A novel use of etomidate for intentional adrenal suppression to control severe hypercortisolemia in childhood*

Mettauer, Nicole; Brierley, Joe

doi:10.1097/pcc.0b013e318198b096

Cited by 16 publications

(6 citation statements)

References 27 publications

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“…Because of these peculiar pharmacokinetic properties, etomidate can be particularly useful in patients with acute and/or lifethreatening complications of CS, such as serious psychosis and severe hypertension (549 -553). Generally, patients with such a severe disease have an ectopic source of CS, but patients with CD treated with etomidate have also been reported (549,(552)(553)(554)(555)(556). Etomidate has been shown to rapidly normalize cortisol levels in almost all patients with CD (549, 552-556).…”

Section: Etomidatementioning

confidence: 99%

“…Pivonello Schulte et al (555) demonstrated that an iv infusion of etomidate at dosages between 0.01 and 0.1 mg/kg/h might be sufficient to inhibit adrenal steroidogenesis within a wide margin of safety. In several subsequent studies, etomidate has been administered as iv infusion at dosages ranging from 0.02 to 0.08 mg/kg/h, occasionally preceded by an etomidate bolus of 0.03 mg/kg (549,552,553,556). Preda et al (549) have recommended low-dose etomidate iv infusion rates of 0.04 -0.05 mg/kg/h, with a dose titration dependent on circulating cortisol levels when a partial blockade is required; indeed, in specific cases, the dosage of etomidate might be 0.5-1 mg/h, when a complete blockade is required; in this latter case, iv hydrocortisone is required to prevent or treat adrenal insufficiency induced by the block of etomidate ("block and replace").…”

Section: Etomidatementioning

confidence: 99%

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The Treatment of Cushing's Disease

et al. 2015

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Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

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Section: Etomidatementioning

confidence: 99%

Section: Etomidatementioning

confidence: 99%

The Treatment of Cushing's Disease

et al. 2015

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“…There are acute clinical situations, such as the association of severe hypercortisolaemia with complications such as respiratory failure or acute psychosis, where rapid control of cortisol secretion is necessary in order to allow emergency therapy such as bilateral adrenalectomy. Intravenous etomidate infusions administered in an intensive care environmentat doses ranging from 1 to 3.5 mg/h have been documented to be effective in suppressing hypercortisolaemia in three paediatric CD patients [ 44 , 46 , 91 ].…”

Section: Treatment Of Paediatric Cushing’s Diseasementioning

confidence: 99%

Paediatric Cushing’s disease: Epidemiology, pathogenesis, clinical management and outcome

Ferrigno

Hasenmajer

Caiulo

et al. 2021

Rev Endocr Metab Disord

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Cushing’s disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing’s syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70–100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised.

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“…Etomidate, a commonly used short-acting intravenous anesthetic, is a potent inhibitor of side chain cleavage enzyme 11-b-hydroxylase, aldosterone synthase, as well as an inhibitor of 17-a-hydroxylase [27,120,124,137]. There have been a number of case reports on the successful use of etomidate in controlling hypercortisolemia in seriously ill patients with CD even in the pediatric population [123,138]. Etomidate's use is limited by the need to be given intravenously.…”

Section: Steroidogenesis Inhibitorsmentioning

confidence: 99%

Molecular basis of pharmacological therapy in Cushing’s disease

Ferone

Pivonello²,

Vitale

et al. 2013

Endocrine

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Cushing's disease (CD) is a severe endocrine condition caused by an adrenocorticotropin (ACTH)-producing pituitary adenoma that chronically stimulates adrenocortical cortisol production and with potentially serious complications if not or inadequately treated. Active CD may produce a fourfold increase in mortality and is associated with significant morbidities. Moreover, excess mortality risk may persist even after CD treatment. Although predictors of risk in treated CD are not fully understood, the importance of early recognition and adequate treatment is well established. Surgery with resection of a pituitary adenoma is still the first line therapy, being successful in about 60-70 % of patients; however, recurrence within 2-4 years may often occur. When surgery fails, medical treatment can reduce cortisol production and ameliorate clinical manifestations while more definitive therapy becomes effective. Compounds that target hypothalamic-pituitary axis, glucocorticoid synthesis or adrenocortical function are currently used to control the deleterious effects of chronic glucocorticoid excess. In this review we describe and analyze the molecular basis of the drugs targeting the disease at central level, suppressing ACTH secretion, as well as at peripheral level, acting as adrenal inhibitors, or glucocorticoid receptor antagonists. Understanding of the underlying molecular mechanisms in CD and of glucocorticoid biology should promote the development of new targeted and more successful therapies in the future. Indeed, most of the drugs discussed have been tested in limited clinical trials, but there is potential therapeutic benefit in compounds with better specificity for the class of receptors expressed by ACTH-secreting tumors. However, long-term follow-up with management of persistent comorbidities is needed even after successful treatment of CD.

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A novel use of etomidate for intentional adrenal suppression to control severe hypercortisolemia in childhood*

Abstract: The adrenal suppression caused by etomidate, so controversial in the care of the critically ill at present, can be therapeutically used for short-term control of severe hypercortisolemia in children.

Cited by 16 publications

References 27 publications

The Treatment of Cushing's Disease

The Treatment of Cushing's Disease

Paediatric Cushing’s disease: Epidemiology, pathogenesis, clinical management and outcome

Molecular basis of pharmacological therapy in Cushing’s disease

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