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      Low-dose etomidate for the management of severe hypercortisolaemia in different clinical scenarios: a case series and review of the literature

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          Abstract

          Background:

          Severe Cushing’s syndrome (SCS) is associated with acute cardiovascular, metabolic and infectious complications. It is considered an emergency, requiring an immediate diagnosis, together with a broad spectrum of supportive and hypocortisolaemic treatments. Surgical intervention, aimed at removing the source of cortisol or adrenocorticotropic hormone (ACTH), is the optimal treatment in most cases of Cushing’s syndrome. However, in hypercortisolaemic states, surgical intervention has high rates of perioperative mortality and morbidity. Oral adrenal steroidogenesis inhibitors, even if more effective in combination, are not always efficient enough or well tolerated. Despite their common use, a more potent, parental, immediate, and thus life-saving, therapy is necessary.

          Methods:

          The authors present three different clinical scenarios of etomidate treatment in patients hospitalized in the third reference endocrinological centre in Poland between 2016 and 2017.

          Results:

          Patients with Cushing’s disease, ectopic Cushing’s syndrome and adrenocortical carcinoma presented with severe hypercortisolaemia and exacerbated cortisol-dependent comorbidities. In these three cases, etomidate acted as an accurate, well tolerated and effective cortisol-lowering drug for several days or even months. Patients were monitored in a general ward setting, and no side effects of the therapy were observed.

          Conclusions:

          In doses far lower than those used for anaesthesia, etomidate works as a useful cortisol-lowering therapy in patients intolerant to or unable to take oral medications. Additionally, if urgent, the most potent and effective medical intervention is necessary, and clinicians should be aware of such a therapeutic option.

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          Most cited references25

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          Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline.

          The objective is to formulate clinical practice guidelines for treating Cushing's syndrome.
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            The Treatment of Cushing's Disease.

            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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              Ketoconazole in Cushing's disease: is it worth a try?

              The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild ( 5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.
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                Author and article information

                Contributors
                Journal
                Ther Adv Endocrinol Metab
                Ther Adv Endocrinol Metab
                TAE
                sptae
                Therapeutic Advances in Endocrinology and Metabolism
                SAGE Publications (Sage UK: London, England )
                2042-0188
                2042-0196
                08 February 2019
                2019
                : 10
                : 2042018819825541
                Affiliations
                [1-2042018819825541]Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital in Warsaw, Cegłowska 80 Street, 01-809 Warsaw, Poland
                [2-2042018819825541]Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital in Warsaw, Poland
                [3-2042018819825541]Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital in Warsaw, Poland
                [4-2042018819825541]Intensive Care Unit, Bielański Hospital in Warsaw, Poland
                [5-2042018819825541]Department of Endocrinological Oncology and Nuclear Medicine, The Maria Skłodowska Curie Cancer Centre and Institute of Oncology, Warsaw, Poland
                [6-2042018819825541]Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital in Warsaw, Poland
                Author notes
                Author information
                https://orcid.org/0000-0002-3804-0273
                Article
                10.1177_2042018819825541
                10.1177/2042018819825541
                6378481
                2afe5b52-0001-45d3-adb4-ceb0c1502ead
                © The Author(s), 2019

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 21 October 2018
                : 1 January 2019
                Categories
                Case Series
                Custom metadata
                January-December 2019

                adrenal steroidogenesis inhibitors,adrenocortical carcinoma,cushing’s disease,ectopic cushing’s syndrome,etomidate,hypercortisolaemia,pituitary corticotropinoma

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