Are One or Two Dangerous? Lidocaine and Topical Anesthetic Exposures in Children

The Journal of Emergency Medicine, Vol. 37, No. 1, pp. 32–39, 2009 Copyright © 2009 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/09 $–see front matter

doi:10.1016/j.jemermed.2007.11.005

Selected Topics: Toxicology

ARE ONE OR TWO DANGEROUS? LIDOCAINE AND TOPICAL ANESTHETIC EXPOSURES IN CHILDREN Liesl A. Curtis,

MD, FACEP,*

Teresa Sullivan Dolan,

MD,*

and H. Edward Seibert,

MD†

*Department of Emergency Medicine, Georgetown University Hospital, Washington, DC and †Department of Emergency Medicine, George Washington University Hospital, Washington, DC Reprint Address: Jeffrey N. Love, MD, Department of Emergency Medicine, Georgetown University Hospital, 3800 Reservoir Rd. NW, Ground Floor CCC Building, Washington, DC 20007

e Abstract—Topical anesthetics are found in a variety of prescription and non-prescription preparations, from teething gels to hemorrhoid creams. In 2003, there were 8576 exposures to local/topical anesthetics reported to the American Association of Poison Control Centers, with 67% of cases in the age group younger than 6 years old. This report reviews the available literature involving topical anesthetic exposures in children younger than 6 years old, including the National Library of Medicine’s Pub Med database (limited to English language) and data from POISINDEX. Additionally, we reviewed the American Association of Poison Control Centers’ annual reports from 1983 to 2003. There were 7 deaths in this age range from topical anesthetics. Although the number of deaths is low, the fact that there have been deaths reveals the serious nature of the toxicity that can result from these readily available non-prescription analgesics. Toxicity may result from topical absorption, ingestion, or aspiration. Additionally, toxicity can result from unintentional as well as therapeutic mishaps. Although the number of cases is limited, these medications can be toxic at low doses—which, in children younger than 6 years of age, may amount to as little as a teaspoon. © 2009 Elsevier Inc.

e Keywords—lidocaine; topical anesthetics; pediatrics; toxicity; overdose

INTRODUCTION Topical anesthetics, of both amide and ester derivation, are found in products ranging from teething gels to hemorrhoid creams to ear preparations. These compounds are available as both prescription and non-prescription preparations (Table 1). Commonly used and readily available, these medications may be dispensed or sold without safety closures, making them more accessible to children. Often, toxic exposures are due to inadvertent but overzealous administration by parents. The effects of such exposures can be devastating. In 2003, there were 8576 exposures to local/topical anesthetics reported to the American Association of Poison Control Centers, with 67% of cases in the age group younger than 6 years old (1). This report reviews the available literature involving topical anesthetic exposures in children younger than 6 years old, including the National Library of Medicine’s Pub Med database (limited to English language) and data from POISINDEX (2). Additionally, we reviewed the American Association of Poison Control Center’s annual reports from 1983 to 2003. There were seven deaths in this age range from topical anesthetics (3). Although the primary toxic effects of amide and ester anesthetics are differ-

Series Editors: Jeffrey N. Love, MD, The Georgetown University Department of Emergency Medicine, Washington, DC; Wendy Klein-Schwartz, PHARMD, MPH, The Maryland Poison Center, Baltimore, MD; Liesl A. Curtis, MD, The Georgetown University Department of Emergency Medicine, Washington, DC.

RECEIVED: 1 September 2005; FINAL ACCEPTED: 22 March 2007

SUBMISSION RECEIVED:

23 August 2006; 32

Lidocaine and Topical Anesthetic Exposure

33

Table 1. Common Topical Anesthetic Preparations Product Name Amide Lidocaine

Uses

5% ointment, 10% oral spray, 5% flavored liquid, 4% topical solution, 2% viscous solution, 2% jelly, patch consisting of an adhesive material incorporating 5% lidocaine Xylocaine®, Lidoderm®, Numby stuff®

Lidocaine ⫹ prilocaine Dibucaine Mepivacaine Prilocaine Bupivacaine Etidocaine Ester Benzocaine

EMLA Nupercainal 0.5% cream, 1% ointment Carbocaine® Citanest® Marcaine® Duranest® Orajel®, Anbesol®, Lanacane®, Americaine Topical Anesthetic First Aid Ointment®, Vagisil Crème®

Cocaine Tetracaine Procaine Proparacaine Butethamine Ethyl aminobenzoate

Pontocaine® Novocain® Ophthaine® Monocaine®

ent, there is some overlap between the two classes. We will review them separately.

AMIDE ANESTHETICS Amide anesthetics (Table 1), such as lidocaine and dibucaine, cause central nervous system (CNS) depression, seizures, and cardiovascular toxicity resulting in dysrhythmias, all of which ultimately may be fatal. Dibucaine is significantly more potent than lidocaine, but is prescribed much less frequently (4). Prilocaine, a key ingredient in EMLA (AstraZeneca Pharmaceuticals LP, Wilmington, DE), differs in that methemoglobinemia is its primary toxicity.

Analgesia for: otitis externa, vaginitis, hemorrhoids, diaper rash, oral thrush and teething in infants. Analgesia for procedures: Bladder catheterization, nasogastric tube placement, treatment of epistaxis Topical anesthetic for intravenous catheter placement Hemorrhoidal cream Local anesthetic Local anesthetic Local anesthetic Local anesthetic Analgesia for: Teething discomfort, burns, dermatitis, vaginitis Treatment of epistaxis Local anesthetic Local anesthetic Ocular topical anesthetic Local anesthetic

for local anesthetics and, therefore, lidocaine-induced seizures may be self-perpetuating and prolonged (8). It is not known if lidocaine is metabolized in the dermis, but it is metabolized rapidly by the liver to a number of metabolites, including monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent than that of lidocaine. MEGX is the more pharmacologically active metabolite, with toxicity similar to lidocaine (7). Lidocaine has a half-life of 0.7 to 1.8 h, whereas MEGX and GX have half-lives of 2 and 10 h, respectively (9). Prilocaine is a toluide derivative rather than a xylidine derivative, as are the other amides. o-Toluidine, a metabolite of prilocaine, acts as an oxidant and blocks the methemoglobin reductase pathways leading to methemoglobinemia (10).

Pathophysiology Clinical Manifestations Local anesthetics work by blocking voltage-gated sodium channels, thereby stabilizing the neuronal membrane, which prevents the propagation of action potentials down the neuron. Lidocaine is a group II, or amide-type, local anesthetic and is categorized as such because it lacks a paminophenyl group. The CNS effects of lidocaine are thought to be caused by selective blocking of inhibitory cortical synapses (5,6). Patients may initially display agitation or confusion, that can progress to generalized tonicclonic seizures, respiratory depression, and coma (7). The resultant respiratory acidosis lowers the seizure threshold

The manifestations of toxicity of amide anesthetics occur predominantly in the CNS and cardiovascular system. The onset of toxic side effects is related to both the concentration and onset of action of the medication used, method of administration, and the accumulation of toxic metabolites (8,11). The onset of action of lidocaine varies depending on the preparation. Topical products have an onset of action within 5 min, with a duration of action under 20 min. The bioavailability of orally ingested lidocaine is only 30 –35% due to “first pass” hepatic

34

L. A. Curtis et al.

metabolism (7,12). Peak plasma concentrations after lidocaine application to tracheal mucosa occur within 10 min, whereas lidocaine that has been swallowed reaches peak concentrations at approximately 40 min (8). Aspiration is thought to be especially dangerous, because lidocaine absorbed through the respiratory tract is delivered straight to the brain, without first being metabolized by the liver (13). The earliest and most frequent manifestations of toxicity from amide anesthetics involve the central nervous system (5,7,11). In general, at concentrations above 6 ␮g/mL, CNS effects are seen, including confusion, hearing loss, dysarthria, visual disturbances, ataxia, agitation, myoclonus and, eventually, seizures and coma (14). Amide anesthetics may cause adverse cardiac events as well, which arise less frequently, and typically after the patient has already manifested signs of CNS toxicity (5). In adults, bradycardia, atrioventricular block, sinus arrest, and ventricular asystole have been reported after i.v. infusion (14). The toxicity of EMLA is two-fold. It contains both lidocaine and prilocaine, therefore, toxicity can manifest as both CNS effects and with methemoglobinemia. Literature Review Lidocaine can cause acute CNS toxicity in small amounts, even with a single dose (Table 2). Seizures after ingestions have typically occurred in pediatric patients with serum lidocaine concentrations within the therapeutic range of 1–5 ␮g/mL (6,8,12,13). Seizures were reported in a 5-month-old several hours after the administration of 1 teaspoon (or 100 mg) of viscous lidocaine by his mother for teething discomfort (12). A 2-year-old who aspirated while ingesting one ounce of viscous lidocaine had convulsions within 10 –15 s, and later developed acute respiratory insufficiency. The patient’s serum lidocaine concentration 4 h after ingestion was 0.5 ␮g/mL. In most documented cases, concentrations were not obtained

within 90 min of ingestion. Concentrations drawn promptly after the initial exposure may not correlate well with the clinical picture, as lidocaine has biphasic elimination with an initial half-life of 7–30 min (9). Although acute exposures are often the source of lidocaine CNS toxicity, there are numerous case reports of seizures in pediatric patients whose parents gave more than the prescribed dose of viscous lidocaine over a time course from 12 h to 1 week (5,6,12). In one case of inadvertent i.v. injection of 50 mg of lidocaine in a 1-month-old child, a peak concentration of 5.39 ␮g/mL (extrapolated from concentrations drawn at 1.2 and 3.5 h), resulted in cardiovascular collapse, respiratory arrest, seizure, and coma (9). In adults, cardiovascular toxicity is most often seen at concentrations above 11 ␮g/mL (14). Although two pediatric deaths after viscous lidocaine ingestion have been described in the literature, the only reports of dysrhythmia occurred after the inadvertent i.v. administration described above, which caused tachycardia with a widened QRS, and tachycardia and hypotension seen in a 22-month-old after viscous lidocaine ingestion (9,15). One of the deaths occurred after overuse of viscous lidocaine, followed by acute ingestion with erythromycin, with a plasma lidocaine concentration of 4.1 ␮g/mL. The child was found comatose and cyanotic (16). The other death was in a 13-month-old boy who was found in cardiopulmonary arrest at home. He had ingested an unknown quantity of an oral lidocaine preparation several hours previously, and had a serum concentration of lidocaine of 19.5 ␮g/mL (17). Dibucaine, however, has caused serious cardiac toxicity and death in pediatric patients at low doses. Dayan et al. described three deaths in children aged 18 months, 21 months, and 2 years from unintentional dibucaine ingestion (Table 3) (4). All three children sustained seizures; the time to the onset of the seizure was unknown in one case and within 20 min in the other two cases. The 18-month-old, who ingested approximately 3 teaspoons of 1% dibucaine ointment (150 mg), had an irregular

Table 2. Cases of Pediatric Single Dose Lidocaine Exposures

Age Method of exposure Dose Symptomatology Lidocaine level Treatment Outcome Length of hospital stay

Sakai and Lattin (15)

Amitai et al. (17)

Garrettson and McGee (13)

22 months Ingestion 50 mg/kg (20–25 cc) Seizure, respiratory arrest Not drawn Intubation, diazepam, supportive Full recovery 48 h

13 months Ingestion Unknown Cardiopulmonary arrest 19.5 ug/mL Intubation, supportive Death

20 months Ingestion/aspiration ⱕ1 ounce Seizure, lethargy

5 months Ingestion 69 mg/kg (5 cc) Seizure

0.5 ug/mL (5 h after dose) Intubation, anticonvulsants, charcoal Full recovery 64 days*

3.9 ug/mL (6 h after dose) Lavage, charcoal, observation Full recovery 48 h

* Patient developed acute respiratory distress syndrome.

Hess and Walson (12)

Lidocaine and Topical Anesthetic Exposure

35

Table 3. Cases of Pediatric Dibucaine Toxicity

Age Method of exposure Dose Time of onset Symptomatology Dibucaine level Treatment Outcome

Dayan et al. (4)

Dayan et al. (4)

Dayan et al. (4)

18 months Ingestion 15 mg/kg 10 min Vomiting, lethargy, seizure, apnea, bradycardia, dysrhythmias Not drawn Intubation, diazepam, phenobarbital, ACLS drugs Death

2 years Ingestion Unknown Unknown Seizure, cardiopulmonary arrest 1.3 ug/mL Intubation, resuscitation

21 months Ingestion 19 mg/kg 20 min Lethargy, seizure, cardiopulmonary arrest, dysrhythmias Not drawn Intubation, diazepam, ACLS drugs

Death

Death

ACLS ⫽ advanced cardiac life support.

bradycardia that did not respond to atropine, ventricular tachycardia, ventricular fibrillation, and asystole, as well as atrial flutter with 2:1 block when perfusion was temporarily restored after cardiopulmonary resuscitation. The 21-month-old, who ingested approximately 225 mg or 19 mg/kg, had a wide-complex bradycardia at presentation, followed by cardiac arrest, whereas the 2-year-old (who ingested an unknown amount of a 0.5% cream) had transient supraventricular tachycardia before death. A dibucaine concentration was obtained only in the 2-yearold and was 1.3 ␮g/mL (4). As an amide anesthetic, dibucaine causes toxicity in the same manner as lidocaine, but is 10 times more potent. Although dibucaine is prescribed, used, and unintentionally ingested considerably less than lidocaine, it is responsible for three of seven deaths attributed to topical anesthetics in 17 years of reported data from the American Association of Poison Control Centers. The other deaths were from viscous lidocaine (two cases) and i.v. lidocaine (iatrogenic), and one case listed as a parenteral exposure and adverse reaction in which lidocaine was not considered the primary substance responsible for the death (3). There are five cases of EMLA toxicity in the English language literature in children younger than 6 years old (Table 4). The toxicity from EMLA can be two-fold. Seizures have been described, as well as methemoglobinemia. The cases resulted from an over-application due to pharmacy dispensing error in one case, and by overapplication by parents in another (18,19). Three of the cases of toxicity are in children with underlying skin conditions that enhanced systemic absorption of the medication, and resulted in increased toxicity (20 –22). Patients younger than 6 months may be more susceptible to methemoglobinemia due to a relative deficiency in methemoglobin reductase levels (23). Frayling et al. studied 48 healthy children (1– 6 years old) receiving EMLA before i.v. insertion for surgery (24). There were 18 control cases who were receiving routine blood work. They found a small but significant

increase in methemoglobin concentrations (0.85% at 10 h vs. 0.46% in control group) in the patients who received the EMLA. At 24 h after EMLA application, these patients still had an increased methemoglobin concentration. Patients who require repetitive doses of EMLA are likely to have a cumulative effect that can result in toxicity (24). Treatment Lidocaine and dibucaine ingestions should be managed with aggressive supportive care. Hypoxia and metabolic acidosis potentiate the CNS and cardiovascular toxicity of amide anesthetics; therefore, management of the airway is paramount. Metabolic acidosis warrants the use of bicarbonate. Phenytoin should be avoided in the treatment of these seizures because it can cause myocardial depression. Benzodiazepines should be used for seizure control, with phenobarbital relegated to second-line treatment due to its ability to cause myocardial depression as well. Management of cardiac dysrhythmias is per Advanced Cardiac Life Support protocols, with the exception that lidocaine is obviously contraindicated in ventricular fibrillation/ventricular tachycardia, and amiodarone has not been studied. Bretylium has been recommended for rapid ventricular dysrhythmias in this situation (4). Induction of emesis is not recommended due to the risk of rapid respiratory and neurologic deterioration and the risk of aspiration. There are no data on gastric lavage, however, if the patient has had a toxic ingestion and presents within 1 h of ingestion, consider lavage with appropriate airway protection considerations. Activated charcoal should be given if the airway is protected, however, its efficacy is unproven (4). Paramount to the treatment for EMLA toxicity is decontamination; immediately remove the EMLA cream. Most cases will require observation only. The treatment of methemoglobinemia will be described in the section on benzocaine.

Recovery

* Pediatric intensive care unit patient, co-morbidities, on inhaled nitric oxide. Decon ⫽ decontamination.

Full

Full Resolution of cyanosis*

Topical 25 gm Approx 6 h Cyanosis, lethargy No labs Not drawn Supportive Topical 25 gm 2.5 h Cyanosis, lethargy, twitching 20.5% Not drawn Decon, supportive

Topical 75 gm 1h Seizure, respiratory depression 8% 2.5 ug/mL (4 h after application) Decon, anti-convulsants, intubation Full Route Dose applied Time to onset Symptoms Met-Hb level Lidocaine level Treatment

Full

7 months Diaphragmatic hernia, pulmonary hypertension Topical 8 cm2 area 5h Cyanosis 16% Not drawn Methylene blue 6 weeks Hemangioma 3 years Molluscum contagiosum 21 months Molluscum contagiosum

Topical 1140 cm2 area 1h Lethargy, seizure, cyanosis 17.7% 3.0 ug/mL Decon, supportive

Recommendations

Age Co-morbidities

Sinisterra et al. (21) Elsner and Dummer (20) Touma and Jackson (19) Rincon et al. (18)

Table 4. Cases of Pediatric EMLA Toxicity

3 years Eczema

L. A. Curtis et al.

Parker et al. (22)

36

The case reports described above, although limited, would support a very conservative approach to lidocaine and dibucaine ingestions. A viscous lidocaine dose as low as 1 teaspoonful in a 5-month-old has resulted in a seizure, and a subacute ingestion of 100 mg (approximately 1 teaspoon of 2% lidocaine) over 2 days in a 2-year-old has resulted in death (12,25). An exact mg/kg dosing for toxicity has not been easily defined after a review of the literature. One confounding factor is that many of toxic ingestions in the case reports are due to an accumulation of doses rather than a single acute ingestion. Dibucaine is 10 times more potent than lidocaine, and is responsible for three of five deaths from topical anesthetics from outpatient exposures. Extrapolating from the available data, it is clear that lidocaine and dibucaine can be toxic in children younger than 6 years old, and that doses as low as a teaspoon can have significant toxicity and require immediate referral to an emergency department (ED) for evaluation. Combining the available clinical experience in the literature and the pharmacokinetics of these drugs, patients who remain asymptomatic for 4 h after a potentially toxic exposure may be discharged. Those with evidence of persistent CNS or cardiovascular toxicity or those with significant co-morbidities should be admitted to a monitored bed or intensive care unit. Patients presenting to the ED with toxicity from EMLA warrant admission for observation. However, one such case was managed by the pediatrician expectantly at home and the child did well (20).

ESTER ANESTHETICS Group I anesthetics, or ester-type compounds (Table 1), contain esters of benzoic acid, p-aminobenzoic acid, and met-aminobenzoic acid. Benzocaine is the most-oftenencountered member of this class involved in toxic exposures. Benzocaine can cause methemoglobinemia after ingestion, aspiration, or cutaneous exposure, but has not resulted in any recorded fatalities (3).

Pathophysiology There are several mechanisms through which benzocaine is believed to produce its toxic effect. Benzocaine is hydrolyzed to ethanol and aminobenzoic acid by serum pseudocholinesterase. Additionally, it is postulated that benzocaine is metabolized to aniline and then to phenylhydroxylamine and nitrosobenzene. These metabolites are methemoglobinforming compounds (26). Methemoglobin is formed by the

Lidocaine and Topical Anesthetic Exposure

oxidation of ferrous iron (Fe⫹⫹) within the hemoglobin molecule to the ferric state (Fe⫹⫹⫹). Methemoglobinemia results in decreased oxygen-carrying capacity and a leftward shift of the oxygen dissociation curve (27).

Clinical Manifestations Oral ingestion of benzocaine can initially result in gastric irritation due to formation of an irritating hydrochloride salt. This may result in vomiting and abdominal pain (26). Ultimately, methemoglobinemia can result, causing a leftward shift of the oxygen dissociation curve and, therefore, decreased oxygen-carrying capacity (27). Methemoglobin concentrations are measured by co-oximetry and expressed as a percent of the total hemoglobin. At concentrations of 15%, cyanosis unresponsive to supplemental oxygen may occur. Blood drawn from the patient develops a characteristic “chocolate-brown” color. Patients may develop general weakness, dyspnea, tachycardia, nausea and vomiting at concentrations over 30%. However, healthy, normocytic patients may remain asymptomatic until concentrations of 30 – 40%. Concentrations ⬎55% can cause dizziness, lethargy, and stupor, whereas those in the 55–70% range may result in circulatory failure, dysrhythmias, seizures, and coma. Death may occur at a concentration over 70% (23,28). The onset of clinical symptoms after a benzocaine exposure usually occurs within 30 – 60 min, but may be delayed up to 6 h (26,29).

Literature Review Benzocaine used in teething gels, hemorrhoid ointments, and anesthetic sprays is a topical ester-type anesthetic known to cause methemoglobinemia, but a review of the literature revealed no documented cases of pediatric deaths due to ingestion or overuse (3). Patients younger than 6 months may be more susceptible to the oxidizing effects of benzocaine due to a relative deficiency in methemoglobin reductase levels, and the majority of reported cases have occurred in children aged younger than 1 year (23). Tush and Kuhn described a case of methemoglobinemia in a 6-day-old boy whose mother applied Vagisil® (benzocaine 5% and resorcinol 2%) to his diaper rash for 2 days (30). The infant’s only symptom was cyanosis with a methemoglobin level of 35% (30). Townes et al. described a case of a single administration of Baby Ora-Jel® (7.5% benzocaine) to a 14-month-old that resulted in cyanosis after 20 –30 min and a methemoglobin level of 33% (31). Potter and Hillman described a case of a 30-month-old who ingested approximately half of a 30-gram tube of 7.5% benzocaine (40 mg/kg) and became cyanotic; the

37

methemoglobin concentration was 59%; she was treated with oxygen and methylene blue (32). Topical administration of 3% benzocaine and 2% resorcinol to denuded skin caused severe cyanosis, decreased level of consciousness, and seizures in a 23-month-old with a methemoglobin level of 42% (Table 5) (33). It has been estimated that 15–25 mg/kg of benzocaine is capable of producing methemoglobinemia with visible cyanosis. Two case reports from the 1960s report rectal administration of 60 mg and 120 mg of benzocainecontaining suppositories in infants that resulted in methemoglobinemia with concentrations of 48% and 54%, respectively. The weights of these patients were not given, however, they were 21 days old and 4 weeks old, respectively, therefore weighing approximately 3– 4 kg, which would calculate to a range of 15– 40 mg/kg exposure (34,35). Revolinski et al. retrospectively reviewed poison center data over 4 years involving 177 benzocaine ingestions (mean and median doses of 94 and 58 mg/kg, respectively, age range 2 months to 68 years) and found no cyanosis or serious symptoms in any of the patients (36). Liebelt and Shannon reviewed benzocaine ingestions in 1993; their review reported ingestions equivalent to 1/4 to 1/2 teaspoon (22– 40 mg/kg) resulting in methemoglobin levels ranging from 33–59% (26). In 2000, Spiller et al. reviewed oral benzocaine exposures in children (29). In 94% of cases, the exposures were in children ⬍6 years old. Mean and median ingested dosages were 86.8 and 50 mg/kg, respectively, with only one case of methemoglobinemia; a 1-year-old child had a methemoglobin level of 19%, which was due to a case of a therapeutic misadventure with a teething gel. Liebelt and Shannon suggest a dose-related toxicity for benzocaine exposures (26). However, Spiller’s review of 188 cases of benzocaine exposures in children ⬍18 years old finds that 55% of cases had an exposure ⬎40 mg/kg and that 92% of these patients were asymptomatic, and the remaining patients had minor symptoms such as oral numbness and vomiting (29). Aside from the one case of methemoglobinemia, there were no other reports of cyanosis, dusky pallor, or shortness of breath. This review supports the notion that methemoglobinemia may be idiosyncratic rather than dose-related (29).

Treatment The recent review by Spiller et al. previously discussed finds no report of serious toxicity in children after benzocaine ingestion. Therefore, careful consideration of the risks and benefits of therapy before gastric lavage and administration of charcoal would be prudent. Revolinski et al. showed no difference in outcome after activated charcoal administration for benzocaine ingestion (36).

Full

Cyanosis 54% Oxygen, ascorbic acid, methylene blue Full Full

Cyanosis 48% Supportive Obs.

Full Recovery

CONCLUSION

Time to onset

Symptoms Met-Hb level Treatment

A recent survey of 76 poison centers in the United States and Canada revealed wide variability in recommendations regarding management of benzocaine exposures (37). The formation of methemoglobin after a benzocaine exposure is rapid, usually within 30 – 60 min. Severe methemoglobinemia can occur and requires immediate attention and evaluation. However, unintentional exposures to non-prescription benzocaine-containing products rarely cause cyanosis and may not be dose related. Expectant management in these cases is reasonable, with care provider observation at home appropriate for most ingestions. Any evidence of cyanosis, dusky coloration, trouble breathing, or change in mental status requires prompt referral to the ED (29).

Full

Cyanosis 33% Ascorbic acid, supportive Full Cyanosis 59% Oxygen, methylene blue

Cyanosis, lethargy, seizure 42% Intubation, methylene blue

20–30 min Unknown

21 days PR ½ benzocaine suppository (1 grain) 2.5 h 14 months Topical Not quantified 30 months PO 7.5 gm (40 mg/kg)

23 months Topical 1.5–2 oz 3% benzocaine cream Unknown

These decontamination methods are for use only with oral ingestions, not with cutaneous exposures or aspiration. Topical decontamination is important in topical exposures. The antidote for benzocaine-induced methemoglobinemia is methylene blue. Methylene blue is contraindicated for patients with G-6-PD deficiency, as it can result in hemolytic anemia. Methylene blue (1–2 mg/kg i.v.) should be considered in patients with serious symptoms or methemoglobin levels ⬎30%. Red blood cells have their own enzymatic reducing agents to counteract endogenous oxidation, and normal individuals can convert methemoglobin to hemoglobin at a rate of about 15% per hour. Therefore, close observation as long as symptoms are resolving is warranted. Exchange transfusion or hyperbaric oxygen should be considered if treatment with methylene blue fails (27). Methylene blue absorbs light at roughly the same wavelength as deoxygenated hemoglobin, which can result in erroneously low oxygen saturations by pulse oximetry for 5–10 min after infusion (28).

Recommendations

6 days Topical Not quantified, 5 doses applied over 1.5 days Exposure occurred over 1.5 days Cyanosis 35% Oxygen, methylene blue Age Route Dose applied

Peterson (34) Eldadah (33) Townes et al. (31) Potter and Hillman (32) Tush and Kuhn (30)

Table 5. Cases of Pediatric Benzocaine Toxicity

4 weeks PR Benzocaine suppository (2 grain) 45 min

L. A. Curtis et al.

Hughes (35)

38

Lidocaine, dibucaine, and other amide-type anesthetics can cause serious toxicity in young children, even with doses as low as 1 teaspoon. Primary CNS manifestations include depressed mental status, confusion, agitation, ataxia and, ultimately, seizures, coma, or death. Cardiovascular toxicity such as hypotension, bradycardia, and various conduction abnormalities are seen less frequently and at higher serum concentrations. Any child who has had a seizure should be admitted to the hospital. A child who remains asymptomatic after 4 h from ingestion may be safely discharged home.

Lidocaine and Topical Anesthetic Exposure

EMLA can result in serious toxicity. It has a mixed toxicity picture with the potential for CNS toxicity and methemoglobinemia. These cases will likely present to the ED only if they are symptomatic and should be admitted for observation. Ester-based anesthetics like benzocaine can cause methemoglobinemia after cutaneous exposure, aspiration, or ingestion, but have not been implicated in any recorded fatalities. It seems that their toxic effect may not be dose-related. Symptoms generally begin within 30 – 60 min from exposure. If a child is asymptomatic after 2 h of observation, he may be discharged home for continued observation by the care provider (29). A patient who is symptomatic should be admitted to the hospital for continued observation and possible treatment with methylene blue. Given the possibility of inadvertent overdosing by parents and the significant toxicity that can result, it is our opinion that alternative therapies to topical anesthetics should be offered for the symptomatic relief of teething and stomatitis in children. REFERENCES 1. 2003 AAPCC TESS Report. American Association of Poison Control Centers website. Available at: http://www.aapcc.org/2003.htm. Accessed March 29, 2005. 2. Poisindex® managements: anesthetics-local. Micromedex® Healthcare Series. Available at http://www.thomsonhc.com/hcs. Accessed June 23, 2005. 3. Poisoning Data – TESS, Annual reports 1983–2003. American Association of Poison Control Centers. Available at http://www. aapcc.org/annual.htm. Accessed March 29, 2005. 4. Dayan PS, Litovitz TL, Crouch BI, et al. Fatal accidental dibucaine poisoning in children. Ann Emerg Med 1996;28:442–5. 5. Mofenson HC, Carracio TR, Miller H, Greensher J. Lidocaine toxicity from topical mucosal application. With a review of the clinical pharmacology of lidocaine. Clin Pediatr (Phila) 1983;22: 190 –2. 6. Smith M, Wolfram W, Rose R. Toxicity-seizures in an infant caused by (or related to) oral viscous lidocaine use. J Emerg Med 1992;10:587–90. 7. Benowitz NL, Meister W. Clinical pharmacokinetics of lidocaine. Clin Pharmacokinet 1978;3:177–201. 8. Rothstein P, Dornbusch J, Shaywitz B. Prolonged seizure associated with the use of viscous lidocaine. J Pediatr 1982;101:461–3. 9. Jonville AP, Barbier P, Blond MH, Bosq M, Autret E, Breteau M. Accidental lidocaine overdosage in an infant. J Toxicol Clin Toxicol 1990;28:101– 6. 10. Klos CP, Hays GL. Prilocaine-induced methemoglobinemia in a child with Shwachman syndrome. J Oral Maxillofac Surg 1985; 43:621–3. 11. Tetzlaff JE. The pharmacology of local anesthetics. Anesthesiol Clin North America 2000;18:217–33. 12. Hess GP, Walson PD. Seizures secondary to oral viscous lidocaine. Ann Emerg Med 1988;17:725–7.

39 13. Garretson LK, McGee EB. Rapid onset of seizures following aspiration of viscous lidocaine. J Toxicol Clin Toxicol 1992;30: 413–22. 14. Brown DL, Skiendzielewski JJ. Lidocaine toxicity. Ann Emerg Med 1980;9:627–9. 15. Sakai RI, Lattin JE. Lidocaine ingestion. Am J Dis Child 1980; 134:323. 16. Litovitz TL, Normann SA, Veltri JC. 1985 Annual Report of the American Association of Poison Control Centers National Data Collecting System. Am J Emerg Med 1986;4:427–58. 17. Amitai Y, Whitesell L, Lovejoy FH. Death following accidental lidocaine overdose in a child. N Engl J Med 1986;314:182–3. 18. Rincon E, Baker R, Iglesias AJ, Duarte AM. CNS toxicity after topical application of EMLA cream on a toddler with molluscum contagiosum. Pediatr Emerg Care 2000;16:252– 4. 19. Touma S, Jackson JB. Lidocaine and prilocaine toxicity in a patient receiving treatment for mollusca contagiosa. J Am Acad Dermatol 2001;44(2 Suppl):399 – 400. 20. Elsner P, Dummer R. Signs of methaemoglobinaemia after topical application of EMLA® cream in an infant with haemangioma. Dermatology 1997;195:153– 4. 21. Sinisterra S, Miravet E, Alfonso I, Soliz A, Papazian O. Methemoglobinemia in an infant receiving nitric oxide after the use of eutectic mixture of local anesthetic. J Pediatr 2002;141:285– 6. 22. Parker JF, Vats A, Bauer G. EMLA toxicity after application for allergy skin testing. Pediatrics 2004;113:410 –1. 23. Rodriguez LF, Smolik LM, Zbehlik AJ. Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature. Ann Pharmacother 1994;28:643– 8. 24. Frayling IM, Addison GM, Chattergee K, Meakin G. Methaemoglobinaemia in children treated with prilocaine-lignocaine cream. BMJ 1990;301:153– 4. 25. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004;22: 335– 404. 26. Liebelt EL, Shannon MW. Small doses, big problems: a selected review of highly toxic common medications. Pediatr Emerg Care 1993;9:292–7. 27. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med 1999;34:646 –56. 28. Vessely MB, Zitsch RP. Topical anesthesia-induced methemoglobinemia: a case report and review of the literature. Otolaryngol Head Neck Surg 1993;108:763–7. 29. Spiller HA, Winter ML, Weber JA, Gorman SE. Multi-center retrospective evaluation of oral benzocaine exposure in children. Vet Human Toxicol 2000;42:228 –31. 30. Tush GM, Kuhn RJ. Methemoglobinemia induced by an over-thecounter medication. Ann Pharmacother 1996;30:1251–3. 31. Townes PL, Geertsma MA, White MR. Benzocaine-induced methmoglobinemia. Am J Dis Child 1977;131:697– 8. 32. Potter JL, Hillman JV. Benzocaine-induced methemoglobinemia. JACEP 1979;8:26 –7. 33. Eldadah M. Methemoglobinemia due to skin application of benzocaine. Clin Pediatr 1993;32:687– 8. 34. Peterson H. Acquired methemoglobinemia in an infant due to benzocaine suppository. N Engl J Med 1960;263:454 –5. 35. Hughes JR. Infantile methemoglobinemia due to benzocaine suppository. J Pediatr 1965;66:797–9. 36. Revolinski DH, Spiller HA, Weber JA, et al. Does ½ tsp of benzocaine have to go to the ER? J Toxicol Clin Toxicol 1997; 35:484 –5. 37. Suchard J, Rudkin S. Poison Control Center management of benzocaine exposures. Calif J Emerg Med 2004;3:55–9.