Increase In Serum Sodium Level Research Articles

MANAGEMENT OF DIABETES INSIPIDUS AFTER SUBLABIAL TRANSSPHENOIDAL HYPOPHYSECTOMY SURGERY

MANAGEMENT OF DIABETES INSIPIDUS AFTER SUBLABIAL TRANSSPHENOIDAL HYPOPHYSECTOMY SURGERY

Relationship between serum sodium level and sepsis-induced coagulopathy.

A discussion about the correlation between the level of serum sodium and sepsis-induced coagulopathy (SIC). A retrospective analysis was conducted on sepsis patients who were admitted to the Intensive Care Unit (ICU) of Nanjing Drum Tower Hospital from January 2021 to December 2022. Based on the presence of coagulation disorders, the patients were divided into two groups: sepsis-induced coagulopathy (SIC) and non-sepsis-induced coagulopathy (non-SIC) groups. We recorded demographic characteristics and laboratory indicators at the time of ICU admission, and analyzed relationship between serum sodium level and SIC. One hundred and twenty-five patients with sepsis were enrolled, among which, the SIC and the non-SIC groups included 62 and 63 patients, respectively. Compared to patients in the non-SIC group, the level of serum sodium of those in the SIC was significantly higher (p < 0.001). Multi-factor logistic regression showed serum sodium level was independently associated with SIC (or = 1.127, p = 0.001). Pearson's correlation analysis indicated that the higher the serum sodium level, the significantly higher the SIC score was (r = 0.373, p < 0.001). Additionally, the mortality rate of patients with sepsis in the ICU were significantly correlated with increased serum sodium levels (p = 0.014). An increase in serum sodium level was independently associated with an increased occurrence of SIC and also associated with the poor prognosis for patients with sepsis.

Effects of Intermediate Frequency (150 kHz) Electromagnetic Radiation on the Vital Organs of Female Sprague Dawley Rats.

Exposure to electromagnetic radiation (EMR) from intermediate frequency sources has increased exponentially in recent years. The consequences of this exposure on biological systems are prompting scientists to study the effects on human health. This current study aimed to determine the effects of intermediate frequency (150 kHz) EMR exposure on the vital organs of female Sprague Dawley rats. The EMR group (n = 10 animals) was exposed to a frequency of 150 kHz with an intensity of 65 ± 15 μW/cm2 for two months. The control group (n = 10 animals) was exposed to an intensity of 35 ± 15 nW/cm2. Haematological, histochemical, gross, and histopathological profiles of all major organs of all animals were then performed using standard procedures. All major organs generally showed no significant detectable effects in either the control or EMR groups. However, gross and histopathological examinations revealed the effects of EMR on the liver and lungs, which showed inflammatory changes without significant biochemical/haematological manifestations. In addition, a significant increase in serum sodium level and a decrease in serum urea level were also observed in the EMR group. It can be concluded that the current frequency and duration of exposure trigger the changes in the liver and lungs but are not sufficient to cause clinical and functional manifestations. Therefore, a long-term exposure study might be helpful to determine the effects of 150 kHz IF EMR on these organs.

Standardized Oral Urea for the Treatment of Hyponatraemic Conditions: Pharmacological and Pharmacoeconomic Consideration

Standardized Oral Urea for the Treatment of Hyponatraemic Conditions: Pharmacological and Pharmacoeconomic Consideration

Risk factors for overcorrection of severe hyponatremia: a post hoc analysis of the SALSA trial.

BackgroundHyponatremia overcorrection can result in irreversible neurologic impairment such as osmotic demyelination syndrome. Few prospective studies have identified patients undergoing hypertonic saline treatment with a high risk of hyponatremia overcorrection.MethodsWe conducted a post hoc analysis of a multicenter, prospective randomized controlled study, the SALSA trial, in 178 patients aged above 18 years with symptomatic hyponatremia (mean age, 73.1 years; mean serum sodium level, 118.2 mEq/L). Overcorrection was defined as an increase in serum sodium levels by >12 or 18 mEq/L within 24 or 48 hours, respectively.ResultsAmong the 178 patients, 37 experienced hyponatremia overcorrection (20.8%), which was independently associated with initial serum sodium level (≤110, 110–115, 115–120, and 120–125 mEq/L with 7, 4, 2, and 0 points, respectively), chronic alcoholism (7 points), severe symptoms of hyponatremia (3 points), and initial potassium level (<3.0 mEq/L, 3 points). The NASK (hypoNatremia, Alcoholism, Severe symptoms, and hypoKalemia) score was derived from four risk factors for hyponatremia overcorrection and was significantly associated with overcorrection (odds ratio, 1.41; 95% confidence interval, 1.24–1.61; p < 0.01) with good discrimination (area under the receiver-operating characteristic [AUROC] curve, 0.76; 95% CI, 0.66–0.85; p < 0.01). The AUROC curve of the NASK score was statistically better compared with those of each risk factor. ConclusionIn treating patients with symptomatic hyponatremia, individuals with high hyponatremia overcorrection risks were predictable using a novel risk score summarizing baseline information.

Менеджмент гиперкалиемии у детей с хронической болезнью почек

Актуальность. Гиперкалиемия является наиболее распространенным электролитным нарушением, наблюдаемым у пациентов с заболеваниями почек, особенно с хронической болезнью почек (ХБП), сахарным диабетом, сердечной недостаточностью или тех, кто находится на лечении антагонистами ренин-ангиотензин-альдостероновой системы. Цель исследования: изучение распространенности гиперкалиемии у детей с ХБП 1–5-й ст. и внедрение поэтапного подхода с использованием калиевого биндера полистиренсульфоната натрия (ПСН) для лечения гиперкалиемии. Материалы и методы. В 300 образцах крови детей с ХБП 1–5-й ст. определяли уровень сывороточного калия (СК). У 23 пациентов с ХБП 1–5-й ст. изучали эффективность и переносимость ПСН для коррекции гиперкалиемии. ПСН назначали перорально из расчета 1 г/кг массы тела в сутки, разделяя рассчитанную дозу на 3 приема. Курс лечения длился 4 недели с последующим переходом на поддерживающую терапию в дозе 0,5 г/кг массы тела. Результаты. Полученные результаты продемонстрировали, что нормокалиемия (уровень СК 3,5–5,4 ммоль/л) имела место у 73,3 % детей с ХБП 1–5-й ст. Диапазон значений СК 5,0–5,4 ммоль/л определен у 60 пациентов (20,0 %) с ХБП 1–5-й ст. Легкая степень гиперкалиемии (5,5–5,9 ммоль/л) регистрировалась у 13,7 % детей с ХБП 1–5-й ст., средняя степень гиперкалиемии (6,0–6,4 ммоль/л) — у 7 %, и тяжелая степень гиперкалиемии (≥ 6,5 ммоль/л) — у 6 % соответственно. Через 4 недели лечения ПСН уровень СК снизился с 5,9 ± 0,4 ммоль/л до 4,7 ± 0,3 ммоль/л (р &lt; 0,05). Использование ПСН сопровождалось незначительным повышением в сыворотке крови уровня натрия (с 138,3 ± 2,4 ммоль/л до 140,7 ± 2,2 ммоль/л), не выходящего за границы нормального диапазона. Терапия ПСН хорошо переносилась, только 1 из 23 пациентов прекратил прием ПСН из-за желудочно-кишечной непереносимости. Выводы. Дисбаланс уровня СК у детей с ХБП 1–5-й ст. начинается с пороговых значений 5,0–5,4 ммоль/л, что требует тщательного контроля и свое­временного поэтапного подхода с целью устранения прогрессирования гиперкалиемии и минимизации возможности возникновения нежелательных последствий. ПСН — калиевый биндер — эффективное медикаментозное средство, которое можно использовать для последовательного и безопасного снижения уровня СК у детей с ХБП с гиперкалиемией в составе комплексной терапии.

Cerebral Salt Wasting Syndrome: A Complication of Meningitis in Hydrocephalus with VP Shunt:

Cerebral salt wasting syndrome (CSWS) is an important cause of persistent hyponatremia in children admitted to the intensive care unit. It needs to be promptly differentiated from the syndrome of inappropriate antidiuretic hormone (SIADH) secretion as a cause of hyponatremia in pediatric neurological patients. These two entities often have similar presenting symptoms however the treatment of both can be drastically different, which makes the distinction critical. We present a 6-month-old male child with hydrocephalus secondary to aqueductal stenosis, a blocked VP shunt, meningitis, and hyponatremia. A diagnosis of CSWS was considered and fludrocortisone was started. The patient improved gradually with a reduction in urine output and a gradual increase in serum sodium levels. A diagnosis of CSWS should be strongly considered in hyponatremic pediatric patients with significant natriuresis and suitable treatment should be initiated promptly to prevent long-term neurologic sequelae.

A Comparative Study of Hypertonic Saline V/S Mannitol in Raised Intracranial Pressure in Children Aged Between 02 to 12 Years

Raised intracranial pressure, the most common problem encountered in critical care unit, is often end result of various neurological disorders1. It is an important independent prognostic factor1 Most of the available therapies in the management of raised intracranial pressure in children are like double edged sword. Hence this study was undertaken, to know the efficacy, safety, complications and outcome of Osmotherapies (hypertonic saline v/s Mannitol). This study was carried out in children aged between 02-12 years, admitted to paediatric critical care Unit in the Department of paediatric, at Vijayanagar institute of medical sciences Ballari, from January-16 to December-16 with features of raised ICP. 50 children were randomly given. Hypertonic saline (HTS) and 50 were given mannitol. Following parameters compared n results drawn: symptomatology, GCS, papilledema, pupillary reactions after 72 hrs of administration and effects on serum electrolytes, urea n creatinine, and osmolarity. We found that out of 50 children who were onmannitol therapy, 12 children needed HTS for sustained reduction of ICP beyond 72 hours (p=0.056). Improvement in GCS was better with use of mannitol (p=0.024) during first 72 hours compared to HTS. Increase in serum sodium levels were seen with use of HTS which was statistically significant (p=0.064). But mortality in both groups was similar. Hence, we concluded that mannitol was a better drug to be used in first 72 hrs but for sustained reduction of ICP beyond 72 hrs hts was better option.

Nephroprotective effect of Bacopa monnieri on gentamicin-induced nephrotoxicity in rodent models

Background: Drug-induced nephrotoxicity has been a significant cause of concern. Nephrotoxicity has been majorly implicated due to drug or toxin exposure. Bacopa monnieri commonly known, as “Brahmi,” is known to have a wide range of pharmacological principles responsible for various curative properties. Aim and Objective: The present study aims to assess the nephroprotective role of B. monnieri extract (BME) in gentamicin (GM)-induced nephrotoxic rodent model. Materials and Methods: Nephroprotective effect of the extract in doses of 100 mg/kg and 200 mg/kg was tested in GM-induced nephrotoxic rodent model. Mean kidney weight, urea, creatinine, blood urea nitrogen, and electrolytes were measured. Renal antioxidants were analyzed. Data were statistically analyzed. Results: Renoprotection in terms of reduced mean kidney weight, urea, creatinine, and blood urea nitrogen post-intoxication was observed maximum at dose of 200 mg/kg when compared with GM intoxicated group. Treatment with BME showed significant increase in serum sodium level and decrease in serum potassium level. Groups treated with BME showed significant increase in glutathione, superoxide dismutase, and catalase values at 100 mg/kg and 200 mg/kg. Conclusion: For progressive situations, nephroprotectant can be of utility. Promising results in terms of biochemical parameters were observed, where significant protection from renal injury can be postulated.

Real-World, Non-Interventional, Retrospective Study (SAMPLE) of Tolvaptan in Patients with Hyponatraemia Secondary to the Syndrome of Inappropriate Antidiuretic Hormone Secretion.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatraemia in hospital inpatients. We present data on treatment setting, patient characteristics, and outcomes for patients treated with tolvaptan for SIADH across a range of real-world settings in Germany and Spain. This was a non-interventional, observational, retrospective chart review study. Management was at the discretion of the treating physician, with tolvaptan prescribed according to local clinical practice. Hospital notes and/or medical charts were reviewed from treatment initiation for 6weeks. Follow-up data were collected when patients were discharged early. Patients were eligible for inclusion if they were ≥ 18years of age and had been treated with ≥ 2 doses of tolvaptan for one episode of hyponatraemia secondary to SIADH in 2014. The Full Analysis Set comprised 100 patients from 8 centres. The mean age of patients was 73.9years. The primary endpoint of the mean increase in serum sodium level from baseline to hospital discharge, or to final available measurement, was 10.3mmol/L (SD 6.4; 95% CI 9.0, 11.6), from 123.0mmol/L (SD 6.0) to 133.3mmol/L (SD 4.9). Seventy-seven patients (77.0%) achieved sodium normalisation within 6weeks of tolvaptan initiation. Mean daily dose of tolvaptan was 12.7mg (SD 9.2), and mean treatment duration 28.0days (SD 16.5). Tolvaptan at off-label doses (< 15mg/day) was prescribed to 72 patients at some point. A favourable safety and tolerability profile was reported. Tolvaptan was well tolerated and effectively corrected sodium levels in hospitalised adults with hyponatraemia secondary to SIADH in real-world settings. CLINICALTRIALS. NCT02545101.

Extrapontine myelinolysis caused by rapid correction of pituitrin-induced severe hyponatremia: A case report

Severe hyponatremia is considered a rare complication of pituitrin, which is widely used for the treatment of pulmonary hemorrhage. However, the management of pituitrin-associated hyponatremia can be challenging because a rapid correction of hyponatremia may cause the development of osmotic demyelination syndrome, resulting in life-threatening neurological injuries. A 20-year-old Chinese man with massive hemoptysis developed symptomatic hyponatremia (116 mmol/L) after therapy by a continuous intravenous drip of pituitrin. To normalize his serum sodium, a hypertonic saline infusion was applied for 3 d, and the pituitrin administration was stopped concurrently. Then, an overly rapid increase in serum sodium level (18 mmol/L in 24 h) was detected after treatment. One day later, the patient experienced a sudden onset of generalized tonic-clonic seizures, as well as subsequent dysarthria and dystonia. Magnetic resonance imaging revealed increased signal intensity in the bilateral symmetric basal ganglia on the T2-weighted images, compatible with a diagnosis of extrapontine myelinolysis. The patient received an intravenous administration of high-dose corticosteroids, rehabilitation, and neurotrophic therapy. Finally, his clinical abnormalities were vastly improved, and he was discharged with few residual symptoms. Physicians should be fully aware that pituitrin can cause profound hyponatremia and its correction must be performed at a controlled rate to prevent the development of osmotic demyelination syndrome.

Osmotic demyelination syndrome in a patient with slowly equalized severe hyponatremia – a case report

Introduction. Osmotic demyelination syndrome (ODS), or central pontine myelinolysis (CPM), is a complication of severe and prolonged hyponatremia, particularly when hyponatremia is corrected too rapidly. However, even slow correction of hyponatremia can result in ODS. Aim. In this paper, we describe a patient who developed ODS following slow correction of hyponatremia. Description of the case. This article describes a case of chronic hyponatremia occurring in the course of alcoholism. The patient was admitted in severe condition with extremely low sodium level. Electrolyte supplementation was carried out according to the European Renal Best Practice (ERBP) guidelines; however, there was a rapid increase in sodium level leading to the development of symptomatic osmotic demyelinating syndrome. Following several weeks of rehabilitation and supplementation of B vitamins, the patient’s condition gradually improved. Conclusion. Sodium deficiency should be equilibrated very carefully, especially in patients with chronic hyponatremia in the course of alcoholism. Even small doses of sodium administered in accordance with the guidelines in chronic hyponatremia can cause a rapid increase in serum sodium level resulting in osmotic demyelination syndrome.

Equivalent Efficacy and Decreased Rate of Overcorrection in Patients With Syndrome of Inappropriate Secretion of Antidiuretic Hormone Given Very Low-Dose Tolvaptan

Rationale & ObjectiveEuvolemic hyponatremia often occurs due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Vasopressin 2 receptor antagonists may be used to treat SIADH. Several of the major trials used 15 mg of tolvaptan as the lowest effective dose in euvolemic and hypervolemic hyponatremia. However, a recent observational study suggested an elevated risk for serum sodium level overcorrection with 15 mg of tolvaptan in patients with SIADH.Study DesignA retrospective chart review study comparing outcomes in patients with SIADH treated with 15 versus 7.5 mg of tolvaptan.Settings & ParticipantsPatients with SIADH who were treated with a very low dose of tolvaptan (7.5 mg) at a single center compared with patients using a 15-mg dose from patient-level data from the observational study described previously.PredictorsTolvaptan dose of 7.5 versus 15 mg daily.OutcomesAppropriate response to tolvaptan, defined as an initial increase in serum sodium level > 3 mEq/L, and overcorrection of serum sodium level (>8 mEq/L per day, and >10 mEq/L per day in sensitivity analyses).Analytical ApproachDescriptive study with additional outcomes compared using t tests and F-tests (Fischer's Exact χ2 Test).ResultsAmong 18 patients receiving 7.5 mg of tolvaptan, the mean rate of correction was 5.6 ± 3.1 mEq/L per day and 2 (11.1%) patients corrected their serum sodium levels by >8 mEq/L per day, with 1 of these increasing by >12 mEq/L per day. Of those receiving tolvaptan 7.5 mg, 14 had efficacy, with increases ≥ 3 mEq/L; similar results were seen with the 15-mg dose (21 of 28). There was a statistically significant higher chance of overcorrection with the use of 15 versus 7.5 mg of tolvaptan (11 of 28 vs 2 of 18; P = 0.05; and 10 of 28 vs 1 of 18; P = 0.03, for >8 mEq/L per day and >10 mEq/L per day, respectively).LimitationsSmall sample size, retrospective, and nonrandomized.ConclusionsTolvaptan, 7.5 mg, daily corrects hyponatremia with similar efficacy and less risk for overcorrection in patients with SIADH versus 15 mg of tolvaptan.

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

To describe the effectiveness and tolerability of conivaptan and tolvaptan for the correction of hyponatremia in neurocritically ill patients. Retrospective cohort study. Neurointensive care units at two academic medical centers. 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. 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. 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.

Relationship of serum sodium level with cerebral edema and prognosis in patients with spontaneous intracerebral hemorrhage

Objective To investigate the association of serum sodium level with cerebral edema and prognosis in patients with spontaneous intracerebral hemorrhage. Methods We prospectively studied 90 patients with spontaneous intracerebral hemorrhage within 24 hours from onset of symptoms. According to the target value of serum sodium level, the patients were divided into 3 groups, relatively low-sodium group (135-140 mmol/L), relatively high-sodium group (140-145 mmol/L), absolute high-sodium group ( 145-155 mmol/L)(n=30 for each). National institutes of health stroke scale (NIHSS), Glasgow coma score (GCS), and blood tests were measured within 24 hours from onset. Hematoma volumes, edema volumes, liver and kidney function were measured within 24 hours, 3 days, 7 days after onset. Modified rankin scale (MRS) were measured at 90 days to assess the recovery of neurological function. Modified rankin scale score ≤ 2 was considered as good outcome. Results The edema volume was smaller in absolute high-sodium group than in relatively low-sodium group and relatively high-sodium group 〔(25.37±26.54) ml vs. (55.21±58.21) ml, (59.48±55.84) ml, F=1.492, P=0.023〕. The percentage of patients with MRS score ≤2 was 70% in absolute high-sodium group, which had a better prognosis as compared with relatively low-sodium and relatively high-sodium group (both P<0.05). The hematoma volume had no significant difference among the three groups. Conclusions The appropriate increase in serum sodium level is safe, which could reduce cerebral edema and get a better prognosis. Key words: Cerebral hemorrhage; Edema; Sodium

Effect of Androctonus bicolor scorpion venom on serum electrolytes in rats: A 24-h time-course study.

Black fat-tailed scorpion (Androctonus bicolor) belongs to the family Buthidae and is one of the most venomous scorpions in the world. The effects of A. bicolor venom on serum electrolytes were not known and therefore investigated in this study. Adult male Wistar rats were randomly divided into seven groups with five animals in each group. One of the groups served as control and received vehicle only. The animals in the remaining groups received a single subcutaneous injection of crude A. bicolor venom (200 μg/kg bodyweight) and were killed at different time intervals including 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after venom injection. The results showed that scorpion venom caused significant increase in serum sodium levels within 30 min after injection which slightly subsided after 1 h and then persisted over 24 h. Serum potassium levels continued to significantly increase until 4 h and then slightly subsided. There were significant decreases in serum magnesium (Mg(+)) levels following scorpion venom injection, at all the time points during the course of study. Serum calcium levels were significantly increased during the entire course of study, whereas serum chloride was significantly decreased. In conclusion, A. bicolor envenomation in rats caused severe and persistent hypomagnesemia with accompanied hypernatremia, hyperkalemia, and hypercalcemia. It is important to measure serum Mg(+) levels in victims of scorpion envenomation, and patients with severe Mg(+) deficiency should be treated accordingly.

Small Cell Lung Cancer Patient with Profound Hyponatremia and Acute Neurological Symptoms: An Effective Treatment with Fludrocortisone.

Hyponatremia is a frequent electrolyte abnormality in patients with small cell lung cancer (SCLC). Being usually asymptomatic, hyponatremia may cause symptoms like nausea, fatigue, disorientation, headache, muscle cramps, or even seizures, particularly if severe and rapid decrease of serum sodium levels occurs. Here we report a case of SCLC patient with severe hyponatremia and acute neurological symptoms that developed 2 days after the first course of second-line chemotherapy, most probably due to the release of antidiuretic hormone (ADH, also known as arginine vasopressin) during lysis of the tumour cells. Initial treatment consisted of continuous administration of hypertonic saline that resulted in improvement of patient's neurological status. However, to obtain a persistent increase in serum sodium level, pharmacological intervention with oral fludrocortisone 0.1 mg twice daily was needed. We can therefore conclude that mineralocorticoids may be used to correct hyponatremia in SCLC patients when appropriate.

Therapeutic Effect of Conivaptan Bolus Dosing in Hyponatremic Neurosurgical Patients

To determine the natremic response of a single 20-mg bolus dose of conivaptan, an arginine vasopressin antagonist, in hyponatremic neurosurgical patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Retrospective medical record review. Neurosurgical intensive care unit of a tertiary care referral hospital. Thirty-two hyponatremic patients with SIADH who were admitted to the neurosurgical intensive care unit and received a single 20-mg bolus dose of conivaptan between January and December 2011. Each patient's natremic response over 48hours was determined. The primary end point was an increase in serum sodium level of 4mEq/L or greater over the first 24hours. The mean ± SD baseline serum sodium level was 129.8±3.4 mEq/L, which increased to 133.1±3.2mEq/L at 6hours after administration of the bolus dose of conivaptan. The serum sodium level at 24hours was 134.2±3.2mEq/L, indicating a 24-hour natremic response of 4.3±2.6mEq/L (range 1-13mEq/L) from baseline (p<0.001). Eighteen patients (56%) met the primary end point. The mean ± SD fluid balance over the first 24hours was -783±440 ml. The mean ± SD change in serum sodium level from 24 to 48hours was 0.5±1.3mEq/L. No adverse effects or injection-site reactions were noted. The patients who failed to reach the primary end point were treated with repeated doses of conivaptan plus other agents. We recommend a single 20-mg dose of conivaptan as the preferred initial approach to treating patients with SIADH who are in the neurosurgical intensive care unit. The 24-hour natremic response should then dictate whether additional doses of conivaptan or other therapeutic interventions are required. We believe that such an approach is safe and will result in a controlled and predictable increase in the serum sodium concentration.

Lixivaptan for Hyponatremia—The Numbers Game

ON SEPTEMBER 13, 2012, THE CARDIOVASCULAR and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) reviewed lixivaptan, a new vasopressin receptor antagonist. These agents correct hyponatremia by producing a selective water diuresis without affecting sodium and potassium excretion; the resultant urinary free water loss raises serum sodium levels. Hyponatremia, diagnosed as a laboratory serum sodium of less than 138 mEq/L, is seen in nearly 38% of hospitalized patients and creates a potentially large population eligible for therapy. Historically, severe reductions in serum sodium levels have been accepted as a surrogate end point by the FDA, leading to approval in the United States of both tolvaptan and conivaptan. The label for these approved drugs specifies an indication for the treatment of severe hyponatremia— a serum sodium level of 125 mEq/L—or less marked hyponatremia that is symptomatic and resistant to correction with fluid restriction in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH), acute decompensated heart failure, or cirrhosis. However, the validity and clinical utility of serum sodium levels as a surrogate marker for clinical benefit remain uncertain. Lixivaptan demonstrated statistically significant improvements in serum sodium levels at day 7, the primary efficacy end point in populations that had either SIADH or acute decompensated heart failure. The magnitude of the improvement, however, was modest: 1.2 mEq/L in acute decompensated heart failure and 2.4 mEq/L in SIADH. In addition, there were no corresponding improvements in symptoms of hyponatremia as assessed by the Trail Making Test Part B, a measure of cognitive processing speed. Moreover, no improvement in the secondary outcomes of days alive out of hospital or hospital length of stay were demonstrated. In the FDA analysis of the population with acute decompensated heart failure, there was a statistically significant, paradoxical improvement in cognitive processing speed favoring placebo and no observed symptomatic benefit of lixivaptan among patients with SIADH. Of greatest concern, an early imbalance in mortality (15 vs 4 sudden deaths in the first 10 days) was observed with lixivaptan in the population with acute decompensated heart failure, although the randomized study included only 652 patients. Ultimately, the advisory committee voted 5 to 3 against approving lixivaptan for treating patients with hyponatremia who had SIADH, and the committee voted unanimously against its approval for patients with acute decompensated heart failure. The tolvaptan study that led to approval demonstrated a mean increase in serum sodium levels of 5 mEq/L vs placebo at day 4, which persisted at day 30. Tolvaptan also improved the Mental Component Summary of the 12-Item Short Form Health Survey (SF-12) at the 30-day followup. However, this symptomatic benefit was not demonstrated from a validated, disease-specific questionnaire. Moreover, when tolvaptan was tested in a trial of 4133 patients hospitalized with acute decompensated heart failure, no clinical improvements in rehospitalization, renal function, or mortality were observed despite a median follow-up of 10 months. Perceived short-term benefits of tolvaptan improving serum sodium therefore need to be weighed against patients who experienced overcorrection of hyponatremia. The risk of drug-induced hypernatremia was higher in the tolvaptan group than in the placebo group (1.7% vs 0.5%). Although the absolute risk of hypernatremia was small within the randomized trial setting, broader use would most likely increase exposure to this risk of irreversible neurologic injury from osmotic demyelination syndrome without a commensurate improvement in clinical outcomes. Overall, in the case of the vasopressin receptor antagonist class, uncertainty remains regarding both expected symptomatic benefits and long-term improvements in health outcomes. Four explanations were highlighted at the advisory committee meeting that could account for the lack of clinical benefit in the vasopressin receptor antagonist class. First, the degree of hyponatremia may not have been severe enough. Mean serum sodium levels among patients treated with tolvaptan were 128 to 129 mEq/L and among patients in the lixivaptan trials were 124 to 132 mEq/L, yet patients with severe hyponatremia may be most likely to derive benefit. Second, symptoms of hyponatremia may be so

Diagnosis and Management of Hyponatremia in Cancer Patients

Hyponatremia, a common electrolyte abnormality in oncology practice, may be a negative prognostic factor in cancer patients based on a systematic analysis of published studies. The largest body of evidence comes from small-cell lung cancer (SCLC), for which hyponatremia was identified as an independent risk factor for poor outcome in six of 13 studies. Hyponatremia in the cancer patient is usually caused by the syndrome of inappropriate antidiuretic hormone (SIADH), which develops more frequently with SCLC than with other malignancies. SIADH may be driven by ectopic production of arginine vasopressin (AVP) by tumors or by effects of anticancer and palliative medications on AVP production or action. Other factors may cause hypovolemic hyponatremia, including diarrhea and vomiting caused by cancer therapy. Hyponatremia may be detected on routine laboratory testing before or during cancer treatment or may be suggested by the presence of mostly neurological symptoms. Treatment depends on several factors, including symptom severity, onset timing, and extracellular volume status. Appropriate diagnosis is important because treatment differs by etiology, and choosing the wrong approach can worsen the electrolyte abnormality. When hyponatremia is caused by SIADH, hypertonic saline is indicated for acute, symptomatic cases, whereas fluid restriction is recommended to achieve a slower rate of correction for chronic asymptomatic hyponatremia. Pharmacological therapy may be necessary when fluid restriction is insufficient. The orally active, selective AVP receptor 2 (V(2))-receptor antagonist tolvaptan provides a mechanism-based option for correcting hyponatremia caused by SIADH or other conditions with inappropriate AVP elevations. By blocking AVP effects in the renal collecting duct, tolvaptan promotes aquaresis, leading to a controlled increase in serum sodium levels.