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Endocrine Care |
National Institute of Diabetes and Digestive and Kidney Diseases (J.K.), National Institutes of Health, Phoenix, Arizona 85014; and Pediatric and Reproductive Endocrinology Branch (C.A.K.), National Institute of Child Health and Human Development (C.A.K., L.K.N.); Clinical Center Pharmacy (K.A.C.); and Surgery Branch, National Cancer Institute (R.H.A.), National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Jonathan Krakoff, M.D., National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, Arizona 85014. E-mail: jkrakoff{at}mail.nih.gov
Abstract
Chronic severe hypercortisolism is associated with life-threatening infections, diabetes and a high surgical mortality rate. Oral medical therapy can inhibit steroidogenesis and reduce the risk of these complications. However, apart from a few reports using an ethyl alcohol formulation of the iv anesthetic etomidate, there is no well-tested parenteral steroidogenesis inhibitor. We used the propylene glycol preparation of etomidate available in the United States to control hypercortisolism in a 39-yr-old man with ectopic ACTH secretion who was unable to take oral medications. Etomidate was administered over a period of 5.5 months. We titrated the dose of etomidate daily using serum cortisol levels, to avoid steroid over replacement and allow for a response to ongoing stress. A reduced dose during a period of acute renal failure achieved adequate control of hypercortisolemia. Suppression of steroidogenesis persisted for at least 14 d and perhaps as long as 6 wk after cessation of the medication. Except for transient myoclonus, the patient tolerated this preparation well. Parenteral propylene glycol containing etomidate can be used safely for a prolonged period to reduce hypercortisolemia in patients unable to take oral medications.
CHRONIC SEVERE HYPERCORTISOLISM is associated with life-threatening infections (1, 2, 3), hypertension, diabetes, and high rates of surgical mortality (5.6%) and morbidity (40%) (4). When the source of endogenous Cushing’s syndrome (CS) cannot be surgically removed, medical therapy can inhibit steroidogenesis and potentially reduce the risk of complications from hypercortisolism. Although the best studied of these agents can only be given by mouth, limited data suggest that the iv administration of the anesthetic etomidate also reduces cortisol production (5, 6). In Europe, etomidate has been given therapeutically to patients with CS using preparations formulated with ethyl-alcohol (no longer available) and the currently available lipid emulsion (B. Allolio, unpublished observations). To our knowledge, there are no published data on the long-term safety and use of the propylene glycol-containing etomidate formulation for CS, which is available in the United States, and no information about the safety of chronic administration in the setting of renal failure.
We describe a man with severe hypercortisolemia and transient renal failure, who was unable to take medication by mouth. Intravenous administration of the propylene glycol etomidate formulation controlled serum cortisol concentrations for 5.5 months.
Subjects and Methods
Case report
A 39-yr-old man presented with a 3-yr history of a 50 lb weight gain, abdominal striae, enlarging dorsocervical fat pad, decreased libido, hypertension, insomnia, proximal lower extremity muscle weakness, and bipolar disorder. Twenty-four-hour urinary cortisol excretion was 3516 nmol (1274 µg) and 2454 nmol (889 µg) [normal, <138 nmol/d (<50 µg/d)]. An 0800-h serum cortisol level 9 h after administration of 1 mg dexamethasone was 1711 nmol/liter (62 µg/dl). His plasma corticotropin concentration was 57 pmol/liter (260 pg/ml) [normal, 0–5 pmol/liter Mayo (0–23 pg/ml)]. Further evaluation at the NIH confirmed physical and laboratory features of CS and revealed a lack of response to CRH (plasma corticotropin levels increased by 21%) (7), and an 83% decrease in serum cortisol during the high-dose (8 mg) overnight dexamethasone suppression test (8). A pituitary magnetic resonance imaging (MRI) scan was normal. Computed tomographic (CT) and MRI scans of the chest and abdomen were normal, except for enlarged adrenal glands and nodularity of the head of the pancreas. A 111Indium octreoscan using a 6 mCi dose of pentetreotide showed uptake in the area of the pancreatic head. Inferior petrosal sinus sampling did not show a central-to- peripheral gradient of corticotropin. After 6 months of treatment with ketoconazole to control his hypercortisolemia, 111Indium octreoscan and CT and MRI scans of the chest and abdomen were unchanged. An esophagogastroduodenoscopy revealed small duodenal nodules consistent with Brunner gland hyperplasia by pathologic examination. An abdominal CT scan with a water bolus revealed a 1.5-cm mass in the area of the duodenum and pancreatic head. These data were interpreted as consistent with ectopic secretion of corticotropin by a pancreatic tumor, and the patient underwent an exploratory laparotomy. At surgery, the duodenal wall was thickened, but intraoperative ultrasound examination did not confirm a mass in the duodenum or pancreas. A Whipple procedure (pylorus-preserving pancreatico-duodenectomy) was performed. The serum cortisol concentrations increased to 2125 nmol/liter (77 µg/dl) by postoperative d 7. He developed fever, an elevated white blood cell count, acute tubular necrosis, and an acute abdomen. We decided to treat the hypercortisolism with etomidate during and after surgical exploration.
Etomidate, as the propylene glycol preparation (Amidate; Abbott Laboratories, Abbott Park, IL), was diluted in normal saline and administered through a central venous line. This formulation contains 0.1813 g propylene glycol per gram of etomidate. The initial dose of 80 mg was based on the previously reported response of normal subjects to a total 24-h dose of 0.03 mg/kg·h (6). Because of concerns about possible nephrotoxicity of propylene glycol, doses during renal failure were 40 mg/d. To minimize possible toxicity, we aimed to give the smallest possible dose of the etomidate preparation, titrated to a serum cortisol concentration of 414–828 nmol/liter (15–30 µg/dl). The target cortisol range was intended to mimic the values seen in the stress of the intensive care unit (9, 10). The mean 24-h cortisol value in healthy individuals is 160–254 nmol/liter (5.8–9.2 µg/dl) (11, 12, 13).
To monitor the efficacy of etomidate, we measured serum cortisol concentrations just before the infusion, 8 h and 14 h later. We changed the dose at 1800 h after reviewing the daily serum cortisol concentrations.
Assays
Serum cortisol was determined using a fluorescence polarization
immunoassay (Abbott Laboratories). Concentrations of
urinary free cortisol, corticosterone, progesterone,
17-
-hydroxyprogesterone, and aldosterone were measured by RIA
(Endocrine Sciences, Inc., Calabasas Hills, CA).
11-Deoxycortisol was measured by an extraction method with
determination of the free fraction of 11-deoxycortisol and correlation
to a curve generated by purified standards (Endocrine Sciences, Inc.). Plasma corticotropin concentrations were measured by an
immunochemiluminescent assay (Mayo Clinic, Rochester, MN).
Results
Use of etomidate during renal failure
Etomidate (80 mg over 5 h) was administered during surgery (postoperative d 11) for drainage of intra-abdominal abscesses and revealing necrotizing pancreatitis. Serum cortisol fell from 1443 nmol/liter to 273 nmol/liter (52.3 µg/dl to 9.9 µg/dl) over 48 h, but rose to 1132 nmol/liter (41 µg/dl) the following day. The patient was begun on total parenteral nutrition on postoperative d 17. Etomidate was withheld because of worsening renal function. By postoperative d 23, creatinine was 9.9 mg/dl and hemodialysis was started. Because the patient could not take medications by mouth and surgical adrenalectomy was deemed extremely risky, we restarted etomidate. The patient’s serum cortisol concentration decreased from 1904 nmol/liter (69 µg/dl) to 524 nmol/liter (19 µg/dl) in response to etomidate (40 mg over 3 h) and continued to respond to this dose during hemodialysis (Fig. 1).
Treatment during normalization of renal function
As renal function improved, serum cortisol concentrations
increased, requiring larger doses of etomidate and eventual continuous
infusion of 200 mg daily, when serum creatinine fell to 336
µmol/liter (3.8 mg/dl) (Fig. 2
). On
postoperative d 33 we stopped etomidate for 24 h and attempted to
treat the patient with oral ketoconazole. However, the patient’s serum
cortisol increased to 1380 nmol/liter (50 µg/dl), and etomidate was
restarted.
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Cumulative adrenal effects of chronic etomidate administration
After d 50, although serum corticotropin concentrations remained
elevated and renal function was normal, the patient’s serum cortisol
concentrations declined, requiring a reduction of the etomidate dose
(Fig. 2
). Etomidate was stopped on postoperative d 80, at a serum
cortisol concentration of 149 nmol/liter (5.4 µg/dl). Five days
later, the serum cortisol concentration was 94 nmol/liter (3.4 µg/dl)
despite a plasma corticotropin concentration of 46 pmol/liter (210
pg/ml). The patient then received 15 mg iv hydrocortisone for 3
consecutive days. Eight days after stopping etomidate, the patient
became acutely hypotensive with a systolic blood pressure of 50 mm Hg.
The blood pressure normalized within 60 min of administration of 100 mg
iv hydrocortisone, consistent with hypotension secondary to adrenal
insufficiency. Serum cortisol measured after receiving the
hydrocortisone bolus was 1460 nmol/liter (52.9 µg/dl). Hydrocortisone
was tapered and then stopped on postoperative d 94 (14 d after
discontinuation of etomidate). We then performed a 250 µg cosyntropin
stimulation test. Serum cortisol and aldosterone responses to
cosyntropin were subnormal, but basal 11-deoxycortisol values were
elevated above the normal range and increased further after cosyntropin
administration, indicating inhibition of P450c11. Corticosterone,
17-hydroxyprogesterone, and progesterone concentrations were either
suppressed or at the lower limit of the normal range, suggesting
possible inhibition of other steroidogenic enzymes (see Table 1). Abdominal CT scans to monitor fluid
collections did not show evidence for adrenal hemorrhage.
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After postoperative d 94, the patient’s serum cortisol concentrations gradually rose to 607 nmol/liter (22 µg/dl). He received etomidate again intermittently when cortisol concentrations rose above 828 nmol/liter (30 µg/dl). Despite remaining febrile and ventilator dependent, he showed gradual improvement. As he required less sedation, myoclonus and tremor of both hands and a bilateral foot drop were noted. Nerve conduction and electromyographic studies were consistent with a polyneuropathy, but the etiology of myoclonus and tremor was not clear. Tremor and myoclonus improved gradually.
On postoperative d 182, the patient was extubated, the tracheostomy was removed, total parenteral nutrition was discontinued, and the patient was transferred to the inpatient nonintensive ward. Etomidate was discontinued, and oral ketoconazole was started at an initial dose of 200 mg every 12 h then increased to 200 mg every 8 h after 3 d. Over the following 10 d, serum cortisol concentrations were 276–607 nmol/liter (10–22 µg/dl), and the patient was transferred to a rehabilitation facility.
At follow-up 11 months after the initial surgery, imaging remained uninformative regarding the source of the ectopic corticotropin production. Propylene glycol-containing etomidate was again used in preparation for and during recovery from ileostomy closure. The drug was well tolerated, and the patient did not experience tremor or myoclonus. The patient has been receiving ongoing therapy with ketoconazole for the past 18 months with clinical improvement. He has elected to continue medical therapy and not undergo elective adrenalectomy.
Discussion
Adrenalectomy has been the major treatment modality for severe hypercortisolism in patients unable to take oral medication. Whereas elective laparoscopic adrenalectomy has reduced the complications of an open procedure (14, 15), no series has reported the risk of this procedure in seriously ill patients. The mortality and high morbidity rates associated with additional surgery in our severely ill patient prompted the use of etomidate.
Our experience supports the use of a propylene glycol etomidate formulation as a parenteral treatment for hypercortisolemia. This preparation was useful both for perioperative control of hypercortisolism and during prolonged periods when the patient was unable to take oral medications. We used etomidate without apparent toxicity during acute renal failure and hemodialysis.
Etomidate originally was developed as a hypnotic anesthetic agent (16) but was associated with increased mortality in critically ill patients. (17). Etomidate reduced serum concentrations of cortisol and aldosterone but increased serum concentrations of corticotropin, 11-deoxycortisol, and deoxycorticosterone, suggesting inhibition of the P450c11ß enzymatic step in the adrenal steroid biosynthesis pathway (18, 19, 20). Previous investigation in healthy men and women showed a dose-dependent blunting of the cortisol response to exogenous corticotropin after a 5-h infusion of etomidate (6).
Allolio and colleagues (5, 6) first demonstrated that a 24-h infusion of the ethyl-alcohol etomidate formulation could inhibit cortisol secretion in patients with endogenous hypercortisolism. Short-term, continuous infusions reduced serum cortisol concentrations in 11–24 h.
Chronic therapeutic use of the ethyl-alcohol-containing etomidate was effective for 8 wk in a patient with ectopic CS and peritonitis (21). We successfully used a propylene glycol-containing etomidate preparation in our patient for 5.5 months, the longest time period reported thus far.
In the previous report of long-term etomidate use, adrenocortical cortisol production was completely blocked and hydrocortisone replacement therapy was given (21). In contrast, we targeted partial inhibition of adrenocortical steroid biosynthesis to minimize the patient’s exposure to propylene glycol-containing etomidate and to allow appropriate cortisol concentrations for ongoing stress. We titrated the etomidate dose each day using the daily serum cortisol measurements available at our institution. By avoiding complete inhibition of cortisol biosynthesis, we also avoided the risk of possible overreplacement with exogenous steroids.
Possible nephrotoxicity and metabolic acidosis from the propylene glycol or etomidate were concerns while our patient was in acute renal failure and undergoing hemodialysis. Etomidate is metabolized to inactive metabolites primarily by the liver (16, 22). Because 2% of etomidate is excreted unchanged in the urine, (23) the plasma half-life, estimated at 3–5 h, should not be prolonged by renal failure (24). However, the propylene glycol can be nephrotoxic and has been noted to cause metabolic acidosis at very high doses (52.6–90 g/d) (25). The World Health Organization recommended a daily maximal intake of 0.025 g propylene glycol/kg body weight (26). Our patient received 7 g/d during renal failure and as much as 36 g/d as renal function improved, without associated nephrotoxicity or worsening metabolic acidosis. In fact, his renal failure resolved despite regular use of this etomidate preparation.
Our experience suggests that a short (3 h) infusion of etomidate during
renal failure suppressed cortisol as well as the continuous infusion
given after near normalization of renal function (Fig. 1). Most
circulating etomidate is protein bound, and an increase in the
proportion of free etomidate has been observed in renal failure
(27, 28). This could account for the prolonged action of
etomidate during renal failure in our patient. Because hemodialysis
removes relatively little cortisol, it is a minimal confounding factor
in assessing treatment efficacy (29). Our patient
tolerated propylene glycol-containing etomidate well, except for
transient myoclonus. Ten to 86% of patients have transient myoclonus
after etomidate anesthesia (16, 30, 31). It is usually
short-lived and may be dose dependent (32). In our
patient, the myoclonus lasted several weeks, but gradually diminished
over time and was absent at the time of his discharge. We were
surprised when our patient developed adrenal insufficiency after
discontinuation of etomidate. This unanticipated risk may be related to
the long-term use and should be considered during future use of any
etomidate preparation.
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). We considered a variety of causes for persistent hypocortisolism after discontinuation of etomidate, including primary adrenal damage, adrenal inhibition by other medications, and slow clearance of etomidate. CT scans did not suggest either adrenal hemorrhage or an adrenolytic effect of etomidate. Whereas octreotide can suppress tumor corticotropin production (34, 35) and, thus, reduce cortisol concentrations, corticotropin concentrations remained elevated. An ongoing mild synthetic hepatic dysfunction seems unlikely to have prolonged the half-life of etomidate. Because etomidate is a lipophilic compound, storage of the agent in adipose tissue with reequilibration to the plasma compartment provides the most likely explanation for the persistent effect of etomidate noted in our patient.
There are no controlled trials comparing adrenalectomy to long-term adrenostatic therapy in the setting of occult ectopic ACTH secretion. In clinical practice, this decision may be guided by the risk of anesthesia and surgery, effectiveness, and side effects of medical therapy, patient wishes, and need for life-long steroid replacement therapy. In the case of our patient, long-term ketaconazole administration has achieved clinical normalization and has preserved adrenal gland function without adverse effects. It is our hope that we will locate the ectopic source of ACTH and remove it surgically, with discontinuation of ketoconazole and subsequent normalization of endogenous adrenal function. We recognize that this aim may not be achieved and recommend discussion of the option of laparoscopic adrenalectomy with patients regularly.
In conclusion, our experience showed that etomidate formulated with propylene glycol can be used safely for prolonged periods in a hypercortisolemic patient, even during renal failure. A short (3 h) infusion of etomidate can achieve a serum cortisol profile similar to that seen with continuous infusion. We have confirmed that prolonged exposure to etomidate can result in persistent cortisol suppression for as long as 2 wk after cessation of the agent. We have also shown that with regular monitoring of serum cortisol concentrations and clinical assessment, partial inhibition of cortisol production can be accomplished, obviating the need for exogenous glucocorticoid replacement therapy. Taken together with previous studies, it seems that propylene glycol- containing or ethyl alcohol-containing etomidate can be given to patients with hypercortisolism in preparation for surgery and during recovery from surgical procedures, and in other settings when therapy with oral inhibitors of steroidogenesis is not possible.
Acknowledgments
Footnotes
Abbreviations: CS, Cushing’s syndrome; CT, computed tomographic; MRI, magnetic resonance imaging.
Received February 28, 2001.
Accepted May 26, 2001.
References
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 J. B. Lundy, M. L. Slane, and J. D. Frizzi Acute Adrenal Insufficiency After a Single Dose of Etomidate J Intensive Care Med, March 1, 2007; 22(2): 111 - 117. [Abstract] [PDF]
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K. Miehle, A. Tannapfel, P. Lamesch, G. Borte, E. Schenker, R. Kluge, R. A. Ott, V. Wiechmann, M. Koch, W. Kassahun, et al. Pancreatic Neuroendocrine Tumor with Ectopic Adrenocorticotropin Production upon Second Recurrence J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3731 - 3736. [Abstract] [Full Text] [PDF]
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, Creatinine concentrations; •, serum cortisol
concentrations. To convert creatinine to µmol/liter, multiply by
88.4. To convert cortisol to nmol/liter, multiply by 27.59. The
arrows represent the beginning of etomidate infusion.
Forty milligrams of propylene-glycol preparation of etomidate was
infused over 3 h once per day beginning at 1800 h each day.