Increased Serum Sodium Research Articles

Tolvaptan for the Treatment of Hyponatremia and Hypervolemia in Patients With Congestive Heart Failure

Patients with heart failure often show increased arginine vasopressin secretion and enhanced sympathetic and renin-angiotensin-aldosterone activation, which accelerate renal water reabsorption, causing water retention and volume overload. Tolvaptan is an orally active antagonist of arginine vasopressin type 2 receptors in the collecting duct of the kidney that inhibits water reabsorption without substantially affecting the electrolyte balance. Tolvaptan in combination with conventional diuretics improves fluid retention and congestive symptoms in patients with heart failure and volume overload, with minimal effects on hemodynamics and serum potassium. Tolvaptan slightly increases serum sodium concentrations, generally within the normal range. Although it does not seem to affect long-term mortality, tolvaptan does improve short-term water retention and congestive symptoms in heart failure patients with volume overload despite the use of conventional diuretics, and is approved for this indication in Japan.

Increased Serum Sodium Values in Brain-dead Donor's Influences Its Long-term Kidney Function

BackgroundKidney transplantation in Poland predominantly (95%) involves brain dead donors that display associated endocrine disorders. Diabetes insipidus, the most common complication, results in hypernatremia, hypovolemia, and increased plasma osmolality. Hypernatremia in donors is one of the strongest risk factors for the loss of a transplanted liver or heart. However, the influence of donor hypernatremia on early and late kidney graft function has not been entirely established to date. Methods and ResultsWe analyzed data for 80 kidney recipients from 54 brain dead donors during 2006–2008. Donors showed a positive correlation between serum sodium and creatinine concentrations (P = .001) and a negative correlation between serum sodium concentrations and creatinine clearances (P < .005). Donors divided into two groups based on a median sodium concentration of 155 mM revealed significantly lower values of glomerular filtration rate in recipients of the group with sodium concentrations >155 mM. ResultsNo relationship was observed between donor serum sodium concentration and early or 1-year function. There was a negative correlation between donors serum sodium concentration and creatinine clearance in recipients at 2, 3, and 4 years after kidney transplantation (P = .008, .00033, and .02, respectively). Multivariate analysis confirmed the influence of donor sodium concentration on creatinine clearance at 2 and 3 years after renal transplantation (P < .05 and P > .01, respectively). ConclusionHigh serum sodium concentrations and increased plasma osmolality in brain dead kidney donors adversely affect long-term graft function probably due to initiation of an inflammation processes.

Post-operative diabetes insipidus after endoscopic transsphenoidal surgery

Diabetes insipidus (DI) after endoscopic transsphenoidal surgery (ETSS) can lead to increased morbidity, longer hospital stays, and increased medication requirements. Predicting which patients are at high risk for developing DI can help direct services to ensure adequate care and follow-up. The objective of this study was to review our institution's experience with ETSS and determine which clinical/laboratory variables are associated with DI in this patient population. The authors wanted to see if there was an easily determined single value that would help predict which patients develop DI. This represents the largest North American series of this type. We retrospectively reviewed the charts of patients who had undergone ETSS for resection of sellar and parasellar pathology between 2006 and 2011. We examined patient and tumor characteristics and their relationship to postoperative DI. Out of 172 endoscopic transsphenoidal surgeries, there were 15 cases of transient DI (8.7%) and 14 cases of permanent DI (8.1%). Statistically significant predictors of postoperative DI (p < 0.05) included tumor volume and histopathology (Rathke's cleft cyst and craniopharyngioma). Significant indicators of development of DI were postoperative serum sodium, preoperative to postoperative change in sodium level, and urine output prior to administration of 1-deamino-8-D-arginine vasopressin. An increase in serum sodium of ≥2.5 mmol/L is a positive marker of development of DI with 80% specificity, and a postoperative serum sodium of ≥145 mmol/L is a positive indicator with 98% specificity. Identifying perioperative risk factors and objective indicators of DI after ETSS will help physicians care for patients postoperatively. In this large series, we demonstrated that there were multiple perioperative risk factors for the development of DI. These findings, which are consistent with other reports from microscopic surgical series, will help identify patients at risk for diabetes insipidus, aid in planning treatment algorithms, and increase vigilance in high risk patients.

Oral lixivaptan effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia

Hyponatremia is the most common electrolyte disorder in clinical practice. Its incidence increases with age and it is associated with increased morbidity and mortality. Recently, the vaptans, antagonists of the arginine vasopressin pathway, have shown promise for safe treatment of hyponatremia. Here we evaluated the efficacy, safety, and tolerability of oral lixivaptan, a selective vasopressin V2-receptor antagonist, for treatment of nonhospitalized individuals with euvolemic hyponatremia (sodium less than 135 mmol/l) in a multicenter, randomized, double-blind, placebo-controlled, phase III study. About half of the 206 patients were elderly in a chronic care setting. Of these patients, 52 were given a placebo and 154 were given 25-100 mg per day lixivaptan, titrated based on the daily serum sodium measurements. Compared with placebo (0.8 mmol/l), the serum sodium concentration significantly increased by 3.2 mmol/l from baseline to day 7 (primary efficacy endpoint) with lixivaptan treatment. A significantly greater proportion of patients that received lixivaptan achieved normal serum sodium (39.4%) by day 7 relative to placebo (12.2%). Overall, lixivaptan was considered safe and well-tolerated. Thus, oral lixivaptan can be safely initiated in the outpatient setting and effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia.

Lixivaptan: a vasopressin receptor antagonist for the treatment of hyponatremia

Hyponatremia, the most common electrolyte disorder encountered in clinical practice, is associated with significant morbidity and mortality. The introduction of medications that specifically antagonize the vasopressin V2 receptor (vaptans) has provided a safe and effective means of therapy. Lixivaptan is the newest of these agents that reliably increase serum sodium levels in patients with euvolemic hyponatremia. However, significant questions remain regarding the specific indications for vaptans, and their potential impact on morbidity and mortality associated with hyponatremia.

Lessons from liver transplantation

Lessons from liver transplantation

Hyponatriämie

Hyponatremia due to intolerance to water is a frequent clinical condition and associated with increased mortality. Besides the well known neurological symptoms, gait disturbances, falls, fractures and osteoporosis have also been described recently in patients with chronic hyponatremia. Acute hyponatremia is a more dramatic situation and needs rapid action when severe neurological symptoms are present. Hypertonic saline is recommended to treat this condition until relief of severe symptoms. The causes of hyponatremia have to be carefully examined. Especially diuretics, antidepressants and endocrine causes, e.g. hypothyroidism, hypocortisolism and hypoaldosteronism should be excluded by examination of the patient history, clinical examination and by laboratory tests. Patients should be classified as being euvolemic, hypovolemic or hypervolemic. Whereas acute hyponatremia with severe symptom should be treated with hypertonic saline, euvolemic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) with mild and moderate symptoms can now be treated with tolvaptan, a selective V(2)-vasopressin antagonist. Oral tolvaptan has been shown to be an effective and potent aquaretic to treat hyponatremia caused by SIADH as evidenced by a simultaneous increase in serum sodium and a decrease in urine osmolality. The condition of patients with mild or moderate hyponatremia is also improved. Side effects associated with tolvaptan include increased thirst, dry mouth, polyuria and hypernatremia. Rapid increases in serum sodium should be avoided by close monitoring in a hospital setting.

Meta‐analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia

Vaptans may correct hyponatraemia and mobilise ascites through an increased excretion of water. The effect on clinical outcomes is debated. To determine the effects of vaptans (tolvaptan, satavaptan and lixivaptan) on patients with cirrhosis and hyponatraemia or ascites. Systematic review of randomised controlled trials. The primary outcome measure was mortality. Electronic and manual searches were combined (April 2012). Data were extracted from published reports, online information from the Food and Drug Administration website or obtained through correspondence with authors and pharmaceutical companies. The primary meta-analyses were performed using random effects models due to an expected clinical diversity. Twelve trials with a total of 2266 patients were included. Randomisation was adequate in all trials. Eight trials were double-blind. Random effects meta-analyses found no clear differences between vaptans and control groups regarding mortality (RR = 1.06, 95% CI = 0.90-1.26, I(2) = 0%), variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, or renal failure. Vaptans increased serum sodium levels (WMD = 1.8 mmol/L, 95% CI = 0.79-2.96) and lead to reductions in weight and the time to the first paracentesis. Vaptans increased the risk of adverse events (RR = 3.97, 95% CI = 1.78-8.83), including an excessive urine volume (RR = 9.96, 95% CI = 1.38-71.68). Vaptans have a small beneficial effect on hyponatraemia and ascites, but do not affect mortality, complications to cirrhosis or renal failure. The data do not support the routine use of vaptans in cirrhosis.

Initial experience with conivaptan use in critically ill infants with cardiac disease.

Arginine vasopressin (AVP) is the primary regulator of free water retention through its interactions with the AVP type 2 receptor (V(2)). As opposed to the natriuresis and diuresis that occur with loop and thiazide diuretics, conivaptan is an AVP V(1A)/V(2) receptor antagonist, which enhances free water excretion while minimizing sodium loss. We report our preliminary experience with conivaptan to promote diuresis in infants with functional or structural cardiac disease. A retrospective cohort study was conducted of infants who had received conivaptan from August 2007 to January 2008. A loading dose of conivaptan (0.3-0.6 mg/kg) was followed by a continuous infusion of 0.01-0.02 mg/kg/hr for 24 hours. Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, bicarbonate, and urine output were measured prior to the start of conivaptan and at 24 hours after initiation of the infusion. Conivaptan was administered intravenously on 6 occasions to 5 patients with hypervolemic hyponatremia. Patients ranged in age from 8 to179 days, and body weight ranged from 3 to 4.12 kg. Mean sodium concentration increased from 130.17 ± 1.94 mEq/L to 133.67 ± 3.88 mEq/L (p=0.048), and median urine output increased from 4.15 to 5.05 mL/kg/hr (p=0.286). No significant changes were noted in serum potassium, bicarbonate, creatinine, or BUN. No adverse effects were noted during conivaptan infusion. Intravenous conivaptan is effective for increasing serum sodium levels and may be a potential adjuvant to enhance diuresis in children with cardiac disease. Given the potential benefits of conivaptan compared to diuretic therapy, with all their potential complications, prospective trials are warranted.

Efficacy of oral tolvaptan in acute heart failure patients with hypotension and renal impairment

Although congestion is the main reason for admission in patients with worsening acute heart failure syndromes, patients presenting with low SBP and renal impairment often do not respond adequately to and may not tolerate traditional diuretic therapy. We sought to determine the short-term hemodynamic effects of tolvaptan in this high-risk population. In a subset analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, 759 patients (18% of total) had elevated blood urea nitrogen (BUN) (> 20 mg/dl) and low SBP (<105 mmHg) at admission. Of these, 386 were randomized to tolvaptan and 373 to placebo. Demographics and baseline characteristics were similar in both groups. Greater reductions from baseline in body weight were observed for tolvaptan (1.63 ± 2.00 vs. 0.76 ± 1.75 kg, P < 0.0001 at day 1 and 3.23 ± 3.36 vs. 2.10 ± 3.47 kg, P < 0.0001 at day 7 or discharge). Greater increases in serum sodium concentration were also observed in the tolvaptan group as early as day 1 (4.41 ± 3.67 vs. 1.32 ± 3.93 mEq/l, P < 0.0001) and persisted through day 7 or discharge (4.79 ± 4.89 vs. 1.25 ± 5.00 mEq/l, P < 0.0001). Similarly, improvements in patient-reported dyspnea and investigator-assessed orthopnea were significantly greater in the tolvaptan group as early as day 1 of treatment. These changes were not associated with significant differences in heart rate, SBP, DBP or serum creatinine between patients in the two treatment groups during hospitalization. In-hospital mortality rates (total and cause-specific) were comparable to patients who had presented with SBP more than 105 mmHg and BUN less than 20 mg/dl. In this subgroup analysis of patients with hypotension and renal impairment, tolvaptan improved symptoms, reduced body weight and increased serum sodium as early as inpatient day 1 without adversely affecting blood pressure or renal function.

Hyponatremia in Cirrhosis and End-Stage Liver Disease: Treatment with the Vasopressin V2-Receptor Antagonist Tolvaptan

Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance. The primary cause is increased release of arginine vasopressin. Hyponatremia is associated with increased mortality in cirrhotic patients, those with end-stage liver disease (ESLD) on transplant waiting lists, and, in some studies, posttransplantation patients. Clinical evidence suggests that adding serum sodium to model for ESLD (MELD) scoring identifies patients in greatest need of liver transplantation by improving waiting list mortality prediction. Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant. Vasopressin receptor antagonists, which act to increase free water excretion (aquaresis) and thereby increase serum sodium concentration, have been evaluated in patients with hypervolemic hyponatremia (including cirrhosis and heart failure) and euvolemic hyponatremia (SIADH). Tolvaptan, a selective vasopressin V2-receptor antagonist, is the only oral agent in this class approved for raising sodium levels in hypervolemic and euvolemic hyponatremia. The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment. Fluid restriction should be avoided during the first 24 h of treatment to prevent overly rapid correction of hyponatremia, and tolvaptan should not be used in patients who cannot sense/respond to thirst, anuric patients, hypovolemic patients, and/or those requiring urgent intervention to raise serum sodium acutely.

Clinical management of SIADH

Hyponatremia is the most frequent electrolyte disorder and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for approximately one-third of all cases. In the diagnosis of SIADH it is important to ascertain the euvolemic state of extracellular fluid volume, both clinically and by laboratory measurements. SIADH should be treated to cure symptoms. While this is undisputed in the presence of grave or advanced symptoms, the clinical role and the indications for treatment in the presence of mild to moderate symptoms are currently unclear. Therapeutic modalities include nonspecific measures and means (fluid restriction, hypertonic saline, urea, demeclocycline), with fluid restriction and hypertonic saline commonly used. Recently vasopressin receptor antagonists, called vaptans, have been introduced as specific and direct therapy of SIADH. Although clinical experience with vaptans is limited at this time, they appear advantageous to patients because there is no need for fluid restriction and the correction of hyponatremia can be achieved comfortably and within a short time. Vaptans also appear to be beneficial for physicians and staff because of their efficiency and reliability. The side effects are thirst, polydipsia and frequency of urination. In any therapy of chronic SIADH it is important to limit the daily increase of serum sodium to less than 8-10 mmol/liter because higher correction rates have been associated with osmotic demyelination. In the case of vaptan treatment, the first 24 h are critical for prevention of an overly rapid correction of hyponatremia and the serum sodium should be measured after 0, 6, 24 and 48 h of treatment. Discontinuation of any vaptan therapy for longer than 5 or 6 days should be monitored to prevent hyponatremic relapse. It may be necessary to taper the vaptan dose or restrict fluid intake or both.

Significance of Hyponatremia in Heart Failure

Hyponatremia is a common clinical condition among hospitalized heart failure patients, related with increased morbidity and mortality. The pathophysiological mechanisms that relate heart failure with hyponatremia are complex, involving beyond renal dysfunction, neurohormonal activation, as well as diuretic treatment. The pituitary hormone vasopressin seems to play a central role leading to renal water retention and hyponatremia. Although therapeutic strategies (water restriction, hormone inhibition) have shown to increase serum sodium concentration and improve symptoms, no beneficial effect has been detected on clinical outcome. This fact, urges the need for the conduction of further clinical trials, in order to determine the real causality between short- and long-term outcome and serum sodium concentration in heart failure patients .

Hyponatremia, Heart Failure, and the Role of Tolvaptan

Hyponatremia–usually defined by serum sodium < 135 mEq/L–is common in heart failure (HF); it remains unclear whether it worsens HF or is merely a marker of more severe disease. Hyponatremia may develop from causes besides HF and symptoms may be mistakenly attributed to HF. Hyponatremia correction may be required for optimal HF management in some cases, and it can prevent neurologic complications. Symptoms, volume status, and onset timing determine treatment, which should correct serum sodium in a controlled manner. Arginine vasopressin is elevated in hypervolemic/euvolemic hyponatremia, favoring water reabsorption despite low serum osmolality. The oral selective V2-receptor antagonist tolvaptan blocks arginine vasopressin effects in the renal collecting ducts, promoting aquaresis without increasing sodium/potassium excretion. In clinical trials, tolvaptan significantly increased serum sodium in patients with euvolemic/hypervolemic hyponatremia, including HF. When added to conventional HF treatment, tolvaptan produced early symptomatic benefit, without long–term improvement in an HF population consisting primarily of normonatremic patients. Tolvaptan is approved for treatment of clinically significant hypervolemic/euvolemic hyponatremia (serum sodium < 125 mEq/L or less marked symptomatic hyponatremia that has resisted correction with fluid restriction), but not HF without hyponatremia.

Chapter 8. Hyperosmolar therapy

Chapter 8. Hyperosmolar therapy

Apparent Dexmedetomidine-Induced Polyuric Syndrome in an Achondroplastic Patient Undergoing Posterior Spinal Fusion

A 40-year-old achondroplastic patient underwent posterior spinal fusion under general endotracheal anesthesia. Anesthesia was maintained with isoflurane, and sufentanil, dexmedetomidine, and lidocaine infusions. Urine output increased from 150 mL/hr to 950 mL/hr the fourth hour. An increasing serum sodium, low urine-specific gravity, and increased serum osmolarity occurred simultaneously with the polyuria. Within 2 hours of discontinuing the dexmedetomidine infusion urine output greatly decreased. Within 24 hours all signs of the polyuric syndrome resolved spontaneously. Alpha(2) agonists block arginine-vasopressin release and action; however, a polyuric syndrome has not been reported in the human literature.

The efficacy and safety of Tolvaptan on treating congestive heart failure patients with hyponatremia

ObjectiveTo evaluate the efficacy and safety of Tolvaptan on treating congestive heart failure patients with hyponatremia.MethodsThis randomised double-blind placebo–controlled trial enrolled 65 patients with congestive heart failure and hyponatremia (serum...

The efficacy and safety of tolvaptan on treating congestive heart failure patients with hyponatremia

ObjectiveTo evaluate the efficacy and safety of Tolvaptan on treating congestive heart failure patients with hyponatremia.MethodsThis randomised double-blind placebo–controlled trial enrolled 65 patients with congestive heart failure and hyponatremia (serum...

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of Tolvaptan Monotherapy Compared to Furosemide and the Combination of Tolvaptan and Furosemide in Patients With Heart Failure and Systolic Dysfunction

Background Increased vasopressin levels may be present in patient with chronic heart failure (HF) and contribute to pathophysiology through effects on the vasopressin V2 receptor. The presence of background diuretic therapy may confound evaluations of vasopressin receptor antagonists (VRA). Methods and Results Eligible patients had HF (New York Heart Association Class II-III), systolic dysfunction (left ventricular ejection fraction ≤0.40) and signs of congestion (eg, edema, rales). At screening, patients were removed from baseline diuretic therapy and placed on a low-sodium diet (2 g/day). After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), monotherapy with the vasopressin V2 receptor antagonist tolvaptan (TLV) 30 mg (n = 20), monotherapy with furosemide 80 mg (FURO, n = 22) or both TLV 30 mg and FURO 80 mg (n = 20) once daily for 7 days. Patients were on standard background therapy and not fluid-restricted throughout the study. A decrease in body weight of −1.37 ± 1.61, −0.54 ± 1.59, and −1.13 ± 1.49 kg was observed versus baseline for TLV, FURO, and TLV+FURO, respectively, at day 8. At the same point, the placebo group showed a body weight increase of +0.72 ± 2.42 kg versus baseline ( P = .0006 for TLV versus placebo). Increases in urine volume from baseline were greater with TLV alone (2646 ± 1503 mL/24 hours) than with FURO (894 ± 853 mL/24 hours, P < .001), or PLC (423 ± 786 mL/24 hours, P < .001), and similar to TLV+FURO (2585 ± 2119 mL/24 hours). An increase in serum sodium within the normal range was also observed in TLV-treated patients ( P < .02 versus placebo; P < .01 versus FURO). No changes in serum potassium, other laboratory values, or blood pressure were observed. TLV therapy was well tolerated. Conclusions In patients with HF and signs of volume overload, TLV monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and β-blockers.

Use of Intravenous Conivaptan in Neurosurgical Patients With Hyponatremia From Syndrome of Inappropriate Antidiuretic Hormone Secretion

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia in hospitalized patients and is frequently associated with neurologic disorders and neurosurgical procedures. Traditional therapies such as fluid restriction, sodium repletion, and diuretics can help correct hyponatremia but do not address the underlying pathophysiology of excess arginine vasopressin secretion. Conivaptan is an arginine vasopressin receptor antagonist that has been shown to be both safe and effective in the treatment of euvolemic and hypervolemic hyponatremia. To analyze the use of conivaptan to treat SIADH in a mixed neurosurgical population. We conducted a retrospective review of 13 patients with neurosurgical disorders with SIADH that were treated with intravenous conivaptan at our institution between 2007 and 2009. The mean pretreatment serum sodium concentration was 125.8 ± 3.5 mEq/L. Conivaptan administration resulted in a rise in serum sodium to 132.5 ± 5.6 mEq/L at 12 hours (P < .01) and 134.1 ± 4.7 mEq/L at 24 hours posttreatment (P < .01). The mean time to an increase in serum sodium ≥ 6 mEq/L was 17.8 hours. There were no instances of rapid overcorrection. There were 3 cases of asymptomatic hyperkalemia, 3 cases of asymptomatic hypotension, and 1 case of elevated creatinine associated with conivaptan administration. These data provide further support that conivaptan can be safely used for the treatment of SIADH-induced hyponatremia in the neurosurgical arena.