Glucocorticoids with or without fludrocortisone in septic shock: a narrative review from a biochemical and molecular perspective.

Two randomised controlled trials have reported a reduction in mortality when adjunctive hydrocortisone is administered in combination with fludrocortisone compared with placebo in septic shock. A third trial did not support this finding when hydrocortisone administered in combination with fludrocortisone was compared with hydrocortisone alone. The underlying mechanisms for this mortality benefit remain poorly understood. We review the clinical implications and potential mechanisms derived from laboratory and clinical data underlying the beneficial role of adjunctive fludrocortisone with hydrocortisone supplementation in septic shock. Factors including distinct biological effects of glucocorticoids and mineralocorticoids, tissue-specific and mineralocorticoid receptor-independent effects of mineralocorticoids, and differences in downstream signalling pathways between mineralocorticoid and glucocorticoid binding at the mineralocorticoid receptor could contribute to this interaction. Furthermore, pharmacokinetic and pharmacodynamic disparities exist between aldosterone and its synthetic counterpart fludrocortisone, potentially influencing their effects. Pending publication of well-designed, randomised controlled trials, a molecular perspective offers valuable insights and guidance to help inform clinical strategies.

Treatment of congenital adrenal hyperplasia in children aged 0-3 years: a retrospective multicenter analysis of salt supplementation, glucocorticoid and mineralocorticoid medication, growth and blood pressure.

Objectives: International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim: To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0-3 years. Methods: Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results: We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5-4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were observed. Children of the whole cohort showed increased BMI-SDS during the study period and about half of the reported BP readings were >P95. Conclusion: In children treated with additional salt supplementation, FC and HC dosages are lower during the first months of life but without differences in weight, length and BP until 3 years of age compared to NST children. All children showed an increase in BMI-SDS and a high rate of BP readings >P95 until 3 years, indicating the start of weight gain and negative effects on blood pressure already in very early life.

Adrenal insufficiency updates in children.

PURPOSE OF REVIEW: The current article will review the newest diagnostic tools, genetic causes, and treatment of adrenal insufficiency in children. RECENT FINDINGS: It is common practice to perform an adrenocorticotropin hormone (ACTH) stimulation test when adrenal insufficiency is suspected. The indications for use of a high-dose or low-dose of synthetic ACTH in children have been refined. In addition, newer studies propose adding 15 and 30-min serum or salivary cortisol levels to the low-dose ACTH stimulation test to correctly identify adrenal insufficiency. Recent identification of genetic mutations in children with non-classic steroidogenic acute regulatory protein and other mutations associated with primary and secondary adrenal insufficiency have expanded the cause and pathophysiology of monogenic adrenal insufficiency. In addition, newer hydrocortisone formulations and delivery methods and medications to use in combination with hydrocortisone are being explored to improve treatment for children with adrenal insufficiency. SUMMARY: Improved diagnostic aids, detection of newer genetic mutations, and better treatment options and delivery systems will help correctly identify and manage children with adrenal insufficiency to improve health outcomes and quality of life. VIDEO ABSTRACT: http://links.lww.com/COE/A21.

The Cl-/HCO3- exchanger pendrin is downregulated during oral co-administration of exogenous mineralocorticoid and KCl in patients with primary aldosteronism.

In primary aldosteronism (PA), the occurrence of K+ loss and hypertension suggest alterations in renal tubular transport, but the molecular basis of these alterations in humans is unclear. In this study, urinary extracellular vesicles (uEVs) isolated from patients undergoing fludrocortisone suppression testing (FST, as a means of confirming or excluding PA) were analyzed using mass spectrometry-based proteomics to determine the combined effects of an aldosterone analogue, NaCl and KCl supplementation on renal tubular protein abundance. Of quantified proteins, the Cl-/HCO3- exchanger pendrin decreased by a median 37% [-15, 57] (P < 0.01) and the potassium channel ROMK increased by a median 31% [-10, 85] (P < 0.01) during FST among 10 PA subjects. The trends remained, but to a lesser degree, in two subjects cured of PA by unilateral adrenalectomy. In PA subjects, plasma K+ increased from median 3.6 to 4.2 mM (P < 0.01) and 24 h urine K+ from 101 to 202 mmol (P < 0.01), while 24 h urine Na+/K+ decreased from 2.3 to 0.8 (P < 0.01). At baseline, pendrin negatively correlated with plasma K+ (P < 0.05) and positively correlated with plasma aldosterone (P < 0.01). There were no clear correlations between Δ pendrin (Δ = D4-D0) and changes in blood or urine variables, and no correlations between ROMK in any of the blood or urine variables either at baseline or during FST. We conclude that oral co-administration of mineralocorticoid and KCl in PA patients is associated with reduced pendrin and enhanced ROMK in uEVs. Pendrin reduction during FST suggests that the suppressive effects of oral KCl may outweigh pendrin upregulation by mineralocorticoids.

Immune Effects of Corticosteroids in Sepsis.

Sepsis, a life-threatening organ dysfunction, results from a dysregulated host response to invading pathogens that may be characterized by overwhelming systemic inflammation or some sort of immune paralysis. Sepsis remains a major cause of morbidity and mortality. Treatment is nonspecific and relies on source control and organ support. Septic shock, the most severe form of sepsis is associated with the highest rate of mortality. Two large multicentre trials, undertaken 15 years apart, found that the combination of hydrocortisone and fludrocortisone significantly reduces mortality in septic shock. The corticosteroids family is composed of several molecules that are usually characterized according to their glucocorticoid and mineralocorticoid power, relative to hydrocortisone. While the immune effects of glucocorticoids whether mediated or not by the intracellular glucocorticoid receptor have been investigated for several decades, it is only very recently that potential immune effects of mineralocorticoids via non-renal mineralocorticoid receptors have gained popularity. We reviewed the respective role of glucocorticoids and mineralocorticoids in counteracting sepsis-associated dysregulated immune systems.

Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison's disease on glucocorticoid and mineralocorticoid replacement therapy.

PURPOSE: to assess bone damage and metabolic abnormalities in patients with Addison's disease given replacement doses of glucocorticoids and mineralocorticoids. METHODS: A total of 87 patients and 81 age-matched and sex-matched healthy controls were studied. The following parameters were measured: urinary cortisol, serum calcium, phosphorus, creatinine, 24-h urinary calcium excretion, bone alkaline phosphatase, parathyroid hormone, serum CrossLaps, 25 hydroxyvitamin D, and 1,25 dihydroxyvitamin D. Clear vertebral images were obtained with dual-energy X-ray absorptiometry in 61 Addison's disease patients and 47 controls and assessed using Genant's classification. RESULTS: Nineteen Addison's disease patients (31.1%) had at least one morphometric vertebral fracture, as opposed to six controls (12.8%, odds ratio 3.09, 95% confidence interval 1.12-8.52). There were no significant differences in bone mineral density parameters at any site between patients and controls. In Addison's disease patients, there was a positive correlation between urinary cortisol and urinary calcium excretion. Patients with fractures had a longer history of disease than those without fractures. Patients taking fludrocortisone had a higher bone mineral density than untreated patients at all sites except the lumbar spine. CONCLUSIONS: Addison's disease patients have more fragile bones irrespective of any decrease in bone mineral density. Supra-physiological doses of glucocorticoids and longer-standing disease (with a consequently higher glucocorticoid intake) might be the main causes behind patients' increased bone fragility. Associated mineralocorticoid treatment seems to have a protective effect on bone mineral density.

Successful treatment of a cat with primary hypoadrenocorticism and severe hyponatremia with desoxycorticosterone pivalate (DOCP).

A 6-year-old, castrated male Siamese cat was diagnosed with primary hypoadrenocorticism, confirmed by an adrenocorticotopic hormone (ACTH) stimulation test documenting both hypocortisolism and hypoaldosteronism. The cat was successfully treated using a combination of prednisolone and desoxycorticosterone pivalate (DOCP). This case demonstrates that DOCP can be used successfully as mineralocorticoid supplementation in cats with hypoadrenocorticism and may have a longer therapeutic duration than that in dogs.

Traitement réussi d'un chat atteint d'hypoadrénocorticisme primaire et d'hyponatrémie à l'aide de pivalate de désoxycorticostérone (DOCP). Un diagnostic d'hypoadrénocorticisme primaire a été posé pour un chat Siamois castré âgé de 6 ans et confirmé par un test de stimulation de l'hormone adrénocorticotope (ACTH) qui a documenté l'hypocortisolisme et l'hypoaldostéronisme. Le chat a été traité avec succès à l'aide d'une combinaison de prednisolone et de pivalate de désoxycorticostérone (DOCP). Ce cas démontre que le DOCP peut être utilisé avec succès en tant que supplément de minéralocorticoïdes chez les chats atteints d'hypoadrénocorticisme et peut présenter une durée thérapeutique plus longue que chez les chiens.(Traduit par Isabelle Vallières).

Estudio comparativo de la eficacia de los glucocorticoides, mineralocorticoides y vasodilatadores en la recuperación auditiva de pacientes que padecen hipoacusia neurosensorial idiopática de localización coclear. Ensayo clínico preliminar / A comparative study on efficacy of glucocorticoids, mineralocorticoids and vasoactive drugs on reversing hearing loss in patients suffering idiopathic sensorineural cochlear hypoacusis. A preliminary clinical trial

Introducción y objetivos: La hipoacusia neurosensorial (HNS) puede conducir a causar grave deterioro auditivo. Su recuperación funcional parece relacionarse con el control de la homeostasis iónica coclear experimentalmente dependiente de los mineralocorticoides. El objetivo de este trabajo es valorar la eficacia terapéutica comparando 2 modalidades de corticoides frente a los vasodilatadores en pacientes con HNS idopática coclear (HNSIC). Material y métodos: El ensayo dura 3 meses, se realiza en 70 pacientes asignados aleatoriamente en 4 grupos: grupo control, sin medicación, formado por 14 pacientes (8 varones y 6 mujeres); grupo tratado con vasodilatadores formado por 21 pacientes (11 hombres y 10 mujeres); grupo sometido a terapia glucocorticoidea formado por 16 pacientes (10 varones y 6 mujeres); y grupo sometido a terapia mineralocorticoidea formado por 19 pacientes (11 varones y 8 mujeres). La valoración del nivel de pérdida auditiva y su topografía se estiman mediante audiometría tonal liminal (ATL) y potenciales auditivos de tronco cerebral (PEATC). Resultados: Encontramos mejor respuesta al tratamiento con los mineralocorticoides que con los glucocorticoides, siendo la respuesta más pobre para los vasodilatadores. Esta respuesta es mayor en las mujeres que en los hombres, y en general observamos mejor respuesta por parte del oído izquierdo, con independencia del sexo del paciente. Conclusiones: Las ganancias auditivas son significativamente mayores con los mineralocorticoides, seguidas por los glucocorticoides, mientras que con los vasodilatadores las respuestas son pobres y no significativas (AU)

Introduction and objectives: Sensory neural hearing loss (SNHL) is a disorder characterised by an important deterioration of the auditory function. Re-establishing normal ion homeostasis of the endolymph could be related to hearing recovery and it might be mediated by mineralocorticoids. The main purpose of this preliminary, randomized controlled clinical trial was assessing the recovery of idiopathic sensory neural cochlear hearing loss (SNHL) by comparing the efficacy of 2 types of steroids versus vasodilators. Material and methods: The 3-month intervention involved 70 patients, allocated into 4 different groups: a control with no medication, consisting of 14 patients (8 men and 6 women); a vasodilator group of 21 patients (11 men and 10 women); a glucocorticoid group with 16 patients (10 men and 6 women); and a mineralocorticoid therapy group, consisting of 19 patients (11 men and 8 women). The level of hearing loss and its topography were estimated using Liminal Tone Audiometry (LTA) and Auditory Brainstem Response (ABR). Results: Our research found overall greater efficacy of mineralocorticoids versus glucocorticoids and vasodilators. There was better response in women than in men and it was higher from the left ear, regardless of patient gender. Conclusions: The hearing gain was significantly superior in the mineralocorticoid group, followed by the glucocorticoid group. However, the responses to vasodilators were lesser and of low statistical significance (AU)

[A comparative study on efficacy of glucocorticoids, mineralocorticoids and vasoactive drugs on reversing hearing loss in patients suffering idiopathic sensorineural cochlear hypoacusis. A preliminary clinical trial]. / Estudio comparativo de la eficacia de los glucocorticoides, mineralocorticoides y vasodilatadores en la recuperación auditiva de pacientes que padecen hipoacusia neurosensorial idiopática de localización coclear. Ensayo clínico preliminar.

INTRODUCTION AND OBJECTIVES: Sensory neural hearing loss (SNHL) is a disorder characterised by an important deterioration of the auditory function. Re-establishing normal ion homeostasis of the endolymph could be related to hearing recovery and it might be mediated by mineralocorticoids. The main purpose of this preliminary, randomized controlled clinical trial was assessing the recovery of idiopathic sensory neural cochlear hearing loss (SNHL) by comparing the efficacy of 2 types of steroids versus vasodilators. MATERIAL AND METHODS: The 3-month intervention involved 70 patients, allocated into 4 different groups: a control with no medication, consisting of 14 patients (8 men and 6 women); a vasodilator group of 21 patients (11 men and 10 women); a glucocorticoid group with 16 patients (10 men and 6 women); and a mineralocorticoid therapy group, consisting of 19 patients (11 men and 8 women). The level of hearing loss and its topography were estimated using Liminal Tone Audiometry (LTA) and Auditory Brainstem Response (ABR). RESULTS: Our research found overall greater efficacy of mineralocorticoids versus glucocorticoids and vasodilators. There was better response in women than in men and it was higher from the left ear, regardless of patient gender. CONCLUSIONS: The hearing gain was significantly superior in the mineralocorticoid group, followed by the glucocorticoid group. However, the responses to vasodilators were lesser and of low statistical significance.

[Testicular adrenal rest tumors in adolescents]. / Testikuläre adrenale Resttumoren im Hoden bei Adoleszenten.

BACKGROUND: Testicular adrenal rest tumors (TART) frequently occur in patients with congenital adrenal hyperplasia (CAH) and can be detected and treated in childhood as well as in adolescence. Due to the intricate dilimitation to other testicular masses the correct diagnosis of TART can be problematic. An extensive endocrinologic evaluation and ultrasound examination are mandatory. Even though TART are benign lesions a high-dose therapy with glucocorticoid and/or mineralocorticoid suppletion is necessary for protecion or regain of fertility. METHODS: A surgical approach can be considered, depending on stage of disease and response on drug therapy. Consequent treatment and constant therapy monitoring might significantly improve long-term outcome. RESULTS: Currently there is no validated standard therapy concept, which can be explained by the heterogenity of disease patterns progression and the limited data available, respectively. Therefore treatment should be subject to specialized centres.

Molecular testing in congenital adrenal hyperplasia due to 21α-hydroxylase deficiency in the era of newborn screening.

Newborn screening (NBS) identifies the majority of classical [salt-wasting (SW) and simple-virilizing (SV)] cases of congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase (21α-OHase) during the first days of life. Diagnosis of classical CAH is confirmed by follow-up serum 17-hydroxyprogesterone and/or the adrenocorticotropin stimulation test; however, neither test definitively distinguishes between the classical subtypes. After confirmation, all newborns are started on hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment. While initiating fludrocortisone treatment in classical CAH patients, independent of subtype and before SW signs or symptoms occur, prevents a life-threatening SW crisis, it may later complicate distinguishing between the classical subtypes. Genotype-phenotype correlations in 21α-OHase deficiency are excellent; however, molecular testing is not a regular part of the diagnostic workup. Molecular testing on 39 patients (25 identified by NBS) with an already established diagnosis of CAH identified 11 SW patients (8 identified by NBS) whose mutations suggested further biochemical and clinical reassessment of their subtype. Overall, SW accounted for 57.6% of our classical CAH patients, below the generally accepted figure that >75% of classical CAH are comprised of the SW form. In the era of NBS, molecular testing is a valuable supplemental tool identifying patients who may benefit from reassessment of their salt-retaining ability.

Case report: severe neonatal hyperkalemia due to pseudohypoaldosteronism type 1.

Hyponatremia and hyperkalemia in infancy can represent a variety of renal and genetic disorders with significant long-term health implications. We report a newborn with severe hyperkalemia and hyponatremia from autosomal recessive pseudohypoaldosteronism type 1 requiring aggressive therapy. The evaluation and treatment of children with disorders of mineralocorticoid action are discussed.

Corticosteroid physiology and principles of therapy.

The adrenal cortex secretes glucocorticoids (GC), mineralocorticoids (MC) and androgens. GC maintain homeostasis, MC regulate fluid and electrolyte balance and adrenal androgens contribute to development of secondary sexual characteristics. Pharmacologic GC therapy is frequently indicated in the pediatric age group. Besides having many important side effects, prolonged high dose systemic GC therapy has a suppressive effect on endogenous steroid production. Therefore, GC therapy should be withdrawn gradually and stopped based on assessment of hypothalamo-pituitary-adrenal (HPA) axis recovery. Patients with HPA axis suppression require physiological replacement of GC along with enhancement of doses during periods of stress. Due to its immunosuppressive effects, issues about safety and efficacy of live virus vaccines in patients receiving systemic high dose GC therapy must be borne in mind.

Mineralocorticoid effects due to cortisol inactivation overload explain the beneficial use of hydrocortisone in septic shock.

The role of corticosteroids in septic shock remains controversial despite their use for over 50 years. Large prospective trials of their use continue with the aim of resolving the controversy. These may well remain indecisive if basic endocrine principles are ignored. Review of the available evidence suggests that use of synthetic glucocorticoids is harmful but hydrocortisone beneficial. Consideration of the basic properties of the corticosteroids used and their receptors suggest an explanation for their differing therapeutic effects. The harmful synthetic glucocorticoids have no or reduced mineralocorticoid effects in contrast with the significant mineralocorticoid effects of hydrocortisone at the doses which have been found to be beneficial. The potent synthetic mineralocorticoid fludrocortisone is well recognised to raise peripheral resistance by sensitising the resistance vessels to endogenous or exogenous catecholamines and also causes metabolic alkalosis. We provide evidence to support our hypothesis that at the doses of hydrocortisone used, cortisol inactivation overload is the basis of the beneficial effect. The consequent mineralocorticoid effects result in increased sensitivity of the resistance vessels to endogenous and exogenous catecholamines with an increase in peripheral resistance correcting shock. In addition the metabolic alkalotic component of mineralocorticoid effect would tend to correct the prevailing metabolic acidosis. Hydrocortisone also has an attenuating, as opposed to the suppressing effect of synthetic glucocorticoids on the immune response which is also regarded as beneficial.

Revisión a partir de un caso clínico: encefalopatía perdedora de sal secundaria a asfixia por ahorcamiento / Review in relation to a clinical case: cerebral salt wasting secondary to asphyxia by hanging

Siendo la hiponatremia un trastorno frecuente en unidades de tratamiento intensivo en especial neuroquirúrgico, se deben tener en consideración las dos etiologías más frecuentes: SIADH y encepalopatía perdedora de sal. La importancia del diagnóstico diferencial radica en que la forma de aproximación diagnóstica y el tratamiento son diferentes, de tal modo que el manejo inadecuado puede intensificar la hiponatremia poniendo en riesgo vital al paciente. Aún así existen otras causas que pueden aumentar la natriuresis: infusiones prolongadas de soluciones salinas pueden provocar un balance negativo de Na y Cl, por internalización de canales Na/K ATP. Además non todos pacientes con EPS presentan niveles elevados de péptido natriurético cerebral. Por lo que aún está en discusión y no se tiene consenso absoluto respecto de su fisiopatología.

Therapeutic strategies in adrenal insufficiency.

Severe chronic adrenal insufficiency (primary or secondary) is a potentially lethal disorder, unless the patient is regularly substituted with glucocorticoids, usually with hydrocortisone (15-25 mg/day) and with 9 alpha-fluor-hydrocortisone (0.05-0.2 mg/day) in addition in patients with the primary adrenal disorder (Addison's disease). In stressful situations and in febrile disorders, the glucocorticoid dosage must be increased prophylactically in order to prevent an "adrenal crisis". Most women with adrenal insufficiency will profit from the additional substitution of dehydroepiandrosterone (DHEA) with regard to well-being and sexual function. A patient with acute adrenal insufficiency will die if the diagnosis is missed and high-dose glucocorticoid treatment is not instituted immediately. Acute adrenal insufficiency developing de novo in an intensive care patient (e.g. from adrenal hemorrhage or adrenal vein thrombosis) is a most challenging diagnosis. In these patients, however, survival not only depends on glucocorticoid substitution but also on the underlying disease.

Liquorice, growth retardation and Addison's disease.

An 11-year-old boy had hypoparathyroidism and Addison's disease. During treatment with calcitriol, calcium, hydrocortisone and 9-alpha-fluorocortisol, he developed an apparent mineralocorticoid excess and growth retardation. Pseudohyperaldosteronism even persisted after treatment with 9-alpha-fluorocortisol was stopped and hydrocortisone was reduced to 6 mg/m(2). The boy reported an excessive daily intake of 300-400 g liquorice corresponding to 600-800 mg glycyrrhizic acid because of salt craving. After complete withdrawal of liquorice all symptoms of hypermineralocorticoidism diminished and growth velocity increased. We hypothesise that inhibition of 11beta-hydroxysteroid dehydrogenase by liquorice caused hypermineralocorticoidism and growth retardation via increased levels of free cortisol in this patient. We conclude that self-medication with liquorice in children with Addison's disease should be considered during treatment.