Impact of fludrocortisone on the outcomes of subarachnoid hemorrhage patients: A retrospective analysis.

BACKGROUND: Whether the use of fludrocortisone affects outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a retrospective analysis of 78 consecutive patients with a ruptured aSAH at a single academic center in the United States. The primary outcome was the score on the modified Rankin scale (mRS, range, 0 [no symptoms] to 6 [death]) at 90 days. The primary outcome was adjusted for age, hypertension, aSAH grade, and time from aSAH onset to aneurysm treatment. Secondary outcomes were neurologic and cardiopulmonary dysfunction events. RESULTS: Among 78 patients at a single center, the median age was 58 years [IQR, 49 to 64.5]; 64 % were female, and 41 (53 %) received fludrocortisone. The adjusted common odds ratio, aOR, of a proportional odds regression model of fludrocortisone use with mRS was 0.33 (95 % CI, 0.14-0.80; P = 0.02), with values <1.0 favoring fludrocortisone. Organ-specific dysfunction events were not statistically different: delayed cerebral ischemia (22 % vs. 39 %, P = 0.16); cardiac dysfunction (0 % vs. 11 %; P = 0.10); and pulmonary edema (15 % vs. 8 %; P = 0.59). CONCLUSIONS: The risk of disability or death at 90 days was lower with the use of fludrocortisone in aSAH patients.

Fludrocortisone Among Adult Renal Transplant Recipients With Persistent Hyperkalemia: Single-Center Experience.

OBJECTIVES: Calcineurin inhibitors are the cornerstone of immunosuppression following solid-organ transplant. However, hyperkalemia may occur by multiple mechanisms affecting potassium in the distal tubule. Hyperkalemia is commonly observed in renal transplant recipients, and it is dose-dependent. Here, we evaluated the impact of fludrocortisone in the management of calcineurin inhibitor-induced hyperkalemia after renal transplant. MATERIALS AND METHODS: We evaluated newly transplanted patients who developed hyperkalemia or those with hyperkalemia who attended our outpatient renal transplant clinic (Hamed Al-Essa Organ Transplant Center, Kuwait). Clinical and laboratory parameters were collected before starting fludrocortisone (baseline values) and then at 1, 2, 4, and 8 weeks. Drug history was assessed, with any drugs that could induce hyperkalemia being discontinued (such as spironolactone); otherwise, essential drugs like prophylactic agents (sulfamethoxazole-trimethoprim) were maintained. Oral anti-hyperkalemic doses (bicarbonate, resonium calcium, fludrocortisone) were noted. RESULTS: Our study included 29 patients; most were men (aged 45.8 ± 15 years). Body weight did not significantly change after introduction of fludrocortisone (79.53 ± 24.31, 79.82 ± 23.85, 80.62 ± 24.24, 77.03 ± 20.7, and 79.21 ± 27.93 kg at baseline and at postdose week 1, 2, 4, and 8, respectively). Systolic and diastolic blood pressure levels were also similar at baseline versus postdose. Steroid doses (prednisolone) were significantly reduced over 1 month (15.7 ± 12.4, 14.1 ± 10.19, 12.6 ± 8.7, 9.5 ± 5.2, and 9.5 ± 5.2 mg/ day). Serum potassium levels significantly improved (5.18 ± 0.58, 4.9 ± 0.49, 4.8 ± 0.54, 4.8 ± 0.65, and 4.4 ± 0.72 mmol/L). Serum creatinine levels significantly improved by postdose week 8 (129.28 ± 48.9, 130.92 ± 52.2, 127.66 ± 50.9, 121.42 ± 41.7, and 124.1 ± 51.27 µmol/L). Serum bicarbonate levels remained similar. CONCLUSIONS: Fludrocortisone was a safe and effective option in management of calcineurin inhibitor-induced hyperkalemia among renal transplant recipients.

Orthostatic Hypotension: A Practical Approach.

Orthostatic hypotension is defined as a decrease in blood pressure of 20 mm Hg or more systolic or 10 mm Hg or more diastolic within three minutes of standing from the supine position or on assuming a head-up position of at least 60 degrees during tilt table testing. Symptoms are due to inadequate physiologic compensation and organ hypoperfusion and include headache, lightheadedness, shoulder and neck pain (coat hanger syndrome), visual disturbances, dyspnea, and chest pain. Prevalence of orthostatic hypotension in the community setting is 20% in older adults and 5% in middle-aged adults. Risk factors such as diabetes mellitus increase the prevalence of orthostatic hypotension in all age groups. Orthostatic hypotension is associated with a significant increase in cardiovascular risk and falls, and up to a 50% increase in relative risk of all-cause mortality. Diagnosis is confirmed by performing a bedside simplified Schellong test, which consists of blood pressure and heart rate measurements after five minutes in the supine position and three minutes after moving to a standing position. If the patient is unable to stand safely or the clinical suspicion for orthostatic hypotension is high despite normal findings on the bedside test, head-up tilt table testing is recommended. Orthostatic hypotension is classified as neurogenic or nonneurogenic, depending on etiology and heart rate response. Treatment goals for orthostatic hypotension are reducing symptoms and improving quality of life. Initial treatment focuses on the underlying cause and adjusting potentially causative medications. Nonpharmacologic strategies include dietary modifications, compression garments, physical maneuvers, and avoiding environments that exacerbate symptoms. First-line medications include midodrine and droxidopa. Although fludrocortisone improves symptoms, it has concerning long-term effects.

Co-existence of Congenital Adrenal Hyperplasia and Familial Hypokalemic Periodic Paralysis due to CYP21A2 and SCN4A Pathogenic Variants

Steroid 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH), usually due to biallelic variants in CYP21A2. Classical 21-hydroxylase deficiency is characterised by virilisation of the external genitalia in females and hypocortisolism. Hyponatremia and hyperkalemia are among the common biochemical findings. Familial hypokalemic periodic paralysis (FHPP) is a rare disorder in which affected individuals may experience paralytic episodes associated with hypokalemia, caused by pathogenic variants in SCN4A or CACNA1S. A 14-year-old female, who had been diagnosed with classical 21-hydroxylase deficiency and treated with hydrocortisone and fludrocortisone since early infancy, presented with acute onset weakness. The laboratory results revealed a remarkably low serum potassium level. The family history revealed that both her father and uncle had the same hypokalemic symptoms, which suggested an FHPP diagnosis. We found two previously reported homozygous variants in the CYP21A2 (p.Ile173Asn) and SCN4A (p.Arg672His) genes in the patient. Therefore, diagnoses of simple virilising 21-hydroxylase deficiency and FHPP were genetically confirmed. Here, FPHH and chronic overtreatment with fludrocortisone may explain the presentation of our patient with severe hypokalemia. The family's medical history, which is always a valuable clue, should be investigated in detail since rare inherited conditions may co-occur in geographies where consanguineous marriages are common and the genetic pool is diverse. In patients with CAH, care should be taken to avoid overtreatment with fludrocortisone. Androgens may have triggered the hypokalemic attack in FHPP, as supported in a previous study.

What factors have impact on glucocorticoid replacement in adrenal insufficiency: a real-life study.

PURPOSE: The impact of patient's characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies. METHODS: We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI. RESULTS: At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02). CONCLUSIONS: Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

Does fludrocortisone treatment cause hypomagnesemia in children with primary adrenal insufficiency?

Background/aim: Aldosterone is a mineralocorticoid that secreted from adrenal glands and a known factor to increase magnesium excretion by direct and indirect effects on renal tubular cells. Although the frequency of hypomagnesemia was found to be approximately 5% in adult studies, there is no study in the literature investigating the frequency of hypomagnesemia in children by using fludrocortisone, which has a mineralocorticoid activity. Materials and methods: A multi-center retrospective study was conducted, including children who were under fludrocortisone treatment for primary adrenal insufficiency and applied to participant pediatric endocrinology outpatient clinics. Results: Forty-three patients (58.1% male, 41.9% prepubertal) included in the study, whose median age was 9.18 (0.61-19) years, and the most common diagnosis among the patients was a salt-wasting form of congenital adrenal hyperplasia (67.4%). Mean serum magnesium level was 2.05 (±0.13) mg/dL, and hypomagnesemia was not observed in any of the patients treated with fludrocortisone. None of the patients had increased urinary excretion of magnesium. Conclusion: Unlike the studies performed in adults, we could not find any evidence of magnesium wasting effect of fludrocortisone treatment with normal or even high doses in children and adolescents.

Assessment of Machine Learning to Estimate the Individual Treatment Effect of Corticosteroids in Septic Shock.

Importance: The survival benefit of corticosteroids in septic shock remains uncertain. Objective: To estimate the individual treatment effect (ITE) of corticosteroids in adults with septic shock in intensive care units using machine learning and to evaluate the net benefit of corticosteroids when the decision to treat is based on the individual estimated absolute treatment effect. Design, Setting, and Participants: This cohort study used individual patient data from 4 trials on steroid supplementation in adults with septic shock as a training cohort to model the ITE using an ensemble machine learning approach. Data from a double-blinded, placebo-controlled randomized clinical trial comparing hydrocortisone with placebo were used for external validation. Data analysis was conducted from September 2019 to February 2020. Exposures: Intravenous hydrocortisone 50 mg dose every 6 hours for 5 to 7 days with or without enteral 50 µg of fludrocortisone daily for 7 days. The control was either the placebo or usual care. Main Outcomes and Measures: All-cause 90-day mortality. Results: A total of 2548 participants were included in the development cohort, with median (interquartile range [IQR]) age of 66 (55-76) years and 1656 (65.0%) men. The median (IQR) Simplified Acute Physiology Score (SAPS II) was 55 [42-69], and median (IQR) Sepsis-related Organ Failure Assessment score on day 1 was 11 (9-13). The crude pooled relative risk (RR) of death at 90 days was 0.89 (95% CI, 0.83 to 0.96) in favor of corticosteroids. According to the optimal individual model, the estimated median absolute risk reduction was of 2.90% (95% CI, 2.79% to 3.01%). In the external validation cohort of 75 patients, the area under the curve of the optimal individual model was 0.77 (95% CI, 0.59 to 0.92). For any number willing to treat (NWT; defined as the acceptable number of people to treat to avoid 1 additional outcome considering the risk of harm associated with the treatment) less than 25, the net benefit of treating all patients vs treating nobody was negative. When the NWT was 25, the net benefit was 0.01 for the treat all with hydrocortisone strategy, -0.01 for treat all with hydrocortisone and fludrocortisone strategy, 0.06 for the treat by SAPS II strategy, and 0.31 for the treat by optimal individual model strategy. The net benefit of the SAPS II and the optimal individual model treatment strategies converged to zero for a smaller number willing to treat, but the individual model was consistently superior than model based on the SAPS II score. Conclusions and Relevance: These findings suggest that an individualized treatment strategy to decide which patient with septic shock to treat with corticosteroids yielded positive net benefit regardless of potential corticosteroid-associated side effects.

Current Management and Outcome of Pregnancies in Women With Adrenal Insufficiency: Experience from a Multicenter Survey.

CONTEXT: Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. OBJECTIVE: Multicenter survey on current clinical approaches in managing AI during pregnancy. DESIGN: Retrospective anonymized data collection from 19 international centers from 2013 to 2019. SETTING AND PATIENTS: 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). RESULTS: Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. CONCLUSIONS: This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

Safety and Efficacy of Fludrocortisone in the Treatment of Cerebral Salt Wasting in Patients With Tuberculous Meningitis: A Randomized Clinical Trial.

Importance: Tuberculous meningitis is associated with high frequency of cerebral salt wasting. There is a paucity of objective information regarding the best method of treatment of this condition. Objective: To evaluate the efficacy and safety of fludrocortisone in the treatment of cerebral salt wasting in patients with tuberculous meningitis. Design, Setting, and Participants: This is a single-center, open-label, randomized clinical trial conducted from October 2015 to April 2017 in India. Patients were randomized in a 1:1 ratio to arms receiving saline only or saline plus fludrocortisone, in addition to a standard treatment of 4 antitubercular drugs, prednisolone, and aspirin. The 2 arms were matched for demographic, clinical, and magnetic resonance imaging findings. The patients were followed up for at least 6 months. Interventions: Patients were randomized to a 0.9% solution of intravenous saline with 5 to 12 g per day of oral salt supplementation, with or without the addition of 0.1 to 0.4 mg of fludrocortisone per day. Main Outcomes and Measures: The primary end point was the time needed to correct serum sodium levels; secondary end points were in-hospital deaths, disability at 3 months, disability at 6 months, occurence of stroke, and serious adverse reactions. Results: Ninety-three patients with suspected tuberculous meningitis were recruited; 12 did not meet the inclusion criteria, including 4 with alternate diagnoses. A total of 37 patients with cerebral salt wasting were eligible for the study. One refused to participate, and therefore 36 patients were included, with 18 randomized to each group. The median (range) age was 30 (20-46) years, and 19 were male (52.8%). Those receiving fludrocortisone regained normal serum sodium levels after 4 days, significantly earlier than those receiving saline only (15 days; P = .004). In an intention-to-treat analysis, hospital mortality, disability at 3 months, and disability at 6 months did not differ significantly, but fewer infarcts occurred in the deep border zone in the group receiving fludrocortisone (1 of 18 [6%]) vs those in the control arm (6 of 18 [33%]; P = .04). Fludrocortisone was associated with severe hypokalemia and hypertension in 2 patients each, and pulmonary edema occurred in 1 patient. These adverse reactions necessitated discontinuation of fludrocortisone in 2 patients. Conclusions and Relevance: Fludrocortisone results in earlier normalization of serum sodium levels, but did not affect outcomes at 6 months. Fludrocortisone had to be withdrawn in 2 patients because of severe adverse effects. This study provides class II evidence on the role of fludrocortisone in treatment of hyponatremia associated with cerebral salt wasting in patients with tuberculous meningitis. Trial Registration: Clinical Trials Registry of India (ctri.nic.in) Identifier: CTRI/2017/10/010255.

Renal tubule insulin receptor modestly promotes elevated blood pressure and markedly stimulates glucose reabsorption.

Although the cause of hypertension among individuals with obesity and insulin resistance is unknown, increased plasma insulin, acting in the kidney to increase sodium reabsorption, has been proposed as a potential mechanism. Insulin may also stimulate glucose uptake, but the contributions of tubular insulin signaling to sodium or glucose transport in the setting of insulin resistance is unknown. To directly study the role of insulin signaling in the kidney, we generated inducible renal tubule-specific insulin receptor-KO mice and used high-fat feeding and mineralocorticoids to model obesity and insulin resistance. Insulin receptor deletion did not alter blood pressure or sodium excretion in mice on a high-fat diet alone, but it mildly attenuated the increase in blood pressure with mineralocorticoid supplementation. Under these conditions, KO mice developed profound glucosuria. Insulin receptor deletion significantly reduced SGLT2 expression and increased urinary glucose excretion and urine flow. These data demonstrate a direct role for insulin receptor-stimulated sodium and glucose transport and a functional interaction of insulin signaling with mineralocorticoids in vivo. These studies uncover a potential mechanistic link between preserved insulin sensitivity and renal glucose handling in obesity and insulin resistance.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD9977, a novel, selective mineralocorticoid receptor modulator.

AIMS: AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977. METHODS: A first-in-human trial explored doses from 5 to 1200 mg. To study effects on urinary electrolyte excretion an additional randomized placebo controlled cross-over four-period clinical trial was performed. Twenty-three healthy volunteers were administered fludrocortisone alone or in combination with AZD9977, eplerenone or both. AZD9977/eplerenone combination was given to assess if AZD9977 can attenuate eplerenone induced natriuresis. RESULTS: AZD9977 at doses from 5 to 1200 mg was safe and well tolerated and pharmacokinetics were compatible with further development. AZD9977 exhibited similar effects on urinary ln [Na+ ]/[K+ ] as eplerenone when using fludrocortisone as mineralocorticoid receptor agonist, and the combination had an additive effect on ln [Na+ K+ ]. CONCLUSIONS: The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 has minimal electrolyte effects. Future clinical studies with AZD9977 should be performed in presence of endogenous or exogenous aldosterone to assess potential benefit of AZD9977 in patients.

Vaginal bleeding and a giant ovarian cyst in an infant with 21-hydroxylase deficiency.

BACKGROUND: Increased adrenal androgen hormones in congenital adrenal hyperplasia (CAH) can rarely cause giant ovarian cysts in the neonatal period. Although the exact mechanism of the development of ovarian cysts is unknown, it is thought that increased androgen levels stimulate folicle development by increasing follicle stimulating hormone (FSH) levels. CASE PRESENTATION: A 16-day-old newborn with ambiguous genitalia was presented to our clinic. Laboratory test results were as follows: sodium: 126 mEq/L, potassium: 5.4 mEq/L, renin: 132 pg/mL, adrenocorticotropic hormone (ACTH): 207 pg/mL, cortisole: 7.8 µg/dL, basal 17OH progesterone: 21 ng/mL, androstenedione: 5.1 ng/mL, testosterone: 1188 ng/dL and dehydroepiandrosterone sulfate (DHEAS)>1500 µg/dL. Karyotype analysis resulted in 46,XX. A homozygous mutation of R356W was detected in the CYP21A2 gene. The classical severe form of salt wasting 21 hydroxylase deficiency was diagnosed and treatment was started with hydrocortisone and fludrocortisone. Good metabolic control was ensured by monthly visits but the baby presented with vaginal bleeding as soiling at 4 months. The cystic lesion which extended to the epigastric area from the pelvis in the midline abdomen, had a size of 90×80×60 mm and medially, thin ovarian parenchyma was detected in ultrasonography. CONCLUSIONS: The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels and the giant cyst is developed by activation of gonadotropin cascade and increased gonadotropin receptors, instead of androgens.

Fludrocortisone Is Associated With a Higher Risk of All-Cause Hospitalizations Compared With Midodrine in Patients With Orthostatic Hypotension.

BACKGROUND: Orthostatic hypotension causes ≈80 000 hospitalizations per year in the United States. Treatments for orthostatic hypotension include fludrocortisone, a mineralocorticoid analog that promotes sodium reabsorption; and midodrine, an α-1 adrenergic agonist that is a direct vasoconstrictor. Although both medications are used to treat orthostatic hypotension, few studies have compared their relative safety. METHODS AND RESULTS: We compared incidence rates of hospitalizations for all causes, and for congestive heart failure between users of fludrocortisone and users of midodrine in a retrospective cohort study of Tennessee Medicaid adult enrollees (1995-2009). Adjusted incidence rate ratios were calculated using negative binomial regression models. Subgroup analyses based on history of congestive heart failure were conducted. We studied 1324 patients initiating fludrocortisone and 797 patients initiating midodrine. Compared with fludrocortisone users, midodrine users had higher prevalence of cardiovascular conditions. Incidence rates of all-cause hospitalizations for fludrocortisone and midodrine users were 1489 and 1330 per 1000 person-years, respectively (adjusted incidence-rate ratio 1.20, 95% confidence interval, 1.02-1.40). The respective rates of heart failure-related hospitalization were 76 and 84 per 1000 person-years (adjusted incidence-rate ratio: 1.33, 95% confidence interval, 0.79-2.56). Among patients with a history of congestive heart failure, the rates of all-cause hospitalization for fludrocortisone and midodrine were 2448 and 1820 per 1000 person-years (adjusted incidence-rate ratio: 1.42, 95% confidence interval, 1.07-1.90), and the respective rates of heart failure exacerbation-related hospitalizations were 297 and 263 per 1000 person-years (adjusted incidence-rate ratio: 1.48, 95% confidence interval, 0.69-3.16). CONCLUSIONS: Compared with users of midodrine, users of fludrocortisone had higher rates of all-cause hospitalizations, especially among patients with congestive heart failure.

Takotsubo-like syndrome triggered by fludrocortisone overdose for Addison's disease: a case report.

BACKGROUND: Reversible left ventricular dysfunction, also termed Takotsubo cardiomyopathy, is rarely reported in Addison's disease after initiation of hormone replacement therapy. The pathogenesis of this cardiomyopathy is unknown. CASE PRESENTATION: A 41-year-old white woman with a history of autoimmune Hashimoto thyroiditis diagnosed 3 years earlier and acute adrenal insufficiency diagnosed 3 weeks earlier presented with new onset of heart failure New York Heart Association class IV, which had started shortly after initiation of hormone replacement therapy with hydrocortisone 20 mg/day and fludrocortisone 0.3 mg/day. Nine days before admission she had collapsed because of dizziness and had a cerebral concussion and open fracture of her nasal bone, however, no further investigations were carried out at that time. A physical examination revealed leg edema, tachycardia, tachypnea, bilateral basal crepitations, and blood pressure 110/70 mmHg. An electrocardiogram showed sinus tachycardia, low voltage, negative T-waves in V5 and V6 and a corrected QT interval of 590 ms. Echocardiography revealed a reduced left ventricular systolic function with an ejection fraction of 30 %, and septal, apical, and anterior wall akinesia. Cardiac magnetic resonance imaging showed relative enhancement of gadolinium, indicating hyperemia and capillary leakage, and no myocardial scars. Because of the improvement in her cardiac function, lack of cardiovascular risk factors, and lack of signs for ischemia on magnetic resonance imaging, no coronary angiography was carried out. The results of sellar and renal magnetic resonance imaging were normal. Her troponin T was slightly elevated. Bisoprolol and ramipril were started. Her fludrocortisone dose was reduced to 0.05 mg/day. Her electrocardiogram and systolic function, documented by echocardiography and magnetic resonance imaging, normalized within 6 months. CONCLUSIONS: Although we could not exclude coronary artery disease by coronary angiography, her clinical course and instrumental findings suggest Takotsubo cardiomyopathy of the apical type. Fludrocortisone overdosage and increased myocardial vulnerability due to cortisol deficiency might be pathogenetic factors, whereas myocarditis is unlikely. When hormone replacement in patients with Addison's disease is initiated, cardiac function should be monitored by electrocardiogram and echocardiography.

Hypertension in children with congenital adrenal hyperplasia.

OBJECTIVES: Estimates of high blood pressure (BP) incidence in children with congenital adrenal hyperplasia (CAH) vary widely; risk factors are poorly understood. We estimated incidence of hypertension by CAH subtype and sex, and assessed its association with body mass index, hydrocortisone and fludrocortisone. DESIGN: Longitudinal. PATIENTS: Chart review of 180 paediatric CAH patients (120 salt wasting; 60 simple virilizing; 93 females) seen from 1970 to 2013. MEASUREMENTS: High BP was diagnosed by diastolic or systolic blood pressure measurement ≥95th percentile for age, sex and height; hypertension was diagnosed with high BP on at least three clinic visits. RESULTS: Children with classic CAH who received fludrocortisone had a significantly higher rate of hypertension (55% vs 31%) than those who did not. Hypertension incidence was higher in salt-wasting CAH (58%) than in simple-virilizing CAH (35%). Hypertension first occurred before age 5 years in 91% of salt-wasting males and 50% of cases in salt-wasting females; most simple-virilizing cases occurred during ages 10-18 years. Rates of hypertension were higher in children who had three or more measurements with 17-OHP < 400 ng/dl (12·12 nmol/l), and this difference was significant in salt-wasting males. Children on fludrocortisone who had three or more readings of 17-OHP < 400 ng/dl (12·12 nmol/l) had a significantly higher rate of hypertension than those who did not. Hydrocortisone dose was not associated with hypertension. CONCLUSION: Children with CAH are at higher risk for hypertension than the general paediatric population, and incidence differs by sex and CAH subtype. Hypertension was higher in children on fludrocortisone and who were oversuppressed.

[TRANSURETHRAL URETEROLITHOTRIPSY FOR UPPER URINARY TRACT STONE IN SMALL CHILDREN WEIGHNING AROUND 10KG].

Management strategy for upper urinary tract calculi in small children is still a matter controversial. We report successful management of ureteral stone with transurethral ureterolithotripsy (TUL) in 2 boys weighing around 10 kg. Case 1: A 2-year-old boy (78 cm in height, 9.6 kg in weight), who received hydrocortisone and fludrocortisone for the treatment of 21-hydroxylase deficiency, was referred to our hospital with a right 9-mm lower ureteral stone. For TUL, a 7.5 Fr rigid cystoscope was introduced into the ureter directly after dilation of the ureteral orifice. By using Holmium:YAG laser for lithotripsy, complete stone evacuation was achieved. Stone analysis showed the composition of calcium phosphate and calcium oxalate. Case 2: A 1-year-old boy (80 cm in height, 10.5 kg in weight) with neurofibromatosis type 1 was referred to our hospital with a left 7.5-mm ureteral stone at the ureteropelvic junction. TUL was performed using a 4.5 F rigid ureteroscope and Holmium:YAG laser. No residual stone was identified. Stone analysis showed the composition of calcium oxalate. TUL is a safe and feasible option for small children, even in boys weighing approximately 10 kg.

Blood pressure, fludrocortisone dose and plasma renin activity in children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency followed from birth to 4 years of age.

INTRODUCTION: Infants with congenital adrenal hyperplasia (CAH) require higher doses of fludrocortisone (FC) due to physiological mineralocorticoid resistance. The adequacy of mineralocorticoid replacement should be closely monitored to avoid hypertension. OBJECTIVE: To evaluate blood pressure (BP) in infants with CAH due to 21-hydroxylase deficiency. PATIENTS AND METHODS: Thirty-three patients (18f/15 m) diagnosed by newborn screening were followed until the age of 4 years. Mean start of HC and FC treatment was day 9·8 ± 9·2 postnatally. Mean daily HC dose ranged from 8·6 to 12·3 mg/m(2) /day. RESULTS: During the first year of life prevalence of systolic hypertension was up to 45·5%. At 12 and at 18 months, BP was highest. Prevalence of systolic hypertension was up to 57·6% at 18 months of age. After 24 months BP levels were lower and at 48 months prevalence of hypertension decreased to 15·2%. Systolic and diastolic BP correlated significantly with the administered fludrocortisone dose (r = 0·3, P = 0·005), but not with body mass index. Hypertensive children received significantly higher FC doses and had significantly lower plasma renin activity during the study period. CONCLUSION: High prevalence of transient, most likely FC induced hypertension was found in young children with classic CAH diagnosed by newborn screening. The changing mineralocorticoid sensitivity in infants is a risk factor for the development of hypertension in patients with CAH, who are treated with FC. Therefore suppressed plasma renin activity should be avoided to prevent arterial hypertension.