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Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.
Sevransky, JE, Rothman, RE, Hager, DN, Bernard, GR, Brown, SM, Buchman, TG, Busse, LW, Coopersmith, CM, DeWilde, C, Ely, EW, et al
JAMA. 2021;(8):742-750
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Abstract
IMPORTANCE Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. OBJECTIVE To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. INTERVENTIONS Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. MAIN OUTCOMES AND MEASURES The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. RESULTS Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. CONCLUSIONS AND RELEVANCE Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03509350.
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Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study.
Cohen, J, Bellomo, R, Billot, L, Burrell, LM, Evans, DM, Finfer, S, Hammond, NE, Li, Q, Liu, D, McArthur, C, et al
American journal of respiratory and critical care medicine. 2020;(5):700-707
Abstract
Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.
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Association between hair cortisol concentration and dietary intake among normal weight preschool children predisposed to overweight and obesity.
Larsen, SC, Rohde, JF, Olsen, NJ, Händel, MN, Stougaard, M, Fahrenkrug, J, Heitmann, BL
PloS one. 2019;(3):e0213573
Abstract
BACKGROUND The association between chronically elevated cortisol, as measured by hair cortisol concentration (HCC), and dietary intake among children has generally not been explored. Moreover, it is unknown whether there is an association between parental HCC and dietary intake among their children. OBJECTIVE To examine associations between HCC and dietary intake among children, and to explore the association between parental HCC and dietary intake among their children. METHODS We conducted a cross-sectional study based on 296 children predisposed to overweight and obesity who participated in the Healthy Start study. Multiple Linear regression analyses were conducted to assess the association between HCC and total energy intake, macronutrients, fruit and vegetables, added sugar, sugar-sweetened beverages (SSB), and a diet quality index (DQI). RESULTS Among the children, we found that higher HCC was associated with a lower consumption of dietary fat (β: -0.7 g/day [95% CI: -1.3, -0.0] per 100 pg/mg HCC). We found no statistically significant association between HCC and intake of total energy, protein, carbohydrate, fruit and vegetables, added sugar, SSB or DQI. We found no association between parental HCC and intake of total energy, added sugar, selected food groups or DQI among their children. However, stratified analyses showed that paternal HCC was associated with a borderline significant lower total energy intake and significantly lower protein intake, but only among daughters (adjusted β: -42 kcal/day [95% CI: -85, 0] and -2.6 g/day [95% CI: -4.4, -0.8] per 100 pg/mg HCC, respectively). CONCLUSION Among children, chronic stress as measured by HCC may be associated with a lower fat consumption, and paternal HCC may be associated with a lower intake of energy and protein among their daughters. However, the associations observed were weak, and any clinical relevance of these findings remains questionable.
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Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.
Lindsell, CJ, McGlothlin, A, Nwosu, S, Rice, TW, Hall, A, Bernard, GR, Busse, LW, Ely, EW, Fowler, AA, Gaieski, DF, et al
Trials. 2019;(1):670
Abstract
BACKGROUND Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018.
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Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.
Nilsson, AG, Bergthorsdottir, R, Burman, P, Dahlqvist, P, Ekman, B, Engström, BE, Ragnarsson, O, Skrtic, S, Wahlberg, J, Achenbach, H, et al
European journal of endocrinology. 2017;(6):715-725
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Abstract
OBJECTIVE To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). DESIGN Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. METHODS Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. RESULTS Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). CONCLUSIONS In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.
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A Probabilistic Model for Cushing's Syndrome Screening in At-Risk Populations: A Prospective Multicenter Study.
León-Justel, A, Madrazo-Atutxa, A, Alvarez-Rios, AI, Infantes-Fontán, R, Garcia-Arnés, JA, Lillo-Muñoz, JA, Aulinas, A, Urgell-Rull, E, Boronat, M, Sánchez-de-Abajo, A, et al
The Journal of clinical endocrinology and metabolism. 2016;(10):3747-3754
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CONTEXT Cushing's syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed. OBJECTIVE To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test. DESIGN Observational, prospective, multicenter. SETTING Referral hospital. PATIENTS A cohort of 353 patients attending endocrinology units for outpatient visits. INTERVENTIONS All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS. MAIN OUTCOME MEASURES Diagnosis or exclusion of CS. RESULTS Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%. CONCLUSIONS We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.
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Late-night salivary cortisol may be valuable for assessing treatment response in patients with Cushing's disease: 12-month, Phase III pasireotide study.
Findling, JW, Fleseriu, M, Newell-Price, J, Petersenn, S, Pivonello, R, Kandra, A, Pedroncelli, AM, Biller, BM
Endocrine. 2016;(2):516-523
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Measuring salivary cortisol is a simple, convenient and accurate technique with potential value in monitoring patients with hypercortisolism. This analysis reports changes in late-night salivary cortisol (LNSC) during a 12-month, multicentre, Phase III study of patients with Cushing's disease who were randomized to pasireotide 600 or 900 μg sc bid. LNSC assessment was an exploratory objective based on a single, optional measurement at midnight ± 1 h on the same day as one of the 24-h urinary free cortisol (UFC) measurements. Of 162 enrolled patients, baseline LNSC was measured in 93. Sixty-seven patients had levels above the upper limit of normal (ULN); median baseline levels were 19.7 and 20.7 nmol/L in the groups subsequently randomized to 600 μg (n = 40) and 900 μg (n = 27), respectively. Median LNSC levels decreased from baseline to month 12; median changes in patients who had baseline LNSC > ULN in the 600 and 900 μg groups were -13.4 nmol/L (-52.6 %; n = 19) and -11.8 nmol/L (-56.1 %; n = 14), respectively. LNSC normalized at months 6 and 12 in 25/67 (37.3 %) and 13/67 (19.4 %) patients, respectively; 10/25 and 8/13 patients also had normalized UFC, and 7/25 and 4/13 had partial UFC control (UFC > ULN and ≥50 % decrease from baseline). There was a moderate correlation (r = 0.55) on the log scale between individual patient LNSC and UFC values when all time points were pooled. Pasireotide decreased LNSC levels during 12 months of treatment. Salivary cortisol may be a simple, convenient biomarker for assessing treatment response in patients with Cushing's disease.
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Evidence for a Complex Relationship Among Weight Retention, Cortisol and Breastfeeding in Postpartum Women.
Straub, H, Simon, C, Plunkett, BA, Endres, L, Adam, EK, Mckinney, C, Hobel, CJ, Thorp, JM, Raju, T, Shalowitz, M
Maternal and child health journal. 2016;(7):1375-83
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Objective To assess the relationship between cortisol slope, a biologic marker of stress, and postpartum weight retention. Methods We included 696 women in a secondary analysis from a multi-site study conducted using principles of community-based participatory research to study multi-level sources of stress on pregnancy outcomes. As a stress marker, we included salivary cortisol slope; the rate of cortisol decline across the day. Pre-pregnancy weight and demographic data were obtained from the medical records. At 6 months postpartum, patients were weighed and returned saliva samples. We built stepwise regression models to assess the effect of demographic variables, cortisol slope and cortisol covariates (wake time, tobacco use and breastfeeding) on postpartum weight retention. Results 45.5 % of participants were African American, 29.2 % White, and 25.3 % Hispanic. Of the Hispanic women 62.5 % were Spanish speaking and 37.5 % were English speaking. In general, participants were young, multiparous, and overweight. Postpartum, almost half (47.6 %) of women studied retained >10 lbs. In multivariable analysis including age, pre-pregnancy BMI and public insurance, cortisol slope was significantly associated with weight retention (β = -1.90, 95 % CI = 0.22-3.58). However, when the model was adjusted for the cortisol covariates, breastfeeding (β = -0.63, 95 % CI = -1.01 to -0.24) and public insurance (β = 0.62, 95 % CI = 0.20-1.04) were the two strongest correlates of weight retention. Conclusions for Practice The association between cortisol slope and postpartum weight retention appears to be influenced breastfeeding status.
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Elevated plasma-free cortisol concentrations and ratios are associated with increased mortality even in the presence of statin therapy in patients with severe sepsis.
Venkatesh, B, Imeson, L, Kruger, P, Cohen, J, Jones, M, Bellomo, R, , , ,
Critical care medicine. 2015;(3):630-5
Abstract
BACKGROUND Dissociation between plasma-free cortisol and total cortisol profiles exists in critical illness. Data on plasma-free cortisol are based on either calculated values or immunoassay-based measurements. Both have significant limitations. Statins have been advocated as a therapy in sepsis. Whether they impact on plasma cortisol through inhibition of cholesterol synthesis is unclear. OBJECTIVES In patients enrolled into a randomized trial of statins in sepsis (n = 250), we examined the association of mass spectrometry measured plasma-free cortisol, plasma-free cortisol/plasma total cortisol ratios, and outcome and the impact of concomitant statin therapy on cortisol profiles in 80 steroid naïve patients. PATIENTS Two hundred twenty serial measurements of plasma-free cortisol, plasma total cortisol, and interleukin-6 were collected from 80 patients (43 placebo and 37 statins). Data from 10 volunteers were used as controls. MEASUREMENTS AND MAIN RESULTS Data are presented as median and interquartile range. Compared with controls, in severe sepsis, baseline plasma total cortisol was elevated two-fold (463 nmol/L [284-742 nmol/L] vs 245 nmol/L [200-299 nmol/L], p < 0.001), plasma-free cortisol 20-fold (75 nmol/L [20-151 nmol/L] vs 5 nmol/L [5-7 nmol/L], p < 0.001), and plasma-free cortisol/plasma total cortisol ratio six-fold (0.15 vs 0.02, p = 0.058). Baseline interleukin-6 was elevated at 121 pg/mL (65-611 pg/mL). In severe sepsis, there were no differences in plasma total cortisol (p = 0.66), plasma-free cortisol (p = 0.77), and interleukin-6 (p = 0.29) between statins and placebo groups. Plasma-free cortisol, plasma total cortisol, and plasma-free cortisol/plasma total cortisol were positively correlated with interleukin-6 (p = 0.0001, p < 0.0004, and p < 0.001, respectively) and day 90 mortality (p = 0.03, p = 0.03, and p = 0.058, respectively). Elevated plasma-free cortisol/plasma total cortisol ratios were associated with increased length of stay (p = 0.04). Baseline plasma-free cortisol, plasma total cortisol, and plasma-free cortisol/plasma total cortisol ratios were higher in nonsurvivors as compared with survivors (174 nmol/L [77-329 nmol/L] vs 57 nmol/L [17-122 nmol/L], p = 0.016; 890 nmol/L [333-1,430 nmol/L] vs 408 nmol/L [269-681 nmol/L], p = 0.035; and 0.19 [0.13-0.29] vs 0.14 [0.07-0.20]; p = 0.054, respectively). CONCLUSIONS In severe sepsis, plasma-free cortisol increase is 10-fold greater than that of plasma total cortisol. Both are similarly associated with inflammatory response and mortality. Elevated plasma-free cortisol/plasma total cortisol ratios were associated with increased length of stay. Statin therapy does not influence the plasma cortisol profiles in patients with severe sepsis.
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Gluco- and mineralocorticoid biological effects of a 7-day treatment with low doses of hydrocortisone and fludrocortisone in septic shock.
Laviolle, B, Annane, D, Fougerou, C, Bellissant, E
Intensive care medicine. 2012;(8):1306-14
Abstract
PURPOSE The benefits of low-dose steroids in septic shock remain controversial. We investigated if these low doses were able to induce their expected hormonal effects by analyzing the biological modifications observed during the study, which first demonstrated the survival benefit of low-dose steroids. METHODS This was a multicenter, placebo-controlled, randomized, double-blind study in which 299 septic shock patients received a 7-day treatment with a combination of hydrocortisone (50 mg intravenously four times daily) and fludrocortisone (50 μg orally once daily) or matching placebos. Gluco- and mineralocorticoid biological effects observed during the 7 days of treatment were compared between groups. RESULTS Steroids significantly decreased eosinophil counts from day 2 to day 7. Steroids significantly increased plasma glucose from day 2 (compared with placebos: +0.8 mmol/l) to day 7 (+1.8 mmol/l) and cholesterol from day 3 (+0.54 mmol/l) to day 7 (+0.39 mmol/l). Steroids significantly increased plasma sodium from day 3 (+2 mmol/l) to day 7 (+5 mmol/l) and significantly decreased plasma potassium on day 7 (-0.2 mmol/l). Steroids significantly decreased urinary sodium/potassium ratio from day 2 (-47 %) to day 7 (-57 %) and sodium fractional excretion from day 3 (-25 %) to day 7 (-66 %). Steroids significantly increased urine output on day 4 and 5 and osmolar clearance from day 4 to day 7, and decreased free-water clearance from day 4 to day 7, this effect being significant on day 4 and 6. CONCLUSIONS In septic shock, low-dose steroids induced both gluco- and mineralocorticoid biological effects and seemed to improve renal function. Most of these effects appeared after 2-3 days of treatment and lasted at least until the end of treatment.