title: Identification of N-Hydroxy-para-aminobenzoic acid in a cyanotic child after benzocaine exposure.
abstract: BACKGROUND
  Methemoglobinemia (MetHb) after exposure to benzocaine (BZC) has been reported for more than 50 years, however the pathophysiologic mechanism has not been previously established. Direct administration of BZC to blood does not produce MetHb. After topical use, due to the lipophilicity and rapid acetylation in the tissue, little BZC reaches the liver for hepatic biotransformation. However, isolated human livers have been shown to produce MetHb forming N-hydroxyl metabolites from BZC. We report a case of BZC-induced MetHb with the first identification and quantification of the reactive metabolite responsible for the oxidative stress: N-Hydroxy-Para-amino benzoic acid (N-OH-PABA).
  
  
  METHODS
  An 8 year old male was admitted to a hospital for an appendectomy. Several applications of BZC spray were used during multiple attempts at nasogastric tube placement. In various attempts to achieve local anesthesia, benzocaine spray was used in both nares and through the mouth aimed at the posterior oropharynx. The patient subsequently became cyanotic with an initial MetHb level of 32.9 %. Methylene blue was administered and the patient promptly responded with resolution of cyanosis. Blood taken within 20 min of the initial symptoms contained benzocaine (5.2ug/mL), bupivacaine (740ng/mL), lidocaine (530ng/mL), acetaminophen (12ug/mL), midazolam (60ng/mL), PABA and N-OH-PABA (35ng/mL). Serum was analyzed using Liquid Chromatography- Quadrupole Time-of-Flight Mass Spectrometry. Mass spectrometry was done using an electrospray ionization source run in negative and positive polarities. A reference standard for N-OH-PABA was synthesized for confirmation and quantification.
  
  
  CONCLUSIONS
  The rare and idiopathic nature of methemoglobinemia after benzocaine use has made study of the pathophysiologic mechanism in humans difficult. Lack of understanding has brought calls for restriction of use of the widely used medication that may not be based on evidence. Our case presents several unique features: 1) benzocaine absorption after topical administration was documented with serum concentrations 2) confirmation of an in vivo formation of MetHb-forming n-hydroxyl-metabolite after benzocaine use and 3) the documentation of N-OH-PABA in humans within 20 min of MetHb post-benzocaine administration.
authors.affiliation: Central Ohio Poison Center, Nationwide Children's Hospital , Columbus, OH , USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Spiller
authors.forename: J L
authors.initials: JL
authors.lastname: Russell
authors.forename: M J
authors.initials: MJ
authors.lastname: Casavant
authors.forename: R Y
authors.initials: RY
authors.lastname: Ho
authors.forename: R R
authors.initials: RR
authors.lastname: Gerona
mesh_terms: D010129:4-Aminobenzoic Acid / Q000097:blood*; D000082:Acetaminophen / Q000097:blood; D000287:Administration, Topical; D001566:Benzocaine / Q000633:toxicity*; D002045:Bupivacaine / Q000097:blood; D002648:Child; D003490:Cyanosis / Q000097:blood* / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006898:Hydroxylamines / Q000097:blood*; D008012:Lidocaine / Q000097:blood; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008751:Methylene Blue / Q000008:administration & dosage; D008874:Midazolam / Q000097:blood; D062366:para-Aminobenzoates / Q000097:blood*
chemical_list: D006898:Hydroxylamines; C000593867:N-hydroxy-p-aminobenzoic acid; D062366:para-Aminobenzoates; D000082:Acetaminophen; D008012:Lidocaine; D008874:Midazolam; D008751:Methylene Blue; D010129:4-Aminobenzoic Acid; D001566:Benzocaine; D002045:Bupivacaine
keywords: benzocaine; metabolite; methemoglobin