Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate.
BACKGROUND
Etomidate is no longer administered as a continuous infusion for anesthetic maintenance or sedation, because it results in profound and persistent suppression of adrenocortical steroid synthesis with potentially lethal consequences in critically ill patients. We hypothesized that rapidly metabolized soft analogues of etomidate could be developed that do not produce persistent adrenocortical dysfunction even after prolonged continuous infusion. We hope that such agents might also provide more rapid and predictable anesthetic emergence. We have developed the soft etomidate analogue cyclopropyl-methoxycarbonyl etomidate (CPMM). Upon termination of 120-minute continuous infusions, hypnotic and encephalographic recoveries occur in four minutes. The aims of this study were to assess adrenocortical function during and following 120-minute continuous infusion of CPMM and to compare the results with those obtained using etomidate.


METHODS
Dexamethasone-suppressed rats were randomized into an etomidate group, CPMM group, or control group. Rats in the etomidate and CPMM groups received 120-minute continuous infusions of etomidate and CPMM, respectively. Rats in the control group received neither hypnotic. In the first study, adrenocortical function during hypnotic infusion was assessed by administering adrenocorticotropic hormone (ACTH) 90 minutes after the start of the hypnotic infusion and measuring plasma corticosterone concentrations at the end of the infusion 30 minutes later. In the second study, adrenocortical recovery following hypnotic infusion was assessed by administering ACTH every 30 minutes after infusion termination and measuring plasma corticosterone concentrations 30 minutes after each ACTH dose.


RESULTS
During hypnotic infusion, ACTH-stimulated serum corticosterone concentrations were significantly lower in the CPMM and etomidate groups than in the control group (100 ± 64 ng/ml and 33 ± 32 ng/ml versus 615 ± 265 ng/ml, respectively). After hypnotic infusion, ACTH-stimulated serum corticosterone concentrations recovered to control values within 30 minutes in the CPMM group but remained suppressed relative to those in the control group for more than 3 hours in the etomidate group.


CONCLUSIONS
Both CPMM and etomidate suppress adrenocortical function during continuous infusion. However, recovery occurs significantly more rapidly following infusion of CPMM.
Rile
R
Ge
Ervin
E
Pejo
Joseph F
JF
Cotten
Douglas E
DE
Raines
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D005045:Etomidate / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*
D006993:Hypnotics and Sedatives; C543057:methoxycarbonyletomidate; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D005045:Etomidate