Treatment of glucocorticoid- induced hyperglycemia in hospitalized patients - a systematic review and meta- analysis.

PURPOSE: Glucocorticoid (GC)-induced hyperglycemia is a frequent issue, however there are no specific guidelines for this diabetes subtype. Although treat-to-target insulin is recommended in general to correct hyperglycemia, it remains unclear which treatment strategy has a positive effect on outcomes. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess whether treating GC-induced hyperglycemia improves clinical outcomes. METHODS: MEDLINE and EMBASE were systematically searched for RCTs on adults reporting treatment and outcomes of GC-induced hyperglycemia since the beginning of the data bases until October 21, 2023. Glucose-lowering strategies as compared to usual care were investigated. RESULTS: We found 17 RCTs with 808 patients and included seven trials in the quantitative analysis. Patients with an intensive glucose-lowering strategy had lower standardized mean glucose levels of - 0.29 mmol/l (95%CI -0.64 to -0.05) compared to usual care group patients. There was no increase in hypoglycemic events in the intensively treated groups (RR 0.91, 95%CI 0.70-1.17). Overall, we did not have enough trials reporting clinical outcomes for a quantitative analysis with only one trial reporting mortality. CONCLUSION: In GC-induced hyperglycemia, tight glucose control has a moderate effect on mean glucose levels with no apparent harmful effect regarding hypoglycemia. There is insufficient data whether insulin treatment improves clinical outcomes, and data on non-insulin based treatment regimens are currently too sparse to draw any conclusions. SYSTEMATIC REVIEW REGISTRATION: Registered as CRD42020147409 at PROSPERO ( https://www.crd.york.ac.uk/prospero/ ) on April 28, 2020.

Adjunct prednisone in community-acquired pneumonia: 180-day outcome of a multicentre, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Several trials and meta-analyses found a benefit of adjunct corticosteroids for community-acquired pneumonia with respect to short-term outcome, but there is uncertainty about longer-term health effects. Herein, we evaluated clinical outcomes at long term in patients participating in the STEP trial (Corticosteroid Treatment for Community-Acquired Pneumonia). METHODS: This predefined secondary analysis investigated 180-day outcomes in 785 adult patients hospitalized with community-acquired pneumonia included in STEP, a randomised, placebo-controlled, double-blind trial. The primary endpoint was time to death from any cause at 180 days verified by telephone interview. Additional secondary endpoints included pneumonia-related death, readmission, recurrent pneumonia, secondary infections, new hypertension, and new insulin dependence. RESULTS: From the originally included 785 patients, 727 were available for intention-to-treat analysis at day 180. There was no difference between groups with respect to time to death from any cause (HR for corticosteroid use 1.15, 95% CI 0.68 to 1.95, p = 0.601). Compared to placebo, corticosteroid-treated patients had significantly higher risks for recurrent pneumonia (OR 2.57, 95% CI 1.29 to 5.12, p = 0.007), secondary infections (OR 1.94, 95% CI 1.25 to 3.03, p = 0.003) and new insulin dependence (OR 8.73, 95% CI 1.10 to 69.62, p = 0.041). There was no difference regarding pneumonia-related death, readmission and new hypertension. CONCLUSIONS: In patients with community-acquired pneumonia, corticosteroid use was associated with an increased risk for recurrent pneumonia, secondary infections and new insulin dependence at 180 days. Currently, it is uncertain whether these long-term adverse effects outweigh the short-term effects of corticosteroids in moderate CAP. TRIAL REGISTRATION: This trial was registered with ClinicalTrials. gov, number NCT00973154 before the recruitment of the first patient. First posted: September 9, 2009. Last update posted: April 21, 2015.

Performance of synacthen test in chronic hemodialysis patients.

BACKGROUND: Adrenal function tests (Synacthen test) in chronic hemodialysis (HD) patients are currently performed off dialysis. The study aimed to demonstrate equivalence of serum cortisol concentrations pre- and during HD, each for standard-dose (250 µg) and low-dose (1 µg) Synacthen test. METHODS: In a single-center cross-over diagnostic equivalence study, Synacthen tests were performed in four settings, in standard- and low-dose as well as pre- and during HD. Serum cortisol concentration was measured at 30 and 60 min after Synacthen administration, and additionally at 20 min in low dose test. Based on a multivariable linear mixed model the means of cortisol concentration on log-scale were estimated in each dose and test time combination. Differences in means were calculated and the TOST approach was applied to test for equivalence. Equivalence was proven if the 90% confidence interval of the difference of two cortisol means was entirely between - 0.22 and 0.22. RESULTS: In 28 chronic HD patients, serum cortisol concentrations at 30 and 60 min after Synacthen administration in both standard- and low-dose were shown to be equivalent pre- and during HD. In 10 of 56 low-dose tests, the cortisol peak was already reached after 20 min. However, cortisol concentrations at 20 and 30 min after low-dose Synacthen test pre- and during HD showed no significant difference. CONCLUSION: These results suggest that the adrenal function test may be carried out during an ongoing HD session, leading to a more patient-friendly performance of the test, less organizational effort and potentially earlier diagnosis of adrenal insufficiency.

Glucocorticoid withdrawal and glucocorticoid-induced adrenal insufficiency: Study protocol of the randomized controlled «TOASST" (Taper Or Abrupt Steroid STop) multicenter trial.

BACKGROUND: Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. METHODS: We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. CONCLUSION: This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.

Brolucizumab in Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: Ophthalmology and Diabetology Treatment Aspects.

Anti-vascular endothelial growth factor (anti-VEGF) therapies have become the standard of care in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), resulting in a remarkable decrease in disease-related vision loss. However, the need for regular injections places a significant burden on patients, caregivers, and the healthcare system and improvements in vision may not be maintained long term. As a result of its drying potency and duration of action, brolucizumab, an intravitreal anti-VEGF therapy approved for the treatment of nAMD and DME, could decrease injection frequency for patients and provide an efficacious treatment; however, balancing its benefits and risks can be challenging. There have been reports of intraocular inflammation (IOI) in patients treated with brolucizumab, which, if left untreated, may result in severe vision loss. Recent evidence, however, indicates that early recognition of IOI and prompt and aggressive systemic corticosteroid treatment in response to posterior segment involvement can lead to favorable outcomes in these relatively rare but severe cases. A series of consensus meetings were conducted in 2022 between Swiss medical retina experts and diabetologists, discussing the current data for brolucizumab and exploring various challenges to its use, including the associated risk of IOI. The outcome is a collation of practical insights and guidance for ophthalmologists on the use of brolucizumab in patients with nAMD and DME, including patient selection and assessment, treatment regimen and monitoring, and the recognition and management of adverse events.

No obesity paradox in patients with community-acquired pneumonia - secondary analysis of a randomized controlled trial.

BACKGROUND: Obesity is associated with an increased risk for several chronic conditions and mortality. However, there are data in support of beneficial outcome in acute medical conditions such as community-acquired pneumonia (CAP), termed "obesity paradox". The aim of this study was to test the association of BMI with clinical outcomes in a large randomized clinical trial of patients hospitalized with CAP. DESIGN AND METHODS: In total, 773 patients hospitalized with CAP were included in this study. Patients were stratified into four groups according to their baseline BMI (underweight <18.5, normal weight 18.5-25, overweight 25-30, and obese >30 kg/m2). The primary endpoint was time to clinical stability (TTCS). Secondary endpoints included 30-day mortality, ICU admission rate, CAP complications, and duration of antibiotic treatment. RESULTS: BMI and TTCS had a U-shaped association with shortest TTCS among patients at an overweight BMI of 28 kg/m2. In patients with obesity, there was a trend towards reduced hazards to reach clinical stability when compared to patients with normal weight (HR 0.82; 95%CI, 0.67-1.02; p = 0.07). In underweight BMI group TTCS was prolonged by 1 day (HR 0.63; 95%CI, 0.45-0.89; p = 0.008). There was no difference in mortality or ICU admission rates between BMI groups (p > 0.05). While in the underweight BMI group the total duration of antibiotic treatment was prolonged by 2.5 days (95%CI, 0.88-4.20, p = 0.003), there was no difference in patients with obesity. CONCLUSIONS: The overweight BMI group had shortest time to clinical stability. While underweight patients face adverse clinical outcomes, there is neither beneficial, nor adverse outcome in patients with obesity hospitalized for CAP. CLINICALTRIALS: gov (registration no. NCT00973154).

Relevance of cortisol and copeptin blood concentration changes in an experimental pain model.

The effect of pain and analgesics on stress biomarkers is not well studied. We evaluated the effect of acute pain and analgesics on serum cortisol and copeptin in an experimental pain model in healthy volunteers. Healthy volunteers presented at 8 a.m. for an experimental pain stimulation. Cortisol and copeptin levels were measured before, during and after electrophysiological stimulation, first before and then during opioid delivery. Difference in biomarker levels compared to baseline levels was calculated, and potential influencing factors were evaluated by linear regression analysis. Cortisol decreased by 13% during the 10 min of rest at baseline, but copeptin did not change significantly. Cortisol had a median decrease of -24% or -83 nmol/l (-44 to -124 nmol/l, p = 0.0002) during the electrophysiological stimulation training session, while the median difference for copeptin was -22% or -1.01 pmol/l (-2.35 to 0.08 pmol/l, p = 0.0003). After administration of opioids, cortisol did not decrease but increased by 3% (p = 0.043), indicating an increasing opioids effect on cortisol. This effect was not visible for copeptin (median change -0.003 pmol/l (-0.50 to 0.24), p = 0.45). In this experimental pain model performed in the morning, moderate pain did not have a relevant effect on cortisol or copeptin levels, whereas opioids led to a discrete peak of cortisol.Clinicaltrials.gov identifier: NCT01975753 (registered on November 5, 2013, before start of recruitment).

Community-acquired pneumonia subgroups and differential response to corticosteroids: a secondary analysis of controlled studies.

BACKGROUND: Latent class analysis (LCA) has identified subgroups with meaningful treatment implications in acute respiratory distress syndrome. We performed a secondary analysis of three studies to assess whether LCA can identify clinically distinct subgroups in community-acquired pneumonia (CAP) and whether the treatment effect of adjunctive corticosteroids differs between subgroups. METHODS: LCA was performed on baseline clinical and biomarker data from the Ovidius trial (n=304) and the Steroids in Pneumonia (STEP) trial (n=727), both randomised controlled trials investigating adjunctive corticosteroid treatment in CAP, and the observational TripleP cohort (n=201). Analyses were conducted independently in two cohorts (Ovidius-TripleP combined and the STEP trial). In both cohorts, differences in clinical outcomes and response to adjunctive corticosteroid treatment were examined between subgroups identified through LCA. RESULTS: A two-class model fitted both cohorts best. Class 2 patients had more signs of systemic inflammation compared to class 1. In both cohorts, length of stay was longer and in-hospital mortality rate was higher in class 2. In the Ovidius trial, corticosteroids reduced the median length of stay in class 2 (6.5 versus 9.5 days) but not in class 1 (p-value for interaction=0.02). In the STEP trial, there was no significant interaction for length of stay. We found no significant interaction between class assignment and adjunctive corticosteroid treatment for secondary outcomes. CONCLUSIONS: In two independent cohorts, LCA identified two classes of CAP patients with different clinical characteristics and outcomes. Given the different response to adjunctive corticosteroids in the Ovidius trial, LCA might provide a useful basis to improve patient selection for future trials.

Glucose control after glucocorticoid administration in hospitalized patients - a retrospective analysis.

BACKGROUND: Glucocorticoid (GC)-induced hyperglycemia is a frequent adverse effect in hospitalized patients. Guidelines recommend insulin treatment to a target range of 6-10 mmol/L (108-180 mg/dl), but efficacies of particular regimes have not been well-studied. METHODS: In this retrospective cohort study, hospitalized patients receiving GCs at the medical ward were analyzed by treatment (basal-bolus vs. bolus-only vs. pre-mixed insulin) and compared to a non-insulin-therapy reference group. Coefficients of glucose variation (CV), percentage of glucose readings in range (4-10 mmol/L (72-180 mg/dl)) and hypoglycemia (< 4 mmol/L (< 72 mg/dl)) were evaluated. RESULTS: Of 2424 hospitalized patients receiving systemic GCs, 875 (36%) developed GC-induced hyperglycemia. 427 patients (17%) had a previous diagnosis of diabetes. Adjusted relative risk ratios (RRR) for the top tertile of CV (> 29%) were 1.47 (95% Cl 1.01-2.15) for bolus-only insulin, 4.77 (95% CI 2.67-8.51) for basal-bolus insulin, and 4.98 (95% CI 2.02-12.31) for premixed insulin, respectively. Adjusted RRR for percentages of glucose readings in range were 0.98 (95% Cl 0.97-0.99) for basal-bolus insulin, 0.99 (95% Cl 0.98-1.00) for premixed insulin, and 1.01 (95% Cl 1.00-1.01) for bolus-only insulin, respectively. Adjusted RRR for hypoglycemia was 13.17 (95% Cl 4.35-39.90) for basal-bolus insulin, 8.92 (95% Cl 2.60-30.63) for premixed insulin, and 2.99 (95% Cl 1.01-8.87) for bolus-only insulin, respectively. CONCLUSIONS: Current guidelines recommend a basal-bolus regimen for treatment of GC-induced hyperglycemia, but we found similar outcomes with pre-mixed and bolus-only insulin regimens. As GC-induced hyperglycemia is a frequent issue in hospitalized patients, it might be reasonable to prospectively study the ideal regimen.

Adrenal function testing in dialysis patients - a review of the literature.

BACKGROUND: Secondary adrenal insufficiency is a frequent issue in patients with renal replacement therapy. There are concerns about metabolism and clearance for adrenocorticotropic hormone (ACTH) and cortisol in addition to hemoconcentration as confounding factors during hemodialysis (HD). Therefore, ACTH testing is currently performed before or in between HD sessions. This review of the literature aims to evaluate the current evidence for validity of testing for adrenal insufficiency in patients on chronic renal replacement therapy. METHODS: A literature search of PubMed database for interventional and observational clinical trials was performed. Case reports and reviews were excluded. The search included all articles published until July 2020. RESULTS: Of 218 potentially eligible articles, 16 studies involving 381 participants were included. Seven studies performed an ACTH test before HD or in between HD sessions. There was no data available regarding ACTH testing during HD. But there was evidence of decreased cortisol levels during HD as compared to afterwards. All included 16 studies measured basal cortisol, and seven studies performed an ACTH test. Seven trials had comparable data of baseline cortisol for a quantitative analysis. Standardized mean difference of overall cortisol was 0.18 nmol/l (95%CI - 0.08 to 0.44) in the case group. CONCLUSIONS: In patients undergoing renal replacement therapy, basal serum cortisol values are comparable to healthy volunteers. There is limited data on the validity of stimulated cortisol in these patients, especially during HD. TRIAL REGISTRATION: Registration no. CRD42020199245 .