© 2006 American Thoracic Society doi: 10.1164/rccm.200608-1168ED
Relative Adrenal Insufficiency in the ICU: Can We at Least Make the Diagnosis?Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois The use of corticosteroids for patients with septic shock has long been controversial. As early as 1950, small studies suggested a potential benefit of corticosteroids in the setting of suppurative streptococcal infection (1). In 1976, one clinical trial found a dramatic reduction in mortality for patients with bacteremic septic shock treated with high dose corticosteroids (2), but a larger subsequent trial did not (3). To reconcile these disparate results, a large multicentered trial was conducted in which patients received methylprednisolone or placebo within two hours of meeting study criteria. Not only did corticosteroids not confer benefit, but a trend toward increased mortality was observed (4). In the late 1990s the concept of relative adrenal insufficiency (RAI) in septic shock emerged. While absolute adrenal insufficiency in the setting of septic shock appears rare (5, 6), a lack of adrenocortical reserve, as determined by an inadequate response to synthetic corticotropin stimulation, is both common and associated with increased mortality (5, 7, 8). Extrapolating from these observations, Annane and colleagues undertook a randomized placebo-controlled trial of low-dose hydrocortisone and fludrocortisone replacement therapy in patients with septic shock (9). Patients were also tested for RAI, defined as an increase in serum cortisol less than 9 µg/dl after stimulation with 250 µg of synthetic corticotropin. When analyzed by intention to treat, there was no difference in overall mortality between the groups receiving steroid replacement or placebo. By post hoc analysis, in the subset of patients meeting the predefined definition of RAI, adrenal replacement therapy did decrease 28-d, ICU, and hospital mortality. This trial no doubt resurrected the use of steroids for patients with septic shock by many clinicians, but it again stoked the fires of controversy. Importantly, survival benefit has yet to be confirmed. Equally controversial is the ability to actually make a diagnosis of RAI in patients with septic schock. If baseline levels of cortisol under conditions of extreme stress are very low, does not this alone signal RAI, quite apart from a failure to increase levels with exogenous stimulation? If baseline levels are high, are measures of further stimulation relevant? Was the corticotropin test the best for classification, when it yields a diagnosis of RAI in approximately 75% of all patients with septic shock (9)? What of the potential for failure to diagnose secondary adrenal insufficiency with the corticotropin test? Would a more thorough test of the hypothalamic pituitary adrenal axis—such as insulin tolerance or metyrapone testing—better identify RAI? As critically ill patients frequently develop hypoproteinemia and more than 90% of circulating cortisol is protein-bound, can we rely on judgments made by measuring total serum cortisol levels in the critically ill? (10). Finally, what is the level of cortisol in the tissues during critical illness and how do serum levels—basal or provocative—indicate the true glucocorticoid status of individual organs and tissues? In this issue of the Journal, Dr. Annane and colleagues (pp. 1319–1326) go a long way toward answering these questions and concerns (11). Using the overnight metyrapone test—sensitive to the detection of both primary and secondary adrenal insufficiency—as a "gold standard," they confirm that diminished adrenocortical reserve is indeed common among patients with severe septic shock, occurring in approximately 60%. In addition, they validate both the corticotropin test and absolute cut-offs for both free and total cortisol levels to define RAI. The strongest predictors of adrenal insufficiency were baseline total cortisol level less than 10 µg/dl, baseline free cortisol level less than 0.8 µg/dl, or a change in cortisol after corticotropin stimulation less than 9 µg/dl (total cortisol) or 2 µg/dl (free cortisol). Conversely, adrenal function was most likely to be intact when the corticotropin-stimulated total cortisol level was greater than 44 µg/dl or when the change after corticotropin was greater than 17 µg/dl. As centers have debated over how best to spend precious resources on diagnostic tests, many have questioned the utility of using random cortisol levels or free cortisol levels in attempting to diagnose adrenal insufficiency. Free cortisol performed no better than total cortisol for any diagnostic parameter, rendering unnecessary the extra expenditure for free cortisol levels. The best predictor of adrenal insufficiency was the presence of baseline cortisol < 10 µg/dl or delta cortisol < 9 µg/dl, with a specificity of 96%, positive predictive value of 94%, and positive likelihood ratio of over 10. Several surprises emerge from this study. It was shown that 12.5% of patients with septic shock had absolute adrenal insufficiency as defined by a baseline total cortisol level below 10 µg/dl. This rate is approximately four times higher than has been reported in the past (5), and lends credence to the usefulness of baseline cortisol levels done routinely as part of a corticotropin test. Even more surprising, the vast majority (71%) of patients with severe septic shock with adrenal insufficiency were found to have secondary, as opposed to primary, adrenal insufficiency as determined by the metyrapone test. While this constitutes the first report of metyrapone testing in critically ill patients, the distinctly different patterns for the patients without septic shock but who were critically ill as compared with patients with septic shock suggests a specific interplay between the physiology of sepsis and the activity of the hypothalamic pituitary adrenal axis. Hypothalamic pituitary dysfunction is also believed to underlie the "euthyroid sick" and "eugonadal sick" syndromes observed in critical illness (12); however, whereas treatment of RAI in sepsis apparently impacts outcomes, treatment of thyroid or gonadal hypofunction—given the limits of our present knowledge—does not. Potential mechanisms for this neuroendocrine insufficiency may include sepsis-induced hypothalamic or pituitary apoptosis (13), or depletion of adrenocorticotropic hormone (ACTH) brain stores in the face of persistently high demands, a condition akin to vasopressin depletion in patients with septic shock (14). The present study does not address treatment of relative adrenal insufficiency, and thus cannot diffuse the remaining controversy regarding the size of treatment effect or the necessity of fludrocortisone. We await the results of a large multicenter trial, the Corticosteroid Therapy of Septic Shock (CORTICUS) trial, which is anticipated to enroll 800 patients and could validate the mortality benefit of steroids in ACTH nonresponders in septic shock (15, 16). In the meantime, we have at least been provided an elegant algorithmic approach to the diagnosis of RAI in severe sepsis and septic shock, a necessary starting point for all rational treatment decisions. NOTE: Metapyrone is no longer available in the United States, so these studies will be difficult to replicate here. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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