Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient

Kwame Asare, Pharm.D.


Pharmacotherapy. 2007;27(11):1512-1528. 

In This Article

Diagnostic Tests

A comparison of the different diagnostic tests is presented in Table 5 .

Measurement of cortisol levels with the ACTH stimulation test is the standard and the most convenient test for diagnosing adrenal insufficiency in the ICU. The test is based on the inability of a diseased adrenal gland to secrete adequate cortisol after injection of corticotropin. The test is quick, simple, insensitive to interferences, reliable, and essentially free of adverse effects aside from occasional anaphylactic reactions. However, its interpretation has generated some controversy. A normal response to the test does not rule out adrenal insufficiency since patients with acute-onset adrenal insufficiency (it may take up to 3 wks for the adrenal cortex to readjust to the reduced level of ACTH secretion[41]) and ACTH resistance may respond normally to the test. Also, since the test stimulates the adrenal gland directly, thereby bypassing the hypothalamus and pituitary gland, patients with defects in these organs may be missed by the test.

Corticotropin is a synthetic peptide that consists of the first 24 amino acids of human ACTH. After drawing a baseline blood sample, it is given any time of the day at a dose of 1 μg (low dose) or at a supraphysiologic dose of 250 μg (high or conventional dose), stimulating adrenocortical steroidogenesis. Blood samples for the measurement of serum cortisol are drawn at time 0 (baseline), 30, 60, and sometimes 90 minutes. Ideally, if there is clinical suspicion, clinicians should perform the ACTH stimulation test at the outset rather than wait for the results of a baseline measurement of cortisol.[41]

High- versus Low-dose Adrenocorticotropic Hormone Stimulation Test. Use of the low-dose test has been proposed by some clinicians.[42,43] It is prepared by diluting the 250-μg vial in 250 ml of normal saline to obtain a concentration of 1 μg/ml and using a 1-ml syringe to accurately draw a dose. The syringes can be kept at 4°C for up to 4 months without any decline in biologic activity.[44] Results from a number of studies indicate that the low-dose test is more sensitive that the high-dose test for diagnosing adrenal insufficiency, but it is not as sensitive as the insulin tolerance test.[42,43,45,46] In a recent study, low-dose and high-dose ACTH stimulation tests were compared in 46 patients with septic shock.[46] The two tests were performed consecutively at an interval of more than 4 hours. In each test, the cortisol level was measured at baseline, 30, 60, and 90 minutes. Responders were defined as those with a maximal increase in cortisol level over baseline of at least 9 μg/dl. The authors concluded that the low-dose test identified a subgroup of patients in septic shock with inadequate adrenal reserve who had poor outcomes and would have been missed by the high-dose test. Although the authors stopped short of suggesting that the low-dose test should replace the high dose-test, they expressed interest in the evaluation of glucocorticoid replacement therapy in patients with normal high-dose tests but abnormal low-dose tests. No published, large, randomized, controlled trials have shown that this patient population will actually benefit from glucocorticoid therapy.

The high-dose test is performed by direct intravenous or intramuscular injection of the 250-μg dose of ACTH. Because high-dose ACTH reaches plasma levels approximately 1000 times the values of maximally stressed healthy individuals, it overrides adrenal resistance to ACTH and results in a falsely high normal response in patients with adrenal insufficiency,[45,46] a mechanism similar to the effect of insulin in patients with type 2 diabetes.[25] In healthy individuals, as little as 5 μg of synthetic ACTH or 10 μg of human ACTH maximally stimulates the adrenal cortex.[47] In one study, several patients were characterized as nonresponders with the low-dose test even though they responded adequately to the high-dose test.[31] Thus, the reliance on the high-dose test as the sole measure of adrenal function may cause the withholding of a lifesaving therapy in a significant number of patients.[48]

Four studies have been published that compared the low-dose and high-dose tests in critically ill patients.[31,46,49,50] All four studies concluded that the low-dose test is more sensitive than the high-dose test. Based on these studies, it seems reasonable that therapeutic decisions can be made by using the low-dose test.[51] In a classic review article,[27] the author proposed that because the low-dose test is simple to perform, potentially more sensitive than the high-dose test, and less expensive (a single 250- μg vial of ACTH can be used to test multiple patients), it should be the routine test used in the evaluation of primary and secondary adrenal insufficiency. In contrast, a meta-analysis of the available data on different patient populations reported that the predictive value of the low-dose test was not superior to that of the high-dose test in diagnosing secondary adrenal insufficiency.[52] However, this meta-analysis did not provide any data on the use of the low-dose test for diagnosing primary adrenal insufficiency or its use in critically ill patients.

In 2003, critical care and infectious disease experts from 11 international organizations developed management guidelines for the use of corticosteroids in patients with sepsis and septic shock. They concluded that, although the lowdose test has been shown to have a higher sensitivity and specificity in testing for adrenal insufficiency, the high-dose test is still preferred.[30] The reason for this is that the lowdose stimulation test has not been well validated in critically ill patients and patients with septic shock,[41,47] since all the diagnostic thresholds for the ACTH stimulation tests were set with use of the high dose. In other words, no specific diagnostic or prognostic threshold has been set with use of the low-dose test.[46]

The comparison of the high- and low-dose ACTH stimulation tests will not be complete without a mention of sampling times. Many studies used the same sampling times for both tests (0, 30, and 60 min), although there are differences in cortisol kinetics of the two tests. The maximum cortisol concentration is reached after 30 minutes for the low-dose test and returns to baseline after 2 hours, whereas the high-dose test peaks in 90 minutes and returns to baseline after 4 hours.[46] To improve the interpretation of the test results, it has been proposed that three samples should be taken at 30, 60, and 90 minutes after the ACTH injection. If a clinician is interested in taking only two samples, the 30- and 60-minute times are preferred for the lowdose test and 60 and 90 minutes for the highdose test.[46] In critically ill patients, if the two tests are to be given, they should be separated by at least 4 hours to allow cortisol concentrations to return to baseline.[51,53] In a very recent European, retrospective, multicenter, cohort study,[54] the investigators found that very few patients are mistakenly classified as nonresponders when using a 60-minute ACTH-stimulated cortisol level (250-μg dose) instead of the maximum value between the 30- and 60-minute levels. They suggested the 30-minute level may not provide any benefit in terms of diagnostic accuracy. Thus, the test can be performed with just the baseline and 60-minute ACTH-stimulated levels.

In the ambulatory patient, the initial baseline cortisol level should be checked between 6 and 8 A.M. because the cortisol level peaks in the early morning.[55] For critically ill patients, it is not necessary to obtain cortisol levels at a specific time of the day because most patients lose the diurnal variation in their cortisol levels.[2,33] It has been proposed that random cortisol testing, measured any time of the day, may be a more useful tool for diagnosing adrenal insufficiency. One group of authors studied the HPA axis in a group of surgical patients who were vasopressor dependent and suggested that a random cortisol level of less than 25 μg/dl is associated with steroid-responsive hypotension.[56]

Another group compared the sensitivity and specificity of the low-dose ACTH stimulation test, the high-dose ACTH stimulation test, and random cortisol concentrations in 59 patients with septic shock.[31] After measurement of a baseline cortisol level within 48 hours of admission, patients received ACTH 1 μg (lowdose test), followed 60 minutes later by a 249-μg dose (high-dose test). The authors defined relative adrenal insufficiency as a random cortisol level of less than 25 μg/dl. They concluded that the sensitivity (the positivity or ability of a test to identify those patients who will respond to steroids) for random cortisol, low-dose, and high-dose tests were 96%, 54%, and 22%, respectively. The specificity (the negativity or ability of a test to correctly identify those patients who will not respond to steroid therapy) was found to be 57%, 97%, and 100%, respectively. In other words, 96%, 54%, and 22% of the patients who fail the random, low-dose, or highdose test, respectively, will respond to steroids. Because of its high sensitivity, the authors concluded that random cortisol testing is a useful diagnostic threshold for the diagnosis of adrenal insufficiency. It has even been suggested by others that, in critically ill patients, ACTH testing is not necessary to diagnose adrenal insufficiency since patients are severely stressed and therefore the HPA axis is already maximally activated with maximum cortisol secretion. These patients may be unable to further increase their cortisol secretion after the ACTH stimulation test. In these patients, a random cortisol level provides significant information on the function of the entire HPA axis.[25]

It has been firmly established that both low (< 15 μg/dl) and high (> 34 μg/dl) cortisol levels are associated with poor prognosis.[57] One group of authors measured the admission cortisol levels of 260 patients in an ICU and found the mean cortisol level to be 27 μg/dl in survivors compared with 47 μg/dl in nonsurvivors.[58] They concluded that the serum cortisol level is an independent predictor of outcome. Despite this, the threshold for diagnosing adrenal insufficiency is surrounded by controversy.

Different threshold levels have been proposed by different studies during critical illness, but none is entirely acceptable or satisfactory.[59] Some authors have proposed a basal plasma cortisol concentration (measured at early morning) of less than 15 μg/dl as indicative of adrenal insufficiency,[41,60] whereas others suggest that because patients are maximally stressed during septic shock, a plasma cortisol concentration (measured at any time of the day) less than 20-25 μg/dl is more appropriate.[2,31,56,61] Other approaches have used maximum cortisol levels (irrespective of the baseline cortisol) of less than 18, 20, and 25-30 μg/dl, measured after an ACTH stimulation test,[61,62,63,64,65] whereas others have used a cutoff cortisol increment of less than 9 μg/dl after ACTH administration.[10,57,62,65,66] This incremental response of 9 μg/dl approach has been criticized by some investigators because critically ill patients are maximally stressed with already maximum cortisol release, so any further increase is expected to be a measure of adrenal reserve and not adrenal insufficiency.[31] For example, a critically ill patient with a baseline cortisol level of 40 μg/dl that increases to 45 μg/dl lacks sufficient adrenal reserve but is not adrenally insufficient, according to this school of thought. In other words, it is the absolute level that is important and not the change in cortisol level.[25]

One group suggested that adrenal insufficiency is unlikely when a random cortisol measurement is greater than 34 μg/dl and likely if the measurement is less than 15 μg/dl during critical illness.[41] For cortisol levels between 15 and 34 μg/dl, they suggest performing the ACTH stimulation test; an incremental response less than 9 μg/dl is indicative of adrenal insufficiency (Figure 2), and the administration of a low-dose corticosteroid may be helpful. The author of an editorial added to the controversy by recommending the use of a peak cortisol concentration of less than 20 μg/dl or an incremental response of less than 9 μg/dl after the high-dose ACTH stimulation test to define adrenal insufficiency in critically ill patients.[65] The diagnosis of adrenal insufficiency using the ACTH stimulation test is less problematic in the absence of acute illness.[38]

Investigation of adrenal corticosteroid function in critically ill patients on the basis of cortisol levels and response to the adrenocorticotropic hormone (ACTH) stimulation test. From reference 41 with permission.

In a landmark study, the authors identified three groups of patient prognoses by using the ACTH stimulation test.[66] They determined that patients with septic shock with a baseline cortisol level of greater than 34 μg/dl and an increase of 9 μg/dl or less after the ACTH stimulation test are associated with the highest mortality, followed by those with baseline levels greater than 34 μg/dl with an increase of greater than 9 μg/dl. The lowest mortality risk was found in those with baseline cortisol levels of 34 μg/dl or lower and an increase of greater than 9 μg/dl. In other words, the higher the basal plasma cortisol level and weaker the response to the ACTH stimulation test, the higher the mortality rate ( Table 6 ). In another study, the authors reported that the breakpoint for a 50% mortality rate in patients with septic shock was a change in cortisol of 13.4 μg/dl, and they concluded that the lower the response, the greater the mortality rate.[11] In a third study,[10] there was 100% mortality in patients with a cortisol response of 9.1 μg/dl or less and only 32% mortality if the response was greater than 9.1 μg/dl. These studies support the hypothesis that the magnitude of change after the ACTH stimulation test may have a predictive value with regard to mortality.

It is the opinion of this author, as well as many others, that the strongest evidence supports a basal cortisol level of less than 15 μg/dl with an increase of less than 9 μg/dl after administration of the ACTH stimulation test[57,63,64] or a random cortisol level of less than 25 μg/dl[25,31,56] as the best thresholds for diagnosing adrenal insufficiency, whereas the basal cortisol level of 34 μg/dl and an incremental response of 9 μg/dl is the best cutoff to discriminate between survivors and nonsurvivors of septic shock.[66]

Because more than 90% of circulating cortisol is bound to protein, changes in protein binding can affect total serum cortisol concentrations without affecting free-cortisol concentrations. The effect of a decrease in serum proteins (corticosteroid-binding globulin and albumin) on measured total cortisol has been realized by studies in patients with trauma or sepsis[18] and those undergoing major surgery.[67] These studies recommend the use of a correction factor known as the free-cortisol index (defined as the total cortisol concentration divided by corticosteroidbinding globulin concentration) as a surrogate marker for serum cortisol concentration. In critically ill patients, some evidence suggests that there is a decrease in cortisol binding and an increase in free cortisol.[18,19]

In a recent study, baseline serum cortisol, ACTH-stimulated total cortisol, aldosterone, and free-cortisol concentrations were measured in 66 critically ill patients and 33 healthy subjects.[19] The critically ill patients were divided into two groups, with the healthy subjects serving as the control group. Group 1 was made up of patients with albumin levels of 2.5 g/dl or less, and group 2 patients had albumin levels above 2.5 g/dl. The two study groups had similar characteristics except for their serum albumin, total protein, and corticosteroid-binding globulin concentrations. The high-dose ACTH stimulation tests were performed in the two study groups and the control group. Both the baseline and ACTH-stimulated total cortisol concentrations were found to be lower in group 1 (low-albumin group) compared with group 2 (normal-albumin group) and the control group. The free-cortisol level, however, in groups 1 and 2 was much higher than that in the control group. Baseline and ACTH-stimulated serum aldosterone concentrations were similar in all groups.

The authors concluded that in critically ill patients with hypoalbuminemia, although the total serum cortisol level may be low, their freecortisol level (the biologically active part) may be normal, and hence, their adrenal function may be intact.[19] In other words, the interpretation of baseline and total cortisol levels after ACTH stimulation should be done with respect to a patient's protein status since hypoproteinemia results in lower concentrations of total cortisol than expected in critically ill patients. These data suggest that measurement of a serum free-cortisol level is a better indicator of adrenal function and may prevent the unnecessary use of glucocorticoid therapy.

The authors go further to recommend a threshold of less than 2 μg/dl at baseline and less than 3.1 μg/dl after the ACTH stimulation test for identifying patients at risk for adrenal insufficiency.[19] This study has been criticized because, although 18 of the 66 patients had sepsis, none had septic shock or multiple organ failure, a rather significant oversight. Also, the technique used for measuring free cortisol is technically difficult, likely to be expensive, and not widely available. Furthermore, there are no published, randomized, controlled studies that have determined normal free-cortisol concentrations in critically ill patients.[19] Finally, the authors did not correlate the measured serum free-cortisol value with the free-cortisol index to determine the compatibility of the two measurements.

Several experts, including the authors of the above study,[19,68] have proposed using total cortisol concentrations until more data and the measurement of free cortisol become widely available.

Insulin Tolerance Test. The insulin tolerance test measures a patient's response to insulin-induced hypoglycemia. It is considered by many to be the gold standard because it tests the integrity of the entire HPAaxis system.[27,41] Insulin is administered to the patient until the serum glucose level decreases to below 40 mg/dl, causing severe hypoglycemia. Hypoglycemia, a potent stressor, then causes the release of ACTH and, hence, cortisol. It has been proposed by others that glucose levels below 30 mg/dl improve the specificity of the test.[69] Usually the dose of insulin administered is 0.1 U/kg. In obese patients with insulin resistance, the dose should be increased to 0.15 U/kg.[70] Cortisol levels are checked at baseline, as well as after insulin administration every 15 minutes over the subsequent 2 hours. A peak plasma cortisol level of less than 18 μg/dl[27] or less than 20 μg/dl[71] at any time during the test is indicative of adrenal insufficiency. The use of the higher cutoff point is preferred because it minimizes underdiagnosis of adrenal insufficiency.[47] An abnormal result implies a problem that can be occurring anywhere between the hypothalamus and the adrenal gland. The insulin tolerance test is labor intensive, requires constant medical supervision, and lacks a clear cutoff level. In addition, it is contraindicated in patients older than 60 years and in those with ischemic heart disease, seizures, or severe cortisol deficiency (cortisol level < 7 μg/dl at 9 A.M.[41]). Because of the small but significant risk of seizures, coma, or precipitation of angina, use of the insulin tolerance test is not safe in the unconscious critically ill patient; thus, it is not commonly used clinically in the ICU.

This is another well-established test for evaluating the HPA axis. Metyrapone, a drug that interferes with cortisol synthesis, is administered to the patient. The reduction of cortisol concentration will provoke an increase in cortisol levels in patients with normal adrenal function. Patients with adrenal insufficiency will not have the compensatory increase in cortisol. In other words, the test measures the ability of the HPA axis to respond to an acute reduction in serum cortisol. Metyrapone 30 mg/kg (maximum 3000 mg) is administered at midnight, and blood samples are drawn in the early morning for cortisol and its precursor, 11-deoxycortisol. In response to metyrapone administration, cortisol should decrease to less than 5 μg/dl and 11- deoxycortisol should increase to greater than 7 μg/dl in patients with adrenal insufficiency.[27] It has been proposed that the sum of cortisol and 11-deoxycortisol in the early morning should be greater than 16.5 μg/dl.[72] Comparison of the metyrapone test, insulin tolerance test, and ACTH stimulation test in patients with suspected HPA-axis suppression (resulting from previous use of corticosteroid or pituitary surgery) showed that the metyrapone test was better in detecting subtle abnormalities of the HPA axis.[73] However, because of the time involved, the risk of further reducing potentially low cortisol levels, and the intermittent availability of metyrapone, this test is rarely used clinically in the ICU.

This is a relatively new test. It measures the ability of the pituitary gland to secrete ACTH in response to exogenous CRH, with a subsequent increase in cortisol secretion by the adrenal gland. Impaired response to CRH is associated with increased mortality.[11,74] Although this test bypasses the hypothalamus, it does test the integrity of the pituitary and adrenal glands. Serum cortisol levels are measured at baseline, and after injection of 100 μg or 1 μg/kg of intravenous CRH, serum cortisol and ACTH levels are measured at 15, 30, 45, and 60 minutes. The serum ACTH level usually peaks at 15 or 30 minutes, whereas the cortisol level peaks at 30 or 45 minutes.[75] The proposed cutoff for this test is a cortisol level of 18.5 or 20 μg/dl with a specificity as low as 33%.[76] Some authors have defined a normal response as an increase in cortisol value of 20% or greater from baseline.[77] This test can also be used to distinguish between ACTH deficiency and deficiency in CRH.[47] The CRH stimulation test has been shown to be comparable to the insulin tolerance test in diagnosing adrenal insufficiency.[78] The limitations of the CRH stimulation test are the lack of studies and standardization in critically ill patients and its high cost.


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