A Single, Post-ACTH Cortisol Measurement to Screen for Adrenal Insufficiency in the Hospitalized Patient

Testing for adrenal insufficiency (AI) is common in the hospital setting. The gold standard remains the insulin tolerance test (ITT), in which cortisol concentration is measured after the induction of hypoglycemia to <35 mg/dL.¹ Alternatively, metyrapone testing works by blocking cortisol synthesis. If pretest adrenocorticotropic hormone (ACTH) concentrations are low and ACTH concentrations do not rise after the administration of metyrapone, the patient is given a diagnosis of AI. Both assays pose some risk to patients with AI and are typically only performed as confirmatory tests. Morning random cortisol concentrations can be used to suggest AI if concentrations are <3 mcg/dL, but they often provide indeterminate results if concentrations are between 3 and 15 mcg/dL.² Thus, morning cortisol concentrations in isolation are not diagnostic of AI. For these reasons, most experts recommend a dynamic, high-dose cosyntropin stimulation testing (CST) with 250 mcg of intravenous cosyntropin to screen for AI. The test can be done any time of day.³ Historically, an incremental response to cosyntropin, or “delta,” was also required to indicate a normal response to stimulation.⁴ However, the baseline cortisol concentration is dependent on circadian rhythm and level of stress. For this reason, a delta, whether large or small, has been abandoned as a requisite for the diagnosis of AI.^5-7 A normal CST is widely accepted to be identified by any cortisol concentration >18 mcg/dL during the test (basal or poststimulation).⁸

The seminal studies by Lindholm, Kehlet, and coauthors^9-11 validated the CST against the gold standard ITT and utilized only 0- and 30-minute cortisol concentrations. A later study in patients with pituitary disease demonstrated that 30-minute concentrations had a stronger correlation with the ITT than 60-minute concentrations (false-negative rate: 10% vs 27%).¹² However, in that study, a higher threshold was used for the 60-minute concentration than for what was obtained at 30 minutes (25.4 vs 21.8 mcg/dL, respectively). Multiple studies have shown that the 60-minute concentration is higher than the 30-minute concentration after cosyntropin stimulation.^4,5,13 Subsequent, small studies of patients who were known to have AI have shown that 60-minute concentrations are as useful as 30-minute concentrations.^5,14,15 Because 30-minute cortisol concentrations are often lower than 60-minute concentrations, a single 30-minute result may lead to a falsely abnormal test.^16,17 As such, the use of a single 60-minute test may be more appropriate. Indeed, some authors have suggested that measuring only 30-minute concentrations may lead to overdiagnosis of AI by missing an appropriate response, serum cortisol >18 mcg/dL, at 60 minutes.^17-19 Peak cortisol concentrations after low-dose cosyntropin stimulation (1 mcg) are seen at 60 minutes, and low-dose stimulation has been shown to be more variable than in the high-dose test (250 mg).^19,20

There is a lack of consensus to guide clinicians as to when cortisol concentrations should be measured after stimulation, and standard references lack uniformity. Commonly accessed medical resources—such as UpToDate and Jameson’s Endocrinology—recommend basal, 30-minute, and 60-minute cortisol concentrations, while Williams Textbook of Endocrinology recommends basal and 30-minute concentrations, and the Washington Manual recommends only a single 30-minute concentration.^7,21,22 Goldman-Cecil Medicine⁸ recommends checking a cortisol concentration between 30 and 60 minutes and recommends the same 18 mcg/dL cutoff for any test obtained in this time period. As a result of these variable recommendations, all 3 time points are often obtained. Prominent review articles continue to recommend checking all 3 concentrations while presenting evidence of peak cortisol response at 60 minutes poststimulation.¹³

In this study, we retrospectively examined CSTs in hospitalized, adult patients both in the intensive care unit (ICU) and hospital ward and/or floor settings to evaluate for significant differences in 30- and 60-minute cortisol concentrations and compare the concordance of screening at each time point alone with traditional CST at all 3 time points. By using these results, we discuss the utility of obtaining 3 cortisol samples.

After receiving approval from the institutional review board, we retrospectively reviewed all standard, high-dose CSTs performed on adult inpatients at the Barnes-Jewish Hospital laboratory from January 1, 2012, to August 31, 2013. All patients received the same standard dose (250 mcg cosyntropin, a synthetic ACTH, at a concentration of 1 mcg/mL administered over 2 minutes) regardless of age or weight. We collected patient gender; age; time of baseline cortisol measurement; cortisol results at baseline, 30, and 60 minutes; and patient location (inpatient floor vs ICU status). Tests were included if results from all 3 time points (0, 30, 60 minute) were available.