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"Bogatsch, Holger"
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Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study
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
.
Journal Article
Influence of anterior chamber depth, anterior chamber volume, axial length, and lens density on postoperative endothelial cell loss
Purpose
To evaluate the influence of anterior chamber depth (ACD), anterior chamber volume (ACV), lens density (LD), and axial length (AL) as risk factors on endothelial cell loss 3 months after cataract surgery.
Methods
We enrolled 47 patients with senile cataract who were operated between July 2012 and March 2013 by the same surgeon using torsional phacoemulsification. Preoperatively, we measured ACD, ACV, and LD using the Oculus Pentacam®. The AL was determined using the IOL Master®. Primary outcomes were central endothelial density (ECD) and corrected distance visual acuity (CDVA) 3 months after surgery We evaluated the effect of ACD, ACV, LD, and AL as possible risk factors of postoperative percentage endothelial cell loss (ECL).
Results
The median age was 72 years. The median CDVA before surgery was 0.5 improving to 1.0 postoperatively. The median ECL was 5.2 % (range 1.7 %–7.6 %). These results are comparable to our previous study (median ECL 6.9 % after 3 months) [Reuschel et al. (
2010
) J Cataract Refract Surg]. The median ACD in our study was 2.56 mm (range 2.26 mm–2.8 mm). Median ACV was 144 mm
3
(range 121 mm
3
–158 mm
3
]. The median LD was 12.4 (range 11.4–13.7). Median AL was 23.1 mm (range 22.7 mm–23.9 mm). Our correlation analysis showed no significant correlation between ACD, ACV, LD, AL, and postoperative ECL.
Conclusion
ACD, ACV, AL, and LD were not identified as risk factors of postoperative endothelial cell loss in our analysis.
Journal Article
Epidemiology of sepsis in Germany: results from a national prospective multicenter study
To determine the prevalence and mortality of ICU patients with severe sepsis in Germany, with consideration of hospital size.
Prospective, observational, cross-sectional 1-day point-prevalence study.
454 ICUs from a representative nationwide sample of 310 hospitals stratified by size. Data were collected via 1-day on-site audits by trained external study physicians. Visits were randomly distributed over 1 year (2003).
Inflammatory response of all ICU patients was assessed using the ACCP/SCCM consensus conference criteria. Patients with severe sepsis were followed up after 3 months for hospital mortality and length of ICU stay.
Main outcome measures were prevalence and mortality. A total of 3,877 patients were screened. Prevalence was 12.4% (95% CI, 10.9-13.8%) for sepsis and 11.0% (95% CI, 9.7-12.2%) for severe sepsis including septic shock. The ICU and hospital mortality of patients with severe sepsis was 48.4 and 55.2%, respectively, without significant differences between hospital size. Prevalence and mean length of ICU stay of patients with severe sepsis were significantly higher in larger hospitals and universities (
Journal Article
Treatment effect of intravenous high-dose selenium in sepsis phenotypes: a retrospective analysis of a large multicenter randomized controlled trial
Background
Treatment effect of high-dose intravenous selenium remains controversial in patients with sepsis or septic shock. Here, we reanalyzed data from the randomized placebo-controlled trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT) to reveal possible treatment differences according to established sepsis phenotypes.
Methods
In this secondary data analysis of the SISPCT trial all 1089 patients of the original study were included. Patients were assigned to one of the four phenotypes by comparing patient variables with the Sepsis Endotyping in Emergency Care (SENECA) validation cohort. Survival analyses were performed using Kaplan–Meier and log-rank tests.
Results
No robust effect of selenium on mortality and other outcome parameters could be determined in any sepsis phenotype. Phenotype frequencies were markedly different in our study cohort compared to previous reports (
α
: 2.2%,
β
: 6.3%,
γ
: 68.0%,
δ
: 23.4%). Differences in mortality between the respective phenotypes were not significant overall; however, 28-day mortality showed a lower mortality for the
α
- (20.8%) and
β
-phenotype (20.3%), followed by the
γ
- (27.1%), and
δ
-phenotype (28.5%).
Conclusions
Application of the four sepsis phenotypes to the SISPCT study cohort showed discrete but non-significant mortality differences within 28 days. However, beneficial treatment effects of high-dose intravenous selenium were still not detectable after categorizing the SISPCT study cohort according to four phenotype criteria.
Journal Article
A Comprehensive Cohort Analysis Comparing Growth and GH Therapy Response in IGF1R Mutation Carriers and SGA Children
Abstract
Context
IGF1 receptor mutations (IGF1RM) are rare; however, patients exhibit pronounced growth retardation without catch-up. Although several case reports exist, a comprehensive statistical analysis investigating growth profile and benefit of recombinant human growth hormone (rhGH) treatment is still missing.
Objective and methods
Here, we compared IGF1RM carriers (n = 23) retrospectively regarding birth parameters, growth response to rhGH therapy, near final height, and glucose/insulin homeostasis to treated children born small for gestational age (SGA) (n = 34). Additionally, health profiles of adult IGF1RM carriers were surveyed by a questionnaire.
Results
IGF1RM carriers were significantly smaller at rhGH initiation and had a diminished first-year response compared to SGA children (Δ height standard deviation score: 0.29 vs. 0.65), resulting in a lower growth response under therapy. Interestingly, the number of poor therapy responders was three times higher for IGF1RM carriers than for SGA patients (53 % vs. 17 %). However, most IGF1RM good responders showed catch-up growth to the levels of SGA patients. Moreover, we observed no differences in homeostasis model assessment of insulin resistance before treatment, but during treatment insulin resistance was significantly increased in IGF1RM carriers compared to SGA children. Analyses in adult mutation carriers indicated no increased occurrence of comorbidities later in life compared to SGA controls.
Conclusion
In summary, IGF1RM carriers showed a more pronounced growth retardation and lower response to rhGH therapy compared to non-mutation carriers, with high individual variability. Therefore, a critical reevaluation of success should be performed periodically. In adulthood, we could not observe a significant influence of IGF1RM on metabolism and health of carriers.
Journal Article
Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock
Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) ( n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies in vitro revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.
Journal Article
Incidence of Sepsis-Induced Coagulopathy (INSIC) Trial: Study Protocol of a Combined Retrospective and Prospective, Multicenter, International, Cross-Sectional, Longitudinal, and Epidemiological Observational Trial
Background/Objectives: Sepsis and septic shock are the most severe forms of infection. Due to the intensive cross-talk of the coagulation and immune system, coagulopathies regularly occur in sepsis. The International Society on Thrombosis and Hemostasis refers to these coagulation abnormalities as sepsis-induced coagulopathies (SICs). The presence of SICs can be assessed using the SIC score. In parallel, a score for “sepsis-associated coagulopathy” (SAC) was introduced that, in contrast to the SIC score, allows coagulopathy to be classified according to its severity. In the past, multicenter, randomized controlled trials have repeatedly failed to prove the efficacy of specific therapeutic measures targeting SICs or SACs. This could potentially be explained by insufficient knowledge about the prevalence and incidence of SIC and the rate of spontaneous recovery. The Incidence of Sepsis-Induced Coagulopathy (INSIC) trial is intended to address this problem. Methods: The aim of the INSIC trial is to measure the incidence and prevalence of SIC—in addition to the rate of spontaneous SIC recoveries—during the first days of sepsis treatment to provide a solid base of data for future interventional trials. We aim to include all patients with sepsis treated in any one of 150 participating intensive care units in 100 hospitals located in Austria, Luxembourg, and Germany to determine the prevalence of SIC (on day 1 of the study period as well as on three selected days in the fourth quarter of each year from 2019 to 2024). SIC incidence will be assessed over a 14-day period starting on 10 March 2025. Secondary endpoints are 28-day survival and the occurrence of severe thromboembolic events and bleeding. In addition, each of the aforementioned outcome parameters will be assessed for correlation with the severity classification of the SAC score. Conclusions: The INSIC trial is the first study to determine the prevalence as well as the incidence of SIC, to prospectively examine the course of SIC longitudinally over a 14-day period, and to determine the rate of spontaneous recoveries within 72 h under standard treatment in a large cohort of patients. This information will provide a sound basis for future studies.
Journal Article
Treatment of adult attention-deficit hyperactivity disorder
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation treatment used as an alternative or complementary treatment for various neuropsychiatric disorders, and could be an alternative or add-on therapy to psychostimulants in attention-deficit hyperactivity disorder (ADHD). Previous studies provided some evidence for improvements in cognition and clinical symptoms in pediatric and adult ADHD patients. However, data from multi-center randomized controlled trials (RCTs) for this condition are lacking. Thus, our aim is to evaluate short- and mid-term effects of tDCS in this multi-center, randomized, double blind, and sham-controlled, parallel group clinical trial with a 1:1 randomization ratio. Primary endpoint is the total score of DSM-IV scale of the internationally established Conners' Adult ADHD Rating Scales (German self-report screening version, CAARS-S-SR), at day 14 post-intervention (p.i.) to detect short-term lasting effects analyzed via analyses of covariance (ANCOVAs). In case of significant between-groups differences at day 14 p.i., hierarchically ordered hypotheses on mid-term lasting effects will be investigated by linear mixed models with visit (5 time points), treatment, treatment by visit interaction, and covariates as fixed categorical effects plus a patient-specific visit random effect, using an unstructured covariance structure to model the residual within-patient errors. Positive results of this clinical trial will expand the treatment options for adult ADHD patients with tDCS and provide an alternative or add-on therapy to psychostimulants with a low risk for side effects.
Journal Article
Corticosteroids for adult patients hospitalised with non-viral community-acquired pneumonia: a systematic review and meta-analysis
Purpose
International clinical practice guidelines addressing corticosteroid treatment for patients hospitalised with non-viral community-acquired pneumonia (CAP) are inconsistent.
Methods
We conducted a systematic review of randomized controlled trials (RCTs) evaluating the use of corticosteroids in hospitalised adult patients with suspected or probable CAP. We performed random effects pairwise, Bayesian, and dose–response meta-analyses using the restricted maximum likelihood (REML) heterogeneity estimator. We assessed certainty of evidence using GRADE methodology.
Results
We identified 30 eligible RCTs, including a total of 7519 patients. The prednisone-equivalent doses ranged between 29 mg/day and 100 mg/day. Corticosteroids probably reduced short-term (28–30 days) mortality (RR 0.82 [95% CI 0.74–0.91]; moderate certainty) while the reduction in longer term (60–90 day) mortality is less certain (RR 0.89 [95% CI 0.76–1.03]; low certainty). Corticosteroids reduced the need for invasive mechanical ventilation (IMV) (RR 0.63 [95% CI 0.48–0.82]; high certainty) and may reduce duration of ICU stay (MD 1.53 days fewer [95% CI 0.31–2.75 days fewer]; low certainty), and hospital stay (MD 2.30 days fewer [95% CI 0.81–3.81 days fewer]; low certainty). Corticosteroids probably increased hyperglycaemia requiring intervention (RR 1.32 [95% CI 1.12–1.56]; moderate certainty) but probably have no effect on secondary infections (RR 0.97 [95% CI 0.85–1.11]; moderate certainty).
Conclusion
Corticosteroids probably reduced short-term mortality and reduce the need for invasive mechanical ventilation in hospitalised patients with CAP.
PROSPERO registration number
CRD42024521536.
Journal Article
Treatment of adult attention-deficit hyperactivity disorder (ADHD) with transcranial direct current stimulation (tDCS): study protocol for a parallel, randomized, double-blinded, sham-controlled, multicenter trial (Stim-ADHD)
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation treatment used as an alternative or complementary treatment for various neuropsychiatric disorders, and could be an alternative or add-on therapy to psychostimulants in attention-deficit hyperactivity disorder (ADHD). Previous studies provided some evidence for improvements in cognition and clinical symptoms in pediatric and adult ADHD patients. However, data from multi-center randomized controlled trials (RCTs) for this condition are lacking. Thus, our aim is to evaluate short- and mid-term effects of tDCS in this multi-center, randomized, double blind, and sham-controlled, parallel group clinical trial with a 1:1 randomization ratio. Primary endpoint is the total score of DSM-IV scale of the internationally established Conners’ Adult ADHD Rating Scales (German self-report screening version, CAARS-S-SR), at day 14 post-intervention (p.i.) to detect short-term lasting effects analyzed via analyses of covariance (ANCOVAs). In case of significant between-groups differences at day 14 p.i., hierarchically ordered hypotheses on mid-term lasting effects will be investigated by linear mixed models with visit (5 time points), treatment, treatment by visit interaction, and covariates as fixed categorical effects plus a patient-specific visit random effect, using an unstructured covariance structure to model the residual within-patient errors. Positive results of this clinical trial will expand the treatment options for adult ADHD patients with tDCS and provide an alternative or add-on therapy to psychostimulants with a low risk for side effects.
Trial Registration
The trial was registered on July 29, 2022 in the German Clinical Trials Register (DRKS00028148).
Journal Article