical effects
Seizures	24 (66.7)	11 (84.6)	13 (56.5)
Status epilepticus	6 (16.7)	2 (15.4)	4 (17.4)
Dysrhythmias, any	24 (66.7)	6 (46.2)	18 (78.2)
Asystole	12 (33.3)	—	12 (52.2)
Pulseless electrical activity	4 (11.1)	—	4 (17.4)
Ventricular tachycardia	4 (11.1)	2 (15.4)	2 (8.7)
Ventricular fibrillation	8 (22.2)	3 (23.1)	5 (21.7)
Other	2 (5.6)	1 (7.7)	1 (4.3)
Cardiac arrest	29 (80.6)	6 (46.2)	23 (100)
ROSC	23 (63.9)	6 (46.2)	17 (73.9)
Tachycardia	17 (47.2)	6 (46.2)	11 (47.8)
Hypotension	18 (50.0)	4 (30.8)	14 (60.9)
Treatments performed
Activated charcoal	5 (13.9)	3 (23.1)	2 (8.7)
Gastric lavage	3 (8.3)	2 (15.4)	1 (4.3)
Vasopressors	20 (55.6)	5 (38.4)	15 (65.2)
Benzodiazepines	11 (30.6)	4 (30.8)	7 (30.4)
Sodium bicarbonate	13 (36.1)	3 (23.1)	10 (43.4)
Intravenous fluids	18 (50.0)	3 (23.1)	15 (65.2)
Intravenous lipid emulsion	6 (16.7)	1 (7.7)	5 (21.7)
Intubation	26 (72.2)	7 (53.8)	19 (82.6)
CPR	28 (77.8)	6 (46.2)	22 (95.7)

CPR, cardiopulmonary resuscitation; IQR, interquartile range; n, number; ROSC, return of spontaneous circulation; SD, standard deviation.

N’s for individual parameters if different from the total N defined above are stated within the respective column.

Table 2.

Individual included cases.

Author, year	Age, sex	Survival	Co-ingestants	Dose, route	Time to symptom onset (min)	Symptoms	Sequelae	Treatments	Concentrations	Notes
Full-text manuscripts
*Cohan, 1986⁷	18 mo, F	No		Unk, oral	<5	CAR	N/A	CPR	4 mg/L blood, 184 mg in stomach, 30 mg/kg liver, 5 mg/kg brain,	Dead, presumed from choking r/t oral anesthesia
*Cohan, 1986⁷	18 yr, M	No	PHY	Unk, oral	35	CAR	N/A	NaB, NAL, Physostigmine	35 mg/L blood; 22 mg/kg brain, 1.5 mg/kg kidney
*Crouch, 1998³	12 mo, M	No		Unk, oral		SZ, CAR	N/A	CPR
Crouch, 1998³	39 yr, M	Yes	EtOH	3600 mg, oral	<60	SZ, Vtach, CAR, QRSw		AC, GL, CPR	2.5 mcg/mL plasma	QRS 110 msec; ROSC
*Cohen, 2011⁸	17 yr, F	Yes		2000 mg, oral	<5	SZ x 3, SE, Vtach, HoTN	Rhabdomyolysis, blindness, basal ganglia infarcts, confabulation	AC, GL, CPR, EPI, BZD, NaB, IVF, INT, amiodarone, defib, Mg, dopamine, vasopressin, atropine, mannitol, PROP, TTM, VEC		Dose suspected to be 2,000 mg, but not verified; ROSC
Thimann, 2012⁵	13 yr, F	Yes	chlorpheniramine; dextromethorphan	4000 mg, oral		SZ, Tachy, HoTN, coma	n/a	IVF
Yoshioka, 2016⁹	17 yr, F	Yes		2400 mg, oral	30	SZ, Vfib, QRS	pneumothorax, HypoK, HypoMg, memory impairment	Etomidate, succinylcholine, PROP, Ca, TTM		QRS 114 msec; ROSC
Jin, 2019⁴	37 yr, F	No	EtOH	<6000 mg, oral	120	SZ, asystole	ABI, DIC	TTM		Dose < 30 capsules
Abstract publication
Sheen, 1997¹⁰	12 mo, M	Yes		Unk, oral	<5	SZ		Suctioning
Shropshire, 1999¹¹	21 yr, M	No		Unk, IV		CAR, Vtach, Vfib	SAH, pulmonary edema, coagulopathy, acidosis	VASO, CPR, INT		ROSC
Lewis-Younger, 2001¹²	35 yr, F	No		Unk, oral		CAR, Vfib	ABI	VASO, defib, LIDO, CPR, INT		ROSC
Weber, 2003¹³	27 yr,F	Yes		100 mg, IV	10	SZ, CAR, Vfib, HoTN		VASO, BZD, CPR, INT, VEC		ROSC
Boehm, 2005¹⁴	11 mo, M	Yes		800 mg, oral		SZ, SE	PNA	AC, BZD, ABX
*Doyon, 2005¹⁵	43 yr, M	Yes		100 mg, IV	<5	Tachy; HTN; COMA	ARDS	INT; Tracheostomy		3 weeks in ICU, 6 in hospital
*Schwarz, 2006¹⁶	6–19 yr, unk	Yes		2000 mg, oral		CAR		CPR		ROSC
Schwarz, 2006¹⁶	6–19 yr, Unk	Yes		Unk, oral		SZ, CAR		CPR		ROSC
Schwarz, 2006¹⁶	30 yr, M	Yes		600 mg, oral		SZ
Fleenor, 2009¹⁷	20 yr, M	Yes		Handful, oral	<5	SZ, CAR, Vfib, Tachy	ABI	Tracheostomy	13 mcg/mL urine
Morgan, 2015¹⁸	39 yr, F	Yes	IBU; APAP	3000 mg, oral		SZ, WCT, HoTN, QRS		VASO, BZD, NaB, IVF, INT
NPDS death abstracts
2001	35 yr, F	No		Unk, oral		CAR, Vfib, HoTN	Global hypokinesia of myocardium	VASO, BZD, IVF, CPR, INT, LIDO		ROSC
*2004	2 yr, F	No		Unk, oral		SZ, CAR		VASO, CPR, INT		ROSC, death subsequently presumed due to aspiration of capsule
2007	25 yr, M	No		Unk, oral		SZ, PEA, Tachy, HoTN		VASO, NaB, IVF, CPR, INT, atropine, Ca, NAL		ROSC
2008	26 yr, F	No	EtOH	Unk, oral		SZ, CAR, HoTN	DIC, cerebral edema, global ischemic injury, AKI	VASO, IVF, CPR, INT, blood		ROSC
*2009	11 yr, F	No		Unk, oral	<5	Vtach, Vfib, CAR		NaB, IVF, CPR, INT, K, Ca
*2011	9 mo, M	No		400 mg, oral	<5	CAR		CPR, ILE
*2012	4 yr, F	No		Unk, oral		SZ, CAR		VASO, BZD, NaB, IVF, CPR, INT, atropine, insulin		ROSC, death subsequently presumed due to aspiration of capsule
2014	12 yr, F	No		10000 mg, oral		SZ, CAR, Tachy	Aspiration	AC, VASO, BZD, IVF, CPR, ILE, Ca, cardioversion, LEV, VPA, INT		ROSC
2014	12 yr, F	No		Unk, oral	60	PEA, Vfib, CAR, Tachy, HoTN	ABI	VASO, IVF, CPR, ILE, INT, defibrillation		ROSC, QRS 70
2015	15 yr, F	No	benzocaine/ trimethobenzamide	Unk, oral		PEA, CAR, Tachy, HoTN		VASO, NaB, IVF, CPR, INT, milrinone, K, analgesics, sedatives, TTM		ROSC
*2015	11 yr, F	No		Unk, oral		SZ, SE, CAR, Tachy	ABI	BZD, NaB, IVF, CPR, INT, PHB, PHY, LEV		ROSC
2016	20 yr, M	No	EtOH	1200–2400 mg, oral	<5	SZ, CAR, Tachy, HoTN	Cerebral edema	VASO, BZD, IVF, CPR, PHY, LEV, PROP, TTM		ROSC
2016	38 yr, F	No	APAP	3000–6000 mg, oral		SZ, SE, Tachy, HoTN, CAR	ABI	VASO, BZD, NaB, IVF, CPR, INT, PHY, PROP, LEV, TTM, paralysis		ROSC
2016	43 yr, F	No	EtOH	5200 mg, oral	<5	SE, CAR, Tachy, HoTN	Brain death, encephalopathy, ABI	BZD, NaB, IVF, CPR, ILE, INT, K, Mg, Ca, LEV,		EtOH level 210, QRS 90, ROSC
2016	16 yr, F	No	ASA, IBU	Unk, oral		SZ x 2, CAR, HoTN, QRSw		VASO, NaB, IVF, CPR, INT, Ca, glucagon, HDI		QRS 138
2017	17 yr, F	No	meclizine	Unk, oral	<5	SE, PEA, CAR, Tachy, HoTN, QRSw		AC, GL, VASO, NaB, IVF, CPR, ILE, INT, TTM, NAC, PROP, LEV, PHB, Insulin	680 mcg/L blood	ROSC
2017	16 yr, F	No	caffeine	Unk, oral		Dysrhythmia, CAR, Tachy, HoTN	ABI	VASO, IVF, CPR, ILE, INT		ROSC

ABI, anoxic brain injury; AC, activated charcoal; AKI, acute kidney injury; APAP, Acetaminophen; ASA, aspirin; BZD, benzodiazepine; CAR, cardiac arrest; CPR, cardiopulmonary resuscitation; DIC, disseminated intravascular coagulopathy; GL, gastric lavage; HDI, high dose insulin euglycemic therapy; HoTN, hypotension; IBU, ibuprofen; INT, intubation; ILE, intravenous lipid emulsion; IVF, intravenous fluids; LEV, levetiracetam; mo, month; NaB, Sodium bicarbonate; NAC, n-acetylcysteine; NAL, naloxone; PEA, pulseless electrical activity; PHB, phenobarbital; PHY, phenytoin; PROP, propofol; QRSw, QRS interval widening; ROSC, return of spontaneous circulation; SE, status epilepticus; SZ, seizure; TTM, targeted temperature management; UNK, unknown; VASO, vasopressor; VEC, vecuronium Vfib, ventricular fibrillation; Vtach, ventricular tachycardia; VPA, valproic acid; yr, year.

* Unintentional exposure.

Treatments included intubation (26), cardiopulmonary resuscitation (28), vasopressors (20) and others. Six patients received intravenous lipid emulsion (ILE) therapy, one of which survived. Return of spontaneous circulation was achieved in 23/28 (83%) patients, but most had significant neurologic deficits or other end organ damage and only 5 survived with a good neurologic outcome. Three young children (18 months, 2 years, 4 years) died possibly as the result of aspiration of the capsule, possibly from numbing of the oropharyngeal zone. Patients who survived had resolution of cardiovascular symptoms within 2 hours and most were extubated within the day. Some had prolonged hospitalization due to aspiration.

Discussion

This study highlights the clinical effects of severe benzonatate ingestions. Published cases were identified as early as 1986 and were infrequently published up through 2019. Data from poison centers was only available through 2018 and deaths occurred almost every year. All cases were primarily large intentional ingestions in adolescents or adults, but 7/36 were under 5 years of age; a little over half were female (22/36). Published cases had a greater than 60% survival. In general, onset of effects is rapid and within minutes after ingestion, although some cases may have been delayed up to 2 h.^4,7,8 However, when evaluating the pharmacokinetics of benzonatate, this timeframe does not make sense.

Time to maximal concentration (Tmax) occurs at 30 min with a rapid decline to nearly undetectable serum concentrations by the 2-h mark.¹⁹ The primary analytical metabolite, 4-(butylamino)benzoic acid (BABA) peaks at the same time as benzonatate with a similar rapid decline.¹⁹ Although both may have detectable concentrations at 2 h after ingestion, these low serum concentrations are not expected to cause significant toxicity. Additionally, BABA does not have appreciable sodium channel inhibition.²⁰ Another argument for the delayed onset of toxicity could be potential pharmacobezoar formation delaying the dissolution and absorption phases. Anecdotally, capsules are known to stick together in a container when exposed to moisture, so this may be possible, but pharmacobezoar formation with liquid filled capsules seems unlikely. The more likely case, as is with most intentional ingestions, is that the reported timeframe of ingestion is not accurate.

Early symptoms reported in many of the patients were either seizures or dysrhythmias. This is consistent with other sodium channel blocking local anesthetics like lidocaine, bupivacaine, etc. which makes sense pharmacologically as benzonatate is structurally related to tetracaine and procaine.^21,22 Twenty-four patients experienced seizures and six these developed status epilepticus. Resolution of acute drug effect was fairly rapid, correlating with the 1 h half-life of benzonatate. Return of spontaneous circulation was reported in the majority of cases. Despite rapid resolution of direct drug effect, many had anoxic brain injuries and/or cerebral edema that ultimately resulted in mortality. Two patients that survived noted to have long-term neurologic dysfunction.^8,17

Confirmatory concentrations were infrequently reported in these cases. Previous methods of determining benzonatate in plasma had several practical issues that limited detection and identification of benzonatate as the cause of death.^19,22 Benzonatate and its primary degradation metabolite, 4-(butylamino)benzoic acid (BABA) are not routinely measured in hospital laboratories and are probably found by specific investigation by medical examiners rather than mass screening.²² Systemic concentrations reported included 2.5 mcg/mL in plasma and 0.680 mcg/mL to 35 mcg/mL in blood.⁷ In one of the few pharmacokinetic studies, peak concentrations of benzonatate were under 1 mcg/mL.¹⁹ Difficulties with determining benzonatate concentrations means that death from benzonatate is likely significantly underreported.

In general, patients received only supportive measures. Six patients received ILE. Intravenous lipid emulsion is recommended for life-threatening local anesthetic systemic toxicity but, it is unclear that it would benefit these patients.²³ Benzonatate is a unique anesthetic as it does not have a logD (0.32) that is favorable for ILE therapy, and as displayed in Table 1, only 1 out of 6 survived. It was unclear whether ILE benefited this patient with the numerous interventions ongoing in their care. Regardless it does not appear that ILE has a benefit in benzonatate ingestions.

This was a retrospective study and carries all the expected limitations with this type of research. As the majority of cases do not reach a full manuscript and many only in abstract form, there is significant publication bias; we were limited in what information was available for analysis from the published literature along with selection bias by limiting it to only the English language. Additionally, from the NPDS portion, poison control centers are receiving information about cases secondhand for the purposes of patient care and not research. Minor details of cases and information are often not reported in poison center data systems resulting in reporting biases. The addition of the fatality abstracts however adds more description to the cases we evaluated from NPDS. Although we included all fatalities, we did not include any “major” outcome cases as the limited information from just the coded data may not be as useful and studies utilizing coded data have already been performed.^2,24 This exclusion of major or moderate cases biases the outcomes toward fatality. There is a risk of duplicating cases from the published literature and the NPDS fatality module. However, since we only included cases with descriptions of the clinical course, there were none which appeared to be the same case. There was one case published as both poster and manuscript that was resolved by reaching out to authors.

Conclusion

Supplemental material

Supplemental Material, sj-pdf-1-het-10.1177_09603271211030560 - A description of the clinical course of severe benzonatate poisonings reported in the literature and to NPDS: A systematic review supplemented with NPDS cases

Supplemental Material, sj-pdf-1-het-10.1177_09603271211030560 for A description of the clinical course of severe benzonatate poisonings reported in the literature and to NPDS: A systematic review supplemented with NPDS cases by FS Minhaj and JB Leonard in Human & Experimental Toxicology

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

FS Minhaj

Supplemental material

Supplemental material for this article is available online.

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