title: Electroencephalographic and hypnotic recoveries after brief and prolonged infusions of etomidate and optimized soft etomidate analogs.
abstract: BACKGROUND
  Methoxycarbonyl etomidate is the prototypical soft etomidate analog. Because it has relatively low potency and is extremely rapidly metabolized, large quantities must be infused to maintain hypnosis. Consequently with prolonged infusion, metabolite reaches sufficient concentrations to delay recovery. Dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) are methoxycarbonyl etomidate analogs with higher potencies and slower clearance. Because of these properties, we hypothesized that dosing would be lower and electroencephalographic and hypnotic recoveries would be faster - and less context-sensitive - with DMMM or CPMM versus methoxycarbonyl etomidate or etomidate.
  
  
  METHODS
  Etomidate, DMMM, and CPMM where infused into rats (n = 6 per group) for either 5 min or 120 min. After infusion termination, electroencephalographic and hypnotic recovery times were measured. The immobilizing ED50 infusion rates were determined using a tail clamp assay.
  
  
  RESULTS
  Upon terminating 5-min infusions, electroencephalographic and hypnotic recovery times were not different among hypnotics. However, upon terminating 120-min infusions, recovery times varied significantly with respective values (mean ± SD) 48 ± 13 min and 31 ± 6.5 min (etomidate), 17 ± 7.0 min and 14 ± 3.4 min (DMMM), and 4.5 ± 1.1 min and 4.2 ± 1.6 min (CPMM). The immobilizing ED50 infusion rates were (mean ± SD) 0.19 ± 0.03 mg · kg · min (etomidate), 0.60 ± 0.12 mg · kg · min (DMMM), and 0.89 ± 0.18 mg · kg · min (CPMM).
  
  
  CONCLUSIONS
  Electroencephalographic and hypnotic recoveries following prolonged infusions of DMMM and CPMM are faster than those following methoxycarbonyl etomidate or etomidate. In the case of CPMM infusion, recovery times are 4 min and context-insensitive.
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Rile
authors.initials: R
authors.lastname: Ge
authors.forename: Ervin
authors.initials: E
authors.lastname: Pejo
authors.forename: S Shaukat
authors.initials: SS
authors.lastname: Husain
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cotten
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Raines
mesh_terms: D000818:Animals; D004569:Electroencephalography / Q000187:drug effects* / Q000379:methods; D005045:Etomidate / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000737:chemistry*; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D057897:Reflex, Righting / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D006993:Hypnotics and Sedatives; D005045:Etomidate