Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study

Objective and design Most cases of euvolaemic hyponatraemia are associated with elevated plasma levels of AVP. Conivaptan is a high‐affinity, nonpeptide vasopressin V_1A/V₂‐receptor antagonist. We performed a subgroup analysis of a multicentre, randomized, placebo‐controlled, double‐blind, parallel‐group study to evaluate the efficacy and safety of intravenous (i.v.) conivaptan for the treatment of euvolaemic hyponatraemia. Patients Fifty‐six euvolaemic patients with serum [Na⁺] of 115 to < 130 mmol/l received conivaptan 40 or 80 mg/day or placebo via continuous i.v. infusion for 4 days. A 20‐mg loading dose was administered intravenously over 30 min in the conivaptan groups; the placebo group received a placebo loading dose. Measurements Change in serum [Na⁺], measured by the baseline‐adjusted area under the serum [Na⁺]–time curve (AUC), was the primary efficacy parameter. Secondary efficacy measures included the time from the first dose to a confirmed ≥ 4 mmol/l increase in serum [Na⁺], total time with serum [Na⁺] ≥ 4 mmol/l above baseline, change in serum [Na⁺] from baseline, and number of patients with a confirmed ≥ 6 mmol/l increase in serum [Na⁺] or normal [Na⁺]. Safety assessments included adverse events (AE), incidence of overly rapid correction of serum [Na⁺], and changes in vital signs and electrocardiographic and clinical laboratory parameters. Results During the first 2 days of treatment, and over the entire 4‐day treatment period, both conivaptan doses significantly increased the serum [Na⁺] AUC more than placebo (P < 0·01). Conivaptan 40 and 80 mg/day significantly improved all secondary efficacy measures. Conivaptan was generally well tolerated; infusion‐site reaction was the most common AE. Conclusions In hospitalized patients with euvolaemic hyponatraemia, i.v. conivaptan significantly increased serum [Na⁺] promptly and was well tolerated.     

Management of Hyperkalemia in Hospitalized Patients

PurposeThe aim of this study was to determine the incidence of treatment of hyperkalemia in hospitalized patients.MethodsThis is a prospective chart review of adults in a tertiary care hospital with hyperkalemia (serum potassium [K⁺] ≥ 5.1 mEq/L) over a 6-month period. The treatments and their effectiveness, causative factors and associated electrocardiographic (ECG) changes were examined.ResultsThere were 154 hyperkalemic episodes, 32 with K⁺ ≥ 6.5 mEq/L and 122 with K⁺< 6.5 mEq/L. Overall, 97% received treatment for an average K⁺ of 5.9 mEq/L. Sodium polystyrene sulfonate (SPS) was included in 95% of the regimens. incremental doses of sPs monotherapy yielded potassium reductions between 0.7 and 1.1 mEq/L, and inadequate responses (K⁺ < 0.5 mEq/L) were less frequent with higher doses. There were no differences in the effectiveness of SPS among dialysis-dependent, chronic kidney disease, or nonchronic kidney disease patients. Greater reductions in potassium were observed using a combination of treatments. ECGs were performed in 44% of patients, and 50% showed no ECG changes despite K⁺ being ≥ 6.5 mEq/L. The most common abnormality, peaked T waves, was associated with a higher frequency of calcium administration but not with the number of K⁺-lowering therapies.ConclusionsAlmost all the patients were treated for hyperkalemia. Oral SPS monotherapy was the predominant treatment with the best response at the highest dose. Some combination therapies had greater K⁺ reductions but were used infrequently. An ECG was obtained in about 50% of the cases, but two thirds showed no K⁺-related changes. Reduced kidney function was associated with 70% of hyperkalemic episodes. Angiotensin-converting enzyme inhibitors and trimethoprim were the most commonly implicated medications.     

Hypernatremia and moderate-to-severe hyponatremia are independent predictors of mortality in septic patients at emergency department presentation: A sub-group analysis of the need-speed trial

Study objectiveEarly risk stratification of septic patients presenting to the emergency department (ED) is challenging. The aim of the study was to evaluate the prognostic role of plasmatic sodium level (_PNa⁺) derangements at ED presentation in septic patients.MethodsAccording to _PNa⁺ at ED presentation patients were divided in eunatremic (136–145 mEq/L), hypernatremic (>145 mEq/L) and hyponatremic (<136 mEq/L). Hyponatremic patients were subsequently divided in mild (130–135 mEq/L), moderate (125–129 mEq/L) and severe (<125 mEq/L). 7 and 30-day mortality was evaluated according to _PNa⁺ derangements and the degree of hyponatremia. The same analysis was then performed only in respiratory tract infection-related (RTI-r) sepsis patients.Results879 septic patients were included in this analysis, 40.3% had hyponatremia, 5.7% hypernatremia. Hypernatremia showed higher mortality rates at both endpoints compared to eunatremia and hyponatremia (p<0.0001 for both). Eunatremia and mild hyponatremia were compared vs. moderate-to-severe hyponatremia showing a significant difference in terms of 7 and 30-day survival (p = 0.004 and p = 0.007, respectively). The Cox proportional model identified as independent predictors of 7 and 30-day mortality moderate-to-severe hyponatremia (HR 4.89[2.38–10.03] and 1.79[1.07–3.01], respectively) and hypernatremia (HR 3.52[1.58–7.82] and 2.14[1.17–3.92], respectively). The same analysis was performed in patients with respiratory tract infection-related sepsis (n = 549), with similar results.ConclusionBoth hypernatremia and moderate-to-severe hyponatremia at ED presentation independently predict mortality in septic patients, allowing early risk stratification and suggesting more aggressive therapeutic strategies.     

Severe hypernatremia correction rate and mortality in hospitalized patients

IntroductionHypernatremia is a common problem in hospitalized patients and is associated with high morbidity and mortality. This study was designed to evaluate whether physicians follow the recommended guidelines for the rate of correction of hypernatremia of ≤ 0.5 mEq/L/hr and to evaluate the effect of the rate of correction of severe hypernatremia on the mortality of hospitalized patients.MethodsA retrospective chart review of 131 consecutively hospitalized patients with severe hypernatremia (serum sodium ≥ 155 mEq/L) was performed. Primary outcomes were 30-day patient mortality and 72- hour hypernatremia correction. The first 24-hour serum sodium (Na⁺) correction rate was tested as a categorical variable; slow rate (< 0.25 mEq/L/hr) and fast rate (≥ 0.25 mEq/L/hr).ResultsThe mean admission serum Na⁺ level was 159 ± 3 mEq/L. Ninety percent of patients received the recommended < 0.5 mEq/L/hr serum Na⁺ correction rate; however, hypernatremia was corrected only in 27% of patients after 72 hours of treatment. Thirty-day patient mortality rate was 37%. In multivariable analysis, do not resuscitate status [hazards ratio (HR), 3.85; P < 0.0001], slower correction rate of hypernatremia (HR, 2.63; P = 0.02) and high heart rate (> 100 beats/min; HR, 1.99; P = 0.03) were the independent predictors of 30-day mortality.ConclusionIn patients with severe hypernatremia, the rate of correction of hypernatremia was slow and resulted in inadequate correction in majority of the patients. Both slow rate of hypernatremia correction during the first 24 hours and do not resuscitate status were found to be significant predictors of 30-day patient mortality.     

Short-term efficacy and safety of vasopressin receptor antagonists for treatment of hyponatremia

Background

We performed a meta-analysis to systematically measure efficacy and safety of vasopressin receptor antagonists (VRAs) tested in randomized controlled trials for treatment of hyponatremia.

Methods

MEDLINE, ClinicalTrials.gov, and scientific abstracts were searched without language restriction. Two authors independently screened citations and extracted data on patient characteristics, quality of reports, and efficacy and safety endpoints.

Results

Eleven trials were identified (1094 patients). By meta-analysis, VRAs achieved a net increase in serum sodium concentration ([Na⁺]_serum) relative to placebo of 3.3 mEq/L at day 1 (95% confidence interval [CI], 2.7-3.8), and 4.2 mEq/L at day 2 (95% CI, 3.6-4.8), persisting at days 3-5. Larger net increases in [Na⁺]_serum at days 1-4 were observed in euvolemic hyponatremia and with higher doses. VRAs induced a net increase in effective water clearance relative to placebo of 1244 mL at day 1 (95% CI, 920-1567), persisting at days 2 and 4. VRAs were associated with odds ratios of 3.0 for overly rapid correction of [Na⁺]_serum (P <.001), 7.8 for development of hypernatremia (P <.001), 3.3 for thirst development (P <.001), and 2.2 for postural hypotension (P = .04).

Conclusions

Short-term use of VRAs in treating hyponatremia was successful at raising [Na⁺]_serum. Additional experience is required to guide their optimal use and minimize safety concerns.     

Sodium levels on admission are associated with mortality risk in hospitalized patients

AimsAbnormal sodium values are common among hospitalized patients. We aimed to investigate the association of admission sodium values and mortality.MethodsHistorical prospectively data of adult patients hospitalized to medical wards between January 2011 and December 2013. Admission sodium values were classified to five categories: severe hyponatremia (< 125 mEq/L), mild hyponatremia (125–135 mEq/L), normal sodium values (135–145 mEq/L), mild hypernatremia (145–150 mEq/L) and severe hypernatremia (> 150 mEq/L). Main outcomes were length of hospitalization, in-hospital mortality and mortality at the end-of-follow-up.ResultsThe cohort included 27,889 patients (mean age 67 ± 18 years, 52% males). The total follow-up was 1065 days. Most patients had normal sodium values (76%), 22% had hyponatremia, 3% had hypernatremia. Mean age increased with increase in severity of hyponatremia or hypernatremia. Median length of hospitalization was longer with mild and severe hypernatremia (7 and 5 days, respectively) or with mild and severe hyponatremia (4 and 4 days, respectively), compared to normal sodium levels (3 days). Compared to in-hospital mortality with normal sodium levels (5%), mortality was higher with mild and severe hyponatremia (9% and 14%, respectively) and was highest with mild (28%), and severe hypernatremia (52%). Mortality rate at the end of follow-up was 28% with normal sodium levels, 44% and 48% with mild and severe hyponatremia, 66% and 90% with mild and severe hypernatremia, respectively.ConclusionsAbnormal sodium values on admission were associated with longer hospitalization and increased short- and long-term mortality. Mortality risk was higher with hypernatremia, compared to hyponatremia.     

Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized,placebo-controlled, 26-week trial in patients with type 2 diabetes

AimsTo assess efficacy and safety of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in combination therapy with metformin (≥ 1500 mg/day) and pioglitazone (≥ 30 mg/day) in patients with type 2 diabetes (T2DM) with inadequate glycemic control (hemoglobin A_1c [HbA_1c] ≥ 7.5% and ≤ 11%).MethodsThis placebo-controlled, double-blind study included 313 patients, mean baseline HbA_1c = 8.7%, who were randomized to receive sitagliptin 100 mg/day or placebo for 26 weeks.ResultsThe addition of sitagliptin led to significant (P < .001) mean changes from baseline relative to placebo in HbA_1c (? 0.7%), fasting plasma glucose (? 1.0 mmol/L), and 2-h post-meal glucose (? 2.2 mmol/L). In patients with baseline HbA_1c ≥ 9.0%, mean changes from baseline in HbA_1c were ? 1.6% and ? 0.8% for the sitagliptin and placebo groups, respectively (between-group difference ?0.8%; P < .001). The incidences of reported adverse events were generally similar between the treatment groups. Incidences of symptomatic hypoglycemia were 7/157 [4.5%] and 6/156 [3.8%] in the sitagliptin and placebo groups, respectively (P = .786). Two patients, both in the placebo group, experienced an episode of hypoglycemia that required non-medical assistance.ConclusionsIn this 26-week study, addition of sitagliptin to combination therapy with metformin and pioglitazone improved glycemic control and was generally well tolerated.     

NO levels in diabetes mellitus: Effects of l-NAME and insulin on LCAT,Na+/K+ ATPase activity and lipid profile

ObjectivesDiabetes mellitus (DM) is a chronic disease and one of the most important health problems. Several factors may be responsible for the complications of diabetes mellitus including alterations in the activities of sodium–potassium adenosine triphosphatase (Na⁺/K⁺ ATPase) and lecithin:cholesterol acyltransferase (LCAT) and also levels of nitric oxide (NO). We have investigated the effects of alterations in serum NO levels on activities of erythrocyte membran Na/K ATPase and serum LCAT enzymes.Materials and methodsThe experiments were performed on male rats divided into four groups: group 1, control (standart diet); group 2, diabetic control (single dose of 65 mg/kg of streptozotocin (STZ), i.p); group 3, STZ + insulin (8 IU/kg/day s.c.); group 4 (STZ + l-NAME 5 mg/kg/day orally).ResultStreptozotocin-induced diabetic rats, showed a significant increase in blood glucose and serum cholesterol (C) and triglyceride (TG). Compared to the control group with diabetic group plasma LCAT concentrations and erythrocyte membrane Na⁺/K⁺ ATPase were found to be decreased. Activities of Na⁺/K⁺ ATPase and serum NO level were decreased with the administration of l-NAME. We observed that insulin was ameliorated in all parameters.ConclusionsSerum NO levels is related to erythrocyte membrane Na⁺/K⁺ ATPase activity. But serum NO levels did not affect the plasma LCAT activity and serum lipid profiles.     

Clinical analysis of risk factors for severe COVID-19 patients with type 2 diabetes

AimsTo describe characteristics of COVID-19 patients with type 2 diabetes and to analyze risk factors for severity.MethodsDemographics, comorbidities, symptoms, laboratory findings, treatments and outcomes of COVID-19 patients with diabetes were collected and analyzed.ResultsSeventy-four COVID-19 patients with diabetes were included. Twenty-seven patients (36.5%) were severe and 10 patients (13.5%) died. Higher levels of blood glucose, serum amyloid A (SAA), C reactive protein and interleukin 6 were associated with severe patients compared to non-severe ones (P < 0.05). Levels of albumin, cholesterol, high density lipoprotein, small and dense low density lipoprotein and CD4⁺ T lymphocyte counts in severe patients were lower than those in non-severe patients (P < 0.05). Logistic regression analysis identified decreased CD4⁺ T lymphocyte counts (odds ratio [OR] = 0.988, 95%Confidence interval [95%CI] 0.979–0.997) and increased SAA levels (OR = 1.029, 95%CI 1.002–1.058) as risk factors for severity of COVID-19 with diabetes (P < 0.05).ConclusionsType 2 diabetic patients were more susceptible to COVID-19 than overall population, which might be associated with hyperglycemia and dyslipidemia. Aggressive treatment should be suggested, especially when these patients had low CD4⁺ T lymphocyte counts and high SAA levels.     

Hyponatremia is an independent predictor of adverse clinical outcomes in hospitalized patients due to worsening heart failure

Background and purposeHyponatremia is common and is associated with poor in-hospital outcomes in patients hospitalized with heart failure (HF). However, it is unknown whether hyponatremia is associated with long-term adverse outcomes. The purpose of this study was to clarify the characteristics, clinical status on admission, and management during hospitalization according to the serum sodium concentration on admission, and determine whether hyponatremia was associated with in-hospital as well as long-term outcomes in 1677 patients hospitalized with worsening HF on index hospitalization registered in the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).Methods and subjectsWe studied the characteristics and in-hospital treatment in 1659 patients hospitalized with worsening HF by using the JCARE-CARD database. Patients were divided into 2 groups according to serum sodium concentration on admission <135 mEq/mL (n = 176; 10.6%) or ≥135 mEq/mL (n = 1483; 89.4%).ResultsThe mean age was 70.7 years and 59.2% were male. Etiology was ischemic in 33.9% and mean left ventricular ejection fraction was 42.4%. After adjustment for covariates, hyponatremia was independently associated with in-hospital death [adjusted odds ratio (OR) 2.453, 95% confidence interval (CI) 1.265–4.755, p = 0.008]. It was significantly associated also with adverse long-term (mean 2.1 ± 0.8 years) outcomes including all-cause death (OR 1.952, 95% CI 1.433–2.657), cardiac death (OR 2.053, 95% CI 1.413–2.983), and rehospitalization due to worsening HF (OR 1.488, 95% CI 1.134–1.953).ConclusionsHyponatremia was independently associated with not only in-hospital but also long-term adverse outcomes in patients hospitalized with worsening HF.     

Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia

CONTEXT: Hyponatremia [serum sodium concentration ([Na(+)]), <135 mEq/liter] is the most common fluid and electrolyte abnormality among hospitalized patients. It is frequently caused by the inappropriate release of arginine vasopressin. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of oral conivaptan, a vasopressin V(1A)/V(2) receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia. DESIGN: The study design was a 5-d placebo-controlled, randomized, double-blind study. SETTING: The study was performed at a hospital. Intervention: Oral conivaptan (40 or 80 mg/d) or placebo was given in two divided doses. PATIENTS: Seventy-four patients (average baseline serum [Na(+)], 115 to <130 mEq/liter) were studied. MAIN OUTCOME MEASURE: The main outcome measure was the change from baseline in serum [Na(+)] area under the curve. RESULTS: The least-squares mean change from baseline in the serum [Na(+)] area under the curve with conivaptan (40 and 80 mg/d) was 2.0-fold (P = 0.03) and 2.5-fold (P < 0.001) greater, respectively, than that with placebo. The median time to achieve a confirmed increase in serum [Na(+)] of 4 mEq/liter or more from baseline was 71.7 h for placebo, 27.5 h for 40 mg/d conivaptan (P = 0.044), and 12.1 h for 80 mg/d conivaptan (P = 0.002). The mean total times during which patients had a serum [Na(+)] level of 4 mEq/liter or more above baseline were 46.5, 69.8, and 88.8 h (P = 0.001), respectively. The least-squares mean change in serum [Na(+)] from baseline to end of treatment was 3.4 mEq/liter for placebo, 6.4 mEq/liter for 40 mg/d conivaptan, and 8.2 mEq/liter for 80 mg/d conivaptan (P = 0.002). A confirmed normal serum [Na(+)] (>/=135 mEq/liter) or increase of 6 mEq/liter or more was observed in 48% of patients given placebo, 71% given 40 mg/d conivaptan, and 82% given 80 mg/d conivaptan (P = 0.014). Headache, hypotension, nausea, constipation, and postural hypotension were the most common adverse events. CONCLUSION: Oral conivaptan (40 and 80 mg/d) was well tolerated and efficacious in correcting serum [Na(+)] in hyponatremia.     

Clinical Course of Patients With Hyponatremia and Decompensated Systolic Heart Failure and the Effect of Vasopressin Receptor Antagonism With Tolvaptan

BackgroundPatients with decompensated heart failure, volume overload, and hyponatremia are challenging to manage. Relatively little has been documented regarding the clinical course of these patients during standard in-hospital management or with vasopressin antagonism.Methods and ResultsThe Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan database was examined to assess the short-term clinical course of patients hospitalized with heart failure and hyponatremia and the effect of tolvaptan on outcomes. In the placebo group, patients with hyponatremia (serum Na⁺ <135mEq/L; n = 232), compared with those with normonatremia at baseline (n = 1785), had less relief of dyspnea despite receiving higher doses of diuretics (59.2% vs 69.2% improved; P < .01) and worse long-term outcomes. In the hyponatremia subgroup from the entire trial cohort (n = 475), tolvaptan was associated with greater likelihood of normalization of serum sodium than placebo (58% vs 20% and 64% vs 29% for day 1 and discharge, respectively; P < .001 for both comparisons), greater weight reduction at day 1 and discharge (0.7 kg and 0.8 kg differences, respectively; P < .001 and P = .008), and greater relief of dyspnea (P = .03). Among all hyponatremic patients, there was no effect of tolvaptan on long-term outcomes compared with placebo. In patients with pronounced hyponatremia (<130 mEq/L; n = 92), tolvaptan was associated with reduced cardiovascular morbidity and mortality after discharge (P = .04).ConclusionsIn patients with decompensated heart failure and hyponatremia, standard therapy is associated with less weight loss and dyspnea relief, and unfavorable longer-term outcomes compared to those with normonatremia. Tolvaptan is associated with more favorable in-hospital effects and, possibly, long-term outcomes in patients with severe hyponatremia.     

Trayectoria precoz del sodio urinario y riesgo de eventos adversos en insuficiencia cardiaca aguda y disfunción renal

Introduction and objectivesUrinary sodium (UNa⁺) has emerged as a useful biomarker of poor clinical outcomes in acute heart failure (AHF). Here, we sought to evaluate: a) the usefulness of a single early determination of UNa⁺ for predicting adverse outcomes in patients with AHF and renal dysfunction, and b) whether the change in UNa⁺ at 24 hours (ΔUNa24 h) adds any additional prognostic information over baseline values.MethodsThis is a post-hoc analysis of a multicenter, open-label, randomized clinical trial (IMPROVE-HF) (ClinicalTrials.gov NCT02643147) that randomized 160 patients with AHF and renal dysfunction on admission to a) the standard diuretic strategy, or b) a carbohydrate antigen 125-guided diuretic strategy. The primary end point was all-cause mortality and total all-cause readmissions.ResultsThe mean age was 78 ± 8 years, and the mean glomerular filtration rate was 34.0 ± 8.5 mL/min/1.73 m². The median UNa⁺ was 90 (65-111) mmol/L. At a median follow-up of 1.73 years [interquartile range, 0.48-2.35], 83 deaths (51.9%) were registered, as well as 263 all-cause readmissions in 110 patients. UNa⁺ was independently associated with mortality (HR, 0.75; 95%CI, 0.65-0.87; P < .001) and all-cause readmissions (HR, 0.92; 95%CI, 0.88-0.96; P < .001). The prognostic usefulness of the ΔUNa24 h varied according to UNa⁺ at admission (P for interaction < .05). The ΔUNa24 h was inversely associated with both end points only in the group with UNa⁺ ≤ 50 mmol/L. Conversely, no effect was found in the group with UNa⁺ > 50 mmol/L.ConclusionsIn patients with AHF and renal dysfunction, a single early determination of UNa⁺ ≤ 50 mmol/L identifies patients with a higher risk of all-cause mortality and readmission. The ΔUNa24 h adds prognostic information over baseline values only when UNa⁺ at admission is ≤ 50 mmol/L.     

A randomised controlled trial of high dose vitamin D in recent-onset type 2 diabetes

AimsVitamin D insufficiency has been associated with impaired pancreatic beta-cell function. We aimed to determine if high dose oral vitamin D3 (D) improves beta-cell function and glycaemia in type 2 diabetes.MethodsFifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000 IU D (n = 26) or placebo (n = 24) daily for 6 months. Beta-cell function was measured by glucagon-stimulated serum C-peptide (delta C-peptide [DCP], nmol/l). Secondary outcome measures were fasting plasma glucose (FPG), post-prandial blood glucose (PPG), HbA1c and insulin resistance (HOMA-IR).ResultsIn the D group, median serum 25D (nmol/l) increased from 59 to 150 (3 months) and 128 (6 months) and median serum 1,25D (pmol/l) from 135 to 200 and 190. After 3 months, change in DCP from baseline in D (+0.04) and placebo (−0.08) was not different (P = 0.112). However, change in FPG (mmol/l) was significantly lower in D (−0.40) compared to placebo (+0.1) (P = 0.007), as was the change in PPG in D (−0.30) compared to placebo (+0.8) (P = 0.005). Change in HbA1c (%) between D (−0.20) and placebo (−0.10) was not different (P = 0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups.ConclusionOral D3 supplementation in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function this effect is unlikely to be biologically significant. High dose D3 therefore appears to offer little or no therapeutic benefit in type 2 diabetes.     

Factors affecting prognosis of the patients with severe hyponatremia

IntroductionHyponatremia is one of the most common electrolyte abnormalities in clinical practice. Data regarding factors that have impact on mortality of severe hyponatremia and outcomes of its therapeutic management is insufficient. The present study aimed to examine the factors associated with mortality and the outcomes of treatment in patients with severe hyponatremia.Materials and methodsPatients with serum Na ≤ 115 mequiv./L who were admitted to Ordu State Hospital and Ordu University Training and Research Hospital between 2014 and 2018 were included in the study. Demographic and laboratory features, severity of the symptoms, comorbid diseases, medications, and clinical outcome measures of the patients were obtained retrospectively from their medical records. Factors associated with in-hospital mortality, overcorrection and undercorrection were assessed.ResultsA total of 145 patients (median age 69 years and 58.6% female) met inclusion criteria. Diuretic use was the most common etiologic factor for severe hyponatremia that present in 50 (34.5%) patients. Sixty-seven (46.2%) patients had moderately severe while 8 patients (5.5%) had severe symptoms. The median increase in serum Na 24 h after admission in the study population was 8.9 mequiv./L (?6 to 19). Nonoptimal correction was seen in 92 (63.4%) patients. Hypertonic saline use was associated with overcorrection (OR, 3.07; 95% CI: 1.47–6.39; p = 0.002). Avoidance of hypertonic saline (aOR, 2.52; 95% CI: 1.12–5.66; p = 0.029) and having neuropsychiatric disorder (aOR, 2.60; 95% CI: 1.10–6.11; p = 0.025) were associated with undercorrection. In-hospital mortality rate was 12.4% and having CKD and cancer, undercorrection of sodium and presence of severe symptoms were significantly associated with in-hospital mortality.ConclusionSevere hyponatremia in hospitalized patients is associated with substantial mortality. The incidence of non-optimal correction of serum Na is high; under-correction, presence of severe symptoms, chronic kidney disease and cancer were the factors that increase mortality rate.     

Mitochondrial calcium and the regulation of metabolism in the heart

Consumption of adenosine triphosphate (ATP) by the heart can change dramatically as the energetic demands increase from a period of rest to strenuous activity. Mitochondrial ATP production is central to this metabolic response since the heart relies largely on oxidative phosphorylation as its source of intracellular ATP. Significant evidence has been acquired indicating that Ca^2 + plays a critical role in regulating ATP production by the mitochondria. Here the evidence that the Ca^2 + concentration in the mitochondrial matrix ([Ca^2 +]_m) plays a pivotal role in regulating ATP production by the mitochondria is critically reviewed and aspects of this process that are under current active investigation are highlighted. Importantly, current quantitative information on the bidirectional Ca^2 + movement across the inner mitochondrial membrane (IMM) is examined in two parts. First, we review how Ca^2 + influx into the mitochondrial matrix depends on the mitochondrial Ca^2 + channel (i.e., the mitochondrial calcium uniporter or MCU). This discussion includes how the MCU open probability (P_O) depends on the cytosolic Ca^2 + concentration ([Ca^2 +]_i) and on the mitochondrial membrane potential (ΔΨ_m). Second, we discuss how steady-state [Ca^2 +]_m is determined by the dynamic balance between this MCU-based Ca^2 + influx and mitochondrial Na⁺/Ca^2 + exchanger (NCLX) based Ca^2 + efflux. These steady-state [Ca^2 +]_m levels are suggested to regulate the metabolic energy supply due to Ca^2 +-dependent regulation of mitochondrial enzymes of the tricarboxylic acid cycle (TCA), the proteins of the electron transport chain (ETC), and the F₁F₀ ATP synthase itself. We conclude by discussing the roles played by [Ca^2 +]_m in influencing mitochondrial responses under pathological conditions. This article is part of a Special Issue entitled "Mitochondria: From BasicMitochondrial Biology to Cardiovascular Disease."     

A meta-analysis of efficacy of topical steroids in eosinophilic esophagitis: From the perspective of histologic,clinical, and endoscopic outcome

BackgroundSwallowed topical steroids are a mainstay drug therapy for eosinophilic esophagitis (EoE), studies have demonstrated good histologic response, but with enormous discrepancy in clinical and endoscopic improvement. We conducted this meta-analysis to investigate the efficacy of topical steroids in EoE in histological, clinical and endoscopic improvement.MethodsSeveral databases were searched from inception to August 1, 2019 for randomized controlled trials (RCTs) comparing topical steroids with placebo for EoE in the short-term. The outcomes of interest mainly included basic characteristics of the studies, histologic, clinical, endoscopic response rate and adverse events. The results were pooled together using Reviewer Manager 5.3.5 software, and inconsistency was quantified using I² statistics.ResultsNine studies were eventually selected. The results showed that topical steroids were effective in inducing histologic response compared with placebo for both complete (OR 35.82, 95% CI 14.98–85.64, P < 0.0001; I² = 0, P = 0.72) and partial response (OR 28.44, 95% CI 8.56–94.47, P < 0.0001; I² = 70%, P = 0.0009). Moreover, topical steroids were useful in gaining clinical response (OR 2.53, 95% CI 1.14–5.60, P = 0.02; I² = 60%, P = 0.02) and endoscopic response (OR 3.51, 95% CI 1.47–8.36, P = 0.005; I² = 0, P = 0.57). Generally, topical steroids are well tolerated. The most common adverse events are infections and infestations (59 cases).ConclusionTopical steroids were effective in inducing histological, clinical and endoscopic response in the short-term, and the adverse events were almost tolerable; however, we should interpret the result of clinical and endoscopic response with caution.     

Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: Insights from a patient-level pooled analysis of six randomized clinical trials

AimsTo quantify the effect of liraglutide on systolic blood pressure (SBP) and pulse in patients with type 2 diabetes (T2D), and assess the influence of covariates on observed SBP reductions.MethodsA patient-level pooled analysis of six phase 3, randomized trials was conducted.ResultsThe analysis included 2792 randomized patients. In the intention-to-treat population (n = 2783), mean [± SE] SBP reductions from baseline with liraglutide 1.2 mg (2.7 [0.8] mmHg) and 1.8 mg (2.9 [0.7] mmHg) once daily were significantly greater than with placebo (0.5 [0.9] mmHg; P = 0.0029 and P = 0.0004, respectively) after 26 weeks, and were evident after 2 weeks. Liraglutide was also associated with significantly greater SBP reductions than glimepiride and, at a dose of 1.8 mg, insulin glargine and rosiglitazone. SBP reductions with liraglutide weakly correlated with weight loss (Pearson’s correlation coefficient: 0.08–0.12; P ≤ 0.0148). No dependence of these reductions on concomitant antihypertensive medications was detected (P = 0.1304). Liraglutide 1.2 and 1.8 mg were associated with mean increases in pulse of 3 beats per minute (bpm), versus a 1 bpm increase with placebo (P < 0.0001 for each dose versus placebo).ConclusionsLiraglutide reduces SBP in patients with T2D, including those receiving concomitant antihypertensive medication.     

Relationship between circulating endothelial progenitor cells and insulin resistance in non-diabetic patients with ischemic chronic heart failure

AimThe objective of this study was to assess a relationship between insulin resistance (IR) and counts of CD45⁻CD34⁺, CD14⁺CD309⁺, and CD14⁺CD309⁺Tie2⁺ phenotyped circulating endothelial progenitor cells (EPCs) in patients with ischemic chronic heart failure (CHF).MethodsThe study involved 300 CHF patients (186 males) aged 48–62 years with angiografically proven coronary artery disease and/or previously defined myocardial infarction. Insulin resistance was assessed by the homeostasis model assessment for insulin resistance (HOMA-IR). EPC populations were phenotyped by flow cytofluorimetry.ResultsCirculating EPCs counts were statistically significantly lower in CHF patients with IR than in patients without IR. We found that the most valuable multivariable predictors of the depletion of the CD45⁺CD34⁺ EPCs were NT-pro-brain natriuretic peptide (BNP) (1.32; 95% CI = 1.19–2.77; P = 0.001), left ventricular ejection fraction (OR = 1.30; 95% CI = 1.09–1.60; P = 0.002), NYHA class (OR = 1.12; 95% CI = 1.02–1.19; P = 0.001). NT-pro-BNP (OR = 1.45; 95% CI = 1.15–2.90; P = 0.003), left ventricular ejection fraction (OR = 1.32; 95% CI = 1.11–1.65; P = 0.001) were found as powerful predictors for depletion in CD45⁻CD34⁺ EPCs. We also identified six independent variables with high predictive value for depletion of CD14⁺CD309⁺ EPCs: NT-pro-BNP (OR = 1.41; 95% CI = 1.15–2.90; P = 0.003), left ventricular ejection fraction (OR = 1.18; 95% CI = 1.10–1.76; P = 0.036), NYHA class (OR = 1.15; 95% CI = 1.07–1.22; P = 0.001), hs-C reactive protein (OR = 1.02; 95% CI = 1.01–1.05; P = 0.012). As independent multivariable predictors for depletion in CD14⁺CD309⁺Tie2⁺ EPCs were selected five variables: NT-pro-BNP (OR = 1.65; 95% CI = 1.44–4.70; P = 0.006), left ventricular ejection fraction (OR = 1.07; 95% CI = 1.02–1.12; P = 0.018), NYHA class (OR = 1.13; 95% CI = 1.06–1.21; P = 0.001), hs-C-reactive protein (OR = 1.08; 95% CI = 1.03–1.16; P = 0.002).ConclusionIR may be an additional factor contributing decreased circulating level of proangiogenic EPCs in non-diabetic CHF patients.     

Contribution of common variants of ENPP1, IGF2BP2, KCNJ11, MLXIPL,PPARγ, SLC30A8 and TCF7L2 to the risk of type 2 diabetes in Lebanese and Tunisian Arabs

BackgroundWhile several type 2 diabetes mellitus (T2DM) susceptibility loci identified through genome-wide association studies (GWAS) have been replicated in many populations, their association in Arabs has not been reported. For this reason, the present study looked at the contribution of ENNP1 (rs1044498), IGF2BP2 (rs1470579), KCNJ11 (rs5219), MLXIPL (rs7800944), PPARγ (rs1801282), SLC30A8 (rs13266634) and TCF7L2 (rs7903146) SNPs to the risk of T2DM in Lebanese and Tunisian Arabs.MethodsStudy subjects (case/controls) were Lebanese (751/918) and Tunisians (1470/838). Genotyping was carried out by the allelic discrimination method.ResultsIn Lebanese and Tunisians, neither ENNP1 nor MLXIPL was associated with T2DM, whereas TCF7L2 was significantly associated with an increased risk of T2DM in both the Lebanese [P < 0.001; OR (95% CI): 1.38 (1.20–1.59)] and Tunisians [P < 0.001; OR (95% CI): 1.36 (1.18–1.56)]. Differential associations of IGF2BP2, KCNJ11, PPARγ and SLC30A8 with T2DM were noted in the two populations. IGF2BP2 [P = 1.3 × 10^?5; OR (95% CI): 1.66 (1.42–1.94)] and PPARγ [P = 0.005; OR (95% CI): 1.41 (1.10–1.80)] were associated with T2DM in the Lebanese, but not Tunisians, while KCNJ11 [P = 8.0 × 10^?4; OR (95% CI): 1.27 (1.09–1.47)] and SLC30A8 [P = 1.6 × 10^?5; OR (95% CI): 1.37 (1.15–1.62)] were associated with T2DM in the Tunisians, but not Lebanese, after adjusting for gender and body mass index.ConclusionT2DM susceptibility loci SNPs identified through GWAS showed differential associations with T2DM in two Arab populations, thus further confirming the ethnic contributions of these variants to T2DM susceptibility.