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BENZOCAINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Benzocaine is a local anesthetic, the ethyl ester of aminobenzoic acid.

Specific Substances

    1) Anesthamine
    2) Anaesthesinum
    3) Anesthesin
    4) Benzocaine
    5) Ethoforme
    6) Ethyl 4-aminobenzoate
    7) Ethyl aminobenzoate
    8) Orthocesin
    9) Parathesin
    10) CAS 94-09-7
    11) ETHYL-P-AMINOBENZOATE

Available Forms Sources

    A) FORMS
    1) Mouthrinses may contain 0.1 to 5%.
    2) Lozenges may contain 2 to 15 mg.
    3) Oral anesthetics may contain 5 to 20%.
    B) USES
    1) Benzocaine has been used to cut street cocaine (McKinney et al, 1992).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: A local anesthetic available as over-the-counter throat lozenges and topical ointments, creams, gels, solutions, aerosols, and sprays, in concentrations up to 20%.
    B) PHARMACOLOGY: Decreases sodium ion permeability through reversible stabilization of the neuronal membrane. This action inhibits depolarization of the neuronal membrane which blocks the initiation and conduction of nerve impulses.
    C) TOXICOLOGY: Benzocaine is metabolized to aniline, which is further metabolized to phenylhydroxylamine and nitrobenzene, which are capable of oxidizing hemoglobin to methemoglobin. Oxidization of iron in the hemoglobin ring to the ferric form leads to the inability of hemoglobin to bind or transport oxygen. Heme in the ferric (Fe3+) state also induces a hemoglobin conformational change, increasing oxygen affinity of the remaining binding sites and decreasing the oxygen dissociation. Cyanosis occurs when more than 1.5 g/dL of hemoglobin is in the methemoglobin form, compared to 5 g/dL of deoxyhemoglobin to yield similar cyanosis.
    D) EPIDEMIOLOGY: Poisoning may be common due to the availability of over-the-counter products, with methemoglobinemia as the primary toxic effect; however, clinically significant symptoms are uncommon, and severe toxicity is rare.
    E) WITH THERAPEUTIC USE
    1) ACID/BASE: Metabolic acidosis may develop secondary to tissue hypoxia or seizures.
    2) CARDIOVASCULAR: Dysrhythmias and hypotension may occur in severe cases. Myocardial infarction is a rare manifestation of severe methemoglobinemia.
    3) GASTROINTESTINAL: Nausea and vomiting may occur.
    4) HEMATOLOGIC: Chocolate brown blood is classic.
    5) NEUROLOGIC: CNS effects include headache, dizziness, altered consciousness, confusion, lethargy progressing to coma, seizures, and syncope which usually occurs secondary to hypoxia at levels typically of 20% or greater.
    6) RESPIRATORY: Dyspnea and tachypnea may occur.
    7) RISK FACTORS: Patients with underlying medical conditions such as COPD, anemia, or coronary artery disease, recent surgery, or increased metabolic demand (eg, shock, infection) are more susceptible to developing symptoms. The very young (younger than 4 months) and the elderly are at greater risk of developing symptomatic methemoglobinemia. In addition, individuals with a genetic deficiency of G-6-PD or nicotinamide adenine dinucleotide methemoglobin reductase are at greater risk of developing methemoglobinemia.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Cyanosis occurs at methemoglobin levels more than 1.5 g/dL. Cyanosis that is unresponsive to supplemental oxygen, or significant cyanosis in a patient with minimal symptoms should raise the suspicion of methemoglobinemia.
    2) SEVERE TOXICITY: Clinical severity increases with increased methemoglobin levels. Patients who have methemoglobin levels greater than 30% are more likely to develop severe symptoms.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Hypotension, tachycardia, and hyperpnea may occur in patients with significant methemoglobinemia.

Laboratory Monitoring

    A) In a cyanotic patient, a methemoglobin level should be obtained to confirm the diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
    B) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
    C) An ECG should be obtained to screen for myocardial ischemia. Cardiac biomarkers should be obtained if evidence of ischemia is present on ECG.
    D) A CBC with microscopy should be performed to evaluate for hemolysis.
    E) Blood with more than 15% methemoglobinemia will appear chocolate brown and may be an early bedside indication of methemoglobinemia.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Patients with mild to moderate toxicity can be treated with supportive care. Intravenous fluids should be given to maintain urine output and supplemental oxygen applied.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients with evidence of end-organ ischemia should be treated with methylene blue regardless of the methemoglobin concentration. However, patients are unlikely to have end-organ ischemia with concentrations less than 20%. Treatment with methylene blue should result in resolution of all symptoms attributable to methemoglobinemia within 2 hours. Patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or children younger than 3 months may require exchange transfusion or treatment with hyperbaric oxygen as they may not respond to methylene blue. Treat seizures with IV benzodiazepines or barbiturates.
    C) DECONTAMINATION
    1) PREHOSPITAL: Patients should be placed on oxygen. Following dermal exposure, skin should be thoroughly washed with soap and water. Otherwise, no field decontamination is required.
    2) HOSPITAL: Consider activated charcoal soon after large ingestions. Following dermal exposure, skin should be thoroughly washed with soap and water.
    D) AIRWAY MANAGEMENT
    1) Patients with severe dyspnea, tachypnea, seizure, or evidence of end-organ ischemia may require intubation for airway protection or to minimize excessive work of breathing.
    E) ANTIDOTE
    1) METHEMOGLOBINEMIA: Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Children with accidental exposure to an OTC benzocaine product can be safely managed at home with telephone follow-up and referral to a healthcare facility if cyanosis, dusky pallor, shortness of breath or change in mental status develop.
    2) OBSERVATION CRITERIA: Patients should be observed for 8 hours after methylene blue administration to rule out recurrence of methemoglobinemia or adverse reaction to the antidote.
    3) ADMISSION CRITERIA: Patients with recurrent methemoglobinemia should be admitted. Any cyanotic or dyspneic patient with clinically significant methemoglobinemia, or any patient with a methemoglobin level greater than 20%, should be admitted to the intensive care unit, even if improvement has occurred after appropriate emergency department management.
    4) CONSULT CRITERIA: A medical toxicologist or poison control center should be consulted for patients with methemoglobin concentrations above 30% or for symptomatic patients with lower concentrations. Consultation is recommended for patients with familial methemoglobinemia or G-6-PD deficiency.
    G) PITFALLS
    1) Failure of the patient to improve following two doses of methylene blue suggests: inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M, sulfhemoglobinemia, or G-6-PD deficiency. Failure to stabilize and treat the sequelae of end-organ ischemia can lead to significant morbidity and mortality.
    H) TOXICOKINETICS
    1) Benzocaine is metabolized to aniline, which is further metabolized to phenylhydroxylamine and nitrobenzene, which are capable of oxidizing hemoglobin to methemoglobin.
    I) DIFFERENTIAL DIAGNOSIS
    1) Sulfhemoglobinemia is clinically indistinguishable from methemoglobinemia. This diagnosis should be considered if a patient is unresponsive to 2 doses of methylene blue. Sulfhemoglobin is a very stable entity and may require exchange transfusion, although patients usually have minimal symptoms and often require no treatment. Other medical conditions that lead to cyanosis, such as emphysema, congestive heart failure, pulmonary shunts, as well as, other primary lung pathologies, must be considered.

Range Of Toxicity

    A) TOXICITY: ADULT: Severe methemoglobinemia has occurred after 3 or 4 one-second sprays with 20% benzocaine. CHILDREN: Methemoglobinemia has occurred with oral or rectal administration of as little as 100 mg (1/4 teaspoonful of 7.5% gel) in infants under 1 year, and with 22 to 40 mg/kg or more than 240 mg (approximately 1/2 teaspoonful of 7.5% gel) in older children. CAUTION: Severe methemoglobinemia may develop in some individuals (particularly G6PD or NADPH-dependent methemoglobin reductase deficient individuals) at low doses.
    B) THERAPEUTIC: ADULTS AND CHILDREN: Apply topically to affected areas up to 4 times daily.

Clinical Effects

Summary Of Exposure

    A) USES: A local anesthetic available as over-the-counter throat lozenges and topical ointments, creams, gels, solutions, aerosols, and sprays, in concentrations up to 20%.
    B) PHARMACOLOGY: Decreases sodium ion permeability through reversible stabilization of the neuronal membrane. This action inhibits depolarization of the neuronal membrane which blocks the initiation and conduction of nerve impulses.
    C) TOXICOLOGY: Benzocaine is metabolized to aniline, which is further metabolized to phenylhydroxylamine and nitrobenzene, which are capable of oxidizing hemoglobin to methemoglobin. Oxidization of iron in the hemoglobin ring to the ferric form leads to the inability of hemoglobin to bind or transport oxygen. Heme in the ferric (Fe3+) state also induces a hemoglobin conformational change, increasing oxygen affinity of the remaining binding sites and decreasing the oxygen dissociation. Cyanosis occurs when more than 1.5 g/dL of hemoglobin is in the methemoglobin form, compared to 5 g/dL of deoxyhemoglobin to yield similar cyanosis.
    D) EPIDEMIOLOGY: Poisoning may be common due to the availability of over-the-counter products, with methemoglobinemia as the primary toxic effect; however, clinically significant symptoms are uncommon, and severe toxicity is rare.
    E) WITH THERAPEUTIC USE
    1) ACID/BASE: Metabolic acidosis may develop secondary to tissue hypoxia or seizures.
    2) CARDIOVASCULAR: Dysrhythmias and hypotension may occur in severe cases. Myocardial infarction is a rare manifestation of severe methemoglobinemia.
    3) GASTROINTESTINAL: Nausea and vomiting may occur.
    4) HEMATOLOGIC: Chocolate brown blood is classic.
    5) NEUROLOGIC: CNS effects include headache, dizziness, altered consciousness, confusion, lethargy progressing to coma, seizures, and syncope which usually occurs secondary to hypoxia at levels typically of 20% or greater.
    6) RESPIRATORY: Dyspnea and tachypnea may occur.
    7) RISK FACTORS: Patients with underlying medical conditions such as COPD, anemia, or coronary artery disease, recent surgery, or increased metabolic demand (eg, shock, infection) are more susceptible to developing symptoms. The very young (younger than 4 months) and the elderly are at greater risk of developing symptomatic methemoglobinemia. In addition, individuals with a genetic deficiency of G-6-PD or nicotinamide adenine dinucleotide methemoglobin reductase are at greater risk of developing methemoglobinemia.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Cyanosis occurs at methemoglobin levels more than 1.5 g/dL. Cyanosis that is unresponsive to supplemental oxygen, or significant cyanosis in a patient with minimal symptoms should raise the suspicion of methemoglobinemia.
    2) SEVERE TOXICITY: Clinical severity increases with increased methemoglobin levels. Patients who have methemoglobin levels greater than 30% are more likely to develop severe symptoms.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypotension, tachycardia, and hyperpnea may occur in patients with significant methemoglobinemia.
    3.3.2) RESPIRATIONS
    A) WITH THERAPEUTIC USE
    1) Hyperpnea and dyspnea may occur secondary to significant methemoglobinemia induced by benzocaine (Ramsakal et al, 2001; Bhutani et al, 1992; Collins, 1990).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension may occur secondary to significant methemoglobinemia (Udeh et al, 2001; Wurdeman et al, 2000; Collins, 1990; Linares et al, 1990).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Tachycardia may occur secondary to significant methemoglobinemia (generally greater than 40%) (Eldadah & Fitzgerald, 1993).

Heent

    3.4.3) EYES
    A) RABBITS: No eye irritation was seen when 4% to 20% solutions in polyethylene glycol were applied to rabbit corneas (FDA, 1982).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia may occur secondary to significant methemoglobinemia (generally greater than 40%).
    b) CASE REPORT: A 23-month-old child developed a methemoglobin level of 42% and tachycardia (180 beats/min) after dermal application of a cream containing benzocaine (Eldadah & Fitzgerald, 1993).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension may occur secondary to significant methemoglobinemia (Wurdeman et al, 2000).
    b) CASE REPORT: A 41-year-old man developed a methemoglobin level of 74.7% and hypotension 10 minutes after receiving benzocaine 20% spray and diazepam 10 mg IV for endoscopy (Collins, 1990).
    c) CASE REPORT: A 73-year-old man developed a methemoglobin level of 48.5% and hypotension after receiving 4 sprays of benzocaine 20% for endoscopy (Linares et al, 1990).
    d) CASE REPORT: A 65-year-old man developed hypotension (70/40), bradycardia (42 beats/min), and severe methemoglobinemia (55%) after receiving benzocaine 20% topically for fiberoptic laryngoscopy (Udeh et al, 2001).
    C) ATRIAL FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 41-year-old man developed a methemoglobin level of 74.7%, hypotension, and atrial fibrillation 10 minutes after receiving benzocaine 20% spray and diazepam 10 mg IV for endoscopy. He converted back to sinus rhythm after treatment with methylene blue (Collins, 1990).
    D) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 46-year-old man developed substernal chest pain, diaphoresis, and cyanosis within minutes after administration of a topical benzocaine spray for removal of a gastrostomy tube. The patient's methemoglobin level was 66.2%, and the ECG showed diffuse ST segment depression consistent with subendocardial injury. Acute myocardial infarction was diagnosed by serial CK-MB enzyme levels and MB index (Rynn et al, 1995).
    E) ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 71-year-old man with a past medical history of severe peripheral vascular disease, type 2 diabetes mellitus, Crohn disease, and sigmoid adenocarcinoma status post resection and ileo-colic anastomosis developed cyanosis, dyspnea (oxygen saturations 76% on pulse oximetry), and chest pain within minutes after the administration of a topical benzocaine 20% solution (3 sprays) during an elective esophageogastroduodenoscopy. Cardiac enzyme estimation revealed a mild elevation of cardiac troponin I levels (0.71 ng/mL) and an ECG revealed ST depression in the lateral leads V4, V5, and V6. Co-oximetry showed a methemoglobin concentration of 17% and an oxyhemoglobin concentration of 82.2%. He was treated with methylene blue (1 mg/kg IV over 5 minutes) and his methemoglobinemia resolved, his chest pain improved, and his troponin levels declined to normal (Saha et al, 2006).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) Hyperpnea and dyspnea may occur secondary to significant methemoglobinemia induced by benzocaine (Ramsakal et al, 2001; Bhutani et al, 1992; Collins, 1990) .
    B) APNEA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 15-year-old girl developed a methemoglobin level of 54% and lethargy followed by coma and respiratory arrest 30 minutes after endoscopy for which she had received 3 to 4 sprays of benzocaine 20% and midazolam 6 mg IV (Bhutani et al, 1992).
    C) HYPOXEMIA
    1) WITH THERAPEUTIC USE
    a) Patients who develop significant methemoglobinemia after benzocaine exposure may manifest signs and symptoms of end organ hypoxia including tachycardia, tachypnea, lethargy, and confusion (Ramsakal et al, 2001; Wurdeman et al, 2000).
    b) CASE REPORT: Benzocaine 20% topical spray was used to anesthetize the upper airway of a 71-year-old man undergoing a bronchoscopic procedure. After the procedure, the oxygen saturation of the patient decreased to less than 85%, despite receiving supplemental oxygen. The patient became tachycardic, tachypneic, and cyanotic. An arterial blood gas was drawn, revealing a methemoglobin level of 19.4%, confirming a diagnosis of benzocaine-induced methemoglobinemia. The patient recovered following intravenous administration of methylene blue (Slaughter et al, 1999a).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures are not common following exposure to benzocaine, presumably due to low oral and mucosal absorption. Seizures have been reported in a patient with benzocaine-induced methemoglobinemia.
    b) CASE REPORT: A 23-month-old child developed a methemoglobin level of 42% and seizures after dermal application of a cream containing benzocaine (Eldadah & Fitzgerald, 1993).
    c) BENZOCAINE-ADULTERATED COCAINE: A 34-year-old man, who ingested a packet of cocaine, developed seizures approximately 1 hour after presenting to the emergency department. The patient's skin was blue in color, arterial blood gas analysis revealed a PaO2 of 65.1 kPa and a true fraction of hemoglobin bound to oxygen of 82.5%, and the patient's blood was dark in color. Co-oximetry determined the methemoglobin concentration of 13.8%, indicating methemoglobinemia. Urine mass spectrometry confirmed the presence of cocaine, phenytoin, lidocaine, and benzocaine. It is suspected that the seizures and the methemoglobinemia were the result of ingesting benzocaine-adulterated cocaine (Chakladar et al, 2010)
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) Lethargy may occur with very high levels of methemoglobin.
    b) CASE REPORT: A 41-year-old man developed a methemoglobin level of 74.7% and lethargy 10 minutes after receiving benzocaine 20% spray and diazepam 10 mg IV for endoscopy (Collins, 1990).
    c) CASE REPORT: A 15-year-old girl developed a methemoglobin level of 54% and lethargy followed by coma and respiratory arrest 30 minutes after endoscopy for which she had received 3 to 4 sprays of benzocaine 20% and midazolam 6 mg IV (Bhutani et al, 1992).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Headache developed in a patient with benzocaine-induced methemoglobinemia (Vessely & Zitsch, 1993).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Profound weakness may develop in patients with significant methemoglobinemia secondary to benzocaine (Vessely & Zitsch, 1993; Dinneen et al, 1994).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported in patients who developed severe methemoglobinemia (greater than 40%) from benzocaine (Collins, 1990; Linares et al, 1990) .

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Metabolic acidosis may occur secondary to cellular anoxia and anaerobic metabolism (Eldadah & Fitzgerald, 1993a).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) Numerous reports of methemoglobinemia secondary to benzocaine have appeared in the literature, with most cases associated with infants and young children. In these cases, methemoglobinemia has resulted from the topical application of benzocaine as a dermatologic ointment, rectal suppository, perineal cream, lubricant for insertion of a rectal temperature probe, lubricant for an esophageal stethoscope, mucous membrane spray, lubricant for an endotracheal tube, and teething preparation (Ferraro-Borgida et al, 1996; Bhatt et al, 1985; Seibert & Seibert, 1984; Kellett & Copeland, 1983a; McGuigan, 1981a; Potter & Hillman, 1979a; Sherman, 1979; Townes et al, 1977a; Hughes, 1965a; Steinberg & Zepernick, 1962; Goluboff & MacFayen, 1955).
    b) Up until March 16, 2011, the US Food and Drug Administration (FDA) has received a total of 21 cases of methemoglobinemia, including 10 categorized as life-threatening, associated with the use of over-the counter benzocaine gel or liquid products. In general, the benzocaine products were used at home by pediatric patients (n=15), most of whom were 2 years of age or younger (n=11), for teething pain (gel). Six cases occurred in adult patients who applied benzocaine gel or liquid to relieve toothache. Although excessive amounts were applied in some cases, methemoglobinemia was also reported after the administration of a single benzocaine dose; symptoms occurred within minutes to 1 or 2 hours after use. Methemoglobinemia has been reported with all strengths of benzocaine gels and liquids, including concentrations as low as 7.5%. Infants younger than four months, elderly patients, or those with certain inborn defects may be at a greater risk of developing methemoglobinemia, and patients with heart disease, lung disease (eg, asthma, bronchitis, emphysema), or who smoke are at greater risk for complications related to the event (U.S. Food and Drug Administration (FDA), 2011).
    c) CASE REPORT: A 74-year-old man acquired methemoglobinemia from topical application of benzocaine. Benzocaine 14% was administered to his oropharynx in preparation for transesophageal echocardiography. The patient became somnolent and cyanotic; arterial blood gas values checked at that time were pH 7.33, pCO2 52, pO2 279.6, oxyhemoglobin 40.3%, and methemoglobin 59.7%. Treatment with methylene blue 2 mg/kg improved the cyanosis. Repeat blood gases were pH 7.46, pCO2 36, pO2 163, and methemoglobin 0.6%. The author concluded that this rare adverse effect is potentially fatal, and must be treated promptly once diagnosed (Stoiber, 1999). A similar case report was presented in a 71-year-old man who received benzocaine for bronchoscopy. Management and outcome were comparable to the previous report (Slaughter et al, 1999).
    d) CASE REPORT: Benzocaine-induced methemoglobinemia was reported in a 34-year-old woman who was using benzocaine-containing over-the-counter products. The patient was self-medicating with miconazole nitrate vaginal suppositories and a topical cream (Yeast Gard(R)) for vaginal discharge and vulvar irritation. The regular strength cream contains benzocaine 5% and resorcinol 2%, and the maximum strength cream contains benzocaine 20% and resorcinol 2%; both creams were used by the patient. Upon admission to the emergency department, the patient complained of weakness, palpitations, and shortness of breath, and presented with blue lips and nail beds. Blood chemistry was consistent with the diagnosis of methemoglobinemia. After treatment with methylene blue 100 mg IV, the patient's signs and symptoms dramatically improved (Ferraro-Borgida et al, 1996).
    e) ONSET: Methemoglobinemia has developed in adult patients within 3 hours of ingestion of 162.5 to 325 mg; and within minutes after topical application (Wolff, 1975; Bernstein, 1960; (Guerriero, 1997; Ho et al, 1998).
    f) CASE REPORT: A methemoglobin level of 26% was reported in an adult patient who received 140 mg of benzocaine topically to facilitate intubation (Anderson et al, 1988).
    g) BENZOCAINE-ADULTERATED COCAINE: A 34-year-old man, who ingested a packet of cocaine, developed seizures approximately 1 hour after presenting to the emergency department. The patient's skin was blue in color, arterial blood gas analysis revealed a PaO2 of 65.1 kPa and a true fraction of hemoglobin bound to oxygen of 82.5%, and the patient's blood was dark in color. Co-oximetry determined the methemoglobin concentration of 13.8%, indicating methemoglobinemia. Urine mass spectrometry confirmed the presence of cocaine, phenytoin, lidocaine, and benzocaine. It is suspected that the seizures and the methemoglobinemia were the result of ingesting benzocaine-adulterated cocaine (Chakladar et al, 2010).
    h) CASE REPORT: A 39-year-old man presented to the emergency department with a 1-week history of dental pain, radiating from his jaw to his ear, that became progressively worse. Interview of the patient revealed that he had taken 2400 mg ibuprofen over the previous 8 hours and had used 1.5 tubes of Anbesol (R), each tube containing 7 mL 20% benzocaine, within 2 hours prior to presentation. The patient's lips were cyanotic and an initial oxygen saturation (O2sat) measurement was 90%. He was administered a local anesthetic for the pain. Prior to discharge, a repeat O2sat had decreased to 87%, and an arterial blood gas measurement indicated a methemoglobin level of 33.2%. Following IV methylene blue administration, the patient recovered and was discharged with a methemoglobin level of 2.2% and an O2sat of 98% (Orr & Orr, 2011).
    i) CASE REPORT: A 47-year-old woman with vulvar carcinoma presented to the emergency department with progressive dyspnea, fatigue, and cyanosis. Oxygen saturation was 78% on room air. Initial methemoglobin level was 49%, and treatment with methylene blue (1 mg/kg IV over 5 minutes) was initiated. Interview of the patient revealed that she had been applying a 20% benzocaine cream every 2 hours to the vulvar area to alleviate pain and irritation secondary to radiation and a yeast infection. After receiving a total methylene blue dose of 6 mg/kg, decontamination with soapy water, and vaginal lavage with 60 mL of normal saline, the patient recovered and was discharged on hospital day 5. At the time of discharge, her methemoglobin level had decreased to 5.4% (Afeld et al, 2015).
    j) CASE REPORT: A 60-year-old woman received IV midazolam and IV fentanyl for conscious sedation and 20% benzocaine spray topically for oropharyngeal anesthesia in preparation for a transesophageal echocardiography. Following the procedure, the patient was arousable but drowsy, and showed a decrease in oxygen saturation. Despite administration of IV naloxone for sedation reversal, her oxygen saturation continued to decrease and the patient appeared cyanotic and pale. Arterial blood gas analysis revealed chocolate-colored blood, a pH of 7.43, oxygen saturation of 68%, pO2 416 mmHg, pCO2 30 mmHg, and a hemoglobin level of 32.1%. Two doses of IV methylene blue 1 mg/kg, administered approximately 1 hour apart, resulted in patient improvement with a methemoglobin level of 0.4% and complete resolution of cyanosis (Lata & Janardhanan, 2015).
    k) CASE REPORT/INFANT: A 6-day-old infant presented with methemoglobinemia (methemoglobin peak level of 35%) approximately 36 hours after the mother began administering a topical anesthetic cream containing benzocaine 5% and resorcinol 2% for treatment of diaper rash. The infant recovered following IV administration of 3 mg (1mg/kg) of methylene blue (Tush & Kuhn, 1996).
    l) CASE REPORT/CHILD: A 6-year-old child presented with vomiting, apnea, and cyanosis, necessitating intubation, following suspected ingestion of a sensitive-formula toothpaste containing benzocaine. Medical history of the child noted that she had been a 27-week premature infant with grade IV intracranial hemorrhage and developmental delay. On hospital arrival, her blood was chocolate-brown and treatment with methylene blue 1 mg/kg was initiated. Laboratory analysis revealed an initial methemoglobin level of 86.2%. Following 4 doses of methylene blue and an exchange transfusion, her methemoglobin level decreased to 36.4%. A urine toxicology screen was positive for amphetamines and benzodiazepines. With continued supportive care, the patient gradually recovered and was discharged on hospital day 6 to the state child protective services (Geib et al, 2015).
    m) DOSE-RESPONSE: Methemoglobinemia has been reported with levels up to 59% in children after ingestion of 22 to 40 mg/kg (Autret et al, 1989) (Bechmann et al, 1986) (Potter & Hillman, 1979; Townes et al, 1977).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity with contact dermatitis occurs in 3.3% to 5% of patients. There is little evidence that cross-sensitivity to other local anesthetics is common (FDA, 1982).
    b) CASE REPORT: A 72-year-old woman developed allergic contact dermatitis from topical benzocaine 20% ointment used to treat herpes zoster (Roos & Merk, 2001).
    c) CASE REPORT: Contact urticaria and contact dermatitis were described in a 39-year-old male dental patient during topical use of benzocaine (Hurricaine(R) Gel). On 2 occasions, the patient developed swelling of the gingival and buccal mucosae, with later progression to vesiculation, following application of benzocaine. The patient gave a history of sensitivity to an anesthetic burn ointment and an otic solution containing benzocaine. Open testing on the forearm revealed an immediate urticarial reaction, and closed patch tests were positive after 48 hours. The contact dermatitis was consistent with a delayed-type hypersensitivity. However, it appeared that a nonimmunologic mechanism produced the contact urticaria, as passive transfer was negative in the patient (Ryan et al, 1980)
    B) CYANOSIS
    1) WITH THERAPEUTIC USE
    a) Cyanosis is a typical clinical finding and usually occurs with a methemoglobin of 1.5 g/dL, which represents only 10% conversion of hemoglobin to methemoglobin if the baseline hemoglobin is 15 g/dL (Price, 2006).
    b) Profound central and peripheral cyanosis that does not respond to oxygen administration may occur secondary to significant benzocaine-induced methemoglobinemia (Ellis et al, 1995; Brown et al, 1994; Dinneen et al, 1994; Vessely & Zitsch, 1993; Grum & Rice, 1990) .
    c) Cyanosis and decreased oxygen saturation measured by pulse oximetry that are unresponsive to oxygen administration are often the first clinical indications of methemoglobinemia secondary to benzocaine administration, especially in patients who are undergoing procedures that also involve sedation (Gunaratnam et al, 2000; Gupta et al, 2000).
    C) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Diaphoresis has been reported in patients who developed severe benzocaine-induced methemoglobinemia (Linares et al, 1990).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis is rarely reported (Hesch, 1960).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) In a cyanotic patient, a methemoglobin level should be obtained to confirm the diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
    B) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
    C) An ECG should be obtained to screen for myocardial ischemia. Cardiac biomarkers should be obtained if evidence of ischemia is present on ECG.
    D) A CBC with microscopy should be performed to evaluate for hemolysis.
    E) Blood with more than 15% methemoglobinemia will appear chocolate brown and may be an early bedside indication of methemoglobinemia.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Obtain arterial blood gases on patients who are cyanotic or symptomatic; significant disparity between the calculated and measured O2 saturation suggests methemoglobinemia.
    a) PO2 is usually normal, even in the presence of severe methemoglobinemia.
    b) METHEMOGLOBIN LEVEL (% of total hemoglobin): Diagnostic; levels greater than 15% usually produce symptoms; cyanosis may be present with level of 15%. Methemoglobin levels will be reduced if blood is not analyzed rapidly (few hours) by endogenous methemoglobin reductase. The development of methemoglobinemia may be delayed with some chemical exposures.
    2) Methemoglobin is incapable of binding with oxygen. Metabolic acidosis occurs when the methemoglobin level is high enough to result in tissue hypoxia (generally greater than 50%). Partial respiratory compensation for the metabolic acidosis usually occurs.
    3) OXYGEN SATURATION: The PO2 and calculated O2 saturation percentages are usually normal. Measured O2 saturation will be decreased.
    a) PO2 is a measurement of the partial pressure of oxygen dissolved in plasma. Calculated oxygen saturation (O2 saturation of SO2) is computed fro pH and PO2 utilizing a standardized oxygen dissociation curve and assuming normal hemoglobin. Calculated O2 saturation is unreliable in cases of abnormal hemoglobin (methemoglobin, sulfhemoglobin, carboxyhemoglobin) or in some cases of abnormal pH, temperature or DPG concentrations.
    b) Hypoxia may result from loss of respiratory drive if the patient is comatose.
    4) Pulse oximetry overestimates oxygen saturation in patients with significant methemoglobinemia and should not be used to reflect arterial oxygen content or tissue oxygen delivery (Watcha et al, 1989; Barker et al, 1989; Varon, 1992; Delwood et al, 1991).
    a) Although pulse oximetry is considered inaccurate in the presence of methemoglobin, it may have a role in the unsuspected case of methemoglobinemia. Because digital pulse oximetry is not an accurate reflection of oxyhemoglobin, a pulse oximetry value at or trending towards 85% despite supplemental oxygen may actually be an early indication to suspect methemoglobinemia.
    b) Treatment of methemoglobinemia should be guided by patient signs and symptoms. Monitor therapy with direct measurements of oxyhemoglobin using a co-oximeter and not on the basis of measurements using pulse oximetry or on estimates of saturations calculated from the PO2 and the oxyhemoglobin dissociation curve (Watcha et al, 1989). Pulse oximetry may actually register a transient decrease following treatment with methylene blue.
    1) Pulse oximetry; however, may have a role in comparing the arterial blood gas findings. If a difference between the measured oxyhemoglobin saturation of the pulse oximeter (SpO2) and the calculated oxyhemoglobin saturation of the arterial blood gas (pO2) is different than a saturation gap exists. In this setting, the calculated SpO2 will be greater than the measured SpO2 if methemoglobin is present (Price, 2006).
    5) Hemoglobin should be obtained; anemic patients may have greater symptoms and require treatment at lower methemoglobin levels because of decreased oxygen carrying capacity.
    B) BLOOD/SERUM CHEMISTRY
    1) Serum benzocaine levels are not clinically useful.
    4.1.3) URINE
    A) URINALYSIS
    1) Urinalysis may show brown or black discoloration, casts, and protein.
    4.1.4) OTHER
    A) OTHER
    1) OXYGEN SATURATION
    a) PULSE OXIMETRY: Saturation determined by pulse oximetry will be low in the presence of significant methemoglobinemia, the pulse oximetry reading may either underestimate or overestimate the actual measured saturation (Anderson et al, 1988; Wong, 1995).
    1) If the actual hemoglobin saturation is more than 85% the pulse oximeter will tend to underestimate hemoglobin saturation; if the actual saturation is less than 85% the pulse oximeter will overestimate hemoglobin saturation (Wong, 1995).
    2) ECG
    a) Cardiac monitoring is recommended, especially in patients with underlying diseases known to increase susceptibility.
    b) Sinus tachycardia is frequently present and may be secondary to anxiety, tissue hypoxia or acidosis. If the acidosis and tissue hypoxia are severe enough, ischemic changes, ventricular dysrhythmias and cardiac arrest may result.

Methods

    A) OTHER
    1) Methemoglobin levels are available in most hospitals, and are usually reported as a percent of total hemoglobin. Serial methemoglobin levels should be followed in cyanotic patients.
    2) If a rapid methemoglobin determination cannot be done, a simple test can help to confirm methemoglobinemia. Both sample and control blood are placed on filter paper and exposed to room air; the control blood will be red, whereas the blood containing large amounts of methemoglobin (greater than 15%) will have a deep chocolate brown color.
    a) In clinical practice, physicians may delay diagnosis of methemoglobinemia through overreliance on their bedside acumen in detecting chocolate-brown blood. Subtle changes in the appearance of sampled blood may be easily missed if the clinician is not looking specifically for them. In addition, the chocolate-brown color is difficult to identify (Henretig et al, 1988).
    b) In an asymptomatic but cyanotic patient in whom methemoglobinemia is suspected, none of the bedside techniques commonly recommended are completely reliable. Diagnosis should be pursued with a spectrophotometric analysis.
    c) One study recommended a bedside test using a color chart (red, green, and blue) to provide an accurate quantitative estimate of the percentage of methemoglobin present in a blood sample. A 10 microliter drop of blood is placed on white absorbent paper and compared with the color chart; in clinical use the color chart showed good agreement with measured methemoglobin concentration (Shihana et al, 2010).
    3) The methemoglobin level will be reduced if blood is not analyzed rapidly (few hours) by endogenous methemoglobin reductase.
    4) BUBBLING OXYGEN: This involves bubbling 100% oxygen through a sample of venous blood. Whereas normal hemoglobin will turn bright red, methemoglobin will not.
    5) OXIMETERS: Dotsch et al (1999) conducted an in vitro study to compare 6 different commercially available oximeters used to measure hemoglobin derivatives with a manual conventional (photometric) method (Dotsch et al, 1999).
    a) It was found that each device was comparable in accuracy and reproducibility, whereas the photometric method failed to produce accurate methemoglobin concentrations. Methylene blue interfered with methemoglobin measurements in all devices in a dose-dependent manner.
    b) The oximeters tested were the CO-Oximeter 270 (Chiron Diagnostics, Fernwald, Germany); CO-Oximeter 865 (Chiron Diagnostics); ABL 520 Hemioximeter (Radiometer, Frankfurt, Germany); AVL omni 6 (AVL, Bad Homburg, Germany); Stat Profil Ultra C (NOVA, Rodermark, Germany); AVOXImeter 1000E (Avox Systems, San Antonio, TX).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with recurrent methemoglobinemia should be admitted.
    B) Any cyanotic or dyspneic patient with clinically significant methemoglobinemia, or any patient with a methemoglobin level greater than 20%, should be admitted to the intensive care unit, even if improvement has occurred after appropriate emergency department management.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children with accidental exposure to an OTC benzocaine product can be safely managed at home with telephone follow-up and referral to a healthcare facility if cyanosis, dusky pallor, shortness of breath or change in mental status develop (Spiller et al, 2000).
    B) CASE SERIES: Spiller et al (2000) reviewed 188 charts of children with benzocaine exposure and found that accidental exposure of OTC benzocaine rarely resulted in any clinical effects. In this series 92% (173 patients) remained asymptomatic, 8 patients developed oral numbness, 3 vomited and one patient each developed oral irritation, dizziness or nausea. Fifty seven patients (30%) were evaluated in the emergency department and 8 had methemoglobin levels determined. One 1-year-old patient had a methemoglobin level of 19% after receiving 1 ml of an OTC teething gel 5 to 10 times over 24 hours. He was cyanotic but otherwise asymptomatic. No other children developed cyanosis, dusky pallor or shortness of breath (Spiller et al, 2000).
    1) The patients ranged in age from 2 months to 17 years; 94% (177 patients) were 6-years-old or less; 65 (35%) were less than 2 years old. Mean and median doses ingested were 86.8 (+/- 89.5) mg/kg and 50 mg/kg, respectively (Spiller et al, 2000).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) A medical toxicologist or poison control center should be consulted for patients with methemoglobin concentrations above 30% or for symptomatic patients with lower concentrations. Consultation is recommended for patients with familial methemoglobinemia or G-6-PD deficiency.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients should be observed for 8 hours after methylene blue administration to rule out recurrence of methemoglobinemia or adverse reaction to the antidote.

Monitoring

    A) In a cyanotic patient, a methemoglobin level should be obtained to confirm the diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
    B) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
    C) An ECG should be obtained to screen for myocardial ischemia. Cardiac biomarkers should be obtained if evidence of ischemia is present on ECG.
    D) A CBC with microscopy should be performed to evaluate for hemolysis.
    E) Blood with more than 15% methemoglobinemia will appear chocolate brown and may be an early bedside indication of methemoglobinemia.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Patients should be placed on oxygen. Following dermal exposure, skin should be thoroughly washed with soap and water. Otherwise, no field decontamination is required.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Prevention of absorption may be accomplished by activated charcoal after large ingestions. Emesis should be avoided due to the rapid onset of cyanosis and potential respiratory distress. Accidental exposures in children to OTC benzocaine preparations rarely result in significant toxicity and generally do NOT require gastrointestinal decontamination.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) OXYGEN
    1) INDICATIONS: 100% oxygen should be administered to all cyanotic patients until the methemoglobin level is below 20% and the patient is in no respiratory distress.
    2) The lack of clinical response to 100% oxygen indicates the presence of dyshemoglobinemia (methemoglobinemia or sulfhemoglobinemia) or the presence of an anatomic or physiologic shunt.
    a) With a normal circulation, the inhalation of 100% oxygen rapidly improves peripheral cyanosis (nail beds, mucous membranes, distal extremities) associated with cardiovascular or pulmonary disease. In patients with methemoglobinemia, cyanosis does not improve when 100% oxygen is administered. Likewise, cyanotic patients with sulfhemoglobinemia will not respond to inhalation of 100% oxygen.
    B) MONITORING OF PATIENT
    1) In a cyanotic patient, a methemoglobin level should be obtained to confirm diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
    2) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
    3) An ECG should be obtained to screen for myocardial ischemia. Cardiac biomarkers should be obtained if evidence of ischemia is present on ECG.
    4) A CBC with microscopy should be performed to evaluate for hemolysis.
    5) Blood with more than 15% methemoglobinemia will appear chocolate brown and may be an early bedside indication of methemoglobinemia.
    C) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    4) ADVERSE EFFECTS
    a) METHEMOGLOBINEMIA: Although methylene blue itself has been reported to cause methemoglobin formation up to about 7% of total hemoglobin (Whitwam et al, 1979; Goluboff & Wheaton, 1961; Nadler et al, 1934), this hypothesis has been disputed (Stossel & Jennings, 1966; Rentsch & Wittekind, 1967), and the amounts said to be induced are clinically insignificant (Hall et al, 1986).
    b) HEMOLYSIS
    1) Repeated large doses (up to 15 milligrams/kilogram) may cause hemolysis (Jaffe, 1979; Harvey & Keitt, 1983), particularly in the presence of G-6-PD deficiency. Methylene blue may be ineffective in patients with G-6-PD deficiency (Rosen et al, 1971).
    2) The dangers of repeated appropriate doses of methylene blue (1 to 2 milligrams/kilogram) are uncertain, but it is recommended that, with rare exceptions, the total dosage should not exceed 7 milligrams/kilogram (Wintrobe, 1974; Harvey & Keitt, 1983).
    c) OTHER: Include chest pain, dyspnea, anxiety, and tremors (Nadler et al, 1934).
    5) FALSE POSITIVE CO-OXIMETER RESULTS: Methylene blue may cause a false-positive methemoglobin level when a co-oximeter is used to measure arterial blood gases (Kirlangitis et al, 1990).
    D) SEIZURE
    1) Seizures occur generally secondary to tissue hypoxia; treatment of seizures in this setting should be focused on relieving tissue hypoxia and treating methemoglobinemia. Administer 100% supplemental oxygen and administer methylene blue as described above. Anticonvulsant therapy may be used as an adjunct.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) HYPERBARIC OXYGEN THERAPY
    1) If the patient is not responsive to methylene blue, hyperbaric oxygen has been recommended as adjunctive therapy in severe cases (Donovan, 1983).
    2) In animals, HBO has been shown to decrease mortality, alone or in combination with methylene blue (Sheehy & Way, 1974; Goldstein & Doull, 1971).
    F) EXCHANGE TRANSFUSION
    1) Exchange transfusion should be done if the methemoglobinemia is not responsive to methylene blue and is progressive in a symptomatic individual.
    2) Should be considered if the methemoglobin level approaches 70% and cannot be controlled by the use of methylene blue.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Following dermal exposure, skin should be thoroughly washed with soap and water.

Range Of Toxicity

Summary

    A) TOXICITY: ADULT: Severe methemoglobinemia has occurred after 3 or 4 one-second sprays with 20% benzocaine. CHILDREN: Methemoglobinemia has occurred with oral or rectal administration of as little as 100 mg (1/4 teaspoonful of 7.5% gel) in infants under 1 year, and with 22 to 40 mg/kg or more than 240 mg (approximately 1/2 teaspoonful of 7.5% gel) in older children. CAUTION: Severe methemoglobinemia may develop in some individuals (particularly G6PD or NADPH-dependent methemoglobin reductase deficient individuals) at low doses.
    B) THERAPEUTIC: ADULTS AND CHILDREN: Apply topically to affected areas up to 4 times daily.

Therapeutic Dose

    7.2.1) ADULT
    A) INDICATION
    1) OTITIS: Instill 4 to 5 drops of otic solution into external ear canal of affected ear(s), repeat every 1 to 2 hours if necessary (Prod Info Americaine(R) Otic, 2002).
    2) TOPICAL ANESTHETIC FOR PAIN RELIEF: Apply gel, liquid, or ointment topically to affected areas up to 4 times daily (Prod Info ANBESOL(R) MAXIMUM STRENGTH oral liquid, 2007; Prod Info ORAJEL(R) MAXIMUM STRENGTH oral gel, 2007; Prod Info ORABASE(R) oral paste, 2007).
    7.2.2) PEDIATRIC
    A) INDICATION
    1) OTITIS: age 1 year and older: Instill 4 to 5 drops of otic solution into external ear canal of affected ear(s), repeat every 1 to 2 hours if necessary (Prod Info Americaine(R) Otic, 2002).
    2) TOPICAL ANESTHETIC FOR PAIN RELIEF: 2 years and older: Apply gel, liquid, or ointment topically to affected areas up to 4 times daily (Prod Info ANBESOL(R) MAXIMUM STRENGTH oral liquid, 2007; Prod Info ORAJEL(R) MAXIMUM STRENGTH oral gel, 2007; Prod Info ORABASE(R) oral paste, 2007).

Maximum Tolerated Exposure

    A) GENERAL
    1) IDIOSYNCRATIC RESPONSES: Certain individuals with inherited disorders (eg, NADPH-dependent methemoglobin reductase or G6PD deficiency) in methemoglobin reducing capacity may also display an idiosyncratic response to extremely small amounts.
    B) INFANTS
    1) Methemoglobinemia may occur with lower doses and with greater severity in children under 1 year of age.
    2) ORAL
    a) Ingestion of 100 milligrams and rectal administration of 30 to 120 milligrams have produced severe toxicity in infants under 6 months of age in isolated cases (McGuigan, 1981; Kellett & Copeland, 1983; Peterson, 1960; Hughes, 1965).
    b) This amount is contained in 1/4 teaspoonful of Baby Orajel (7.5 percent benzocaine).
    c) However, deliberate oral administration of 1000 mg to 20 infants aged 1 day to 6 months produced insignificant increases in methemoglobin blood levels to an average of 4.5 percent in another study (Rao et al, 1978).
    d) A 13-month-old child developed lethargy, cyanosis, and a methemoglobin level of 57% following 10 to 15 applications of Oral-jel maximum strength(R) (20% benzocaine) to the gums for teething discomfort (Gentile, 1987).
    3) TOPICAL
    a) Liberal application of 3% to 10% ointment to denuded diaper areas has produced methemoglobinemia in infants less than 3 months of age (Goluboff & MacFayden, 1955; Goluboff, 1958; Wolff, 1957; Haggerty, 1962).
    C) CHILDREN
    1) ORAL
    a) In older children aged 14 to 60 months, oral ingestion of 22 to 40 mg/kg (total 247 to 560 mg) has produced methemoglobinemia (Townes et al, 1977; Potter & Hillman, 1979; Bachmann et al, 1986), with levels ranged from 33% to 59%. One-half teaspoonful of Baby Orajel (7.5% benzocaine) contains 187 mg of benzocaine.
    b) LACK OF EFFECT
    1) CASE SERIES: Spiller et al (2000) reviewed 188 charts of children with benzocaine exposure and found that accidental exposure of OTC benzocaine rarely resulted in any clinical effects. In this series 92% (173 patients) remained asymptomatic, 8 patients developed oral numbness, 3 vomited and one patient each developed oral irritation, dizziness or nausea. Fifty seven patients (30%) were evaluated in the emergency department and 8 had methemoglobin levels determined. One one-year-old patient had a methemoglobin level of 19% after receiving 1 ml of an OTC teething gel 5 to 10 times over 24 hours. He was cyanotic but otherwise asymptomatic. No other children developed cyanosis, dusky pallor or shortness of breath (Spiller et al, 2000).
    2) The patients ranged in age from 2 months to 17 years; 94% (177 patients) were 6-years-old or less; 65 (35%) were less than 2 years old. Mean and median doses ingested were 86.8 (+/- 89.5) mg/kg and 50 mg/kg, respectively. It is suggested that these cases could be safely managed at home with telephone follow-up and referral to a healthcare facility if cyanosis, dusky pallor, shortness of breath or change in mental status develop (Spiller et al, 2000).
    D) ADULT
    1) ORAL
    a) In adults, both dose-related and idiosyncratic responses have been seen.
    b) Oral ingestion of as little as 150 to 300 mg produced symptoms in 4 adults, but no information on genetic susceptibility was presented (Bernstein, 1950).
    c) In another study of 30 normal adults given 1000 mg, methemoglobin levels of more than 4.5% were reported, without signs of toxicity (Rao et al, 1978).
    2) INTRATRACHEAL
    a) Administration of 800 to 1500 mg has produced methemoglobinemia in adults (O'Donohue et al, 1980).
    b) However, in one study this occurred in only 1 of 144,000 patients of all ages (including neonates) treated similarly (Adriani & Zepernick, 1964).
    1) This patient was a 38-year-old black man and apparently had an idiosyncratic reaction which was reproduced by application of very small amounts (Adriani & Zepernick, 1964).
    3) TOPICAL NASOPHARYNGEAL AND LARYNGEAL
    a) Administration of 140 mg topically to facilitate intubation produced methemoglobinemia in a 52-year-old man. The presence of squamous cell cancer may have facilitated absorption and some intratracheal absorption may have occurred. This patient also received lidocaine 100 mg (Anderson et al, 1988).
    b) Nasopharyngeal application of Cetacaine(R) spray (benzocaine 14%, tetracaine 2%) prior to esophagoscopy resulted in cyanosis, hypotension, and a methemoglobin level of 48.5% within 5 minutes of use in a 73-year-old man (Ferraro et al, 1988). Several sprays of Cetacaine(R) along with 200 mg of lidocaine applied to the nose, pharynx, and larynx prior to bronchoscopy resulted in a methemoglobin level of 72% in a 30 year old man (Kotler et al, 1989).
    c) Excessive self-administration of Hurricaine(R) spray (20% benzocaine) for oral pain resulted in a methemoglobin level of 71% in a 33-year-old man (Muchmore & Dahl, 1992).
    d) Three to four 1-second sprays with 20% benzocaine to facilitate endoscopy has resulted in methemoglobin levels greater than 40% in several case reports (Bhutani et al, 1992; Dinneen et al, 1994; Rodriguez et al, 1994; Collins, 1990; Linares et al, 1990).
    e) In a crossover study of 91 subjects (80 patients and 11 volunteers), one 2-second spray of 20% benzocaine induced a statistically significant but clinically insignificant increase in methemoglobin level from 0.8 % at baseline to 0.9% at 20, 40 and 60 minutes after administration (Guertler & Pearce, 1994).
    f) CASE REPORT (ADULT): A 39-year-old man presented to the ED with a 1 week history of dental pain, radiating from his jaw to his ear, that became progressively worse. Interview of the patient revealed that he had taken 2400 mg ibuprofen over the previous 8 hours and had used 1.5 tubes of Anbesol (R), each tube containing 7 mL 20% benzocaine, within 2 hours prior to presentation. The patient's lips were cyanotic and an initial oxygen saturation (O2sat) measurement was 90%. He was administered a local anesthetic for the pain. Prior to discharge, a repeat O2sat had decreased to 87%, and an arterial blood gas measurement indicated a methemoglobin level of 33.2%. Following IV methylene blue administration, the patient recovered and was discharged with a methemoglobin level of 2.2% and an O2sat of 98% (Orr & Orr, 2011).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 2500 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)RAT:
    a) 3042 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Benzocaine acts on axonal membranes to interrupt nerve conduction. It stabilizes the membrane and prevents passage of sodium ions into the axonal cytoplasm, thereby preventing depolarization.
    B) In the presence of hydrochloric acid, benzocaine is hydrolyzed and converted to aminobenzoic acid and ethyl alcohol, resulting in partial or total loss of anesthetic activity.

Toxicologic Mechanism

    A) It is postulated that benzocaine may be metabolized to aniline, which is then transformed to phenylhydroxylamine and nitrosobenzene, both methemoglobin-forming compounds (Karzel, 1982).

Physicochemical

Physical Characteristics

    A) odorless with a somewhat bitter taste

Molecular Weight

    A) 165.19

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Application of a skin lotion containing 5% benzocaine produced clinical shock within a few hours. Methemoglobin was as high as 51% of total hemoglobin. These symptoms were seen in dogs with pruritic skin conditions, but not normal dogs (Harvey et al, 1979).
    11.1.6) FELINE/CAT
    A) Cat hemoglobin is extremely susceptible to the action of oxidant drugs. Methemoglobinemia was evident in 100% of cats receiving a laryngeal anesthetic spray containing benzocaine. Peak concentrations occurred at 20 to 30 minutes and ranged widely from 0.26 to 3.25 g/dL (Krake et al, 1985).
    B) A 2 kg cat was treated on the tailhead and caudal thigh with a 3% benzocaine cream and developed vomiting, open-mouth breathing, and collapsed within 20 minutes.
    1) Cyanotic mucous membranes, respiratory distress, and chocolate brown blood was noted. Methylene blue was given and the cat recovered normal respiration within 2 hours (Wilkie & Kirby, 1988).
    11.1.9) OVINE/SHEEP
    A) Lagutchik et al (1992) report that METHEMOGLOBINEMIA developed in sheep following topical nasal application of a benzocaine-containing anesthetic spray. Mean methemoglobin concentration, 10 to 20 minutes after application, was 22.6%.

Treatment

    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.5) TREATMENT
    A) GENERAL TREATMENT
    1) METHYLENE BLUE - Administer 1.5 mg/kg as a 1% solution intravenously. Methylene blue may produce Heinz body anemia in cats and dogs. It is recommended that the animal's blood be monitored for at least one week after this therapy (Harvey et al, 1979).

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Adriani J & Zepernick R: Clinical effectiveness of drugs used for topical anesthesia. JAMA 1964; 188:711-716.
    3) Afeld JL, Hieger MA, Emswiler MP, et al: Persistent Methemoglobinemia Due to Occult Vulvar Benzocaine Application (abstracts). Clin Toxicol (Phila) 2015; 53(7):772.
    4) Anderson ST, Hajduczek J, & Barker SJ: Benzocaine-induced methemoglobinemia in an adult: accuracy of pulse oximetry with methemoglobinemia. Anesth Analg 1988; 67:1099-1101.
    5) Autret E, Forveille-Fournier E, & Marchand S: Methemoglobinemie apres ingestion accidentelle de Nestosyl(R) (Methemoglobinemia after accidental Nestosyl(R) ingestion). Arch Fr Pediatr 1989; 46:271-272.
    6) Bachmann P, Berthier JC, & Storme B: Methemoglobinemia from benzocaine ingestion: a propos of a case of pediatric poisoning. (French). J Toxicol Clin Exp 1986; 6:123-128.
    7) Barker SJ, Tremper KK, & Hyatt J: Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology 1989; 70:112-117.
    8) Bernstein BM: Cyanosis following use of anesthesin (ethyl-amino-benzoate). Rev Gastroenterol 1950; 17:123-124.
    9) Bhatt DN, Bifano EM, & Stark DCC: Postoperative methemoglobinemia in a neonate. Anesthesiology 1985; 62:210-211.
    10) Bhutani A, Bhutani MS, & Patel R: Methemoglobinemia in a patient undergoing gastrointestinal endoscopy. Ann Pharmacother 1992; 26:1239-1240.
    11) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    12) Brown CM, Levy SA, & Susann PW: Methemoglobinemia: life-threatening complication of endoscopy premedication. Am J Gastroenterol 1994; 89:1108-1109.
    13) Chakladar A , Willers JW , Pereskokova E , et al: White powder, blue patient: methaemoglobinaemia associated with benzocaine-adulterated cocaine. Resuscitation 2010; 81(1):138-139.
    14) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    15) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    16) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    17) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    18) Collins JF: Methemoglobinemia as a complication of 20% benzocaine spray for endoscopy. Gastroenterology 1990; 98:211-213.
    19) Delwood L, O'Flaherty D, & Prejean EJ III: Methemoglobinemia and its effect on pulse oximetry (letter). Crit Care Med 1991; 19:988.
    20) Dinneen SF, Mohr DN, & Fairbanks VF: Methemoglobinemia from topically applied anesthetic spray. Mayo Clin Proc 1994; 69:886-888.
    21) Donovan JW: Methemoglobinemia, In: Haddad LM and Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, WB Saunders, Philadelphia, PA, 1983, pp 905-909.
    22) Dotsch J, Demirakca S, & Hahn D: Accuracy of methemoglobin measurements: comparison of six different commercial devices and one manual method. Crit Care Med 1999; 27:1191-1194.
    23) Dunipace AJ, Beaven R, Noblitt T, et al: Mutagenic potential of toluidine blue evaluated in the Ames test. Mutat Res 1992; 279(4):255-259.
    24) Eldadah M & Fitzgerald M: Methemoglobinemia due to skin application of benzocaine. Clin Pediatr 1993; 32:687-688.
    25) Eldadah M & Fitzgerald M: Methemoglobinemia due to skin application of benzocaine. Clin Pediatr 1993a; 687-688.
    26) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    27) Ellis FD, Seiler JG, & Palmore MM: Methemoglobinemia: a complication after fiberoptic orotracheal intubation with benzocaine spray. J Bone Joint Surg 1995; 77A:937-939.
    28) FDA: Federal Register: Drug products for the relief of oral discomfort for over-the-counter human use; establishment of a monograph, 47, Government Printing Office, Washington, DC, 1982, pp 22712-22809.
    29) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    30) Ferraro L, Zeichner S, & Greenblott G: Cetacaine-induced methemoglobinemia. Anesthesiology 1988; 69:614-615.
    31) Ferraro-Borgida MJ, Mulhern SA, DeMeo MO, et al: Methemoglobinemia from perineal application of an anesthetic cream. Ann Emerg Med 1996; 27:785-788.
    32) Geib AJ, Saltzman DW, & Fincham K: Survival from Supralethal Methemoglobin Level (abstracts). Clin Toxicol (Phila) 2015; 53(7):694.
    33) Gentile DA: Severe methemoglobinemia induced by a topical teething preparation. pediatr Emerg Care 1987; 3:171-175.
    34) Goldstein GM & Doull J: Treatment of nitrite-induced methemoglobinemia with hyperbaric oxygen. Proc Soc Exp Biol Med 1971; 138:137-139.
    35) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    36) Goluboff N & MacFayden DJ: Methemoglobinemia in an infant. J Pediatr 1955; 47:222-226.
    37) Goluboff N & MacFayen DJ: Methemoglobinemia in infant, associated with application of tar-benzocaine ointment. J Pediatr 1955; 47:222-226.
    38) Goluboff N & Wheaton R: Methylene blue induced cyanosis and acute hemolytic anemia complicating the treatment of methemoglobinemia. J Pediatr 1961; 58:86-89.
    39) Goluboff N: Methemoglobinemia due to benzocaine (letter). Pediatrics 1958; 21:340-341.
    40) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    41) Grum DF & Rice TW: Methemoglobinemia from topical benzocaine. Cleve Clin J Med 1990; 57:357-359.
    42) Guerriero SE: Methemoglobinemia caused by topical benzocaine. Pharmacother 1997; 17:1038-1040.
    43) Guertler AT & Pearce WA: A prospective evaluation of benzocaine-associated methemoglobinemia in human beings. Ann Emerg Med 1994; 24:626-630.
    44) Gunaratnam NT, Vazquez-Sequeiros E, & Gostout CJ: Methemoglobinemia related to topical benzocaine use: is it time to reconsider the empiric use of topical anesthesia before sedated EGD?. Gastrointest Endoscopy 2000; 52:692-693.
    45) Gupta PM, Lala DS, & Arsura EL: Benzocaine-induced methemoglobinemia. South Med J 2000; 93:83-86.
    46) Haggerty RJ: Hazards to health: blue baby due to methemoglobinemia. N Engl J Med 1962; 267:1303.
    47) Hall AH, Kulig KW, & Rumack BH: Drug- and chemical-induced methaemoglobinaemia: clinical features and management. Med Toxicol 1986; 1:253-260.
    48) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    49) Harvey IW, Sameck JH, & Burgard FJ: Benzocaine-induced methemoglobinemia in dogs. J Am Vet Med Assoc 1979; 175:1171-1175.
    50) Harvey JW & Keitt AS: Studies of the efficacy and potential hazards of methylene blue therapy in aniline-induced methemoglobinemia. Br J Haematology 1983; 54:29-41.
    51) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    52) Henretig FM, Gribetz B, Kearney T, et al: Interpretation of color change in blood with varying degree of methemoglobinemia.. Clin Toxicol 1988; 26:293-301.
    53) Herman MI, Chyka PA, & Butlse AY: Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med 1999; 33:111-113.
    54) Hesch DJ: Anaphylactic death from use of a throat lozenge. JAMA 1960; 172:62-65.
    55) Hix WR & Wilson WR: Toluidine blue staining of the esophagus: a useful adjunct in the panendoscopic evaluation of patients with squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1987; 113(8):864-865.
    56) Hjelt K, Lund JT, Scherling B, et al: Methaemoglobinaemia among neonates in a neonatal intensive care unit. Acta Paediatr 1995; 84(4):365-370.
    57) Ho RT, Nanevicz T, & Yee R: Benzocaine-induced methemoglobinemia - two case reports related to transesophageal echocardiography premedication. Cardiovasc Drugs Ther 1998; 12:311-312.
    58) Howland MA: Antidotes in Depth. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw-Hill, New York, NY, 2006, pp 826-828.
    59) Hughes JR: Infantile methemoglobinemia due to benzocaine suppository. J Pediatr 1965; 66:797-799.
    60) Hughes JR: Infantile methemoglobinemia due to benzocaine suppository. J Pediatr 1965a; 66:797-799.
    61) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    62) Jaffe ER: Methemoglobinemia and sulfhemoglobinemia, In: Cecil Textbook of Medicine, Beeson PB, McDermott W, Wyngaarden JB (Eds), WB Saunders Co, Philadelphia, PA, 1979, pp 1780-1782.
    63) Karzel K: Clinical implications of the biotransformation of local anesthetics. Pharm Int 1982; 3:16-19.
    64) Kellett PB & Copeland CS: Methemoglobinemia associated with benzocaine-containing lubricant. Anesthesiology 1983a; 59:463-464.
    65) Kellett PH & Copeland CS: Methemoglobinemia associated with benzocaine- containing lubricant. Anesthesiology 1983; 59:463-464.
    66) Kiese M , Lorcher W , Weger N , et al: Comparative studies on the effects of toluidine blue and methylene blue on the reduction of ferrihaemoglobin in man and dog. Eur J Clin Pharmacol 1972; 4(2):115-118.
    67) Kirlangitis JJ, Middaugh RE, & Zablocki A: False indication of arterial oxygen desaturation and methemoglobinemia following injection of methylene blue in urological surgery. Milit Med 1990; 155:260-262.
    68) Kotler RL, Hansen-Flaschen J, & Casey MP: Severe methaemoglobinemia after flexible fiberoptic bronchoscopy. Thorax 1989; 44:234-235.
    69) Krake AC, Arendt TD, & Teachout DJ: Cetacaine-induced methemoglobinemia in domestic cats. J Am Anim Hosp Assoc 1985; 21:527-534.
    70) Lata K & Janardhanan R: Methemoglobinemia: a diagnosis not to be missed. Am J Med 2015; 128(10):e45-e46.
    71) Linares LA, Peretz TY, & Chin J: Methemoglobinemia induced by topical anesthetic (benzocaine). Radiother Oncol 1990; 18:267-269.
    72) Lindenmann J, Matzi V, Kaufmann P, et al: Hyperbaric oxygenation in the treatment of life-threatening isobutyl nitrite-induced methemoglobinemia--a case report. Inhal Toxicol 2006; 18(13):1047-1049.
    73) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    74) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    75) Marquez A & Todd M: Acute hemolytic anemia and agranulocytosis following intravenous administration of toluidine blue. Am Pract 1959; 10:1548-1550.
    76) McGuigan MA: Benzocaine-induced methemoglobinemia (letter). Can Med Assoc J 1981; 125:816.
    77) McGuigan MA: Benzocaine-induced methemoglobinemia (letter). Can Med Assoc J 1981a; 125:816.
    78) McKinney CD, Postiglione KF, & Herold DA: Benzocaine-adultered street cocaine in association with methemoglobinemia. Clin Chem 1992; 38:596-597.
    79) Muchmore EA & Dahl BJ: One blue man with mucositis. New Engl J Med 1992; 327:133.
    80) Nadler JE, Green H, & Rosenbaum A: Intravenous injection of methylene blue in man with reference to its toxic symptoms and effect on the electrocardiogram. Am J Med Sci 1934; 188:15-21.
    81) Nemec K: Antidotes in acute poisoning. Eur J Hosp Pharm Sci Pract 2011; 17(4):53-55.
    82) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    83) O'Donohue WJ Jr, Moss LM, & Angelillo VA: Acute methemoglobinemia induced by topical benzocaine and lidocaine. Arch Intern Med 1980; 140:1508-1509.
    84) Orr TM & Orr DL 2nd: Methemoglobinemia secondary to over-the-counter Anbesol. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011; 111(2):e7-e11.
    85) Peterson HDC: Acquired methemoglobinemia in an infant due to benzocaine suppository. N Engl J Med 1960; 263:454-455.
    86) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    87) Potter JL & Hillman JV: Benzocaine-induced methemoglobinemia. J Am Coll Emerg Physians 1979a; 8:26-27.
    88) Potter JL & Hillman JV: Benzocaine-induced methemoglobinemia. JACEP 1979; 8:43-44.
    89) Price D: Methemoglin Inducers. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw Hill, New York, NY, 2006, pp -.
    90) Product Information: ANBESOL(R) MAXIMUM STRENGTH oral liquid, benzocaine, 20% oral liquid. Wyeth Consumer Healthcare, Richmond, VA, 2007.
    91) Product Information: Americaine(R) Otic, benzocaine. Celltech Pharmaceuticals, Rochester, NY, 2002.
    92) Product Information: ORABASE(R) oral paste, benzocaine, 20% oral paste. Colgate Oral Pharmaceuticals,Inc, New York, NY, 2007.
    93) Product Information: ORAJEL(R) MAXIMUM STRENGTH oral gel, benzocaine, 20% oral gel. Del Pharmaceuticals, Uniondale, NY, 2007.
    94) Product Information: PROVAYBLUE(TM) intravenous injection, methylene blue intravenous injection. American Regent (per FDA), Shirley, NY, 2016.
    95) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    96) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    97) Product Information: methylene blue 1% IV injection, methylene blue 1% IV injection. American Regent, Inc (per manufacturer), Shirley, NY, 2011.
    98) Product Information: methylene blue 1% intravenous injection, methylene blue 1% intravenous injection. Akorn, Inc. (per manufacturer), Lake Forest, IL, 2011.
    99) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    100) Ramsakal A, Lezama JL, & Adelman HM: A potentially fatal effect of topical anesthesia. Hosp Pract 2001; 36:13-14.
    101) Rao VK, Naraghi M, & Berger M: Methemoglobinemia following the use of topical local anesthetics, ASA Annual Meeting Abstracts of Scientific Papers, American Society of Anesthesiologists, Park Ridge, IL, 1978, pp 183-184.
    102) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    103) Rentsch G & Wittekind O: Methylene blue and erythrocytes in the living animal. Contribution to the toxicology of methylene blue and formation of Heinz bodies. Toxicol Appl Pharmacol 1967; 11:81-87.
    104) Rodriguez LF, Smolik LM, & Zbehlik AJ: Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature. Ann Parmacother 1994; 28:643-649.
    105) Roos TC & Merk HF: Allergic contact dermatitis from benzocaine ointment during treatment of herpes zoster. Contact Dermatitis 2001; 44:104.
    106) Rosen PJ, Johnson C, & McGehee WG: Failure of methylene blue treatment in toxic methemoglobinemia. Ann Intern Med 1971; 75:83-86.
    107) Ryan ME, Davis BM, & Marks JG Jr: Contact urticaria and allergic contact dermatitis to benzocaine gel. J Am Acad Dermatol 1980; 2:221-223.
    108) Rynn KO, Jahns BE, & Sabbun R: Acute myocardial infarction (AMI) secondary to benzocaine induced methemoglobinemia (abstract). J Tox Clin Tox 1995; 33:495.
    109) Saha SA, Kordouni MR, Siddiqui M, et al: Methemoglobinemia-induced cardio-respiratory failure secondary to topical anesthesia. Am J Ther 2006; 13(6):545-549.
    110) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    111) Seibert RW & Seibert JJ: Infantile methemoglobinemia induced by a topical anesthetic, Cetacaine(R). Laryngoscope 1984; 94:816-817.
    112) Sheehy MH & Way JL: Nitrite intoxication: protection with methylene blue and oxygen. Toxicol Appl Pharmacol 1974; 30:221-226.
    113) Shepherd G & Keyes DC: Methylene blue. In: Dart,RC, ed. Medical Toxicology, 3rd ed. 3rd ed, Philadelphia, PA, 2004, pp -.
    114) Sherman JM: Methemoglobinemia owing to rectal-probe lubrication. Am J Dis Child 1979; 133:439.
    115) Shihana F, Dissanayake DM, Buckley NA, et al: A Simple Quantitative Bedside Test to Determine Methemoglobin. Ann Emerg Med 2010; 55(2):184-189.
    116) Slaughter MS, Gordon PJ, & Roberts JC: An unusual case of hypoxia from benzocaine-induced methemoglobinemia. Ann Thorac Surg 1999a; 67:1776-1778.
    117) Slaughter MS, Gordon PJ, Roberts JC, et al: An unusual case of hypoxia from benzocaine-induced methemoglobinemia. Ann Thorac Surg 1999; 67:1776-1778.
    118) Spiller HA, Revolinski DH, & Winter ML: Multi-center retrospective evaluation of oral benzocaine exposure in children. Vet Human Toxicol 2000; 42:228-231.
    119) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    120) Stanford SC , Stanford BJ , & Gillman PK : Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol 2010; 24(10):1433-1438.
    121) Steinberg JB & Zepernick RG: Methemoglobinemia during anesthesia. J Pediatr 1962; 61:885-886.
    122) Stoiber TR: Toxic methemoglobinemia complicating transesophageal echocardiography. Echocardiography 1999; 16:383-385.
    123) Stossel TP & Jennings RB: Failure of methylene blue to produce methemoglobinemia in vivo. Am J Clin Pathol 1966; 45:600-604.
    124) Teunis BS, Leftwich EI, & Pierce LE: Acute methemoglobinemia and hemolytic anemia due to toluidine blue. Arch Surg 1970; 101:527-531.
    125) Townes PL, Geertsma MA, & White MR: Benzocaine-induced methemoglobinemia. Am J Dis Child 1977; 131:697-698.
    126) Townes PL, Geertsma MA, & White MR: Benzocaine-induced methemoglobinemia. Am J Dis Child 1977a; 131:697-698.
    127) Tush GM & Kuhn RJ: Methemoglobinemia induced by an over-the-counter medication. Ann Pharmacother 1996; 30:1251-1254.
    128) U.S. Food and Drug Administration (FDA): FDA Drug Safety Communication: Reports of a rare, but serious and potentially fatal adverse effect with the over-the-counter (OTC) benzocaine gels and liquid applied to the gums or mouth. U.S. Food and Drug Administration (FDA). Rockville, MD. 2011. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm250024.htm. As accessed 2011-04-07.
    129) U.S. Food and Drug Administration: FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. U.S. Food and Drug Administration. Silver Spring, MD. 2011. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. As accessed 2011-07-26.
    130) Udeh C, Bittikofer J, & Sum-Ping STJ: Severe methemoglobinemia on reexposure to benzocaine. J Clin Anesth 2001; 13:128-130.
    131) Varon AJ: Methemoglobinemia and pulse oximetry (letter). Crit Care Med 1992; 20:1363-1364.
    132) Vessely MB & Zitsch RP: Topical anesthetic-induced methemoglobinemia: a case report and review of the literature. Otolaryngol Head Neck Surg 1993; 108:763-767.
    133) Watcha MF, Connor MT, & Hing AV: Pulse oximetry in methemoglobinemia. AM J Dis Child 1989; 143:845-847.
    134) Whitwam JG, Taylor AR, & White JM: Potential hazard of methylene blue. Anaesthesia 1979; 34:181-182.
    135) Wilkie DA & Kirby R: Methemoglobinemia associated with dermal application of benzocaine cream in a cat. JAVMA 1988; 192:85-86.
    136) Winek CL, Collom WD, & Martineau P: Toluidine blue intoxication. Clin Toxicol 1969; 2:1-3.
    137) Wintrobe M: Clinical Hematology, 75th ed, Lea & Febiger, Philadelphia, PA, 1974, pp 1009-1016.
    138) Wolff JA: Methemoglobinemia due to benzocaine. J Pediatr 1957; 20:915-916.
    139) Wong DH: Methemoglobinemia and oxyhemoglobin concentration (letter). Mayo Clin Proc 1995; 70:197-200.
    140) Wurdeman RL, Mohiuddin SM, & Holmberg MJ: Benzocaine-induced methemoglobinemia during an outpatient procedure. Pharmacother 2000; 20:735-738.
    141) do Nascimento TS, Pereira RO, de Mello HL, et al: Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol 2008; 58(6):651-664.