Increased Serum Sodium Research Articles

Donor Pretreatment With Hypertonic Saline Attenuates Primary Allograft Dysfunction

Hypertonic saline (HTS) has been previously demonstrated to have immune modulatory and vascular protective effects. We assessed the effect of donor pretreatment with HTS on allograft preservation in a porcine model of orthotopic heart transplantation. Orthotopic transplants were performed after 6 hours of cold static allograft storage. Donor pigs were randomly assigned to pretreatment with (n=7) or without (n=6) HTS (4.5 mL/kg of 7.5% NaCl) administered 1 hour before donor heart arrest. Administration of HTS increased serum sodium level from 138+/-2 mmol/L to 154+/-4 mmol/L, which normalized to 144+/-3 mmol/L 1 hour after infusion. Successful weaning from cardiopulmonary bypass was significantly greater in HTS-treated hearts (6/7 vs 1/6; P=0.029). Preload recruitable stroke work after transplantation was improved compared to control (88+/-21% vs 35+/-8% of baseline; P=0.0001). Similarly, end-systolic elastance was improved compared to control (85+/-17% vs 42+/-12% of baseline; P=0.0002). Posttransplantation systolic blood pressure was significantly higher in the donor HTS group (60+/-9 mm Hg vs 35+/-6 mm Hg; P=0.04). Donor HTS treatment improved coronary artery endothelial-dependent vasorelaxation compared with control (Emax: HTS, 59+/-4%; control, 47+/-3%; P=0.04). HTS also resulted in improved endothelial-independent vasorelaxation compared with control (Emax: HTS, 71+/-3%; control, 59+/-4%; P=0.03; ED-50: HTS, 0.56x10 to 6+/-0.23 mol/L; control, 2.5x10 to 6+/-1.0 mol/L; P=0.04). Sensitivity to endothelin-1-induced vasospasm was reduced with HTS pretreatment (% maximum contraction [Cmax]: HTS, 338+/-15%; control, 419+/-40%; P=0.01). Donor HTS pretreatment attenuates posttransplantation cardiac allograft myocardial dysfunction, improves posttransplantation systemic hemodynamic function, and preserves posttransplantation cardiac allograft vascular function. HTS may be a novel organ donor intervention to prevent primary graft dysfunction.

A review of drug-induced hypernatraemia.

Drug-induced electrolyte abnormalities have been increasingly reported and may be associated with considerable morbidity and/or mortality. In clinical practice, hypernatraemia (serum sodium higher than 145 mmol/L) is usually of multifactorial aetiology and drug therapy not infrequently is disregarded as a contributing factor for increased serum sodium concentration. Strategies to prevent this adverse drug effect involve careful consideration of risk factors and clinical and laboratory evaluation in the course of treatment. Herein, we review evidence-based information via PubMed and EMBASE and the relevant literature implicating pharmacologic treatment as an established cause of hypernatraemia and discuss its incidence and the underlying pathophysiologic mechanisms.

Syndrome of Inappropriate Antidiuretic Hormone Secretion as an Initial Presentation of Prostate Cancer

We report a patient with the syndrome of inappropriate antidiuretic hormone secretion (SIADH), viral meningitis, and prostate cancer. After resolution of the viral meningitis, hyponatremia presented. Following a radical prostatectomy, however, the hyponatremia resolved without any therapy that would increase serum sodium. Although SIADH may be present in any type of carcinoma, its frequency in prostate cancer is low. The diagnosis of SIADH in prostate cancer may indicate a poor prognosis.

Patients Presenting with Severe Hypotonic Hyponatremia: Etiological Factors, Assessment, and Outcomes

Background: Although hospital-acquired hyponatremia is well described, severe community-acquired hyponatremia has been studied less extensively. Aim: To assess characteristics and outcomes of patients admitted with severe hypotonic hyponatremia (SHH) (defined as serum sodium ≤ 120 mmol/L). Methods: All patients with serum sodium of ⪙ 120 mmol/L who were admitted to 2 large teaching hospitals from January 2000 to August 2007 were identified, and data were obtained from medical records. Main outcome measures were incidence of osmotic demyelination and mortality. Results: Two hundred fifty-five patients were admitted who had SHH (female to male ratio 2:1), and the mean age was 72 ± 14 years. The most common etiological factors were thiazide/indapamide diuretics (41%), syndrome of inappropriate antidiuretic hormone secretion (38%), and hypovolemia (24%). Inappropriately rapid correction of serum sodium (> 12 mmol/L over the first 24 hours) occurred in 37 patients (15%), with 4 patients (11%) developing osmotic demyelination. Patients who developed osmotic demyelination were more likely to be younger, abuse alcohol (3 of 4 patients), and have lower serum potassium levels. One patient had a hypoxic-anoxic episode at presentation. The patients also had a mean serum sodium increase in the first 24 and 48 hours of 21 ± 5 mmol/L and 28 ± 8 mmol/L, respectively. None of the patients with osmotic demyelination received hypertonic saline. None of the patients in whom the serum sodium increment was limited to ≤ 12 mmol/L developed osmotic demyelination. Overall, mortality was 10% and was not related to sodium level at presentation. Conclusions: Patients treated with thiazide or indapamide (particularly elderly women) may benefit from monitoring of serum sodium levels. Inappropriately rapid serum sodium correction is associated with osmotic demyelination, particularly in patients with risk factors for this condition. In contrast to what has been reported for hyponatremia in hospitalized patients, severity of hyponatremia on admission did not predict increased mortality in our patient population.

Leapfrogging Data

Properly designed and conducted randomized controlled clinical trials (RCTs) are the premier tool for both testing mechanistic hypotheses and critically ascertaining the risks and benefits of a therapy or strategy for clinical care. The sample size of a trial is mainly a function of the rates of its primary objectives and the presumed influence of the intervention. Trials focusing on a primary outcome variable that can be readily quantified in each subject, such as blood pressure or plasma cholesterol levels, require substantially fewer participants and shorter durations to determine whether their predefined measurement is altered compared with a morbidity and mortality trial. Trials designed to determine whether clinical prognosis is altered by an intervention depend on the proportion of patients experiencing the predefined adverse clinical event(s) and often require 100s-fold–greater patient-time exposures to test their primary hypothesis and provide even modest information about safety. These resource-intense morbidity and mortality trials are generally only performed when information from observational studies as well as smaller mechanistic and surrogate- outcomes RCTs are so highly supportive of a favorable outcome that they justify the effort. Despite this understandable stacking of the cards with the best available information, many of the morbidity and mortality trials conducted to test for a potential favorable impact of an intervention conclude by not supporting the prestudy hypothesis-generating data.1 The lessons in humility offered by these neutral or negative outcomes trials underscore the importance of obtaining crucial risk–benefit data before widespread adoption of even an apparently favorable therapy.2 Articles pp 2506 and 2515 For rational therapeutic decision making, we would ideally like to have both a framework of reliable mechanistic information and robust clinical outcomes and safety data. Sometimes major clinical outcomes trials are designed with a complement of embedded ancillary trials to generate a more complete picture …

Determination of tolerable and toxic salt concentrations in drinking water in rat, pig, and rabbit

In some geographical areas human and animal populations are compelled to use salty water. In this study, tolerable and toxic salt concentrations were evaluated in rat, pig, and rabbit. Ninety Wistar rats weighing approximately 250 g were allocated to nine groups for study. For treatment, distilled water, 0.5, 1, 1.2, 1.4, 1.6, 1.8 or 2% salt (NaCl) concentrations were consumed by test groups, while the control group consumed Zanjan potable water. All animals were observed twice daily for mortality or evidence of morbidity. Serum sodium levels and plasma osmolarity were measured at the onset of experiment and 120 h later. Similar experimental conditions were employed in pig and rabbit. Rat tolerated 0.5, 1, and 1.2% NaCl concentrations in drinking water but higher concentrations were toxic and life threatening, accompanied by significantly increased serum sodium levels and plasma osmolarity. This study showed that pig was the most sensitive and rabbit the most resistant species to different NaCl concentrations. Although NaCl concentrations lower than 1.4% was considered as tolerable in rat, the animal health was affected. NaCl concentrations of 1.4% and higher may jeopardize animal health and were considered as toxic amounts.

Abstract 2329: Donor Pretreatment with Hypertonic Saline Attenuates Primary Cardiac Allograft Dysfunction

Objective: Hypertonic saline (HTS) has been previously demonstrated to have immune modulatory and vascular protective effects. We assessed the effect of donor pretreatment with HTS on allograft myocardial function in a porcine model of orthotopic heart transplantation. We hypothesized that HTS infusion prior to donor heart arrest and storage would limit ischemia-reperfusion injury and improve myocardial performance following transplantation. Methods: Orthotopic transplants were performed after 6 hours of ischemic allograft storage. Donor pigs were randomly assigned to pretreatment with (n = 7) or without (n = 6) HTS (4.5 ml/kg of 7.5% NaCl) administered 1 hour prior to donor heart arrest. Left ventricular performance was determined after caval occlusion using a Millar micromanometer and conductance catheter. Hemodynamic measurements were obtained using a Swan-Ganz catheter. Results: Administration of hypertonic saline increased serum sodium level from 138 ± 2 mmol/L to 154 ± 4 mmol/L, which normalized to 144 ± 3 mmol/L 1 hour post-infusion. Weaning from CPB and LV performance after transplantation was improved after donor HTS treatment. Successful weaning from CPB was significantly greater in HTS treated hearts (6/7 versus 1/6, p < 0.05). Preload recruitable stroke work post-transplantation was improved compared to control (88 ± 21% versus 35 ± 8% of baseline, p < 0.01). Similarly, maximal elastance was improved compared to control (85 ± 17% versus 42 ± 12% of baseline, p = 0.03). No significant differences in post-transplant central venous, pulmonary artery or pulmonary capillary wedge pressures were observed between groups. However, post-transplant systolic blood pressure was significantly higher in the donor HTS group (60 ± 9 mmHg versus 35 ± 6 mmHg, p = 0.04). Conculsions: Donor HTS pretreatment attenuates post-transplant cardiac allograft myocardial function and improves post-transplant systemic hemodynamic function. HTS may be a novel organ donor intervention to prevent primary graft dysfunction. Further clinical evaluation of this simple and potentially cost-effective intervention is warranted.

Etiology, diagnostics and therapy of hyponatremias

Etiopathogenesis, diagnostics and therapy of hyponatremias are summarized for clinicians. Hyponatremia is the most common electrolyte abnormality. Mild to moderate hyponatremia and severe hyponatremia are found in 15-30% and 1-4% of hospitalized patients, respectively. Pathophysiologically, hyponatremias are classified into two groups: hyponatremia due to non-osmotic hypersecretion of vasopressin (hypovolemic, hypervolemic, euvolemic) and hyponatremia of non-hypervasopressinemic origin (pseudohyponatremia, water intoxication, cerebral salt wasting syndrome). Patients with mild hyponatremia are almost always asymptomatic. Severe hyponatremia is usually associated with central nervous system symptoms and can be life-threatening. Diagnostic evaluation of patients with hyponatremia is directed toward identifying the extracellular fluid volume status, the neurological symptoms and signs, the severity and duration of hyponatremia, the rate at which hyponatremia developed. The first step to determine the probable cause of hyponatremia is the differentiation of the hypervasopressinemic and non-hypervasopressinemic hyponatremias with measurement of plasma osmolality, glucose, lipids and proteins. For further differential diagnosis of hyponatremia, the determination of urine osmolality, the clinical assessment of extracellular fluid volume status and the measurement of urine sodium concentration provide important information. The most important representative of euvolemic hyponatremias is SIADH. The diagnosis of SIADH is based on the exclusion of other hyponatremic conditions; low plasma osmolality (<275 mosmol/kg) and inappropriate urine concentration (urine osmolality >100 mosmol/kg) are of pathognomic value. Acute (<48 hrs) severe hyponatremia (<120 mmol/l) necessitates emergency care with rapid restoration of normal osmotic milieu (1 mmol/l/hr increase rate of serum sodium). Patients with chronic symptomatic hyponatremia have a high risk of osmotic demyelination syndrome in brain if rapid correction of the plasma sodium occurs (maximal rate of correction of serum sodium should be 0.5 mmol/l/hr or less). The conventional treatments for chronic asymptomatic hyponatremia (except hypovolemic patients) include water restriction and/or the use of demeclocycline or lithium or furosemide and salt supplementation. Vasopressin receptor antagonists have opened a new forthcoming therapeutic era. V2 receptor antagonists, such as lixivaptan, tolvaptan, satavaptan and the V2+V1A receptor antagonist conivaptan promote the electrolyte-sparing excretion of free water and lead to increased serum sodium.

Vasopressin-receptor antagonists in heart failure

The role of arginine vasopressin in heart failure and the use of vasopressin receptor antagonists in the treatment of heart failure are reviewed. Arginine vasopressin (AVP) functions in the regulation of plasma osmolarity and blood pressure. In heart failure, AVP worsens heart failure by causing vasoconstriction of arteries and veins, potentially contributing to remodeling of the left ventricle and causing fluid retention and worsening of hyponatremia. Two V(2)-receptor antagonists, tolvaptan and lixivaptan, and one combined V(1a)- and V(2)-receptor antagonist, conivaptan, have shown promise for use in patients with heart failure. All three agents have been shown to increase free water excretion and increase serum sodium levels while maintaining serum potassium levels. They have not been shown to decrease renal function or the glomerular filtration rate and are well tolerated, with thirst being the major adverse effect during clinical trials. Because of their effects on sodium, vasopressin antagonists need to be carefully monitored to ensure that serum sodium levels do not increase too quickly and put the patient at risk for overcorrection or osmotic demyelination syndrome. In addition, patients need to be monitored for signs of dehydration secondary to increased urine excretion. To date, studies have not consistently shown improvements in patient symptoms or weight reduction. However, early data suggest that at least one agent, tolvaptan, does not alter mortality. Based on data from available clinical trials, vasopressin antagonists may offer a new treatment option for patients with congestive heart failure. However, these agents do not currently appear to delay the progression of heart failure or decrease mortality.

Observations regarding the use of the aquaretic agent conivaptan for treatment of hyponatremia

The treatment of hyponatremia, especially euvolemic and hypervolemic hyponatremia, has changed with the development of drugs which function as vasopressin receptor antagonists. These agents increase solute-free water excretion by the kidney resulting in an aquaresis. Conivaptan, a vasopressin receptor antagonist, has recently been approved by the FDA in the United States for use in the therapy of both euvolemic and hypervolemic hyponatremia. This report summarizes one center's experience with ten patients treated with this new drug. The patients had euvolemic hyponatremia with serum sodium levels less than 128 mEq/l. The same protocol was used in all patients with the conivaptan being given as a 20-mg intravenous loading dose followed by a 20-mg continuous 24-h infusion. Review of the data revealed that six of the ten patients had an excellent response to the therapy, with serum sodium increasing by a mean of 8.5+/-0.8 mEq/l (increases ranged from 7 to 12 mEq/l over 24 h). No significant changes in serum potassium levels or mean arterial pressures were noted. Two of the ten patients experienced a decrease in urine osmolality without a significant increase in serum sodium. Two other patients had only slight decreases in urine osmolality, and no significant increase in serum sodium levels. The data reveal that conivaptan is useful in the management of significant hyponatremia. There were no significant untoward effects, with the exception of one patient whose blood pressure decreased during the conivaptan infusion and who responded to cessation of the infusion and saline replacement therapy. This new class of drugs holds great promise for the treatment of dilutional hyponatremic disorders.

Detoxication Treatment for Carbamazepine and Lithium Overdose

This article reports detoxication treatments of a case of combined overdose of carbamazepine and lithium in a 38-year-old female with bipolar disorder. She was brought to the emergency unit after the family found her unresponsive and lying near empty packages for carbamazepine (corresponded to 7.7 g) and lithium carbonate (corresponded to 6.6 g) tablets. On admission, her blood pressure, heart rate and respiratory rate were 80/55 mmHg, 90 per minute and 13 per minute, respectively. Her GCS was 3 (E1, M1, V1). She received gastric lavage after intratracheal intubation, followed by administration of activated charcoal via gastric tube, and a large volume (800 ml/h) of lactate Ringer's solution by intravenous infusion. The serum levels of carbamazepine and lithium approximately 5 h after ingestion were 56.0 mug/ml and 3.56 mEq/l, respectively. The carbamazepine overdose was mainly treated by a 3 h charcoal hemoperfusion (CHP). The CHP treatment decreased serum carbamazepine levels by approximately 30-40% as compared with the levels simulated by Bayesian analysis using 1-point or 2-points serum level(s) (without detoxication treatment). For lithium overdose continuous infusion of Ringer's solution was effective, which increased serum sodium gradually and facilitated the elimination of lithium. In conclusion, the treatments with CHP and continuous infusion of Ringer's solution were considered to be effective for detoxification of carbamazepine and lithium overdose, respectively, when compared with those drug levels without detoxication treatment that simulated by Bayesian analysis method.

Intravenous Conivaptan

*Conivaptan is an arginine vasopressin V1A and V2 receptor antagonist. The intravenous formulation is approved in the US for use in the treatment of euvolemic and hypervolemic hyponatremia. Conivaptan produces a dose-dependent electrolyte-sparing aquaresis (solute-free water excretion), increasing serum sodium levels. *In a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial in adults with euvolemic or hypervolemic hyponatremia, the area under the serum sodium concentration-time curve over a 4-day treatment duration (primary endpoint) was significantly greater in intravenous conivaptan 40 mg/day recipients than in placebo recipients. *The total time during treatment that patients had serum sodium levels > or = 4 mEq/L above baseline was significantly longer in intravenous conivaptan than placebo recipients. In conivaptan recipients, an increase in serum sodium levels of > or = 4 mEq/L above baseline was achieved approximately 1 day after the first dose of the drug. *In addition, the mean change from baseline in free water clearance and effective water clearance over the first day of treatment was significantly greater with intravenous conivaptan than with placebo. *Given the nature of the treatment, the tolerability profile for intravenous conivaptan was generally acceptable in patients with hyponatremia. The most common adverse events were injection related (e.g. injection-site phlebitis), hypotension, and pyrexia.

Hypertonic Saline for Hyponatremia

Data regarding dosage-response relationships for using hypertonic saline in treatment of hyponatremia are extremely limited. Objectives of this study were to assess adherence to previously published guidelines (limiting correction to <12 mEq/L per d and <18 mEq/L per 48 h) in treating hyponatremia with hypertonic saline and to determine the predictive accuracy of the Adrogué-Madias formula. A retrospective review was conducted of all 62 adult, hyponatremic patients who were treated with hypertonic saline during 5 yr at a 528-bed, acute care, teaching hospital. Median infusion rate was 0.38 ml/kg per h, increasing serum sodium concentration by 0.47 +/- 0.05 mEq/L per h, 7.1 +/- 0.6 mEq/L per 24 h, and 11.3 +/- 0.7 mEq/L per 48 h. In 11.3% of cases, the increase was >12 mEq/L per 24 h and in 9.7% was >18 mEq/L per 48 h. No patient's rate was corrected by >25 mEq/L per 48 h. Among patients with serum sodium <120 mEq/L, the observed increase in sodium exceeded the rise predicted by the Adrogué-Madias formula in 74.2%; the average correction in overcorrectors was 2.4 times the predicted. Inadvertent overcorrection was due to documented water diuresis in 40% of cases. The Adrogué-Madias formula underestimates increase in sodium concentration after hypertonic saline therapy. Unrecognized hypovolemia and other reversible causes of water retention pose a risk for inadvertent overcorrection. Hypertonic saline should be infused at rates lower than those predicted by formulas with close monitoring of serum sodium and urine output.

Hyponatremia and Vasopressin Antagonism in Congestive Heart Failure

In a national heart failure registry, hyponatremia (serum sodium < 130 mEq/L) was initially reported in 5% of patients and considered a risk factor for increased morbidity and mortality. In a chronic heart failure study, serum sodium level on admission predicted an increased length of stay for cardiovascular causes and increased mortality within 60 days of discharge. Hyponatremia in patients with congestive heart failure (CHF) is associated with a higher mortality rate. Also, by monitoring and increasing serum sodium levels during hospitalization for CHF, patient outcomes may improve. This review describes the pathophysiology of hyponatremia in relation to CHF, including the mechanism of action of vasopressin receptors in the kidney, and assesses the preclinical and clinical trials of vasopressin receptor antagonists--agents recently developed to treat hyponatremia. In hospitalized patients with CHF, hyponatremia plays a major role in poor outcomes. Vasopressin receptor antagonists have been shown to be safe and effective in clinical trials in patients with hyponatremia.

Conivaptan: New treatment for hyponatremia

The pharmacology, bioavailability and pharmacokinetics, clinical efficacy, adverse effects and toxicities, drug interactions, dosage and administration, and safety issues related to the use of conivaptan are discussed. Conivaptan hydrochloride is a nonpeptide, V1A and V2 vasopressin-receptor antagonist. It is available as an i.v. formulation in 4-mL ampules containing 20 mg of conivaptan hydrochloride. The drug is active both orally and i.v. Conivaptan injection is approved for the treatment of euvolemic hyponatremia in hospitalized patients. Three double-blind, placebo-controlled, randomized, multicenter studies have been conducted in the United States and internationally. The studies used various dosing regimens for conivaptan but maintained the same efficacy endpoints. Each study showed conivaptan to be effective in increasing serum sodium and in water clearance. Conivaptan is being evaluated in the treatment of acute decompensated heart failure and chronic heart failure, but the safety of this drug has not been fully established. The drug has been generally well tolerated in clinical trials with both oral and i.v. administration. The approved dosing regimen consists of a 20-mg i.v. loading dose administered over 30 minutes, followed by a continuous infusion of 20 mg administered over 24 hours. Clinical studies evaluating conivaptan have been short term; longer-term effects of hemodynamic parameters are unknown. Conivaptan, the first vasopressin antagonist approved for the treatment of euvolemic hyponatremia, has a unique mechanism of action that results in free-water excretion and offers a new option for the treatment of resistant hyponatremia in the acute setting when patients have not responded to standard management.

The Effects of Normal and Hypertonic Saline on Regional Blood Flow and Oxygen Delivery

Boluses of crystalloids are frequently given to patients to optimize vital organ perfusion. However, their effect on regional blood flow and oxygen delivery in the normal mammalian circulation has not been studied. We compared the effects of normal or hypertonic (3%) saline or control on regional blood flow and oxygen delivery in normal animals. We conducted a randomized, controlled animal study in seven merino cross-ewes. We implanted chronic flow probes around aorta, coronary, renal, and mesenteric arteries. We randomized animals to three different interventions: observation (control), normal saline (1 L over 15 min), or 3% saline (300 mL over 15 min). We continuously measured central hemodynamics and organ blood flow for 210 min. Both fluids increased heart rate, cardiac output, central venous pressure, peripheral conductance, coronary and mesenteric blood flow, and conductance in the first hour (P < 0.05). In the second and third hour, both maintained a greater cardiac output, total peripheral conductance, and mesenteric blood flow (P < 0.05) than control, but the difference decreased. In contrast, renal blood flow was unaffected and, because of hemodilution, renal oxygen delivery was decreased in the first hour (P < 0.05). Simultaneously, urine output and creatinine clearance increased (P < 0.05) in both groups. Finally, 3% saline significantly, but transiently, increased serum sodium and osmolarity. Normal and hypertonic saline have similar systemic and regional hemodynamic effects. They also have no effect on renal blood flow and initially decrease renal oxygen delivery while increasing urine output.

Treatment of hyponatraemia by urea decreases risks of brain complications in rats. Brain osmolyte contents analysis

Brain damage (myelinolysis) develops in hyponatraemia after a large increase in serum sodium regardless of the currently available methods of correction. However, a preliminary study suggests that treatment of hyponatraemia with urea limits the risks of brain lesions in rats. Benefits of sustained high blood levels of urea and mechanisms of protection remain hypothetical. In the first part of the study, hyponatraemic rats received repeated (i.p.) doses of urea (2 g/kg b.w./6 h) leading to sustained blood levels (urea+/-230 mg/dl). Neurologic outcome was compared to correction of hyponatraemia by water diuresis. In the second part of the study, we analysed the adaptative response of the brain to correction of hyponatraemia with either urea or water diuresis, by measurement of cerebral osmolyte contents. Despite a large correction of the serum sodium (mean Delta SNa=32 mEq/l/24 h), mortality rate (13%) and neurological symptoms were low in the urea-treated group contrary to control groups treated by water diuresis (mortality: 87%). This shows with stronger evidence the protective effect of urea against brain myelinolysis. In the second part, analysis of brain composition shows that, in the urea groups, 24 h after correction, intracerebral hyperionization (NaCl) was avoided and brain water contents remained normal. No significant changes of the major brain organic osmolyte composition were observed after urea administration except reaccumulation of betaine. No difference in brain composition was noted regarding concomitant plasma urea levels (>or<150 mg/dl). In rats treated by water diuresis, the brain remained also significantly depleted in organic osmolytes 24 h after correction, but contrary to administration of urea, this treatment was associated with a high mortality rate. These comparative results suggest a specific brain-protective effect of urea itself against myelinolysis.

Vaptans: A promising therapy in the management of advanced cirrhosis

Hyponatremia (serum sodium concentration, <135 mmol/L) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V(2)-receptor antagonist that promotes aquaresis--excretion of electrolyte-free water--might be of benefit in hyponatremia. In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. [Abstract reproduced by permission of N Engl J Med 2006;355:2099-2112].

Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial

Hyponatremia predicts poor outcome in patients with acute heart failure syndromes. This study evaluated the relationship between baseline serum sodium, change in serum sodium, and 60-day mortality in hospitalized heart failure patients. A post-hoc analysis of the ACTIV in CHF trial was performed. ACTIV in CHF randomized 319 patients hospitalized for worsening heart failure to placebo or one of three tolvaptan doses. Cox proportional hazards regression-analysis was used to explore the relationship between baseline hyponatremia, sodium change during the hospitalization, and 60-day mortality. Hyponatremia was observed in 69 patients (21.6%). After covariate adjustment, baseline hyponatremia was a statistically significant predictor of 60-day mortality (P = 0.0016). Follow-up serum sodium data were available in 68 patients. At hospital discharge, 45 of 68 (66.2%) hyponatremic patients had improvements in serum sodium levels (> or = 2 mmol/l). Hyponatremic patients with a serum sodium improvement had a mortality rate of 11.1% at 60 days post discharge, compared with a 21.7% mortality rate in those showing no improvement. After covariate adjustment, change in serum sodium was a statistically significant predictor of 60-day mortality (HR: 0.736, 95% CI: 0.569-0.952 for each 1-mmol/l increase in serum sodium from baseline). Serum sodium improvements during hospitalization for heart failure were associated with improved survival at 60 days.

Electrolytes Disturbances and Seizures

Electrolytes Disturbances and Seizures