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Unraveling the mystery of adrenal failure in the critically ill.

Once considered a rare diagnosis in the intensive care unit, adrenal failure is being reported with increased frequency in critically ill patients with sepsis, human immunodeficiency virus infection, acute and subacute liver failure, brain-dead organ donors, and cardiac surgery patients (1–5). Adrenal failure may be associated with structural damage to the adrenal gland, pituitary gland, or hypothalamus; however, many critically ill patients develop reversible failure of the hypothalamic-pituitary-adrenal (HPA) axis (6). In this edition of Critical Care Medicine, Dimopoulou and colleagues (7) report the results of a study in which they assessed the integrity of the HPA axis in 40 patients with moderate to severe traumatic brain injury the day after termination of mechanical ventilation. In this study, six (15%) patients had an abnormal low-dose corticotropin (1 g tetracosactrin (1-24)) stimulation test. Further evaluation with human corticotropin releasing hormone in five of these patients demonstrated a response that was consistent with primary adrenal failure in three patients and secondary adrenal failure in two patients. Proinflammatory mediators released in response to trauma may have played a role in the development of the primary adrenal dysfunction (6). The etiology and reversibility of the secondary adrenal failure is unclear from this report and warrants further study. The study by Dimopoulou et al. (7) and others (6) demonstrates that abnormalities of the hypothalamus/pituitary and adrenal gland may occur in critically ill patients, necessitating evaluation of the entire HPA axis. Activation of the HPA axis with the release of cortisol is an essential component of the general adaptation to illness and stress and contributes to the maintenance of cellular and organ homeostasis. This is clearly demonstrated in adrenalectomized animals who succumb rapidly to hemorrhagic and septic shock with steroid replacement being protective against these challenges (8, 9). In patients with septic shock, treatment with stress-level doses of hydrocortisone (low-dose) has been demonstrated to improve hemodynamic status and down-regulate the proinflammatory response while maintaining immune responsiveness (1, 10). In a landmark study, Annane and colleagues (11) demonstrated that treatment with stress-level doses of hydrocortisone improved the survival of patients with septic shock. The fact that adrenal failure is common in critically ill patients and that treatment with stress-level doses of glucocorticoids may be beneficial is difficult to dispute. What remains controversial at this time and shrouded in mystery is the diagnosis of this disorder. Circulating cortisol is bound to corticosteroid-binding globulin with 10% in the free bioavailable form. During acute illness, there is an acute decline in the concentration of corticosteroid-binding globulin as well as decreased binding affinity for cortisol, resulting in an increase in the free biologically active fraction of the hormone (12). In addition, the number of intracellular glucocorticoid receptors has been reported to be both up-regulated or downregulated (tissue resistance) during stress (13–15). These data suggest that the total circulating cortisol level may be a poor indicator of glucocorticoid activity at the nuclear level. Notwithstanding these caveats and the fact that we currently do not have a test that measures glucocorticoid activity, assessment of the HPA axis is usually made on the basis of a random (stress) cortisol level or the corticotropin stimulation test. In highly stressed patients (e.g., shock or hypoxia), a random cortisol level assesses the integrity of the entire HPA axis, and dysfunction at the hypothalamic, pituitary, and/or adrenal level will result in low circulating cortisol levels ( 25 g/dL). A stress cortisol level of 25 g/dL in a patient with refractory hypotension warrants a trial of low-dose glucocorticoids (6). A random cortisol level of 15 g/dL in a moderately stressed (vasopressor-independent) intensive care unit patient is suggestive of HPA dysfunction (16). In moderately stressed patients, the integrity of the HPA axis can be assessed by sequential lowdose corticotropin and human corticotropin releasing hormone stimulation tests, as performed in the study by Dimopoulou and coworkers (7). A serum cortisol level of 20 g/dL 30 mins after a low-dose corticotropin test is suggestive of primary adrenal failure. Failure of the corticotropin level to increase after human corticotropin releasing hormone is suggestive of secondary adrenal failure. It is important to emphasize that the random and stimulated cortisol levels must be interpreted in conjunction with the severity of illness and the patients clinical features. A moderately stressed intensive care unit patient with a random cortisol level of 15 g/dL or a stimulated level of 20 g/dL who has no clinical signs of adrenal insufficiency (unexplained fever, confusion, hemodynamic instability, or eosinophilia) does not warrant treatment with stress-level doses of glucocorticoids. After the study by Annane and colleagues (11), the change in serum cortisol (delta cortisol) after a high-dose corticotropin (250 g tetracosactrin (1-24)) stimulation test has become regarded as the diagnostic test of choice to diagnose adrenal insufficiency in the intensive care unit. The “Delta 9” has become the magical number that distinguishes normal adrenal function from “relative” adrenal failure. However, the delta cortisol is a measure of adrenal reserve and adrenal responsiveness to corticotropin; it does not assess the integrity of the HPA axis and is not a measure of adrenal function. Indeed, in the paper by Dimopoulou and coauthors (7), 50% of healthy volunteers had a delta cortisol of 9 g/dL. Similarly, in a study of patients with respiratory failure and no evidence of HPA disease, 50% had a delta cortisol of 9 mg/dL after endotracheal intubation with midazolam anesthesia (17). In an elegant case report van Leeuwen et al. (18) describe a vasopressor-dependent septic shock patient with excessive activation of nuclear factorB. Three high-dose cortico*See also p. 404.