Demystifying Adrenal Dysfunction in Severe Illness

Mark S. Cooper


Clin Endocrinol. 2019;91(3):372-373. 

Whether adrenal function is adversely affected by severe illness has been a highly controversial area. Various studies, primarily examining patients with septic shock, have emerged from the critical care setting suggesting that abnormalities of the hypothalamo-pituitary-adrenal (HPA) axis are common and that patients with these abnormalities might benefit from 'replacement' glucocorticoids.[1] This has led to a proliferation of terms such as relative adrenal insufficient and critical illness-related corticosteroid insufficiency with associated diagnostic criteria based on basal cortisol or the peak or increase in cortisol during an adrenocorticotropic (ACTH) stimulation test.[2] The robustness of these concepts in clinical practice has been questionable as has the applicability of the diagnostic criteria to patients outside of the septic shock population. The recent study by Blum et al[3] makes a major contribution to this field by examining the relationship between HPA axis function and response to glucocorticoid treatment in patients with community-acquired pneumonia.

The same researchers had previously demonstrated in a large randomized controlled trial that prednisone treatment (50 mg per day for 7 days) improves time to clinical stability (defined as time until vital signs are stabilized for 24 hours) in patients with community-acquired pneumonia without inducing significant side effects.[4] In a well-designed, prespecified secondary analysis of this trial, the relationship between various concentrations of serum cortisol across a 1 mcg ACTH test (done shortly after enrolment) and the response to prednisone treatment have now been examined. They found that no measure of serum cortisol predicted the effects of prednisone on the time to clinical stability (the primary study end-point) or other important secondary end-points such as mortality. The only significant association was that patients with very high cortisol levels at baseline (≥938 nmol/L) appeared to benefit with a reduced length of hospital stay if they received prednisone. The authors cautioned that this result might be due to chance secondary to multiple testing, but there is a plausibility to glucocorticoids working better in this population since they were the sickest and with the greatest amount of inflammation.

The study is particularly important because it was large with over 600 patients randomized. It was also designed by researchers with a clinical endocrinology background. The study clearly attempted to distinguish between the effects of glucocorticoids as 'replacement therapy' for possible relative adrenal insufficiency and their pharmacological/supraphysiological effects on immune modulation. This conceptual separation between what is replacement and what is treatment is not always evident in trials and guidelines designed and implemented in the critical care realm.

Although this study shows that the benefits of corticosteroid therapy are independent of underlying adrenal function in patients with pneumonia, the study doesn't rule out the development of important and potentially treatable adrenal dysfunction in other groups of critically ill patients. More prolonged critical illness appears to have a greater potential to result in altered HPA axis function with evidence of central suppression and secondary adrenal atrophy.[5] The study also does not address whether other aspects of glucocorticoid signalling aside from serum cortisol levels might become dysfunctional in severe illness. Depletion of high affinity corticosteroid binding globulin (CBG) has been proposed to be an important adverse mechanism in critical illness.[6] In the absence of intact CBG, the delivery of glucocorticoids to tissues might be severely impaired even in the presence of a high serum level of steroid. Other impairments of glucocorticoid signalling have been proposed in prolonged critical illness such as impaired cortisol breakdown and resistance at the level of the glucocorticoid receptor.[1,7] None of these abnormalities would be identifiable from a basal or stimulated serum cortisol level.

The study also has immediate, direct relevance to clinicians looking after sick patients. In this population of moderate to severely ill patients, none of the diagnostic criteria proposed for conditions such as relative adrenal insufficiency or critical illness-related corticosteroid insufficiency had any value in predicting clinical response to glucocorticoids. Although only the 1mcg ACTH test was used the majority of patients had stimulated cortisol values above the thresholds conventionally used for the diagnosis of adrenal insufficiency in patients evaluated in an outpatient setting. These findings indicate that the traditional 250 mcg ACTH stimulation test is reliable in patients admitted for pneumonia. Although there is no substitute for careful consideration of individual patient circumstances, the results support the idea that testing for adrenal insufficiency should only be done where there are clinical features to suggest the diagnosis and the use of conventional thresholds for the diagnosis of adrenal insufficiency can reasonably be applied in this population.

The results of this study suggest that the decision to administer glucocorticoid therapy to improve outcomes in patients with community-acquired pneumonia should not be based on assessment of adrenal dysfunction. As such, at least for the types of patient described by Blum et al,[3] the evaluation of the HPA axis has become clearer.