Context: Activation of the hypothalamic pituitary adrenal (HPA) axis represents one of several important responses to stressful events and critical illnesses. Despite a large volume of published data, several controversies continue to be debated such as the definition of "normal adrenal response", the concept of "relative adrenal insufficiency" and the use of glucocorticoids in the setting of critical illness.

Objectives: The primary objective is to review some of the modulating factors and limitations of currently used methods of assessing HPA function during critical illness and to provide alternative approaches in that setting.

Design: Critical review of relevant data from the literature with inclusion of previously published as well as un-published observations by the author. Data on HPA function during three different forms of critical illnesses are reviewed: Experimental endotoxemia in healthy volunteers, the response to major surgical procedures in patients with normal HPA, and the spontaneous acute to subacute critical illnesses observed in patients treated in intensive care units.

Setting: Academic Medical Center.

Patients/ Participants: Critically ill subjects.

Intervention: None

Main Outcome Measure: Provide data on the superiority of measuring serum free cortisol during critical illness as contrasted to those of total cortisol measurements.

Results: Serum free cortisol measurement is the most reliable method to assess adrenal function in critically-ill, hypoproteinemic patients. A random serum free cortisol is expected to be 1.8 µg/dL in most critically ill patients, irrespective of their serum binding proteins. As the free cortisol assay is not currently available for routine clinical use, alternative approaches to estimate serum free cortisol can be used. These include calculated free cortisol (Coolens' method) and determining the free cortisol index (ratio of serum cortisol/ transcortin concentrations). Preliminary data suggest that salivary cortisol measurements might be another alternative approach to estimating the free cortisol in the circulation. When serum binding proteins (albumin, transcortin) are near normal, measurements of total serum cortisol continues to provide reliable assessment of adrenal function in critically-ill patients, in whom, a random serum total cortisol would be expected to 15 µg/dL in most patients. In hypoproteinemic critically ill subjects, a random serum total cortisol level is expected to be 9.5 µg/dL in most patients. Data on Cosyntropin-stimulated serum total and free cortisol levels should be interpreted with the understanding that the responses in critically ill subjects are higher than those of healthy ambulatory volunteers. The Cosyntropin-induced increment in serum total cortisol should not be used as a criterion for defining adrenal function, especially in critically ill patients.

Conclusions: The routine use of glucocorticoids during critical illness is not justified except in patients where adrenal insufficiency was properly diagnosed, or in others who are hypotensive, septic, and unresponsive to standard therapy. When glucocorticoids are used, hydrocortisone should be the drug of choice and should be given at the lowest dose and for the shortest duration possible. The hydrocortisone dose (50 mg every 6 h) that is mistakenly labeled as "low dose hydrocortisone" leads to excessive elevation in serum cortisol to values several folds greater than those achieved in patients with documented normal adrenal function. The latter data should call into question the current practice of using such doses of hydrocortisone even in the adrenally-insufficient subjects.