Continuous Etomidate Infusion for the Management of Severe Cushing Syndrome

Validation of a Standard Protocol

Ty B. Carroll; William J. Peppard; David J. Herrmann; Bradley R. Javorsky; Tracy S. Wang; Hina Patel; Katarzyna Zarnecki; James W. Findling


J Endo Soc. 2019;3(1):1-12. 

In This Article

Abstract and Introduction


Objective: Demonstrate the safety and efficacy of a standardized intravenous etomidate infusion protocol in normalizing cortisol levels in patients with severe and life-threatening hypercortisolism.

Methods: A retrospective case series of seven patients representing nine episodes of severe hypercortisolism at two large academic medical centers was conducted. Patients were included in this series if they received an etomidate infusion for the treatment of severe and life-threatening hypercortisolism. The etomidate infusion was administered via a newly developed protocol designed to safely reduce cortisol levels until more long-term medical or definitive surgical therapy could be instituted.

Results: Seven patients representing nine episodes received etomidate treatment. In eight of nine episodes of therapy, rapid control of hypercortisolemia was achieved, generally defined as a serum cortisol level of 10 to 20 μg/dL. Patients with a median baseline cortisol of 105 μg/dL (range, 32 to 245 μg/dL) achieved a median nadir serum cortisol of 15.8 μg/dL (range, 6.9 to 27 μg/dL) after a median of 38 hours (range, 26 to 134 hours).

Conclusions: A standardized continuous intravenous etomidate infusion protocol is a safe and effective means of achieving a serum cortisol level of 10 to 20 μg/dL in patients with severe hypercortisolemia.


Endogenous hypercortisolism (Cushing syndrome) is a well-known endocrinopathy whose clinical manifestations include many metabolic disorders (obesity, hypertension, diabetes, and osteoporosis) as well as neurocognitive and neuropsychiatric consequences.[1] Endogenous Cushing syndrome may be the result of an ACTH-secreting pituitary (Cushing disease), nonpituitary (ectopic) tumor, or autonomous cortisol production from adrenal glands.[2] Most patients with Cushing syndrome present with an indolent course over several years before the clinical and biochemical diagnosis is considered and established.[3] It is less appreciated that Cushing syndrome may present as an endocrine emergency because of the prodigious and often rapid onset of hypercortisolism, with very serious and life-threatening metabolic, infectious, and neuropsychiatric sequela. Most of these patients have an ectopic ACTH-secreting tumor; the rapid control of severe cortisol excess is mandatory and may be life-saving.[4]

Medical therapy for severe hypercortisolemia is challenging and options are limited. Inhibition of adrenal steroidogenesis and direct antagonism of glucocorticoid receptors have been used in patients with Cushing syndrome. The most widely used adrenostatic agents, ketoconazole and metyrapone, normalize cortisol secretion in only 50% of patients with Cushing disease.[5] In addition, "serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation has occurred with the use of oral ketoconazole",[6] thus limiting its use in many severely ill patients, whereas metyrapone is difficult to acquire in the United States. Although mifepristone, a glucocorticoid receptor antagonist, ameliorates the signs and symptoms of cortisol excess, particularly hyperglycemia, it has not been extensively studied in critically ill patients with severe hypercortisolemia.[7]

Etomidate, an imidazole derivative similar to ketoconazole, is an intravenous hypnotic nonbarbiturate induction agent often used for intubation. After its introduction in the 1970s, etomidate was shown to substantially and rapidly decrease cortisol secretion.[8,9] Subsequently, it was discovered that etomidate decreases steroidogenesis by inhibiting not only side chain cleavage enzyme but also 11β-hydroxylase, an enzyme that catalyzes the production of cortisol from its immediate precursor, 11-deoxycortisol.[10] Accordingly, reports of the successful use of etomidate to rapidly control severe hypercortisolemia emerged in the late 1980s.[11] Since then, most reports have been isolated case studies, with <20 total patients reported in the literature.[12]

Here we report a standardized intravenous etomidate protocol from our institutions for the control of severe hypercortisolemia that was used in nine separate episodes (seven patients with severe Cushing syndrome, of whom two had two separate episodes of etomidate infusion). This protocol should help clinicians manage patients with severe metabolic and neuropsychiatric consequences of prodigious hypercortisolemia and serve as a bridge to more long-term medical or definitive surgical therapy.