Cosyntropin is synthetic ACTH (1 " “24), which has the full biologic potency of native ACTH (1 " “39). It is a rapid stimulator of cortisol and aldosterone secretion.
Use
This is the initial test used to distinguish primary from secondary adrenal insufficiency.
It is not helpful in the diagnosis of Cushing syndrome. Several protocols are used to assess the response to exogenous ACTH administration (see below).
Low-Dose ACTH Stimulation Test
This test involves physiologic plasma concentrations of ACTH and provides a more sensitive index of adrenocortical responsiveness.
It is performed by measuring serum cortisol immediately before and 30 minutes after IV injection of cosyntropin in a dose of either 1 ˇ ¼g/1.73 m2 or 0.5 ˇ ¼g/1.73 m2.
There is no commercially available preparation of "low-dose " ¯ cosyntropin. The vials of cosyntropin currently available contain 250 ˇ ¼g and come with sterile normal saline to be used as a diluent. One prepares the low-dose solution of cosyntropin locally.
High-Dose ACTH Stimulation Test
This test consists of measuring serum cortisol immediately before and 30 and 60 minutes after IV injection of 250 ˇ ¼g of cosyntropin. This dose of cosyntropin results in pharmacologic plasma ACTH concentrations for the 60-minute duration of the test.
The advantage of the high-dose test is that the cosyntropin can be injected using the IM route, because pharmacologic plasma ACTH concentrations are still achieved.
Salivary cortisol can also be measured during this test. Salivary cortisol increases to 19 ‚ ± 0.8 ng/mL (range: 8.7 " “36 ng/mL) 1 hour after injection.
Eight-Hour ACTH Stimulation Test
The 8-hour test, which is now rarely performed, consists of infusing 250 ˇ ¼g of cosyntropin continuously over 8 hours in 500 mL of isotonic saline. A 24-hour urine specimen is collected the day before and the day of the infusion for cortisol or 17-hydroxycorticoid and creatinine determination, and serum cortisol is determined at the end of the infusion. Plasma ACTH concentrations are supraphysiologic throughout the infusion.
The 24-hour urinary excretion of 17-hydroxycorticoid should increase three- to fivefold over baseline on the day of ACTH infusion.
Two-Day ACTH Infusion Test
The 2-day ACTH infusion test is similar to the 8-hour infusion test, except that the same dose of ACTH is infused for 8 hours on 2 consecutive days.
This test may be helpful in distinguishing secondary from tertiary adrenal insufficiency. The 1-day 8-hour test is too short for this purpose, whereas longer tests add little further useful information.
Urinary excretion of 17-hydroxycorticoid should exceed 27 mg during the first 24 hours of infusion and 47 mg during the second 48 hours.
Interpretation
Low-dose stimulation test: A value of 18 ˇ ¼g/dL or more, before or after ACTH injection, is indicative of normal adrenal function.
High-dose stimulation test: A serum cortisol value of 20 ˇ ¼g/dL or more at any time during the test, including before injection, is indicative of normal adrenal function.
Eight-hour stimulation test: Serum cortisol should reach 20 ˇ ¼g/dL in 30 " “60 minutes after the infusion is begun and exceed 25 ˇ ¼g/mL after 6 " “8 hours.
Two-day infusion test: Serum cortisol should reach 20 ˇ ¼g/mL in 30 " “60 minutes after the ACTH infusion is begun and exceed 25 ˇ ¼g/mL after 6 " “8 hours. Both serum and urinary steroid values increase progressively thereafter, but the ranges of normal are not well defined.
Limitations
In healthy individuals, cortisol responses are greatest in the morning, but in patients with adrenal insufficiency, the response to cosyntropin is the same in the morning and afternoon. Therefore, ACTH stimulation tests should be done in the morning to minimize the risk of misdiagnosis in a normal individual.
The criteria for a minimal normal cortisol response of 18 " “20 ˇ ¼g/dL are derived from the responses of healthy volunteers. However, in some studies, higher cutoff points for the diagnosis of adrenal insufficiency are based on the ACTH test responses of patients known to have an abnormal response to insulin.
Variability in cortisol assays creates an additional problem with setting criteria for a normal response to ACTH that apply to all centers. Studies comparing cortisol results obtained with different assays showed a positive bias of Radioimmunoassays (RIA) and EIAs of 10 " “50% compared to a reference value obtained using isotope dilution GC/MS.
In women, the response to ACTH is affected by the use of oral contraceptives, which increase cortisol-binding globulin levels.
The response to ACTH varies with the underlying disorder. If the patient has hypopituitarism with deficient ACTH secretion and secondary adrenal insufficiency, then the intrinsically normal adrenal gland should respond to maximally stimulating concentrations of exogenous ACTH if given for a sufficiently long time. The response may be less than that in normal subjects and initially sluggish due to adrenal atrophy resulting from chronically low stimulation by endogenous ACTH. If, on the other hand, the patient has primary adrenal insufficiency, endogenous ACTH secretion is already elevated, and there should be little or no adrenal response to exogenous ACTH.
A clearly subnormal response to the low-dose or high-dose ACTH stimulation test is diagnostic of primary or secondary adrenal insufficiency, whereas a normal response excludes both disorders.
Cortisol values between 18.0 and 25.4 ˇ ¼g/dL represent a range of uncertainty in which patients may have discordant responses to ACTH, insulin, and/or metyrapone. Higher concentrations represent a normal response in the non-ICU setting.
The low-dose test is not valid if there has been recent pituitary injury, and it supports the conclusion that a 30-minute serum cortisol concentration <18 ˇ ¼g/dL indicates impaired adrenocortical reserve. In addition, the low-dose test does not reliably indicate hypothalamic " “pituitary " “adrenal axis suppression in preterm infants whose mothers received dexamethasone for <2 weeks before delivery to hasten fetal lung development. The CRH test should be used in this situation.