Prevention of Adrenal Crisis

Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery

Alessandro Prete; Angela E. Taylor; Irina Bancos; David J. Smith; Mark A. Foster; Sibylle Kohler; Violet Fazal-Sanderson; John Komninos; Donna M. O'Neil; Dimitra A. Vassiliadi; Christopher J. Mowatt; Radu Mihai; Joanne L. Fallowfield; Djillali Annane; Janet M. Lord; Brian G. Keevil; John A. H. Wass; Niki Karavitaki; Wiebke Arlt


J Clin Endocrinol Metab. 2020;105(7):2262-2274. 

In This Article

Abstract and Introduction


Context: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based.

Objective: To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress.

Design and Participants: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N = 83], sepsis [N = 100], and combat stress [N = 105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration).

Main Outcome Measure: We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress.

Results: Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50–100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range.

Conclusions: Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.


The activation of the hypothalamic-pituitary-adrenal axis in response to stressful stimuli elicits increased glucocorticoid output aimed at restoring homeostasis. Cortisol is the major glucocorticoid produced by the human adrenal glands and is a key component of the physiological stress response.[1]

Adrenal insufficiency is caused by failure of the adrenal cortex to produce cortisol, which can be caused by loss of function of the adrenal itself or its hypothalamic-pituitary regulatory center or, most commonly, long-term exogenous glucocorticoid treatment for other conditions. Patients with adrenal insufficiency are unable to produce adequate amounts of cortisol in response to stress and, therefore, require increased hydrocortisone replacement doses to avoid life-threatening adrenal crisis during surgery, trauma, or severe infection.[2–4] Prevention of adrenal crisis is challenging[5,6] and studies investigating the optimal dose and mode of steroid cover during major stress are lacking. Currently, administered hydrocortisone doses are chosen empirically rather than based on evidence. There is considerable variability in recommended administration modes, total doses, and dosing intervals.[7] The lack of evidence-based recommendations for dose and mode of glucocorticoid replacement in major stress sends a confusing message to healthcare staff, which regularly exposes patients to harm.[8]

This study was designed to determine the most appropriate hydrocortisone dose and delivery mode for patients with adrenal insufficiency during major stress. We employed tandem mass spectrometry to measure glucocorticoid concentrations in subjects with preserved adrenal function exposed to various conditions of stress and compared them to concentrations achieved after administration of stress dose hydrocortisone by a range of currently used delivery modes in patients with adrenal insufficiency.