Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study

Abstract

Rationale: Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients.

Objectives: We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis.

Methods: An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality.

Measurements and main results: Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality.

Conclusions: In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www.

Clinicaltrials: gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .

Keywords: Corticosterone; Hospital mortality; Hydrocortisone; Mass spectrometry; Sepsis; Septic; Shock; Steroids.

Fig. 1

Outline of the mineralocorticoid and glucocorticoid pathways in steroidogenesis. Corticotropin boosts steroidogenesis including precursors of mineralocorticoids. Aldosterone secretion is predominantly controlled by the renin-angiotensin system. The analyzed corticosteroids are shown in red. HSD: Hydroxysteroid dehydrogenase; H: hydrolase; and L: lyase

Fig. 2

Steroid profile at baseline (b) and 60 min (p) after corticotropin (Synacthen®) in severe sepsis without shock and healthy individuals. 11-Desoxycorticosterone at baseline and after stimulation was elevated in severe sepsis compared to healthy individuals (p < 0.01 Mann–Whitney test). Corticosterone at baseline did not differ between the groups. After stimulation with corticotropin (Synacthen®), corticosterone was significantly lower in sepsis (p < 0.0001). No differences were found for 17-OH-Progesterone (b and p). 11-Desoxycortisol (b and p) and cortisol (b and p) were significantly elevated in sepsis patients compared to healthy individuals indicating a shift toward cortisol synthesis in severe sepsis (all p < 0.0001). Cortisone at baseline was significantly lower in sepsis (p < 0.01) but not after stimulation with corticotropin. In severe sepsis, steroid profiling in combination with corticotropin testing showed activation of the glucocorticoid pathway and, in the mineralocorticoid pathway, an attenuated corticosterone biosynthesis despite high concentrations of its precursor

Fig. 3

Steroid profile in placebo patients with sepsis and healthy individuals at baseline (b) and 60 min (p) after corticotropin (Synacthen®). Again, there is a significant increase in 11-desoxycorticosterone and 11-desoxycortisol in sepsis, consistent with activation of both the mineralocorticoid axis and the glucocorticoid axis. This results in significantly elevated cortisol levels, but not elevated corticosterone levels at baseline. After stimulation with corticotropin, corticosterone was significantly lower in patients who died in hospital compared to patients who survived sepsis and compared to healthy individuals (Kruskal–Wallis test p < 0.0001; Conover post hoc analysis: significant differences between all groups). 17-OH-Progesterone prior and after corticotropin was not different between the three groups. Cortisone at baseline was significantly lower in sepsis (p < 0.01) but not after stimulation with corticotropin

Fig. 4

Receiver operating characteristic (ROC) curve for the ratio of cortisol to corticosterone (RCC) after stimulation corticotropin in the placebo group. A ratio greater than 32.2 was identified as a criterion for predicting in-hospital death

Fig. 5

A and B, C and D Probabilities of septic shock development within 14 days (primary endpoint of HYPRESS) and 90-day survival (secondary endpoint) in the placebo and the hydrocortisone group as stratified by the ratio of cortisol–corticosterone greater or equal 32.2 and less (with 95% confidence interval for the curves). Patients in the placebo group with a cortisol–corticosterone ratio > 32.2 developed septic shock (p < 0.01) more frequently had a higher in-hospital mortality in the 90 days after randomization (p < 0.001). No differences were found in patients treated with hydrocortisone (200 mg for 5 days and a gradual dose reduction for another 6 days) stratified by the cortisol–corticosterone ratio