Administration Of Hydrocortisone Research Articles

Transcriptomic evidence for atopic dermatitis as a systemic disease in NC/Nga mice

BackgroundIn the current study, we evaluated whether atopic dermatitis (AD) affects the entire body rather than being limited to skin barrier damage and inflammation. We hypothesized that medium-term exposure of distant organs to systemic inflammatory cytokines in sub-chronic inflammatory skin diseases has detrimental effects on distant tissues.ResultsOur findings demonstrated the dysregulation of genes and pathways associated with inflammation and the skin barrier, as well as genes and pathways involved in muscle development that respond to chemicals or stress in muscle tissues, all of which were reversed by hydrocortisone (Hc) administration. The expression of Ces1d showed significant differences during disease onset and after treatment in both skin and skeletal muscle, suggesting that Ces1d is likely responsible for the alleviation of subchronic AD.ConclusionsUsing NC/Nga mice with AD-like symptoms, we compared the transcriptomes of the skeletal muscle (a tissue that is relatively distant from the skin) with those of the skin (the lesion induction site) before and after disease induction, after which Hc was administered. Although further study is needed to better understand the effects of Ces1d on AD, skeletal muscle was associated with AD pathogenesis, and AD-like symptoms appeared to affect the body in a systemic manner. Given the importance of evidence-based medicine and the development of precision medicine, our findings provide insights into the mechanisms of AD onset and progression.

Differential effects of oral versus intravenous hydrocortisone and dexamethasone on capillary blood glucose levels in adult inpatients – a single centre study

BackgroundCorticosteroids raise blood glucose concentrations; however, it remains unknown which form of administration, oral or intravenous, is associated with the greatest degree of blood glucose rise in hospitalised patients. Furthermore, whether the pattern of the associated hyperglycaemia throughout the day differs depending on the route of administration. MethodsThis was a single centre retrospective study of 384 adult inpatients receiving oral or intravenous hydrocortisone and dexamethasone. Data on capillary glucose concentrations and time taken over seven days were collected. A mixed model for repeated measures was applied to compare changes in glucose concentration over time for oral and intravenous corticosteroids. An auto-regressive covariance structure was employed to model correlations between repeated measurements. This was adjusted for age, sex, pre-admission diabetes, and/or pre-admission corticosteroid status. ResultsNo significant difference was found between oral and intravenous hydrocortisone on day one or across all seven days (Mean Difference 0.17mmol/l (-1.39, 1.75), p=0.827, and Mean Difference 0.20mmol/l (-0.61, 1.01), p=0.639 respectively). There were no differences in mean glucose concentrations between those on oral or intravenous dexamethasone on day one or across all seven days (Mean Difference 0.41mmol/l (-0.55,1.38), p=0.404 and Mean Difference -0.09mmol/l (-1.05,0.87), p=0.855respectively). ConclusionThis study found that oral and intravenous administration of hydrocortisone and dexamethasone, do not have a significantly differing impact on blood glucose levels. Capillary glucose monitoring is strongly recommended in all individuals who are on either oral or intravenous corticosteroids.

Effect of hydrocortisone on the course of leprosic infection in an experiment

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), accompanied by a violation of various parts of the immune system. In this regard, the development of an experimental model of leprosy may be based on the creation of an artificial defect of the macrophage link, in particular, using glucocorticoids. Aim: To develop and characterize a model of generalized leprosy infection in mice against the background of prolonged administration of hydrocortisone.Material and methods. To conduct the study, the following groups were formed: the control group – 50 mice infected by the Shepard method; the experimental group – 50 mice similarly infected against the background of hydrocortisone administration. Hydrocortisone was administered intramuscularly in a single daily dose of 25 mg/kg on the first day 2 hours before infection with M. leprae suspension, then in the form of four courses of 2 weeks at two-week intervals.Results. The administration of hydrocortisone led to an acceleration of the reproduction of mycobacteria in the paw pad compared with the control (without hydrocortisone). The generalization of leprosy infection is confirmed by the presence of lepromatous structures in the form of granulomas from macrophages with a high content of M. leprae in liver, spleen, lungs and kidneys.Conclusion. This model allows us to study the properties of the pathogen and the mechanisms of pathogenesis of the disease, and to screen pharmacological drugs with potential anti-leprosy activity in the future.

Rapid uptake of adjunctive corticosteroids for critically ill adults with septic shock following publication of ADRENAL trial. A multicenter, retrospective analysis of prescribing practices in Queensland Intensive Care Units

BackgroundSeptic shock is common and associated with significant morbidity and mortality. The ADRENAL trial examined the use of hydrocortisone in patients with septic shock, demonstrating no difference in patient-centred outcomes but a decrease in the time to shock resolution. The change in clinical practice related to the publication of the ADRENAL trial is currently unknown. MethodsA retrospective cohort study examining the use of hydrocortisone in patients with septic shock was conducted in 12 intensive care units (ICUs). A segmented linear regression was performed to identify a stepwise change in hydrocortisone administration and 90-day mortality associated with the publication of the ADRENAL trial. ResultsWe included 4,198 patients with a mean age of 58 years (standard deviation, SD17), and the median noradrenaline equivalent score (NEE) was 0.07 µg/kg/min (IQR 0.02 – 0.17). Segmented regression analysis for hydrocortisone administration identified two breakpoints, 3 months before and 6 months after publication, leading to three periods: Pre-publication, Transition and Post-publication. Compared to the pre-publication period, the Transition and Post-publication cohorts had a higher proportion of hydrocortisone administration (28% vs. 34% vs. 43%; p < 0.0001). Furthermore, after adjustment for temporal change, the transition period had a significant change in the slope of the proportion of patients receiving hydrocortisone (-0.1% per month vs. +1.4% per month; p = 0.026), whereas this was not statistically significant during the post-publication period (+0.1% per month, p = 0.66). After adjusting for confounders, the Transition and Post-publication periods were independently associated with an increase in hydrocortisone (OR 1.4, 95% CI 1.14 – 1.77; p = 0.0015 and OR 2.03; 95% CI 1.74 – 2.36; p < 0.001, respectively). Furthermore, after adjusting for confounders, when compared to the Pre-transition period, the use of hydrocortisone was associated with a statistically significant decrease in 90-day mortality (14% vs. 24% absolute difference, aHR for hydrocortisone effect -0.81; 95% CI 0.65 – 0.99; p = 0.044). ConclusionPublication of the ADRENAL trial changed clinical practice in Queensland ICUs with increased prescription of hydrocortisone for patients with septic shock with an associated reduction in mortality.

Pathophysiology of Hyponatremia in Preterm Infants with Relative Adrenal Insufficiency after the Early Neonatal Period.

Preterm infants often develop relative adrenal insufficiency (RAI) not only within the early neonatal period but also beyond this period. RAI is commonly accompanied by hyponatremia, but the pathogenesis of hyponatremia with RAI has not been clarified. This study aimed to investigate the pathophysiology of hyponatremia in infants with RAI. This is a single-centered retrospective cohort study. Preterm infants born at <30 weeks of gestation or birth weight <1,000 g were enrolled. They were divided into the RAI group and the non-RAI group. The data of serum and urine examination, the amount of sodium intake, and fractional excretion of sodium (FENa) were compared between the two groups. In the RAI group, data before and after the administration of hydrocortisone were also compared. Sixteen infants in the RAI group and 35 infants in the non-RAI group were included in the analysis. In the RAI group, hyponatremia was common and preceded other clinical symptoms, such as oliguria and decreased blood pressure, therefore, hyponatremia with RAI was not likely to be caused by dilution due to oliguria. There was no difference in the FENa between the two groups (adjusted for postconceptional age at examination), therefore, it is not likely that hyponatremia with RAI was mainly caused by excessive renal sodium loss. Since sodium intake was rather higher in the RAI group than in the non-RAI group, it is unlikely that insufficient sodium supplementation was the cause of RAI. Hyponatremia with RAI was considered to be likely caused by vascular hyperpermeability. Hyponatremia is a common symptom among preterm infants with RAI and its pathogenesis can be vascular hyperpermeability. · The pathogenesis of hyponatremia with RAI can be vascular hyperpermeability.. · Hyponatremia is common among preterm infants with RAI.. · Hyponatremia with RAI preceded other clinical symptoms..

High expression of L-GILZ transcript variant 1 (GILZ TV 1) is associated with increased 30-day sepsis mortality, and a high expression ratio possibly contraindicates hydrocortisone administration

BackgroundSepsis presents a challenge due to its complex immune responses, where balance between inflammation and anti-inflammation is critical for survival. Glucocorticoid-induced leucine zipper (GILZ) is key protein in achieving this balance, suppressing inflammation and mediating glucocorticoid response. This study aims to investigate GILZ transcript variants in sepsis patients and explore their potential for patient stratification and optimizing glucocorticoid therapy.MethodsSepsis patients meeting the criteria outlined in Sepsis-3 were enrolled, and RNA was isolated from whole blood samples. Quantitative mRNA expression of GILZ transcript variants in both sepsis patient samples (n = 121) and the monocytic U937 cell line (n = 3), treated with hydrocortisone and lipopolysaccharides, was assessed using quantitative PCR (qPCR).ResultsElevated expression of GILZ transcript variant 1 (GILZ TV 1) serves as a marker for heightened 30-day mortality in septic patients. Increased levels of GILZ TV 1 within the initial day of sepsis onset are associated with a 2.2-[95% CI 1.2–4.3] fold rise in mortality, escalating to an 8.5-[95% CI 2.0–36.4] fold increase by day eight. GILZ TV1 expression is enhanced by glucocorticoids in cell culture but remains unaffected by inflammatory stimuli such as LPS. In septic patients, GILZ TV 1 expression increases over the course of sepsis and in response to hydrocortisone treatment. Furthermore, a high expression ratio of transcript variant 1 relative to all GILZ mRNA TVs correlates with a 2.3-fold higher mortality rate in patients receiving hydrocortisone treatment.ConclusionHigh expression of GILZ TV 1 is associated with a higher 30-day sepsis mortality rate. Moreover, a high expression ratio of GILZ TV 1 relative to all GILZ transcript variants is a parameter for identifying patient subgroups in which hydrocortisone may be contraindicated.

Sheehan’s syndrome presenting with panhypopituitarism and central diabetes insipidus: a case report

BackgroundSheehan’s syndrome is a rare condition, which is classically characterized by anterior pituitary hypofunction following postpartum shock or hemorrhage. While diabetes insipidus (DI) is not commonly associated with Sheehan’s syndrome, we present a rare case of a multiparous female developing rapid-onset panhypopituitarism and DI following severe postpartum hemorrhage.Case presentationA previously healthy 39-year-old woman, gravida 5, para 4, presented with hypovolemic shock after vaginal delivery, attributed to severe postpartum hemorrhage, necessitating emergent hysterectomy. Although her shock episodes resolved during hospitalization, she developed intermittent fever, later diagnosed as adrenal insufficiency. Administration of hydrocortisone effectively resolved the fever. However, she subsequently developed diabetes insipidus. Diagnosis of Sheehan’s syndrome with central diabetes insipidus was confirmed through functional hormonal tests and MRI findings. Treatment consisted of hormone replacement therapy, with persistent panhypopituitarism noted during a ten-year follow-up period.ConclusionsSheehan’s syndrome is a rare complication of postpartum hemorrhage. Central diabetes insipidus should be suspected, although not commonly, while the patient presented polyuria and polydipsia. Besides, the potential necessity for long-term hormonal replacement therapy should be considered.

Transcriptomic and Epigenomic Responses to Cortisol-Mediated Stress in Rainbow Trout (Oncorhynchus mykiss) Skeletal Muscle.

The production and release of cortisol during stress responses are key regulators of growth in teleosts. Understanding the molecular responses to cortisol is crucial for the sustainable farming of rainbow trout (Oncorhynchus mykiss) and other salmonid species. While several studies have explored the genomic and non-genomic impacts of cortisol on fish growth and skeletal muscle development, the long-term effects driven by epigenetic mechanisms, such as cortisol-induced DNA methylation, remain unexplored. In this study, we analyzed the transcriptome and genome-wide DNA methylation in the skeletal muscle of rainbow trout seven days after cortisol administration. We identified 550 differentially expressed genes (DEGs) by RNA-seq and 9059 differentially methylated genes (DMGs) via whole-genome bisulfite sequencing (WGBS) analysis. KEGG enrichment analysis showed that cortisol modulates the differential expression of genes associated with nucleotide metabolism, ECM-receptor interaction, and the regulation of actin cytoskeleton pathways. Similarly, cortisol induced the differential methylation of genes associated with focal adhesion, adrenergic signaling in cardiomyocytes, and Wnt signaling. Through integrative analyses, we determined that 126 genes showed a negative correlation between up-regulated expression and down-regulated methylation. KEGG enrichment analysis of these genes indicated participation in ECM-receptor interaction, regulation of actin cytoskeleton, and focal adhesion. Using RT-qPCR, we confirmed the differential expression of lamb3, itga6, limk2, itgb4, capn2, and thbs1. This study revealed for the first time the molecular responses of skeletal muscle to cortisol at the transcriptomic and whole-genome DNA methylation levels in rainbow trout.

A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy.

Congenital adrenal hyperplasia (CAH) is characterized by impaired adrenal cortisol production. Hydrocortisone (synthetic cortisol) is the drug-of-choice for cortisol replacement therapy, aiming to mimic physiological cortisol circadian rhythm. The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through the pituitary adrenocorticotropic hormone (ACTH) and feedback mechanisms. The aim of this study was to quantify key mechanisms involved in the HPA axis activity regulation and their interaction with hydrocortisone therapy. Data from 30 healthy volunteers was leveraged: Endogenous ACTH and cortisol concentrations without any intervention as well as cortisol concentrations measured after dexamethasone suppression and single dose administration of (i) 0.5-10mg hydrocortisone as granules, (ii) 20mg hydrocortisone as granules and intravenous bolus. A stepwise model development workflow was used: A newly developed model for endogenous ACTH and cortisol was merged with a refined hydrocortisone pharmacokinetic model. The joint model was used to simulate ACTH and cortisol trajectories in CAH patients with varying degrees of enzyme deficiency, with or without hydrocortisone administration, and healthy individuals. Time-dependent ACTH-driven endogenous cortisol production and cortisol-mediated feedback inhibition of ACTH secretion processes were quantified and implemented in the model. Comparison of simulated ACTH and cortisol trajectories between CAH patients and healthy individuals showed the importance of administering hydrocortisone before morning ACTH secretion peak time to suppress ACTH overproduction observed in untreated CAH patients. The developed framework allowed to gain insights on the physiological mechanisms of the HPA axis regulation, its perturbations in CAH and interaction with hydrocortisone administration, paving the way towards cortisol replacement therapy optimization.

An Evaluative Comparison of Continuous Versus Intermittent Hydrocortisone Administration in the Therapeutic Approach to Septic Shock

An Evaluative Comparison of Continuous Versus Intermittent Hydrocortisone Administration in the Therapeutic Approach to Septic Shock

Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

Early intravenous hydrocortisone in sepsis: A randomized control trial (Protocol)

Background: The evidence of the appropriate timing of hydrocortisone is still weak and controversial. Observational studies showed a trend towards greater benefits when hydrocortisone was given earlier in the course of septic shock resuscitation. This study evaluates the effects of early intravenous low-dose hydrocortisone administered at the beginning of the onset of sepsis-induced hypotension compared with standard care. Methods: This study is a single-center, parallel-group, double-blinded, randomized control trial, conducted in a non-trauma emergency department. Adult patients with sepsis-induced hypotension will be included. Patients will be randomly assigned in a 1:1 ratio to receive early intravenous low-dose hydrocortisone or standard care. Blood inflammatory biomarkers at baseline will be collected. The primary outcome is 28-day mortality. Resuscitation-related secondary outcomes and safety outcomes will also be observed. Outcomes will be compared between groups. Subgroup analyses considering inflammatory biomarker levels will also be performed to evaluate the effect of early intravenous hydrocortisone, especially in patients with hyperinflammation. Hypothesis: We hypothesize that early intravenous low-dose hydrocortisone administration in patients with sepsis-induced hypotension would result in less mortality and improve resuscitation outcomes, especially in subgroup of patients with hyperinflammation. Ethics and dissemination: The study protocol was approved by the Siriraj Institutional Review Board with the certificate of approval number Si 917/2023. Trial registration: Clinicaltrial.gov NCT06217939

Comparative development of human filariae Loa loa, Onchocerca volvulus and Mansonella perstans in immunocompromised mouse strains.

Mouse models of human filarial infections are not only urgently needed to investigate the biology of the nematodes and their modulation of the host's immunity, but will also provide a platform to screen and test novel anti-filarial drugs. Recently, murine Loa loa infection models have been stablished using immunocompromised mouse strains, whereas murine Mansonella perstans infections have not been implemented until now. Therefore, we aim to establish experimental M. perstans infections using the immunocompromised mouse strains RAG2IL-2Rγ-/- (lack B, T and natural killer cells), IL-4Rα/IL-5-/- (impaired IL-4/5 signalling and eosinophil activation) and NOD.Cg-PrkdcscidIl2rgtm1Wj l/SzJ (NOD scid gamma, NSG) BALB/c mice (lack mature lymphocytes) through subcutaneous (s.c.) or intraperitoneal (i.p.) inoculation of infective stage 3 larvae (L3) isolated from engorged vectors. In total, 145 immunocompromised mice have been inoculated with 3,250 M. perstans, 3,337 O. volvulus, and 2,720 Loa loa L3 to comparatively analyse which immunocompromised mouse strain is susceptible to human filarial infections. Whereas, no M. perstans and O. volvulus L3 could be recovered upon 2-63 days post-inoculation, a 62-66% Loa loa L3 recovery rate could be achieved in the different mouse strains. Gender of mice, type of inoculation (s.c. or i.p.) or time point of analysis (2-63 days post inoculation) did not interfere with the success of L3 recovery. In addition, administration of the immune suppressants hydrocortisone, prednisolone and cyclophosphamide did not restore M. perstans L3 recovery rates. These findings show that RAG2IL-2Rg-/-BALB/c and C57BL/6, IL-4Rα/IL-5-/- BALB/c and NSG mice were not susceptible to M. perstans and O. volvulus L3 inoculation using the applied methods, whereas Loa loa infection could be maintained. Further studies should investigate if humanized immunocompromised mice might be susceptible to M. perstans. and O. volvulus.

A case report of Paliperidone palmitate-induced anaphylaxis

IntroductionPaliperidone Palmitate (PP) is an atypical antipsychotic, approved by the FDA for acute and maintenance treatment of schizophrenia and schizoaffective disorder.It has a relatively safety profile, and reported cases of paliperidone palmitate-induced angioedema or anaphylaxis are uncommon.ObjectivesWe intend to present a case of paliperidone palmitate-induced anaphylaxis to alert clinicians regarding this rare, but possible complication.MethodsNon-systematic review of the literature and report of a case study.ResultsLong-acting injectable Paliperidone Palmitate (LAIPP) is a safe and effective alternative to oral Paliperidone, with less incidence of disease relapse related to medication non-compliance.Substance use disorder (SUD) is highly prevalent in first-episode psychosis (FEP), and it is associated to decreased treatment compliance, which impairs the outcomes of these patients. Therefore, several authors have been recommended long-acting injectable antipsychotics (LAI-AP), such the LAIPP, as a first line for treatment of FEP-SUD patients.The most common side effects associated with LAIPP are injection site reactions, extrapyramidal symptoms, hyperprolactinemia, sedation, hypersalivation, orthostatic hypotension, tachycardia, and weight gain. Hypersensitivity reactions have rarely been reported and may be dose-dependent.We report a case of a 20-year-old female, without medical history and no history of allergies, who was medicated with once-monthly LAIPP at dose 100 mg for the maintenance treatment of a first psychotic episode associated with cannabis abuse.Approximately 24 hours after the first monthly injection dose, she was admitted in the emergency room (ER) presenting an increasing angioedema associated with stridor, requiring endotracheal intubation and administration of adrenaline, clemastine and hydrocortisone during the assessment in the ER.After clinical stabilization, she was transferred to the internal medicine ward, and following a full recovery, she was discharged 6 days later while being medicated with Olanzapine 15 mg/day, Lorazepam 3 mg/day and Sertraline 50 mg/day. LAIPP was suspected as the etiology of the anaphylaxis reaction due to temporal relationship of its onset with therapy administration and by the exclusion of other potential causes. Consequently, LAIPP was discontinued at discharge.ConclusionsThis report shows the possibility of a late and potentially life-threatening anaphylactic reaction to LAIPP. So, all physicians should be aware of this potential complication, which requires timely recognition and management.Disclosure of InterestNone Declared

Impaired free recall of neutral but not negative material tested 105 min after cortisol administration

Pharmacological studies have consistently shown memory retrieval impairment after administration of cortisol, particularly pronounced for emotional laboratory material (i.e. list of emotional words). However, it is unclear how pharmacological elevation of cortisol affects memory retrieval of ecologically-relevant emotional material (i.e. similar to a newspaper article about an emotional event). In the present study, we aimed to explore whether cortisol administration affects the recall of ecologically-relevant emotional and neutral material, and when memory retrieval occurs after a longer delay (105 min). In this double-blind, pseudo-randomized, placebo-control study, 79 participants learned a negative text and a neutral text. Twenty-four hours later, they were administrated either 10 mg of hydrocortisone or placebo. After 105 min, participants engaged in free recall of both texts. The group with cortisol administration showed significantly reduced free recall compared to the placebo group. Interestingly, this memory retrieval impairment was driven by significantly lower recall after cortisol vs. placebo administration for neutral texts, but not negative texts. The current finding suggests that cortisol administration impairs neutral ecologically-relevant material while leaving emotional material unaffected. These divergent findings, compared to existing literature, emphasize the necessity of employing more ecologically validated material to gain a more comprehensive understanding of the intricate interplay between cortisol administration and memory for ecological material.

Composite adverse events compared early versus conventional cessation of hydrocortisone in patients with septic shock: Randomized-controlled trial (The CESSHYDRO study)

Background: Intravenous hydrocortisone has benefits in the treatment of septic shock patients, but there are adverse events mentioned in the secondary outcomes of several studies, such as hyperglycemia, hypernatremia, secondary infection, and muscle weakness. In addition, there are no recommendations regarding the precise duration and steps to discontinue hydrocortisone administration. The CESSHYDRO trial evaluates the adverse outcomes of intravenous hydrocortisone between early cessation versus conventional cessation of hydrocortisone in septic shock patients. Methods: The CESSHYDRO trial is a single-center, double-blind, randomized controlled clinical trial conducted at Siriraj Hospital. One hundred and eighty septic shock patients receiving vasopressors and hydrocortisone at least 200 mg/day with hemodynamic stability will be included. The patients are randomized into 2 groups: intervention A (early cessation of hydrocortisone) and intervention B (conventional cessation). The primary outcomes were composite adverse events, including hyperglycemia, hypernatremia, muscle weakness, and new infections. Hypothesis: We hypothesize that early cessation of hydrocortisone in patients with septic shock would reduce composite adverse events including hyperglycemia, hypernatremia, muscle weakness, and the new onset of infection. Ethics and dissemination: The trial receives ethical approval from Siriraj Hospital, Mahidol University (COA No.SI012/2023). Trial registration: ClinicalTrials.govNCT05818826. Registered on April 19, 2023.

Alkindi Sprinkle for Pediatric Patients With Primary Adrenocortical Insufficiency: A Narrative Review.

Adrenocortical insufficiency, also known as adrenal insufficiency (AI), is an endocrine disorder characterized by inadequate production of adrenal hormones, including glucocorticoids and mineralocorticoids (MCs). The condition can be categorized as primary, secondary, or tertiary AI, depending on the location of the defect. Classical symptoms of AI include weakness, fatigue, abdominal pain, tachycardia, hypotension, electrolyte imbalances, and hyperpigmentation. In children, the most common cause of AI is classical congenital adrenal hyperplasia, which results from a deficiency in the 21-hydroxylase enzyme. The 21-hydroxylase enzyme produces all steroids, such as cortisol and aldosterone. AI management primarily involves hormone replacement therapy, typically with oral hydrocortisone and MC supplementation. However, the administration of hydrocortisone to pediatric patients presents challenges related to the lack of available dose-appropriate formulations. Historically, crushed or split adult tablets were used for the pediatric treatment of AI, although this poses an increased risk of under- or overtreatment. Inadequate dosing in the pediatric population can adversely affect growth, development, and metabolic health. Alkindi Sprinkle is a pediatric-specific hydrocortisone oral granule preparation that manages cortisol levels to help facilitate accurate therapeutic dosing. Alkindi offers several advantages, including accurate dosing, taste masking, and ease of administration. The present investigation describes AI, the management of AI, and the treatment of pediatric AI using Alkindi Sprinkle, including clinical efficacy.

Diagnosis and management of secondary adrenal crisis.

Adrenal crisis (AC) is a life threatening acute adrenal insufficiency (AI) episode which can occur in patients with primary AI but also secondary AI (SAI), tertiary AI (TAI) and iatrogenic AI (IAI). In SAI, TAI and IAI, AC may develop when the HPA axis is unable to mount an adequate glucocorticoid response to severe stress due to pituitary or hypothalamic disruption. It manifests as an acute deterioration in multi-organ homeostasis that, if untreated, leads to shock and death. Despite the availability of effective preventive strategies, its prevalence is increasing in patients with SAI, TAI and IAI due to more frequent exogenous steroid administration, pituitary immune-related effects of immune checkpoint inhibitors and opioid use in pain management. The delayed diagnosis of acute AI which remains infrequently suspected increases the risk of AC. Its main precipitating factors are infections, emotional distress, surgery, cessation or reduction in GC doses, pituitary infarction or surgical cure of endogenous Cushing's syndrome. In patients not known previously to have SAI/TAI/IAI, recognition of its symptoms, signs, and biochemical abnormalities can be challenging and cause delay in proper diagnosis and therapy. Effective therapy of AC is rapid intravenous administration of hydrocortisone (initial bolus of 100mg followed by 200mg/24h as continuous infusion or bolus of 50mg every 6h) and 0.9% saline. In diagnosed patients, preventive education in sick-day rules adjustment of glucocorticoid replacement and hydrocortisone parenteral self-administration must be performed repeatedly by trained health care providers. Strategies to improve the adequate preventive education in patients at risk for secondary AI should be promoted in collaboration with various medical specialist societies and patients support associations.

Effects of cortisol administration on heart rate variability and functional connectivity across women with different depression histories

Abnormalities within the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system have been implicated in depression. Studies have reported glucocorticoid insensitivity and reduced heart rate variability (HRV) in depressive disorders. However, little is known about the effects of cortisol on HRV and resting-state functional connectivity (rsFC) of the central autonomic network (CAN) in depression. We collected resting-state fMRI and cardiac data for women with different depression histories (n = 61) after administration of cortisol and placebo using a double-blind crossover design. We computed rsFC for R-amygdala and L-amygdala seeds and assessed the change in HRV after cortisol (cortisol-placebo). Analyses examined the effects of acute cortisol administration on HRV and rsFC of the R-amygdala and L-amygdala. There was a significant interaction between HRV and treatment for rsFC between the amygdala and CAN regions. We found lower rsFC between the L-amygdala and putamen for those with a greater decrease in HRV after cortisol. There was also reduced rsFC between the R-amygdala and dorsomedial prefrontal cortex, putamen, middle cingulate cortex, insula, and cerebellum in those with lower HRV after cortisol. These results remained significant after adjusting for depression symptoms, age, and race. Our findings suggest that the effect of cortisol on CAN connectivity is related to its effects on HRV. Overall, these results could inform transdiagnostic interventions targeting HRV and the stress response systems across clinical and non-clinical populations.

Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial

Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.