Adrenal Insufficiency In Severe Sepsis

Key Point

In patients with severe sepsis, adrenal insufficiency is common and can be predicted by baseline total cortisol levels and through the use of the standard cosyntropin stimulation test.

GARCHES, FRANCE—Researchers in France have found that among patients with severe septic shock, adrenal insufficiency is common and can be predicted by baseline total cortisol levels and the use of a corticotropin test.¹

“Diagnosis of adrenal insufficiency in critically ill patients has relied on random or cosyntropin-stimulated cortisol levels, and has not been corroborated by a more accurate diagnostic standard,” Djillali Annane, MD, PhD, Head of Critical Care at the Hôpital Raymond Poincaré in Garches, France, and colleagues stated. The researchers’ findings were based on the overnight me­tyrapone stimulation test, an assessment that is more comprehensive than previous tests.

The researchers measured levels of albumin, corticosteroid-binding globulin serum, and serum cortisol before and after cosyntropin stimulation in sepsis patients from two consecutive cohorts (61 patients in the original cohort and 40 in the validation cohort). These concentrations were also measured in 44 critically ill patients without sepsis and in 32 healthy volunteers. Dr. Annane’s group also measured serum corticotropin, cortisol, and 11β-deoxy­cortisol levels before and after overnight metyrapone stimulation. Among sepsis patients in the validation cohort, 60% met criteria for adrenal insufficiency (defined by postmetyrapone serum 11β-deoxycortisol levels below 7 µg/dL), compared with 7% of patients without sepsis who were found to have adrenal insufficiency. Adrenal insufficiency was also associated with a greater likelihood of vasopressor dependency, severe cardiovascular dysfunction, and higher risk for in-hospital mortality.

The Best Predictors

In a multiple logistic regression analysis, the best independent predictors of adrenal insufficiency were positive blood cultures. Using the overnight single-dose metyr­apone stimulation test as a reference, the best predictor of adrenal insufficiency was the combination of baseline total cortisol level less than 10 µg/dL or a cosyntropin-stimulated total cortisol increment less than 9 µg/dL. The best predictor of normal adrenal response was the combination of cosyntropin-stimulated cortisol level of 44 µg/dL or greater, and an increment in total cortisol of 16.8 µg/dL or greater. This combination had a sensitivity of 0.83 and a specificity of 0.88 for classifying normal adrenal response.

Although baseline free cortisol levels less than 0.8 µg/dL and a change in cortisol level of less than 2 µg/dL after corticotropin stimulation were also strong predictors of adrenal insufficiency, Dr. Annane and colleagues recommended the use of total cortisol levels in patients with sepsis “because free cortisol and corticosteroid-binding globulin cannot be routinely measured in a timely fashion.

“Although most of our patients had septic shock, our findings suggest that adrenal insufficiency might be underappreciated in patients with severe sepsis,” Dr. Annane and colleagues pointed out. Previous studies had used random cortisol levels or rapid corticotropin tests to test for adrenal insufficiency, which “may underdiagnose adrenal failure in comparison with metyrapone testing,” a method that assesses the entire hypothalamic-pituitary-adrenal axis. They added that “physicians should systematically search for adrenal insufficiency in severe sepsis or septic shock, especially when blood cultures are positive.”

"A Necessary Starting Point"

Nuala J. Meyer, MD, and Jesse B. Hall, MD, noted in an accompanying editorial that although Dr. Annane’s research “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,” the study is nonetheless “an elegant algorithmic approach to the diagnosis of relative adrenal insufficiency in severe sepsis and septic shock, a necessary starting point for all rational treatment decisions.”²

—John Merriman

Reference
1. Annane D, Maxime V, Ibrahim F, et al. Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med. 2006;174:1319-1326.
2. Meyer NJ, Hall JB. Relative adrenal insufficiency in the ICU: can we at least make the diagnosis? Am J Respir Crit Care Med. 2006;174:1282-1284.

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