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Patients with salt‐wasting congenital adrenal hyperplasia (SW‐CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW‐CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW‐CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW‐CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy. [ABSTRACT FROM AUTHOR]

Background: The combination of intravenous hydrocortisone and enteral fludrocortisone may reduce mortality in patients with septic shock. The optimal dose and reliability of absorption of fludrocortisone in critically ill patients are unclear. Methods: In a multi-centre, open label, phase II randomized clinical trial, intravenous hydrocortisone alone or in combination with one of three doses of enteral fludrocortisone (50 µg, 100 µg or 200 µg daily) for 7 days was compared in patients with septic shock. The primary outcome was time to shock resolution. We conducted pharmacokinetic studies to assess absorption. Results: Out of 153 enrolled patients, 38 (25%) received hydrocortisone alone, 42 (27%) received additional 50 µg, 36 (24%) received 100 µg and 37 (24%) received 200 µg fludrocortisone. Plasma concentrations of fludrocortisone were detected in 97% of patients at 3 h-median (interquartile range [IQR]) 261 (156–334) ng/L. There was no significant difference in the time to shock resolution between groups with median (IQR) of 3 (2.5–4.5), 3 (2–4), 3 (2–6) and 3 (2–5.5) days in the hydrocortisone alone, 50 µg, 100 µg and 200 µg fludrocortisone groups, respectively. The corresponding 28-day mortality rates were 9/38 (24%), 7/42 (17%), 4/36 (11%) and 4/37 (11%), respectively. There were no significant differences between groups with respect to, recurrence of shock, indices of organ failure or other secondary outcomes. Conclusions: Enteral fludrocortisone resulted in detectable plasma fludrocortisone concentrations in the majority of critically ill patients with septic shock, although they varied widely indicating differing absorption and bioavailability. Its addition to hydrocortisone was not associated with shorter time to shock resolution. [ABSTRACT FROM AUTHOR]

Background & Aims: This study investigated the effect of fludrocortisone treatment on the expression of genes and proteins involved in the implantation process in mice. Materials & Methods: The study involved four groups of mice, and mRNA and protein expression were measured using real-time PCR and western blotting. Results: The results showed that fludrocortisone treatment slightly downregulated the expression of SGK1, ENaC-α, miR-145, and miR-200a, while slightly upregulating the expression of HAND2, miR-451, mTOR, and 4E-BP1 in the endometrial epithelium. mTOR kinase inhibitor PP242 treatment resulted in the upregulation of miR-145 and miR-200a, while partially downregulating the expression of p-4E-BP1, mTOR, SGK1, ENaC-α, HAND2, and miR-451 expression. Combination therapy of fludrocortisone and PP242 resulted in slightly decreased expression of ENaC, SGK1, miR-200a, miR-145, and 4E-BP1, while slightly upregulating the expression of miR-451 and HAND2 in the epithelial endometrium. Conclusion: The findings indicated that fludrocortisone did not disrupt endometrial receptivity and may even enhance it by modulating gene expression through the activation of the mTOR signaling pathway. Overall, the study suggests that fludrocortisone treatment can modulate the expression of genes and proteins involved in the implantation process in mice. The activation of the mTOR signaling pathway was also increased during the treatment. The findings indicate that fludrocortisone may increase endometrial receptivity without disrupting it, which could have implications for fertility treatment.

OBJECTIVES: This systematic review and Bayesian network meta-analysis evaluated the efficacy and safety of hydrocortisone combined with fludrocortisone or hydrocortisone alone, compared with placebo in adult patients with septic shock. DATA SOURCES: By extending a prior Cochrane review, databases, including PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov, along with other relevant websites, were searched until August 31, 2023. STUDY SELECTION: Randomized controlled trials (RCTs) and observational studies using target trial emulation were included. DATA EXTRACTION: The primary outcome was short-term mortality with an emphasis on 28- or 30-day mortality as the main measure and in-hospital or ICU mortality as the nearest surrogate of this measure. Three of the most common adverse events, namely, gastroduodenal bleeding, superinfection, and hyperglycemia, were also considered. DATA SYNTHESIS: A total of 19 studies involving 95,841 patients were included. Hydrocortisone plus fludrocortisone showed the lowest short-term mortality versus placebo (odds ratio [OR]: 0.79; 95% credible interval [CrI], 0.64-0.99; number needed to treat [NNT]: 21, range: 12-500; low certainty of evidence) in terms of informative priors. The surface under the cumulative ranking curve values for hydrocortisone plus fludrocortisone, hydrocortisone alone, and placebo were 0.9469, 0.4542, and 0.0989, respectively. Consistent results were observed in RCTs alone and those using a daily 200-mg dose of hydrocortisone. Although gastroduodenal bleeding or superinfection showed no clear increase, hyperglycemia risk increased. The ORs were 0.53 for placebo versus hydrocortisone plus fludrocortisone and 0.64 for placebo versus hydrocortisone alone, with very low certainty of evidence. CONCLUSIONS: In adults with septic shock, hydrocortisone plus fludrocortisone improved short-term survival with minimal adverse events compared with hydrocortisone alone or placebo. However, these findings are not definitive due to the limited certainty of evidence and wide NNT range. Additional large-scale, placebo-controlled RCTs are needed to provide conclusive evidence. [ABSTRACT FROM AUTHOR]

The article titled "Should Fludrocortisone be Added to Hydrocortisone in Septic Shock? Probably Yes, Based on Available Evidence" discusses the potential benefits of adding fludrocortisone to hydrocortisone in the treatment of septic shock. The authors argue that a targetable endophenotype must first be defined in order to improve outcomes in the right population. They reference several studies and meta-analyses to support their argument, highlighting the importance of Bayesian methods and the synthesis of randomized and non-randomized evidence. The article also explores the immune effects of corticosteroids in sepsis and the biochemical and molecular perspective of glucocorticoids with or without fludrocortisone in septic shock. [Extracted from the article]

The term non-cardiac syncope includes all forms of syncope, in which primary intrinsic cardiac mechanism and non-syncopal transient loss of consciousness can be ruled out. Reflex syncope and orthostatic hypotension are the most frequent aetiologies of non-cardiac syncope. As no specific therapy is effective for all types of non-cardiac syncope, identifying the underlying haemodynamic mechanism is the essential prerequisite for an effective personalized therapy and prevention of syncope recurrences. Indeed, choice of appropriate therapy and its efficacy are largely determined by the syncope mechanism rather than its aetiology and clinical presentation. The two main haemodynamic phenomena leading to non-cardiac syncope include either profound hypotension or extrinsic asystole/pronounced bradycardia, corresponding to two different haemodynamic syncope phenotypes, the hypotensive and bradycardic phenotypes. The choice of therapy—aimed at counteracting hypotension or bradycardia—depends on the given phenotype. Discontinuation of blood pressure–lowering drugs, elastic garments, and blood pressure–elevating agents such as fludrocortisone and midodrine are the most effective therapies in patients with hypotensive phenotype. Cardiac pacing, cardioneuroablation, and drugs preventing bradycardia such as theophylline are the most effective therapies in patients with bradycardic phenotype of extrinsic cause. [ABSTRACT FROM AUTHOR]

Children with salt-wasting adrenal insufficiency are managed with glucocorticoid and mineralocorticoid replacement. Measurement of renin activity or concentration alongside blood electrolyte levels is used to monitor the adequacy of mineralocorticoid replacement. Our unit changed from using renin activity to renin concentration and carried out a service review to assess whether this influenced decision-making for fludrocortisone dosing. In total, 50 measurements of plasma renin activity and 50 of renin concentration were analysed on separate cohorts before and after the assay change, with values standardised to multiples of the upper limit of normal (MoU) to allow comparison between assays. We were more likely to increase the fludrocortisone dose for a raised renin concentration than a raised renin activity. The renin concentration MoU was more strongly related to plasma sodium (negatively) and 17α-hydroxyprogesterone (17α-OHP) (positively) than the renin activity MoU. Using a MoU cut-off of 1.5, a decision to increase the dose of fludrocortisone was more likely to be made when using the renin concentration assay compared with the activity assay. Using a cut-off of 40 nmol/L for 17α-OHP, a decision not to change the fludrocortisone dose when 17α-OHP was

Hyporeninemic hypoaldosteronism has been reported in only a few cases with methylmalonic acidemia (MMA) and has been attributed to the renal involvement. This study aims to investigate renin-aldosterone levels along with the renal functions of the patients with organic acidemia. This is a cross-sectional study conducted in patients with MMA, propionic acidemia (PA), and isovaleric acidemia (IVA). Serum renin, aldosterone, sodium, and potassium levels were measured, and glomerular filtration rates (GFR) were calculated. Comparisons were made between the MMA and non-MMA (PA+IVA) groups. Thirty-two patients (MMA:PA:IVA = 14:13:5) were included. The median GFR was significantly lower in the MMA group than in the non-MMA group (p < 0.001). MMA patients had the highest incidence of kidney damage (71.4%), followed by PA patients (23%), while none of the IVA patients had reduced GFR. GFR positively correlated with renin levels (p = 0.015, r = 0.433). Although renin levels were significantly lower in the MMA group than the non-MMA group (p = 0.026), no significant difference in aldosterone levels was found between the two groups. Hyporeninemic hypoaldosteronism was found in 3 patients with MMA who had different stages of kidney damage, and fludrocortisone was initiated, which normalized serum sodium and potassium levels. Conclusions: This study, which has the largest number of patients among the studies investigating the renin-angiotensin system in organic acidemias to date, has demonstrated that hyporeninemic hypoaldosteronism is not a rare entity in the etiology of hyperkalemia in patients with MMA, and the use of fludrocortisone is an effective treatment of choice in selected cases. What is Known: • Hyperkalemia may be observed in cases of methylmalonic acidemia due to renal involvement and can be particularly prominent during metabolic decompensation. • Hyporeninemic hypoaldosteronism has been reported to be associated with hyperkalemia in only a few cases of methylmalonic acidemia. What is New: • Hyporeninemic hypoaldosteronism was found in one-fifth of cases with methylmalonic acidemia. • Fludrocortisone therapy leads to the normalization of serum sodium and potassium levels. [ABSTRACT FROM AUTHOR]

Background: Trials evaluating hydrocortisone (HC) for septic shock are conflicting with all finding decreased time to shock reversal but few with mortality difference. Those with improved mortality included fludrocortisone (FC), but it is unknown if FC affected the outcome or is coincidental as there are no comparative data. Objective: The objective of this study was to determine the effectiveness and safety of FC + HC versus HC alone as adjunctive therapy in septic shock. Methods: A single-center, retrospective cohort study was conducted of medical intensive care unit (ICU) patients with septic shock refractory to fluids and vasopressors. Patients receiving FC + HC were compared with those receiving HC. Primary outcome was time to shock reversal. Secondary outcomes included in-hospital, 28-, and 90-day mortality; ICU and hospital length of stay (LOS); and safety. Results: There were 251 patients included (FC + HC, n = 114 vs HC, n = 137). There was no difference in time to shock reversal (65.2 vs 71 hours; P = 0.24). Cox proportional hazards model showed time to first corticosteroid dose, full-dose HC duration, and use of FC + HC were associated with shorter shock duration, while time to vasopressor therapy was not. However, in 2 multivariable models controlling for covariates, use of FC + HC was not an independent predictor of shock reversal at greater than 72 hours and in-hospital mortality. No differences were seen in hospital LOS or mortality. Hyperglycemia occurred more frequently with FC + HC (62.3% vs 45.6%; P = 0.01). Conclusion and Relevance: FC + HC was not associated with shock reversal at greater than 72 hours or decreased in-hospital mortality. These data may be useful for determining corticosteroid regimen in patients with septic shock refractory to fluids and vasopressors. Future prospective, randomized studies are needed to further evaluate the role of FC in this patient population. [ABSTRACT FROM AUTHOR]

Background: The standard treatment for congenital adrenal hyperplasia (CAH) in children is still hydrocortisone. Improved strategies for timing of the dose during the day and the dose per square meter body surface area used in children of different ages and developmental phases have improved the situation and outcome for the patients. Neonatal screening enables an earlier diagnosis and initiation of treatment, prevents from adrenal crisis, and improves growth and development also for children with the less severe forms of CAH. Summary: This review describes the current treatment strategies for children with CAH and discusses some potential treatment options that have been developed with the primary aim to decrease the adrenal androgen production. Novel modified release glucocorticoid therapies are also discussed. Key Messages: The long-term effects of the new adjunct therapies are unknown, and some are not suitable for use in children and adolescents. The effects of the new therapies on bone mineral density, gonadal functions, and long-term cognitive development are yet to be assessed. It is not known what levels of adrenal androgens are optimal for normal growth, puberty, and bone health. The basis of using glucocorticoids and mineralocorticoids in the treatment of CAH remains, and in some individuals, it may be beneficial to add therapies to reduce the androgen load during certain life stages. [ABSTRACT FROM AUTHOR]

Sasigarn A Bowden Division of Endocrinology, Department of Pediatrics, Nationwide Children’s Hospital/The Ohio State University College of Medicine, Columbus, OH, USACorrespondence: Sasigarn A Bowden, Nationwide Children’s Hospital, Division of Endocrinology, 700 Children’s Drive, Columbus, OH, 43205, USA, Tel +1 614-722-4118, Fax +1 614-722-4440, Email sasigarn.bowden@nationwidechildrens.orgAbstract: Adrenal insufficiency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deficiency, or by suppression of hypothalamic-pituitary-adrenal axis due to exogenous glucocorticoids. Diagnosis of adrenal insufficiency is usually delayed because the initial presentation is often subtle and nonspecific. Clinician awareness and recognition is crucial for timely diagnosis to avoid adrenal crisis. Current screening strategies for the diagnosis of adrenal insufficiency in children in various clinical situations are discussed in this review.Keywords: adrenal gland, adrenal insufficiency, cortisol, glucocorticoids, hydrocortisone, fludrocortisone, adrenocorticotrophic hormone, aldosterone, renin

IntroductionThe benefits and risks of low-dose hydrocortisone in patients with septic shock have been investigated in numerous randomised controlled trials and trial-level meta-analyses. Yet, the routine use of this treatment remains controversial. To overcome the limitations of previous meta-analyses inherent to the use of aggregate data, we will perform an individual patient data meta-analysis (IPDMA) on the effect of hydrocortisone with or without fludrocortisone compared with placebo or usual care on 90-day mortality and other outcomes in patients with septic shock.Methods and analysisTo assess the benefits and risks of hydrocortisone, with or without fludrocortisone for adults with septic shock, we will search major electronic databases from inception to September 2020 (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Latin American Caribbean Health Sciences Literature), complimented by a search for unpublished trials. The primary analysis will compare hydrocortisone with or without fludrocortisone to placebo or no treatment in adult patients with septic shock. Secondary analyses will compare hydrocortisone to placebo (or usual care), hydrocortisone plus fludrocortisone to placebo (or usual care), and hydrocortisone versus hydrocortisone plus fludrocortisone. The primary outcome will be all cause mortality at 90 days. We will conduct both one-stage IPDMA using mixed-effect models and machine learning with targeted maximum likelihood analyses. We will assess the risk of bias related to unshared data and related to the quality of individual trial.Ethics and disseminationThis IPDMA will use existing data from completed randomised clinical trials and will comply with the ethical and regulatory requirements regarding data sharing for each of the component trials. The findings of this study will be submitted for publication in a peer-review journal with straightforward policy for open access.Prospero registration numberCRD42017062198.

Background: Adrenal metastasis is the most common adrenal malignancy and can be bilateral in up to 43% of patients. Radiotherapy (RT) is one option available to treat adrenal metastases. The risk of primary adrenal insufficiency (PAI) after adrenal RT is unclear. Objective: Determine the incidence and the timeline of PAI in patients undergoing adrenal RT. Design, Setting and Participants: Single‐centre longitudinal retrospective cohort study of adult patients with adrenal metastases treated with RT between 2010 and 2021. Results: Of 56 patients with adrenal metastases treated with adrenal RT, eight (14.3%) patients developed PAI at a median of 6.1 months (interquartile range [IQR]: 3.9–13.8) after RT All patients developing PAI had either unilateral RT in the setting of contralateral adrenalectomy or bilateral adrenal RT. Patients who developed PAI received a median RT dose of 50 Gy (IQR: 44–50 Gy), administered in a median of five fractions (IQR: 5–6). Treated metastases decreased in size and/or metabolic activity on positron emission tomography in seven patients (87.5%). Patients were initiated on hydrocortisone (median daily dose of 20 mg, IQR: 18–40) and fludrocortisone (median daily dose of 0.05 mg, IQR: 0.05–0.05 mg). At the end of the study period, five patients died, all due to extra‐adrenal malignancy, at a median time of 19.7 months (IQR: 16–21.1 months) since RT and median time of 7.7 months (IQR: 2.9–12.5 months) since the diagnosis of PAI. Conclusion: Patients receiving unilateral adrenal RT with two intact adrenal glands have a low risk of PAI. Patients receiving bilateral adrenal RT have a high risk of PAI and require close monitoring. [ABSTRACT FROM AUTHOR]

Simple Summary: Cerebral salt wasting syndrome is defined as a hyponatremic condition due to sodium loss through the kidney during intracranial disorders. A 12-year-old spayed female domestic shorthair cat was referred to our referral animal hospital with tetraplegia and a history of hyponatremia with dehydration from a local hospital after intravenous fluid treatment. The cat was suspected to have intracranial disease after a thorough physical and neurologic examination. MRI revealed bilateral parietal lobe cerebrocortical gray-white matter junction T2/Flair high signal related to rapid electrolyte calibration, and C2 spinal cord ventral area T2 high signal indicated ischemic myelopathy. After 2 days, the cat revisited our hospital with severe lethargy and anorexia. Laboratory examination revealed hyponatremia (136 mEq/L) with dehydration. Through history-taking, laboratory examination, imaging, and fluid therapeutic response, the cerebral salt wasting syndrome was tentatively diagnosed. Electrolytes stabilized after starting treatment with fludrocortisone, and the cat was discharged. After 3 weeks, MRI revealed that the parietal lobe lesion had disappeared; however, the spinal cord ischemic lesion got worse than previous imaging, and the cat was euthanized. This is the first case of suspected cerebral salt-wasting syndrome in a cat. And this syndrome might be included on the differential diagnosis list for cats with intracranial disease, dehydration, and hyponatremia. A 12-year-old spayed female domestic short cat was presented with tetraplegia. The cat also showed signs of hyponatremia and dehydration, which were rapidly corrected by intravenous fluid infusion. Based on thorough physical and neurological examinations, the patient was suspected of having an intracranial disease. MRI revealed a high-signal T2 image of the bilateral parietal cerebral cortical gray matter junction, which is associated with fast electrolyte calibration, and a high-signal T2 image of the C2 spinal cord ventral area, which is associated with ischemic myelopathy. The cat reappeared three days later due to anorexia. Laboratory examinations revealed that the cat was clinically dehydrated and exhibited hyponatremia. Other causes of hyponatremia were excluded through history-taking, laboratory examination, imaging, and therapeutic response to fluid therapy, except for cerebral salt-wasting syndrome (CSWS). The cat was discharged 3 days after the start of fludrocortisone therapy with electrolytes within the normal range. Magnetic resonance imaging (MRI) was performed again 1 month after hospitalization, and the cerebral lesion disappeared, but the spinal cord lesion worsened compared to the previous image. The patient was euthanized due to the progression of the spinal lesion, with a poor prognosis and poor quality of life. This is the first case of suspected CSWS with a cervical spinal lesion in a cat. [ABSTRACT FROM AUTHOR]