Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery

Abstract

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.

Keywords: cortisol; glucocorticoids; hydrocortisone; mass spectrometry; stress; surgery.

Figure 1.

Summary of the studies performed. Assessment of the circulating and urinary glucocorticoid concentrations in response to different stress conditions and to stress dose hydrocortisone administration. Abbreviations: IM, intramuscular injection; IVI, intravenous injection; CIV, continuous intravenous infusion.

Figure 2.

Circulating glucocorticoids during major stress. Serum concentrations of total cortisol (nmol/L) (a), total cortisone (nmol/L) (b), and cortisol (F)/cortisone (E) ratio (c) in healthy controls (N = 122), during combat stress (N = 105), during elective surgery (N = 22), after major trauma (N = 83), and during sepsis (N = 100). In the patients undergoing elective surgery, the maximum serum cortisol levels (and corresponding serum cortisone levels) were used for the calculations. Panel d: reports serum free cortisol concentrations in nmol/L in healthy controls (N = 11), during elective surgery at knife-to-skin (KTS, N = 21), and 4 hours after the start of the operation (N = 21), after major trauma (N = 18), and during sepsis (N = 17). Panel e: reports the 24-hour urinary excretion of cortisol, cortisol metabolites, cortisone, and cortisone metabolites in healthy controls (N = 122), following elective surgery (N = 21) and after major trauma (N = 23). Boxes show median and interquartile range, whiskers are 5^th to 95^th percentile. Symbols: n.s., P > 0.05; *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001.

Figure 3.

Serum total cortisol following hydrocortisone administration. Serum total cortisol (nmol/L) in 10 patients with adrenal insufficiency after hydrocortisone administered ORAL, IM, as IVI, and as CIV. Data are presented as median (black line) and range (shaded grey area).

Figure 4.

Comparison of serum total cortisol during elective surgery of longer duration and following hydrocortisone administration. Serum total cortisol concentrations (nmol/L) in 10 patients with adrenal insufficiency after the administration of 50 mg hydrocortisone over 6 hours (black line: median, whiskers: range) in 4 different modes (ORAL, IM or IVI, or as CIV) projected onto serum cortisol concentrations observed in patients undergoing elective surgery (panels a–d, serum cortisol in 11 patients undergoing elective surgery of longer duration [red line: median; red shaded area: range]; panels e–h, serum cortisol in 11 patients undergoing elective surgery of shorter duration [blue line: median; blue shaded area: range]) from time point knife-to-skin (KTS; 0 hours) to 6 hours post-KTS. All measurements were carried out by tandem mass spectrometry.

Figure 5.

Linear pharmacokinetic modeling of stress dose hydrocortisone administration. Mixed effects linear pharmacokinetic modeling of serum cortisol in response to intravenous hydrocortisone administration modes. Serum cortisol concentrations are presented in nmol/L; the black lines show the fixed effect (central tendency) kinetics, the shaded gray area indicates 90% of between-patient variability. Panels a and b: show cortisol measurements (circles) following 50 mg IV bolus injection and the fitted model over 6 and 24 hours, respectively. The pharmacokinetic modeling was also used to predict the serum cortisol response to 100 mg IV bolus injection over 6 and 24 hours (panels c and d, respectively), as well as initial 50 mg (panel e) and 100 mg (panel f) IV bolus injections followed by CIV infusion of 200 mg per 24-hour hydrocortisone.