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

Materials and Methods

This is a descriptive retrospective analysis of patients who were admitted to Froedtert Hospital in Milwaukee, Wisconsin, or NorthShore University Health System, Evanston, Illinois, and were initiated on a standardized intravenous etomidate protocol for the control of severe hypercortisolemia. The protocol was developed by the surgical intensive care clinical pharmacists in collaboration with endocrinologists and surgeons. Its development was based on the interpretation of published case reports and their understanding of pharmacokinetic and pharmacodynamic principles. At the time of therapy, this protocol was not approved by the institutions' Pharmacy, Nutrition, and Therapeutic Committees, but it existed as a newly developed departmental protocol (Figure 1). Patients were included if they received the etomidate infusion for treatment of hypercortisolism between January 1, 2012, and December 31, 2015. Patients were to be excluded if they were <18 years of age or pregnant, although no patients were ultimately excluded for either of these reasons. This retrospective review was approved by the institutional review boards of Froedtert Hospital and the Medical College of Wisconsin and of NorthShore University Health System.

Figure 1.

Etomidate infusion protocol.

In preparation for etomidate infusion, all patients were admitted to the intensive care unit, where close metabolic, hemodynamic, respiratory, and neurologic monitoring was initiated. Before treatment with etomidate, the following laboratory parameters were obtained: serum basic chemistry (sodium, potassium, chloride, urea nitrogen, creatinine, bicarbonate, calcium), cortisol, and ACTH. In addition, baseline blood pressure, heart rate, respiratory rate, and level of sedation were ascertained. Level of sedation was assessed by using the Richmond Agitation-Sedation Scale (RASS) score, with a target RASS score of 0, which correlates with a patient who is alert and calm.[13,14]

The etomidate infusion was formulated to a concentration of 1 mg/mL (etomidate 40 mg per 40 mL dextrose 5% in water). At the time of our first treatment, no intravenous solution compatibility or stability data were available for etomidate. Because of the low starting dose and resultant infusion flow rate that would be needed, it was necessary to dilute the etomidate. Given the concerns of diluting this relatively insoluble lipophilic medication, we chose to dilute the 2-mg/mL product in a 1:1 ratio with dextrose 5% in water, in EXCEL® IV Containers (B. Braun Medical Inc., Bethlehem, PA). This chosen method was based on our well-documented preparation of a pharmaceutically similar agent, lorazepam for infusion. Lorazepam injection is a water-insoluble drug that is similarly solubilized with propylene glycol. To further safeguard against risk for possible precipitation, similar to lorazepam infusion administration, the etomidate infusion was given through a 0.2-micron inline filter. Given the lack of evidence for long-term stability of this solution, we assigned the prepared solution a 24-hour expiration. Following the baseline patient assessments, an optional 5-mg IV bolus of etomidate was administered over 2 to 3 minutes and a continuous infusion of etomidate was initiated at a rate of 0.02 to 0.04 mg/kg/h. During the etomidate infusion, with an abundance of caution, serum cortisol was measured at least every 6 hours, along with basic chemistry. All measurements of cortisol were performed with the Roche Elecsys® Cortisol I assay (Roche Diagnostics, Risch-Rotkreuz, Switzerland). This assay has a 4.1% cross-reactivity with 11-deoxycortisol, which increases with etomidate use. ACTH was measured by using an electrochemiluminescence immunoassay manufactured by Roche Diagnostics, Inc. (Indianapolis, IN) performed in the Cobas e or Modular system. The detectable range for this assay is 1.0 to 2000 pg/mL.

Vital signs were taken hourly, and sedation assessments were conducted every 4 hours per standard of care for patients receiving a continuous infusion sedative. On the basis of the absolute values and the rate of change in serum cortisol, the etomidate infusion was titrated in increments of 0.01 to 0.02 mg/kg/h to target a default cortisol concentration of 10 to 20 μg/dL. A goal cortisol of 10 to 20 μg/dL was chosen because it is slightly above the "normal" cortisol level and in the range expected for patients with substantial physiological stress. The goal cortisol also allows for a small increase in cortisol that can be attributed to cross-reactivity of other steroid metabolites (such as 11-deoxycortisol) that increase with etomidate use. The goal, as determined by the attending endocrinologist in collaboration with the surgeon in surgical cases, was to achieve the target cortisol concentration during a 24- to 48-hour period. Once the target cortisol concentration was achieved, the etomidate infusion was titrated to maintain serum cortisol in the desired range until long-term medical or definitive surgical treatment could be initiated.

Rate of change of the serum cortisol concentration, time to achieve serum cortisol goal, and continuous infusion rate required to achieve and maintain cortisol in the target range were of particular interest.