Infusion of Low Dose Etomidate: Correction of Hypercortisolemia in Patients with Cushing's Syndrome and Dose-Response Relationship in Normal Subjects

Abstract

To investigate the adrenostatic potential of a nonhypnotic low dose etomidate infusion, we administered 0.03 mg/kg etomidate in a bolus injection, followed by constant infusion of 0.3 mg/kg.h for 24 h to 6 patients with severe Cushing's syndrome. The dose-response relationship also was determined in 15 normal subjects. Three groups of 5 received, respectively, doses of 0.03, 0.1, and 0.3 mg/kg.h etomidate for 5 h after an initial bolus dose of 0.03 mg/kg. The response to exogenously administered ACTH [0.25 mg ACTH-(1-24)], injected after the etomidate or control infusion, was determined in all normal subjects. In the six hypercortisolemic patients, serum cortisol concentrations decreased from 1374 +/- 436 nmol/L (mean +/- SEM) to 188 +/- 91 nmol/L after 11 h of etomidate infusion and remained low until the end of the infusion. Cortisol levels returned to pretreatment concentrations by 24 h. Excretion of urinary free cortisol decreased from 1180 +/- 196 to 185 +/- 66 nmol/day. In the normal subjects, administration of etomidate led to a dose-dependent decrease in serum cortisol from about 550 to 83 nmol/L, while 11-deoxycortisol rose from low or undetectable levels up to 346 nmol/L. In response to ACTH, cortisol levels rose in inverse proportion to the etomidate dose. It was, however, significantly reduced compared to normal saline infusion even after the lowest dose. Changes in aldosterone and corticosterone concentrations were similar to those in cortisol, and 11-deoxycorticosterone changed in a pattern similar to that of 11-deoxycortisol. Two of five normal subjects reported tiredness during the highest etomidate infusion. No other side-effects were noted. We conclude that iv administered etomidate in a low nonhypnotic dose reduces serum cortisol concentrations in a dose-dependent manner in both hyper- and eucortisolemic subjects. This study suggests that etomidate at a dose of 0.1 mg/kg.h or lower may be an effective strategy for the control of severe hypercortisolemia.

Cushing's disease: pathobiology, diagnosis, and management

“…Rarely, parental etomidate (anesthetic induction agent) was used in refractory cases to rapidly reduce supraphysiological cortisol levels but requires careful dose-titration. 91 …”

Treatment of Cushing's disease: a mechanistic update

“…2). It is the only parenteral steroidogenesis inhibitor available and provides rapid hypercortisolemia control , Schulte et al 1990). An i.v.…”

“…An i.v. bolus injection of etomidate at a low non-hypnotic dose (0.03 mg/kg) followed by constant infusion of 0.3 mg/kg per h for 24 h (Table 3) decreases serum cortisol in a dose-dependent manner with significant suppression after the first 5 h with a maximum effect after 11 h , Schulte et al 1990. Glucocorticoid replacement to prevent adrenal insufficiency is warranted after 24 h of etomidate infusion.…”

New developments in the medical treatment of Cushing's syndrome

“…Interestingly, in two patients sustained remission was observed after cessation of ketoconazole and metyrapone, which may in part be explained by effects of these drugs on tumoral ACTH secretion (Sharma & Nieman 2012). Finally, in the intensive care setting, the anesthetic drug etomidate, at dosages between 0.1 and 0.3 mg/kg per h, can be used to rapidly suppress cortisol production in complicated EAS (Schulte et al 1990).…”

“…Originally used as an anesthetic agent, etomidate, which is administered i.v., was soon reported to cause adrenocortical insufficiency in critically ill patients (Fellows et al 1983). Subsequent studies showed that etomidate can be used to induce eucortisolemia in patients with CS (Schulte et al 1990, Krakoff et al 2001. Its suggested mechanism of action is inhibition of the 11b-hydroxylase and cholesterol side-chain cleavage enzymes (Lamberts et al 1987, Schteingart 2009).…”