title: Closed-loop continuous infusions of etomidate and etomidate analogs in rats: a comparative study of dosing and the impact on adrenocortical function.
abstract: BACKGROUND
  Etomidate is a sedative-hypnotic that is often given as a single intravenous bolus but rarely as an infusion because it suppresses adrenocortical function. Methoxycarbonyl etomidate and (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) are etomidate analogs that do not produce significant adrenocortical suppression when given as a single bolus. However, the effects of continuous infusions on adrenocortical function are unknown. In this study, we compared the effects of continuous infusions of etomidate, methoxycarbonyl etomidate, and carboetomidate on adrenocortical function in a rat model.
  
  
  METHODS
  A closed-loop system using the electroencephalographic burst suppression ratio as the feedback was used to administer continuous infusions of etomidate, methoxycarbonyl etomidate, or carboetomidate to Sprague-Dawley rats. Adrenocortical function was assessed during and after infusion by repetitively administering adrenocorticotropic hormone 1-24 and measuring serum corticosterone concentrations every 30 min.
  
  
  RESULTS
  The sedative-hypnotic doses required to maintain a 40% burst suppression ratio in the presence of isoflurane, 1%, and the rate of burst suppression ratio recovery on infusion termination varied (methoxycarbonyl etomidate > carboetomidate > etomidate). Serum corticosterone concentrations were reduced by 85% and 56% during 30-min infusions of etomidate and methoxycarbonyl etomidate, respectively. On infusion termination, serum corticosterone concentrations recovered within 30 min with methoxycarbonyl etomidate but persisted beyond an hour with etomidate. Carboetomidate had no effect on serum corticosterone concentrations during or after continuous infusion.
  
  
  CONCLUSIONS
  Our results suggest that methoxycarbonyl etomidate and carboetomidate may have clinical utility as sedative-hypnotic maintenance agents when hemodynamic stability is desirable.
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cotten
authors.forename: Ri
authors.initials: R
authors.lastname: Le Ge
authors.forename: Natalie
authors.initials: N
authors.lastname: Banacos
authors.forename: Ervin
authors.initials: E
authors.lastname: Pejo
authors.forename: S Shaukat
authors.initials: SS
authors.lastname: Husain
authors.forename: James H
authors.initials: JH
authors.lastname: Williams
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Raines
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects*; D000818:Animals; D001711:Biotransformation; D003345:Corticosterone / Q000097:blood; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005045:Etomidate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006993:Hypnotics and Sedatives; D011758:Pyrroles; C548177:carboetomidate; C543057:methoxycarbonyletomidate; D003345:Corticosterone; D005045:Etomidate