Arginine vasopressin deficiency and conivaptan (a V1a-V2 receptor antagonist) treatment reverses liver damage and fibrosis in rats with chronic portocaval anastomosis.

Arginine vasopressin (AVP) is a naturally occurring hormone synthesized in the hypothalamus. AVP demonstrates pro-fibrotic effects as it stimulates hepatic stellate cells to secrete transforming growth factor-ß (TGF-ß) and collagen. Previous work in liver cirrhotic (CCL4 -induced) hamsters demonstrated that AVP deficiency induced by neurointermediate pituitary lobectomy (NIL) can restore liver function. Therefore, we hypothesized that liver fibrosis would decrease in portocaval anastomosis (PCA) rats, which model chronic liver diseases, when they are treated with the V1a-V2 AVP receptor antagonist conivaptan (CV). In this study, changes in liver histology and gene expression were analysed in five experimental groups: control, PCA, NIL, PCA + NIL and PCA + CV, with NIL surgery or CV treatment administered 8 weeks after PCA surgery. Body weight gain was assessed on a weekly basis, and serum liver function, liver weight and liver glycogen content were assessed following euthanasia. Most PCA-induced phenotypes were reverted to normal levels following AVP-modelled deficiency, though hypoglycemia and ammonium levels remained elevated in the PCA + CV group. Liver histopathological findings showed a significant reversal in collagen content, less fibrosis in the triad and liver septa and increased regenerative nodules. Molecular analyses showed that the expression of fibrogenic genes (TGF-ß and collagen type I) decreased in the PCA + CV group. Our findings strongly suggest that chronic NIL or CV treatment can induce a favourable microenvironment to decrease liver fibrosis and support CV as an alternative treatment for liver fibrosis.

A New Role for Conivaptan in Ulcerative Colitis in Mice: Inhibiting Differentiation of CD4+T Cells into Th1 Cells.

BACKGROUND: Conivaptan, a nonselective antagonist of vasopressin receptors V1a and V2, is the first drug of this class to be used for treating euvolemic and hypervolemic hyponatremia. Recently, increasing evidence supports the involvement of vasopressin in immune responses. AIMS: In this study, we investigated the effect of conivaptan on the modulation of CD4+ T cell homeostasis and the progression of experimental colitis. METHODS: The expression of the V1a receptor on CD4+ T cells was detected by immunofluorescence and western blot. The subset of isolated CD4+ T cells were examined after arginine vasopressin (AVP) incubation. CD4+ T cells were injected into DNBS-induced mice through the tail vein. The severity of colitis was evaluated according to weight, disease activity index (DAI), and morphological injury. Intracellular Ca2+ ([Ca2+]i) signaling in CD4+ T cells was measured using the Fluo-3 AM loading method. T-bet and IFN-γ mRNAs in the colon were detected by real-time polymerase chain reaction (qPCR). RESULTS: We found that CD4+ T cells expressed the V1a receptor. Activation of the V1a receptor significantly promoted the differentiation of CD4+ T cells into T helper 1 (Th1) cells. This process was blocked by conivaptan treatment. However, the activation of the V1a receptor did not evoke an increase in [Ca2+]i in CD4+ T cells. Notably, conivaptan markedly alleviated body weight loss, pathological damage, and expression of T-bet and IFN-γ in the colon of DNBS-treated mice. CONCLUSIONS: For the first time, we report that conivaptan attenuated colitis by inhibiting the differentiation of CD4+ T cells into Th1 cells. Mechanistically, the anti-inflammatory role of conivaptan is independent of [Ca2+]i.

Identification of SARS-CoV-2 surface therapeutic targets and drugs using molecular modeling methods for inhibition of the virus entry.

Although COVID-19 emerged as a major concern to public health around the world, no licensed medication has been found as of yet to efficiently stop the virus spread and treat the infection. The SARS-CoV-2 entry into the host cell is driven by the direct interaction of the S1 domain with the ACE-2 receptor followed by conformational changes in the S2 domain, as a result of which fusion peptide is inserted into the target cell membrane, and the fusion process is mediated by the specific interactions between the heptad repeats 1 and 2 (HR1 and HR2) that form the six-helical bundle. Since blocking this interaction between HRs stops virus fusion and prevents its subsequent replication, the HRs inhibitors can be used as anti-COVID drugs. The initial drug selection is based on existing molecular databases to screen for molecules that may have a therapeutic effect on coronavirus. Based on these premises, we chose two approved drugs to investigate their interactions with the HRs (based on docking methods). To this end, molecular dynamics simulations and molecular docking were carried out to investigate the changes in the structure of the SARS-CoV-2 spike protein. Our results revealed, cefpiramide has the highest affinity to S protein, thereby revealing its potential to become an anti-COVID-19 clinical medicine. Therefore, this study offers new ways to re-use existing drugs to combat SARS-CoV-2 infection.

Efficacy of vaptans for correction of postoperative hyponatremia: A comparison between single intravenous bolus conivaptan vs oral tolvaptan.

BACKGROUND AND AIMS: Hyponatremia is one of the most common electrolyte abnormality encountered in postoperative patients especially in the elderly. We aimed to assess the efficacy of single-dose intravenous conivaptan vs. oral tolvaptan therapy for correction of hyponatremia in postoperative patients. MATERIAL AND METHODS: This prospective randomized study was conducted on 40 patients aged 20-70 years, who had undergone major head and neck surgeries with a serum sodium level of ≤130 mEq/L and were symptomatic. Patients were randomly allocated into two equal groups. Patients belonging to group C received single intravenous bolus dose of conivaptan 20mg, whereas group T received oral tolvaptan 15mg on the first day. At 24h, if sodium correction was <4mEq/L, dose of tolvaptan was increased to 30mg in group T or an infusion of conivaptan 20mg over next 24h was started in group C. RESULTS: Chi-square test, independent sample t-test, and paired t-test were used as applicable. Though there was no significant difference in the baseline sodium values in both groups, at 12 and 24 h group C had significantly high values. At 48h sodium values in both the groups were comparable. Intra-group analysis had shown that there was a significant increase in sodium values from the baseline at 12, 24, and 48 h in both the groups. CONCLUSION: Single-dose intravenous conivaptan as well as oral tolvaptan were safe and effective in correcting hyponatremia in postoperative patients. Conivaptan could be considered superior as it resulted in faster sodium correction with effective aquaresis.

Conivaptan, a Selective Arginine Vasopressin V1a and V2 Receptor Antagonist Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest via Perivascular Pool of Aquaporin-4.

BACKGROUND: Cerebral edema is a major cause of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Arginine vasopressin (AVP) and water channel aquaporin-4 (AQP4) have been implicated in the pathogenesis of CA-evoked cerebral edema. In this study, we examined if conivaptan, a V1a and V2 antagonist, attenuates cerebral edema following CA/CPR in wild type (WT) mice as well as mice with targeted disruption of the gene encoding α-syntrophin (α-syn(-/-)) that demonstrate diminished perivascular AQP4 pool. METHODS: Isoflurane-anesthetized adult male WT C57Bl/6 and α-syn(-/-) mice were subjected to 8 min CA/CPR and treated with either bolus IV injection (0.15 or 0.3 mg/kg) followed by continuous infusion of conivaptan (0.15 mg/kg/day or 0.3 mg/kg/day), or vehicle infusion for 48 h. Serum osmolality, regional brain water content, and blood-brain barrier (BBB) disruption were determined at the end of the experiment. Sham-operated mice in both strains served as controls. RESULTS: Treatment with conivaptan elevated serum osmolality in a dose-dependent manner. In WT mice, conivaptan at 0.3 mg dose significantly attenuated regional water content in the caudoputamen (81.0 ± 0.5 vs. 82.5 ± 0.4% in controls; mean ± SEM) and cortex (78.8 ± 0.2 vs. 79.4 ± 0.2% in controls), while conivaptan at 0.15 mg was not effective. In α-syn(-/-) mice, conivaptan at 0.3 mg dose did not attenuate water content compared with controls. Conivaptan (0.3 mg/kg/day) attenuated post-CA BBB disruption at 48 h in WT mice but not in α-syn(-/-) mice. CONCLUSIONS: Continuous IV infusion of conivaptan attenuates cerebral edema and BBB disruption following CA. These effects of conivaptan that are dependent on the presence of perivascular pool of AQP4 appear be mediated via its dual effect on V1 and V2 receptors.

Efficacy of conivaptan and hypertonic (3%) saline in treating hyponatremia due to syndrome of inappropriate antidiuretic hormone in a tertiary Intensive Care Unit.

BACKGROUND: Hyponatremia is one of the most common electrolyte abnormalities encountered in clinical practice and has a significant impact on morbidity and mortality in hospitalized patients. The optimal management of hyponatremia is still evolving. Over the last decade, vaptans have been increasingly used in clinical practice with promising results. MATERIALS AND METHODS: The study included eighty patients with symptomatic hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH) admitted and treated in Intensive Care Unit (ICU) with either conivaptan or hypertonic (3%) saline. They were compared for time taken to achieve normal serum sodium, length of ICU and hospital stay, and adverse effects. RESULTS: The demographic data and serum sodium levels at admission were comparable between the two groups. After initiating correction, sodium levels at 6, 12, and 24 h were similar between the two groups. However, at 48 h, patients in the conivaptan group (Group C) had higher sodium levels (133.0 ± 3.8 mEq/L) as compared to hypertonic saline group (Group HS) (128.9 ± 2.6 mEq/L), which was statistically significant (P < 0.001). The length of ICU stay was less in the Group C (3.35 ± 0.89 days) when compared with the Group HS (4.61 ± 0.91 days) (P < 0.001). There was no significant difference in mortality between the two groups. CONCLUSION: In patients with symptomatic hyponatremia due to SIADH, conivaptan with its aquaresis property can achieve a significantly better sodium correction, resulting in reduced ICU and hospital stay with no significant adverse effects.

Potential roles of vaptans in heart failure: experience from clinical trials and considerations for optimizing therapy in target patients.

Hyponatremia is a known complication in patients with heart failure (HF). HF patients with severe congestion, hyponatremia, and renal insufficiency are difficult to manage and may have worse outcomes. A main cause of hyponatremia is inappropriately elevated level of plasma arginine vasopressin (AVP), which causes water retention at the collecting duct. AVP antagonists have thus been developed to increase aquaresis and serum sodium levels in patients with euvolemic and hypervolemic hyponatremia. Although tolvaptan, an AVP-2 receptor antagonist, did not show outcomes benefit in patients with decompensated HF, prospective studies are ongoing to evaluate its optimal role in targeted HF patients.

Conivaptan for treatment of hyponatremia in neurologic and neurosurgical adults.

OBJECTIVE: To review the literature evaluating the clinical safety and efficacy of conivaptan in the management of hyponatremia in a neurologic and neuro-surgical adult patient population. DATA SOURCES: A literature search was conducted using MEDLINE, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials (1966-May 2013). Search limits were English, human, and adult using the terms vasopressin receptor antagonist, conivaptan, tolvaptan, lixivaptan, neurology, neurological disorder, neurosurgery, neurointensive care, and neurocritical care. STUDY SELECTION AND DATA EXTRACTION: All case reports, case series, and clinical trials investigating the use of conivaptan in neurosurgical patients were included. DATA SYNTHESIS: Seven reports were identified using conivaptan as monotherapy or adjunctive treatment for hyponatremia in a neurosurgical patient population. One study was a prospective, randomized, controlled trial, while 6 reports were case reports or case series. The prospective randomized trial found a significant increase in serum sodium concentration over baseline with a conivaptan 20-mg intravenous bolus dose followed by a 20-mg/day continuous infusion for 24 hours compared to "usual care" at 6 hours (7.0 ± 1.7 vs -0.6 ± 2.1 mEq/L, respectively; p = 0.008) and 36 hours (8.0 ± 5.6 vs -1.7 ± 2.1 mEq/L, respectively; p = 0.05) after treatment. One case series found that the mean serum sodium remained significantly increased from baseline up to 72 hours (5.12 ± 4.0 mEq/L; p < 0.001) after a single conivaptan 20-mg intravenous bolus dose. All reports demonstrated clinical effectiveness of conivaptan in significantly increasing serum sodium concentrations following administration compared to baseline. However, the clinical significance of this finding remains debatable since some of these patients remained hyponatremic. CONCLUSIONS: Overall, conivaptan is a promising and well-tolerated agent for the management of hyponatremia in neurologic and neurosurgical patients. However, its use should be limited to patients in whom conventional therapies fail or as adjunctive therapy.

Management of Hyponatremia in Heart Failure: Practical Considerations.

Hyponatremia is commonly encountered in the setting of heart failure, especially in decompensated, fluid-overloaded patients. The pathophysiology of hyponatremia in patients with heart failure is complex, including numerous mechanisms: increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system, high levels of arginine vasopressin and diuretic use. Symptoms are usually mild but hyponatremic encephalopathy can occur if there is an acute decrease in serum sodium levels. It is crucial to differentiate between dilutional hyponatremia, where free water excretion should be promoted, and depletional hyponatremia, where administration of saline is needed. An inappropriate correction of hyponatremia may lead to osmotic demyelination syndrome which can cause severe neurological symptoms. Treatment options for hyponatremia in heart failure, such as water restriction or the use of hypertonic saline with loop diuretics, have limited efficacy. The aim of this review is to summarize the principal mechanisms involved in the occurrence of hyponatremia, to present the main guidelines for the treatment of hyponatremia, and to collect and analyze data from studies which target new treatment options, such as vaptans.

Conivaptan and Boric Acid Treatments in Acute Kidney Injury: Is This Combination Effective and Safe?

Acute kidney injury is still a worldwide clinic problem that affects kidney function and associated with high mortality risk. Unfortunately, approximately 1.7 million people are thought to die from acute kidney injury each year. Boron element is defined as an "essential trace element" for plants and thought to have a widespread role in living organisms. Boric acid, which is one of the important forms of boron, has been extensively discussed for both medicinal and nonmedicinal purposes. However, there is a lack of data in the literature to examine the relationship between boric acid and antidiuretic hormone (ADH) antagonism in kidney injury. Thus, we aimed to investigate the effects of conivaptan as an ADH antagonist and boric acid as an antioxidant agent on the post-ischemic renal injury process. In this study, the unilateral ischemia-reperfusion (I/R) injury rat model with contralateral nephrectomy was performed and blood/kidney tissue samples were taken at 6th hours of reperfusion. The effects of 10 mg/mL/kg conivaptan and 50 mg/kg boric acid were examined with the help of some biochemical and histological analyses. We observed that conivaptan generally alleviated the destructive effects of I/R and has therapeutic effects. Also of note is that conivaptan and boric acid combination tended to show negative effects on kidney function, considering the highest BUN (78.46 ± 3.88 mg/dL) and creatinine levels (1.561 ± 0.1018 mg/dL), suggesting possibly drug-drug interaction. Although it has reported that conivaptan can interact with other active substances, no experimental/clinical data on the possible interaction with boric acid have reported so far.

Emerging therapeutic targets for cerebral edema.

INTRODUCTION: Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema. AREAS COVERED: We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, and S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered. EXPERT OPINION: Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema.

Effects of Conivaptan versus Mannitol on Post-Ischemic Brain Injury and Edema.

OBJECTIVE: The aim of this study was to compare the effects of conivaptan, an arginine vasopressin antagonist, and mannitol, a sugar alcohol, on cerebral ischemia-induced brain injury and edema in rats. MATERIALS AND METHODS: Fifty-eight 8-week-old male Sprague Dawley rats were randomly divided into five groups: control, ischemia-reperfusion (I/R)+saline, I/R+mannitol, I/R+10 mg/ml conivaptan, and I/R+20 mg/ml conivaptan. Cerebral ischemia was induced by common carotid artery occlusion for 30 minutes. Saline, mannitol, or conivaptan were administered intravenously at the onset of reperfusion. Blood and brain tissue samples were taken at the 6th hour of reperfusion. The electrolytes (Na+-K+-Cl-), osmolality, arginine vasopressin, albumin, progranulin (PGRN), neuron-specific enolase (NSE), and myeloperoxidase activity were measured in rat serum samples. Brain frontal/hippocampal sections were stained with hematoxylin-eosin and TUNEL techniques to evaluate histopathological changes. RESULTS: Statistical analyses revealed that conivaptan caused significant changes in the electrolyte, NSE, and PGRN levels and osmolality when compared with mannitol. Conivaptan treatment showed positive effects on serum biochemistry and tissue histology. CONCLUSION: Our findings revealed that conivaptan shows more diuretic activity than mannitol and triggers neither any damages nor edema in the brain tissue. This study may provide beneficial information for the development of treatment strategies for ischemia-related cerebrovascular diseases.

Development and validation of an HPLC-MS/MS method for the determination of arginine-vasopressin receptor blocker conivaptan in human plasma and rat liver microsomes: application to a metabolic stability study.

PURPOSE: To develop and validate a bio-analytical HPLC-MS/MS method for the determination of conivaptan (CVA) an arginine-vasopressin receptor blocker in human plasma and in rat liver microsomes (RLMs). METHODS: Analytes were separated on a reversed phase C18 column (50 mm × 2.1 mm, 1.8 µm). The mobile phase was a mixture of acetonitrile and 10 mM ammonium formate (40:60 v/v, pH 4.0) and was pumped isocratically for 4 min at a flow rate of 0.2 ml/min. Multiple reaction monitoring in positive ionization mode was used for the assay. RESULTS: The method yielded a linear calibration plot (r 2 = 0.9977 and 0.9998) over 5-500 ng/ml with a limit of detection at 1.52 and 0.88 ng/ml for human plasma and RLMs, respectively. The reproducibility of detection of CVA in human plasma and RLMs was found to be in an acceptable range. CONCLUSION: The method developed in this study is applicable for accurately quantifying CVA in human plasma and rat liver microsomal samples. The optimized procedure was applied to study of metabolic stability of CVA. Conivaptan concentration rapidly decreased in the first 2 min of RLMs incubation and the conversion reached a plateau for the remainder of the incubation period. The in vitro half-life (t1/2) was estimated at 11.51 min and the intrinsic clearance (CLin) was 13.8 ± 0.48 ml/min/kg.

Cardiorenal Syndrome: Role of Arginine Vasopressin and Vaptans in Heart Failure.

Heart and kidney failure continued to be of increasing prevalence in today's society, and their comorbidity has synergistic effect on the morbidity and mortality of patients. Cardiorenal syndrome (CRS) is a complex disease with multifactorial pathophysiology. Better understanding of this pathophysiological network is crucial for the successful intervention to prevent advancement of the disease process. One of the major factors in this process is neurohormonal activation, predominantly involving renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP). Heart failure causes reduced cardiac output/cardiac index (CO/CI) and fall in renal perfusion pressures resulting in activation of baroreceptors and RAAS, respectively. Activated baroreceptors and RAAS stimulate the release of AVP (non-osmotic pathway), which acts on V2 receptors located in the renal collecting ducts, causing fluid retention and deterioration of heart failure. Effective blockade of AVP action on V2 receptors has emerged as a potential treatment option in volume overload conditions especially in the setting of hyponatremia. Vasopressin receptor antagonists (VRAs), such as vaptans, are potent aquaretics causing electrolyte-free water diuresis without significant electrolyte abnormalities. Vaptans are useful in hypervolemic hyponatremic conditions like heart failure and liver cirrhosis, and euvolemic hyponatremic conditions like syndrome of inappropriate anti-diuretic hormone secretion. Tolvaptan and conivaptan are pharmaceutical agents that are available for the treatment of these conditions.

Effectiveness and Tolerability of Conivaptan and Tolvaptan for the Treatment of Hyponatremia in Neurocritically Ill Patients.

STUDY OBJECTIVE: To describe the effectiveness and tolerability of conivaptan and tolvaptan for the correction of hyponatremia in neurocritically ill patients. DESIGN: Retrospective cohort study. SETTING: Neurointensive care units at two academic medical centers. PATIENTS: Thirty-six adults admitted to the neurocritical care unit who received at least one dose of conivaptan (5 patients) or tolvaptan (31 patients) between June 2012 and May 2013. MEASUREMENTS AND MAIN RESULTS: A single oral dose or intravenous bolus was administered to 23 (74%) patients who received tolvaptan and 2 (40%) patients who received conivaptan, respectively. The mean maximal increase in serum sodium level at 24 hours following the last dose compared with baseline was 5.2 mEq/L for conivaptan (p=0.05) and 7.9 mEq/L for tolvaptan (p<0.001). The mean ± SD maximal increases in serum sodium level at 48, 72, and 96 hours following the last dose of vaptan therapy compared with baseline were 5.5 ± 2.2 mEq/L (p=0.01), 5.6 ± 2.0 mEq/L (p=0.005), and 4.8 ± 2.2 mEq/L (p=0.03), respectively. Sodium overcorrection occurred in six patients (19%) receiving tolvaptan and none of the patients receiving conivaptan. Hypotension occurred in 20% of patients receiving conivaptan and 52% of patients receiving tolvaptan, whereas hypokalemia was observed in 40% of patients receiving conivaptan. CONCLUSION: Use of vaptans in neurocritically ill patients led to a significant increase in serum sodium level at 24 hours after the last dose, which was sustained for 96 hours, with the majority of patients receiving a single dose. Risk of sodium overcorrection was high and necessitates appropriate patient selection and frequent monitoring.

Effectiveness of single dose conivaptan for correction of hyponatraemia in post-operative patients following major head and neck surgeries.

BACKGROUND AND AIMS: Conivaptan, a vasopressin receptor antagonist, is commonly used for the treatment of euvolaemic, hypervolaemic hyponatraemia. Usually, an intravenous (IV) bolus followed by infusion is administered for many days. We decided to assess the effectiveness of single dose conivaptan for correction of hyponatraemia in post-operative patients. METHODS: This was a prospective, randomised trial conducted in 40 symptomatic post-operative Intensive Care Unit (ICU) patients with a serum sodium level of ≤130 mEq/L. Group A patients received IV conivaptan 20 mg over 30 min, whereas in group B infusion of 3% hypertonic saline was started as an infusion at the rate of 20-30 ml/h. Serum sodium levels were measured at 12, 24, 48 and 72 h and the daily fluid balance was measured for 3 days. The Chi-square test, Wilcoxon signed rank test and Mann-Whitney tests were used as applicable. RESULTS: The serum sodium levels before initiating treatment were comparable between groups. However, subsequent sodium levels at 12, 24 and 48 h showed significantly high values in group A. Though at 72 h the mean sodium value was high in group A, it was not statistically significant. Group A showed a significantly high fluid loss on day 1, 2 and 3. The mean volume of hypertonic saline required in group B showed a steady decline from day 1 to 3 and only 13 patients required hypertonic saline on the 3(rd) day. CONCLUSION: Single dose conivaptan is effective in increasing serum sodium levels in post-operative ICU patients up to 72 h associated with a significant negative fluid balance.

Review and analysis of differing regulatory indications and expert panel guidelines for the treatment of hyponatremia.

INTRODUCTION AND OBJECTIVE: As evidence grows about the management of hyponatremia, a number of different international and national recommendations/guidelines from professional organizations have recently been published that offer guidance on decision-making. However, they include several important differences that could confuse practising physicians. This article summarizes the key differences in guideline recommendations by various independent groups, taking the marketing authorizations granted by different regulatory agencies into account. It proposes a synthesis of implications for practising physicians as a practical method for resolving these differences as they relate to everyday clinical practice. METHODS: The authors reviewed all recent guidelines and consensus documents worldwide to assess differences and similarities. They also reviewed licensed indications for therapeutic agents in hyponatremia. RESULTS: The actual indications for the only pharmacological therapy approved across three continents for the treatment of hyponatremia--the vaptans--differ substantially around the world. The numerous treatment guidelines published to date also fail to achieve agreement on hyponatremia management. The possible reasons for these differences are explored in this paper. The authors emphasize the crucial role that clinical judgment must continue to play in decision-making about the management of hyponatremia in individual patients. Such judgments should take into account appropriate appraisals of evidence by authoritative experts in the field, as well as the decisions of regulatory agencies that have based their approvals on a critical review of the efficacy and safety data for approved treatments for hyponatremia. CONCLUSION: It is clinical judgment rather than guidelines that should dictate the ultimate choices physicians make for their patients, not only in hyponatremia, but in all aspects of medicine.

Efficacy of 3% saline vs. conivaptan in achieving hyponatremia treatment goals.

Hyponatremia is the most common electrolyte abnormality encountered in clinical practice, but its optimal management is still evolving. While guidelines for infusion rates of hypertonic saline (HS) have been introduced, there is a risk of underestimating the response in serum sodium concentration after therapy. Guidelines also have evaluated the use of vasopressin receptor antagonists as alternatives or supplements to standard therapies. This single-center retrospective study from The Methodist Hospital (TMH) compared the effect of HS and conivaptan intervention in the management of 49 patients with hyponatremia from January 2009 through November 2010. Demographics, volume status, medical history, medication data, and serum sodium concentration correction over 48 hours were analyzed. No significant difference was noted with regard to age, ethnicity, gender, volume status, use of medications known to cause hyponatremia, or comorbidities. Baseline serum sodium concentration was not significantly different between HS (120.5 ± 3.8 mEq/L) and conivaptan (118.3 ± 6.7 mEq/L) groups. Regardless of whether the patient was euvolemic or hypervolemic, no significant difference was noted in serum sodium concentration at 4, 12, 24, or 48 hours after initiation of treatment or in frequency of over-correction between groups. This study compares the effect of HS to conivaptan intervention in the management of hyponatremia. No significant differences were identified in adherence to treatment guidelines. Further, based on this small retrospective study, neither agent poses a significant risk of over-correction at 4, 24, or 48 hours of therapy.

Use of conivaptan for management of hyponatremia following surgery for Cushing's disease.

BACKGROUND: Hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common osmoregulatory complication following surgery for Cushing's disease. Conventional management includes water restriction and sodium repletion, however this regimen does not address the underlying pathophysiology of excessive vasopressin production. Vaptans are arginine vasopressin receptor antagonists shown to be effective in correcting water excess in other disease states of euvolemic and hypervolemic hyponatremia. The use of these agents has not been reported in Cushing's patients. METHODS: We retrospectively studied Cushing's patients at our institution with post-surgical hyponatremia (Na<130mEq/L) treated with and without conivaptan between 2005 and 2011. We report rates of serum sodium normalization and compare length-of-stay (LOS) between the groups. RESULTS: Hyponatremia developed in six of 98 patients (6.1%) undergoing resection of ACTH-positive pituitary adenomas. Three patients received conivaptan and fluid restriction±sodium supplementation, and three received conventional therapy alone. The rate of serum sodium normalization with conivaptan was 5.8±2.3mEq/L/20mg IV bolus given every 24h. All patients receiving conivaptan were discharged with normal serum sodium values and no instances of rapid overcorrection occurred. A trend toward longer LOS occurred in patients treated with conivaptan (4.6±0.3 days, mean±SE) versus conventional therapy alone (1.6±0.3 days). CONCLUSIONS: Conivaptan is a potentially useful treatment option for hyponatremia in the setting of Cushing's disease patients after pituitary surgery.

Hyponatremia in patients with heart failure.

The present review analyses the mechanisms relating heart failure and hyponatremia, describes the association of hyponatremia with the progress of disease and morbidity/mortality in heart failure patients and presents treatment options focusing on the role of arginine vasopressin (AVP)-receptor antagonists. Hyponatremia is the most common electrolyte disorder in the clinical setting and in hospitalized patients. Patients with hyponatremia may have neurologic symptoms since low sodium concentration produces brain edema, but the rapid correction of hyponatremia is also associated with major neurologic complications. Patients with heart failure often develop hyponatremia owing to the activation of many neurohormonal systems leading to decrease of sodium levels. A large number of clinical studies have associated hyponatremia with increased morbidity and mortality in patients hospitalized for heart failure or outpatients with chronic heart failure. Treatment options for hyponatremia in heart failure, such as water restriction or the use of hypertonic saline with loop diuretics, have limited efficacy. AVP-receptor antagonists increase sodium levels effectively and their use seems promising in patients with hyponatremia. However, the effects of AVP-receptor antagonists on hard outcomes in patients with heart failure and hyponatremia have not been thoroughly examined.