Etomidate Well-tolerated and Effective in Cushing’s Syndrome Patients, Case Series Suggests

Etomidate, a commonly used anaesthetic, is well-tolerated and can be used in low doses to reduce cortisol levels in patients with Cushing’s syndrome, a report of three cases suggests.

The case series, “Low-dose etomidate for the management of severe hypercortisolaemia in different clinical scenarios: a case series and review of the literature,” appeared in the journal Therapeutic Advances in Endocrinology and Metabolism.

Severe Cushing’s syndrome is characterized by marked elevation of serum cortisol levels (hypercortisolemia) or of 24-hour urinary-free cortisol. Removal of the primary lesion causing the condition is the treatment of choice, but patients with overt Cushing’s syndrome require cortisol-lowering therapy, as well as additional treatments, for cortisol-related complications.

Chronic severe hypercortisolemia is associated with immunosuppression, increasing the risk of serious infections or sepsis. Because it affects blood clotting, it also results in a greater risk of cardiovascular complications.

Etomidate, used for the induction of general anesthesia and sedation, is able to rapidly lower cortisol levels and may help improve patient’s condition before other medical or surgical therapies are considered. Researchers at Bielański Hospital in Poland presented three cases of treatment with etomidate in patients hospitalized between 2016 and 2017.

The first patient was a 23-year-old woman with rapidly progressing Cushing’s syndrome due to a metastatic adrenocortical carcinoma. She had received surgery to remove her right adrenal gland two years prior. Imaging revealed a mass in her right side as well as significant liver metastases.

In addition to a second surgery for her recurrent tumor, the patient started daily treatment for excess cortisol with ketoconazole, the chemotherapy Lysodren (mitotane), and later Metopirone (metyrapone). At her fourth hospital admission, her condition was much worse, with symptoms of upper respiratory tract infection, uncontrolled diabetes, and high blood pressure, as well as severely low blood levels of potassium and calcium.

Due to a lack of benefits, treatment with ketoconazole and Metopirone was stopped. Upon continuous intravenous (into-the-vein) infusion of Janssen’s Hypnomidate (etomidate), the patient’s cortisol levels decreased, and her improved clinical status enabled the first course of chemotherapy.

However, the patient was hospitalized again eight days later due to life-threateningly low levels of white blood cells, and reduced levels of neutrophils, anemia, and diarrhea, associated with a recurrence of electrolyte imbalance and a rapid rise in cortisol levels.

Although she restarted treatment with Hypnomidate, a computed tomography (CT) scan revealed rapid cancer progression. As a result, the woman did not receive the next course of chemotherapy and died within two months.

The second patient was a 45-year-old man with insulin-independent diabetes mellitus, refractory low potassium levels, muscle disease, spinal pain, and mild cushingoid features. At admission, a hormonal evaluation revealed adrenocorticotrophic hormone (ACTH)-dependent Cushing’s syndrome, while an abdominal CT showed a suspicious lesion in his pancreas.

The patient started treatment with daily ketoconazole, leading to higher levels of liver enzymes called transaminases. His clinical condition deteriorated on the sixth day of therapy, and he had a fever and severe exhaustion. He was diagnosed with sepsis caused by Staphylococcus aureus, prompting the use of antibiotics.

Because his cortisol levels reached 160 µg/dl, he started receiving intravenous treatment with Etomidate-Lipuro (etomidate), which led to a rapid lowering of hormone concentrations and a gradual improvement of his condition. To the clinicians’ surprise, a diagnosis of pituitary corticotropinoma — a rare subset of pituitary adenomas — was confirmed via bilateral inferior petrosal sinus sampling. As a result, the man underwent an effective surgical tumor removal.

The third patient was a 66-year-old woman with ectopic Cushing’s syndrome — a source of ACTH overproduction other than the pituitary gland — and severe hypercortisolemia due to a metastatic lung tumor with liver lesions. The patient had had her left adrenal gland removed three months earlier as the first step toward complete adrenal gland removal. At referral, she also had uncontrolled diabetes, severe low potassium levels, and mood disorders.

She was negative and aggressive on admission, revealing that she had decided to stop using all her oral medications, including ketoconazole, a few weeks earlier. Treatment with Etomidate-Lipuro led to immediate clinical improvement, although with unsteady cortisol levels. Low-dose ketoconazole was added to the treatment regimen, also without successful stabilization of cortisol levels.

The clinicians hypothesized that this was due to recurrent complications, which included cephalic (head) vein thrombosis, candidiasis, sepsis, and a post-antibiotic inflammation in the colon. However, after 58 days of treatment with etomidate, the patient was able to undergo complete removal of the adrenal glands without further complications.

Noting that the doses used in these patients were lower than those common in anesthesia, the investigators believe that the three cases support “the concept of etomidate as a useful and well tolerated cortisol-lowering therapy.”