Etomidate infusion at low doses is an effective and safe treatment for severe Cushing’s syndrome outside intensive care

Constantinescu, Stefan Matei; Driessens, Natacha; Lefebvre, A.; Furnica, Raluca Maria; Corvilain, Bernard; Maiter, Dominique

doi:10.1530/eje-20-0380

Cited by 26 publications

(9 citation statements)

References 10 publications

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“…Due to the deterioration of the patient’s condition, insufficient response to current treatment, and no clear protocol for the osilodrostat monotherapy in SH, the patient was started on a continuous etomidate infusion. We decided to continue osilodrostat simultaneously and, therefore, the patient did not receive the initial bolus of etomidate, while the starting dose of medication (0.015 mg/kg/h) was lower than that assumed in most treatment protocols [ 2 , 11 , 37 , 38 ]. The premise of that approach was to gradually reduce cortisolemia through combination therapy, with cross-titration of osilodrostat and etomidate so that the etomidate infusion could be stopped with the serum cortisol in the desired range and maintained through osilodrostat monotherapy.…”

Section: Discussionmentioning

confidence: 99%

Cushing’s syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia

Dzialach

Sobolewska

Respondek³

et al. 2022

Hormones

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Endogenous Cushing’s syndrome (CS) is associated with increased morbidity and mortality. Early diagnosis and initiation of therapy are essential, but effective treatment remains a challenge. In a long-term follow-up, biochemical control of hypercortisolemia, especially when severe, is difficult to achieve. Life-threatening hypercortisolemia is difficult to control due to the limitations of pharmacotherapy, including its side effects, and may require etomidate infusion in the intensive care unit (ICU) to rapidly lower cortisol levels. The effectiveness of hypercortisolemia management can be increased by a dual blockade of cortisol production. We report the efficacy, safety, and tolerability of combined therapy with two steroidogenesis inhibitors, etomidate, and osilodrostat, in a 32-year-old woman diagnosed with severe ACTH-dependent hypercortisolemia, subsequently maintaining a stable level of cortisol with osilodrostat monotherapy. This approach enabled achievement of relatively rapid control of the hypercortisolemia while using an etomidate infusion and concomitant increasing doses of oral osilodrostat applying a “titrations strategy.” Our experience shows that it is worth taking advantage of the synergistic anticortisolic action of etomidate with osilodrostat.

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Section: Discussionmentioning

confidence: 99%

Cushing’s syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia

Dzialach

Sobolewska

Respondek³

et al. 2022

Hormones

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“…Approved in Europe, but used off-label in the United States, are metyrapone and ketoconazole. Etomidate, an anesthetic with cortisol-inhibiting properties, is available in an intravenous form and is used for severe, life-threatening hypercortisolism as a bridge therapy to definitive surgical therapy [ 3 , 4 , 72 ]. Mitotane is rarely used in CD cases [ 39 ].…”

Section: Are There Any Benefits In Starting Medical Therapy To Treat ...mentioning

confidence: 99%

“…In addition, because pituitary-targeted therapies have been shown to reduce adenoma size [ 73 , 74 ], there is a theoretical risk that very small adenomas can become even more difficult to identify during surgery. The GC receptor blocker mifepristone has also been used in selected cases with severe diabetes as preoperative treatment [ 3 , 4 , 72 ]; however, it is usually not first line. Of note, high doses of dexamethasone are needed to overcome cortisol receptor blockade [ 38 ] if used preoperatively to avoid intraoperative AI.…”

Section: Are There Any Benefits In Starting Medical Therapy To Treat ...mentioning

confidence: 99%

Perioperative Management of a Patient With Cushing Disease

Varlamov

Vila

Fleseriu

2022

Journal of the Endocrine Society

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Patients with Cushing’s disease (CD) may present with both chronic and acute perioperative complications that necessitate multidisciplinary care. This review highlights several objectives for these patients before and after transsphenoidal surgery. Preoperative management includes treatment of electrolyte disturbances, cardiovascular comorbidities, prediabetes/diabetes, as well as prophylactic consideration(s) for thromboembolism and infection(s). Preoperative medical therapy (PMT) could prove beneficial in patients with severe hypercortisolism or in cases of delayed surgery. Some centers use PMT routinely, although the clinical benefit for all patients is controversial. In this setting, steroidogenesis inhibitors are preferred because of rapid and potent inhibition of cortisol secretion. If glucocorticoids are not used perioperatively, an immediate remission assessment postoperatively is possible. However, perioperative glucocorticoid replacement is sometimes necessary for clinically unstable or medically pretreated patients and for those patients with surgical complications. A nadir serum cortisol < 2-5µg/dl during 24-74 hours postoperatively is generally accepted as remission; higher values suggest non-remission, while a few patients may display delayed remission. If remission is not achieved, additional treatments are pursued. The early postoperative period necessitates multidisciplinary awareness for early diagnosis of adrenal insufficiency (AI) to avoid adrenal crisis, which may be also potentiated by acute postoperative complications. Preferred glucocorticoid replacement is hydrocortisone, if available. Assessment of recovery from postoperative AI should be undertaken periodically. Other postoperative targets include decreasing antihypertensive/diabetic therapy if in remission, thromboprophylaxis, infection prevention/treatment, and management of electrolyte disturbances and/or potential pituitary deficiencies. Evaluation of recovery of thyroid, gonadal and growth hormone deficiencies should be also performed in the following months postoperatively.

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“… 81 The safety of the protocol suggested by this study has led to the proposition that low-dose etomidate infusions can be administered outside of an intensive care setting and without the need for hydrocortisone supplementation. 82 …”

Section: Etomidate Infusion Protocol For the Treatment Of Csmentioning

confidence: 99%

Pharmacological management of severe Cushing’s syndrome: the role of etomidate

Pence

McGrath

Lee

et al. 2022

Therapeutic Advances in Endocrinology

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Cushing’s syndrome (CS) is an endocrine disease characterized by excessive adrenocortical steroid production. One of the mainstay pharmacological treatments for CS are steroidogenesis enzyme inhibitors, including the antifungal agent ketoconazole along with metyrapone, mitotane, and aminoglutethimide. Recently, osilodrostat was added to this drug class and approved by the US Food and Drug Administration (FDA) for the treatment of Cushing’s Disease. Steroidogenesis enzyme inhibitors inhibit various enzymes along the cortisol biosynthetic pathway and may be used preoperatively to lower cortisol levels and reduce surgical risk associated with tumor resection or postoperatively when surgery and/or radiation therapies are not curative. Because their selectivities for steroidogenic enzymes vary, they may even be administered in combination to achieve relatively rapid control of severe hypercortisolemia. Unfortunately, all currently available inhibitors are accompanied by serious adverse side effects that limit dosing and often result in treatment failures. Although more commonly known as a general anesthetic induction agent, etomidate is another member of the steroidogenesis enzyme inhibitor drug class. It suppresses cortisol production primarily by inhibiting 11β-hydroxylase and is the only inhibitor that may be given parenterally. However, the sedative-hypnotic actions of etomidate limit its use as an acute management option for CS. Thus, some have recommended that it be used only in intensive care settings. In this review, we discuss the initial development of etomidate as an anesthetic agent, its subsequent development as a treatment for CS, and the recent advances in dosing and drug development that dissociate sedative-hypnotic and adrenostatic drug actions to facilitate CS treatment in non-critical care settings.

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Etomidate infusion at low doses is an effective and safe treatment for severe Cushing’s syndrome outside intensive care

Cited by 26 publications

References 10 publications

Cushing’s syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia

Cushing’s syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia

Perioperative Management of a Patient With Cushing Disease

Pharmacological management of severe Cushing’s syndrome: the role of etomidate

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