In this study, we report the effectiveness and safety of continuous intravenous low-dose, lipid-formulated etomidate infusion treatment outside the ICU in seven patients with SCS in our center’s experience. All analyzed patients achieved a target cortisol level and normalized serum potassium concentration within a median of 30 and 18 h, respectively. The etomidate infusion served as bridging therapy for osilodrostat monotherapy in four patients and for adrenalectomy in one patient.

SCS is a challenging and life-threatening condition accompanied by acute cardiovascular, infectious and metabolic complications, leading to high mortality. Rapid control of cortisol levels is essential with simultaneous preventive and curative treatments of cortisol-induced comorbidities. In most cases, SCS is associated with EAS—neuroendocrine tumors found in different locations, with varying degrees of histological differentiation and aggressiveness, may secrete ACTH and lead to SCS [7, 11]. Nevertheless, SCS may also occur in patients with CD and ACTH-independent hypercortisolemia.

Etomidate is an imidazole derivative, intravenous anesthetic agent, and one of its side effects includes suppression of adrenocortical function [12, 13]. It reversibly inhibits CYP11B1, CYP17A1 and (at higher doses) CYP11A1, ultimately inhibiting cortisol biosynthesis [13]. Inhibition of adrenal steroid synthesis significantly limits the use of etomidate in anesthetic practice but gives the possibility of its off-label use in patients with SCS. Etomidate allows for highly effective and rapid control of hypercortisolemia, and normalization of cortisol concentration could be achieved within a dozen or so hours [8, 9]. In addition, it is the only steroidogenesis inhibitor which may be administered parenterally, therefore, it can also be used as a first-line treatment in severely ill patients or when oral cortisol-lowering agents cannot be used [5, 9, 10].

Since the first report of etomidate-induced steroidogenesis inhibition [13], several studies of its effectiveness in hypercortisolemia control have been published, and various therapeutic protocols have been proposed [8, 14,15,16,17]. A standard etomidate infusion protocol requires patient hospitalization in the ICU. Initially, the patient receives a bolus etomidate dose of 2.5–5 mg over 2–3 min, followed by a continuous infusion (0.1–1.0 mg/kg/h), titrated according to the therapeutic response. However, such a procedure results in a complete blockade of adrenal steroid biosynthesis and necessitates implementing hydrocortisone substitution [8, 9, 14]. It also increases the risk of adrenal crisis and propylene glycol toxicity if etomidate in propylene glycol formulation is used. Therefore, the possibility of using low-dose etomidate treatment to control SCS was suggested, which does not require hospitalization of the patient in the ICU [16]. Constantinescu et al. studied the outcome of two series of SCS patients treated either with a standard etomidate dose in ICU or a low dose in non-ICU settings. The low-dose group achieved target cortisol levels slower, but without inducing adrenal insufficiency or other side effects, and without the need for intensive care resources [14]. In addition to this data, Carroll et al. proposed a standardized intravenous low-dose etomidate infusion protocol [15].

In our cohort of patients, we used an even lower starting dose of etomidate (0.01–0.02 mg/kg/h) and omitted its initial loading dose. In all patients, etomidate effectively reduced cortisol concentration to the target range in a median time of 30 h. That further confirms the use of a very low dose of etomidate in SCS management. Interestingly, the median time to reach the target cortisol concentration in our group was shorter, despite using lower doses of etomidate compared to the studies mentioned [14, 15]. This could be attributed to the higher target cortisol concentration in some of the septic patients we analyzed and the older age of the group we studied; elderly patients require decreased etomidate doses due to reduced protein binding and clearance [18]. Indeed, the longest time to achieve the target cortisol concentration was observed in the youngest patients in our group. Therefore, doses of etomidate need to be individualized in each clinical situation and rely on patient’s clinical careful assessment. The standard treatment protocol should be rather considered only in the most severe, critical cases requiring hospitalization in the ICU. It is also important to note that the effect of etomidate on adrenal blockage may continue even after treatment discontinuation due to accumulation in the subcutaneous tissue [9].

How to qualify patients with SCS for treatment in or outside the ICU remains to be determined. It was previously recommended that etomidate treatment in patients with SCS only occur in the ICU setting [8]. However, this was mainly related to using a classic therapeutic protocol and high doses of etomidate. In previous years, collected data indicate that low-dose etomidate infusions can be administered outside of the ICU and do not necessarily have to be conducted under anesthesiologic control. In our opinion, the decision regarding the place of treatment should be made primarily based on the patient’s clinical condition and the given center’s experience in managing patients in severe state. In the analyzed group, endocrinologists carried out the treatment within the intensive internist supervision room, a coherent part of our department intended to treat patients in general severe condition. This room has a system of continuous patient monitoring, so its concept is similar to the ICU. Most internal medicine departments in Poland have at least one bed adapted for intensive supervision. In case of any doubts regarding etomidate pharmacotherapy, we could consult the ICU team. Similarly, in case of a sudden deterioration of the general condition, the patient could be qualified for further treatment in the ICU. However, we are aware that in different countries and healthcare systems, the organization of given units varies and the treatment conditions of specific groups of patients may differ significantly. Not all endocrinology centers have the expertize and appropriate facilities to allow treatment to be carried out in a general ward. On the other hand, intensive care specialists might not be familiar with the complexity of SCS and the specifics of therapy for such patients. In such cases, etomidate therapy should be conducted in close cooperation between the endocrinologist, the intensive care specialist, and the anesthesiologist. Some authors suggest that etomidate treatment could be initiated in the ICU and continued in the general ward after the patient has clinically stabilized [19]. However, given the rarity and potentially lethal complications of SCS, we strongly recommend that these patients be managed in tertiary centers with experience in fully managing this condition.

It is considered that formulations of etomidate in a lipid emulsion should be preferred due to possible propylene glycol toxicity [9, 15], which may result in plasma hyperosmolarity, lactic acidosis, thrombosis, and acute kidney injury [10, 15, 20]. However, published data on its use in patients with SCS are lacking, as in the most reports, etomidate in propyl glycol formulation was used [14, 15, 17]. To our knowledge, this report summarizes the largest cohort of patients treated with lipid formulation of etomidate, confirming its equal effectiveness to the propylene glycol formulation. Considering the known and potential complications of propylene glycol toxicity, the lipid formulation of etomidate should be regarded as superior in the case of etomidate use consideration in SCS.

Regardless of the formulation, etomidate treatment appears to have a high safety profile as an cortisol-lowering agent, and its use in SCS has been reported in adolescents [21, 22], children [23], and even infants [24]. Sedation is typically observed at higher doses than those that suppress cortisol production [9, 10]. However, the level of sedation should be assessed through the etomidate treatment, for example, using the RASS score [15]. In our cohort, only one patient experienced slight somnolence with a RASS score of −1 during etomidate infusion. The same patient presented with a brief episode of adrenal insufficiency, requiring temporary hydrocortisone implementation and etomidate dose reduction. However, it occurred during the infusion of a relatively low dose of etomidate (0.015 mg/kg/h) during the second day of the treatment. This patient had significantly increased liver enzyme activity, most likely secondary to numerous liver metastases and cortisol-induced hepatotoxicity. Because hepatic enzymes metabolize etomidate, liver damage presumably led to increased etomidate half-life. Very rarely does etomidate cause significant hepatotoxicity, which, nevertheless, must be considered [18]. However, the increased activity of liver enzymes in our patient was not likely the result of etomidate therapy itself, as it was already observed at baseline before the introduction of etomidate. Although the activity of liver enzymes initially increased during treatment, it significantly improved during subsequent days of therapy. Two of the presented patients died during the etomidate infusion; however, their death was a result of their end-stage malignancy disease and initial hypercortisolemia complications, and was not etomidate-related.

We have previously published our initial experience with etomidate and osilodrostat combination therapy in a 32-year-old female with SCS due to CD [25]. At that time, evidence for the osilodrostat monotherapy in SCS and dose titration strategy was limited. We initiated the patient’s treatment with osilodrostat at a gradually increased dose. After one week, due to an insufficient response, we decided to start treatment with etomidate. However, we continued osilodrostat simultaneously. This approach aimed to control hypercortisolemia quickly and then cross-titrate the doses of osilodrostat and etomidate to eventually discontinue the etomidate infusion and maintain hypercortisolemia control with osilodrostat monotherapy. This patient is also included in the current study. Since then, real-world evidence of osilodrostat use in SCS and EAS has emerged [26, 27], and an algorithm for the practical use of osilodrostat in SCS has been proposed [27]. That raises the question of whether there is still a place for etomidate in managing SCS in the era of new oral steroidogenesis inhibitors.

Despite increasing evidence of the effectiveness of osilodrostat as a first-line therapy in SCS, its global availability, especially considering the treatment price, is limited. For example, in Poland, innovative medications are financed through a specific emergency access procedure. The process of obtaining osilodrostat for a patient takes at least several days. It may not significantly affect the prognosis in cases of milder forms of CS, but in patients with SCS, even a delay of several days in the hypercortisolemia treatment may have disastrous consequences. On the other hand, another oral steroidogenesis inhibitor, ketoconazole, is not registered for the treatment of CS in Poland and currently is unavailable in our country. Moreover, metyrapone is not reimbursed in Poland, and the hospital must cover the eventual treatment fee. Mitotane is an additional therapeutic option, but it is mainly intended for patients with adrenocortical cancer and its use in SCS is limited due to the relatively slow onset of action. Taking this into account, etomidate therapy remains the only salvation for patients with SCS, serving as bridging therapy until the possibility of treatment with osilodrostat is available. Ultimately, the etomidate infusion was followed by combined etomidate and osilodrostat treatment and, eventually, osilodrostat monotherapy in four of the presented patients. Continuous etomidate infusion was maintained while initiating osilodrostat treatment to prevent rebound hypercortisolemia. The combination treatment aimed to provide stable control of hypercortisolemia while increasing the osilodrostat dose and reducing the etomidate dose until its discontinuation. In two patients, the osilodrostat dose was gradually increased, while in the other two patients, osilodrostat was implemented at a high dose with rapid escalation and continued in the „block and replace” regimen. However, no specific protocol was followed, and therapeutic decisions were made based on the patient’s clinical condition and laboratory tests results. This significantly limits the possibility of proposing a specific scheme for transitioning from etomidate to osilodrostat. However, on Fig. 1 we present graphs showing the evolution of the mean serum cortisol concentration to illustrate the combined treatment process with etomidate and osilodrostat.

Our study has several limitations. The most important one is relatively small number of participants; however, it is still significant when taking into account how extremely rare SCS is and how infrequently etomidate is utilized in this indication. Our study also lacks patients with ACTH-independent CS. The study has a retrospective nature, therefore presents the results of real clinical practice, as no strict treatment protocol was followed.