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


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


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


          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.


          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.

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          Most cited references29

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          Hydrocortisone plus Fludrocortisone for Adults with Septic Shock

          Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock.
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            Reduced cortisol metabolism during critical illness.

            Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism. In a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes. Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons). During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 and NCT00115479; and Current Controlled Trials numbers, ISRCTN49433936, ISRCTN49306926, and ISRCTN08083905.).
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              Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.

              Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock. To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency. Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999. Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test. Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days. Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test). One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P =.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P =.001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups. In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.

                Author and article information

                Crit Care
                Critical Care
                BioMed Central (London )
                7 November 2022
                7 November 2022
                : 26
                : 343
                [1 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Department of Anesthesiology, , University Hospital, LMU Munich, ; Munich, Germany
                [2 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Department of Transfusion Medicine, Cellular Therapeutics and Hemostaseology, Department of Anesthesiology, , LMU Munich, ; Munich, Germany
                [3 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Department of Anesthesiology and Intensive Care Medicine, , Charité University Hospital, ; Berlin, Germany
                [4 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Institute of Laboratory Medicine, , University Hospital, LMU Munich, ; Munich, Germany
                [5 ]GRID grid.9647.c, ISNI 0000 0004 7669 9786, Clinical Trial Centre, , Leipzig University, ; Leipzig, Germany
                [6 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Institute for Biomedical Information Processing, Biometry and Epidemiology, , LMU Munich, ; Munich, Germany
                [7 ]GRID grid.50550.35, ISNI 0000 0001 2175 4109, General ICU - Raymond Poincaré Hospital, , Assistance Publique - Hôpitaux de Paris (APHP), ; Paris, France
                [8 ]GRID grid.411095.8, ISNI 0000 0004 0477 2585, Klinik Für Anästhesiologie, , Klinikum der Ludwig-Maximilians-Universität (LMU), ; Marchioninistrasse 15, E 81377 Munich, Germany
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                : 30 August 2022
                : 28 October 2022
                Funded by: Universitätsklinik München (6933)
                Custom metadata
                © The Author(s) 2022

                Emergency medicine & Trauma
                sepsis,shock,septic,steroids,mass spectrometry,corticosterone,hydrocortisone,hospital mortality


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