Overcorrection Of Hyponatremia Research Articles

Evaluating Impact of Implementing Order Questions on Appropriate Prescribing of Tolvaptan

Background Tolvaptan poses a significant risk to patient safety due to its risk of overcorrection of hyponatremia, and its cost-effectiveness is not well established. Kettering Health implemented order questions into Epic in 2019 to drive appropriate use of tolvaptan. Objective: The primary objective was to determine the impact of implementing order questions on appropriate use of tolvaptan. The secondary objectives were to determine if providers are adhering to the order questions meant to ensure appropriate use, to identify if there is provider variance across the network constituting a higher proportion of use outside of network recommendations, and to look at patients with multiple orders for tolvaptan and discern if dose titration was appropriate based on sodium levels. Methods: This study was a retrospective chart review of all patients who received a dose of tolvaptan from 7/3/2019 to 10/15/2020. Results: From July 2019 to October 2020, 211 patients received tolvaptan for hyponatremia, resulting in 598 administrations. Use of urea powder or fluid restriction preceded 248/586 (42.3%) tolvaptan administrations and the patient’s sodium level was < 125 mEq/L or 125–135 mEq/L with documentation of symptoms for 261/586 (44.5%) of the administrations. Medication safety concerns related to monitoring sodium levels were also identified. Conclusions: While tolvaptan use did significantly decrease in Kettering Health since the implementation of order questions, the answers to the questions displayed substantial variability. Further opportunity exists for directing appropriate use of tolvaptan within Kettering Health and additional emphasis should be placed on safe use of this medication.

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.

Osmotic Demyelination Syndrome following Correction of Hyponatremia by ≤10 mEq/L per Day.

Overly rapid correction of chronic hyponatremia may lead to osmotic demyelination syndrome. European guidelines recommend a correction to ≤10 mEq/L in 24 hours to prevent this complication. However, osmotic demyelination syndrome may occur despite adherence to these guidelines. We searched the literature for reports of osmotic demyelination syndrome with rates of correction of hyponatremia ≤10 mEq/L in 24 hours. The reports were reviewed to identify specific risk factors for this complication. We identified 19 publications with a total of 21 patients that were included in our analysis. The mean age was 52 years, of which 67% were male. All of the patients had community-acquired chronic hyponatremia. Twelve patients had an initial serum sodium <115 mEq/L, of which seven had an initial serum sodium ≤105 mEq/L. Other risk factors identified included alcohol use disorder (n=11), hypokalemia (n=5), liver disease (n=6), and malnutrition (n=11). The maximum rate of correction in patients with serum sodium <115 mEq/L was at least 8 mEq/L in all but one patient. In contrast, correction was <8 mEq/L in all but two patients with serum sodium ≥115 mEq/L. Among the latter group, osmotic demyelination syndrome developed before hospital admission or was unrelated to hyponatremia overcorrection. Four patients died (19%), five had full recovery (24%), and nine (42%) had varying degrees of residual neurologic deficits. Osmotic demyelination syndrome can occur in patients with chronic hyponatremia with a serum sodium <115 mEq/L, despite rates of serum sodium correction ≤10 mEq/L in 24 hours. In patients with severe hyponatremia and high-risk features, especially those with serum sodium <115 mEq/L, we recommend limiting serum sodium correction to <8 mEq/L. Thiamine supplementation is advisable for any patient with hyponatremia whose dietary intake has been poor.

Evaluation of Serum Sodium Correction Rates for Management of Hyponatremia in Hospitalized Patients.

Appropriate correction of hyponatremia can reduce complications such as osmotic demyelination syndrome (ODS). To evaluate rates of serum sodium correction in hyponatremic hospitalized patients and identify factors associated with higher rates of overcorrection. This is an institutional review board-approved single-center, retrospective chart review of patients ≥18 years of age with at least 1 serum sodium <130 mEq/L during hospitalization. The primary end point was percentage of patients appropriately corrected for hyponatremia. Appropriate correction was defined as a sodium change ≤12 mEq/L over 24 hours and 18 mEq/L over 48 hours, and overcorrection was defined as an increase in serum sodium exceeding these cutoffs. Secondary end points included incidence of ODS, poor neurological outcome, intensive care unit (ICU) and hospital lengths of stay (LOSs), and in-hospital mortality. Of 234 patients evaluated, 100 were included. Mean age was 72 ± 16 years, and 47% were male. Overcorrection occurred in 14 patients. There was no incidence of ODS. Rates of poor neurological outcome (P = 0.77), ICU (P = 0.09) and hospital LOS (P = 0.13), and in-hospital mortality (P = 0.20) were similar between appropriately corrected and overcorrected patients. Using a logistic regression analysis, severe hyponatremia (serum sodium < 120 mEq/L; P = 0.0122) and history of alcohol use disorder (P < 0.001) were risk factors found to be associated with overcorrection. Overcorrection of hyponatremia occurred in 14% of patients in this study. To minimize this risk, further caution should be taken when managing patients presenting with identified risk factors.

Hyponatraemia and hypernatraemia: Disorders of Water Balance in Neurosurgery.

Disorders of tonicity, hyponatraemia and hypernatraemia, are common in neurosurgical patients. Tonicity is sensed by the circumventricular organs while the volume state is sensed by the kidney and peripheral baroreceptors; these two signals are integrated in the hypothalamus. Volume is maintained through the renin-angiotensin-aldosterone axis, while tonicity is defended by arginine vasopressin (antidiuretic hormone) and the thirst response. Edelman found that plasma sodium is dependent on the exchangeable sodium, potassium and free-water in the body. Thus, changes in tonicity must be due to disproportionate flux of these species in and out of the body. Sodium concentration may be measured by flame photometry and indirect, or direct, ion-sensitive electrodes. Only the latter method is not affected by changes in plasma composition. Classification of hyponatraemia by the volume state is imprecise. We compare the tonicity of the urine, given by the sodium potassium sum, to that of the plasma to determine the renal response to the dysnatraemia. We may then assess the activity of the renin-angiotensin-aldosterone axis using urinary sodium and fractional excretion of sodium, urate or urea. Together, with clinical context, these help us determine the aetiology of the dysnatraemia. Symptomatic individuals and those with intracranial catastrophes require prompt treatment and vigilant monitoring. Otherwise, in the absence of hypovolaemia, free-water restriction and correction of any reversible causes should be the mainstay of treatment for hyponatraemia. Hypernatraemia should be corrected with free-water, and concurrent disorders of volume should be addressed. Monitoring for overcorrection of hyponatraemia is necessary to avoid osmotic demyelination.

Continuous Renal Replacement Therapy (CRRT) for Overcorrection of Hyponatremia After Left Ventricular Assistance Device (LVAD) Placement

Continuous Renal Replacement Therapy (CRRT) for Overcorrection of Hyponatremia After Left Ventricular Assistance Device (LVAD) Placement

Electrolyte Disorders and the Nervous System.

This article provides an overview of the major electrolyte disorders and discusses in detail the homeostasis, etiologies, neurologic manifestations, and treatment of these disorders. The diagnosis and management of hyponatremia continue to evolve. Diagnostic accuracy is improved by assessing serum and urine osmolality as well as urinary sodium. Avoiding overcorrection of hyponatremia is crucial to avoid osmotic demyelination syndrome, although even careful correction can cause osmotic demyelination syndrome in patients who have other risk factors. The clinical presentation of osmotic demyelination syndrome has expanded, with many patients presenting with extrapontine myelinolysis in addition to central pontine myelinolysis. Electrolyte disorders often present with neurologic manifestations. Whereas disorders of some electrolytes, such as sodium, preferentially affect the central nervous system, disorders of others, such as potassium and calcium, have significant neuromuscular manifestations. An understanding of the pathophysiology of these disorders and recognition of these manifestations are crucial for the practicing neurologist as the symptoms are reversible with correct management.

Risk factors for sodium overcorrection in non-hypovolemic hyponatremia patients treated with tolvaptan.

In this study, the risk factors associated with sodium overcorrection were investigated with an optimal cutoff for baseline serum sodium for use in daily clinical practice. Electronic medical records of patients who received tolvaptan for non-hypovolemic hyponatremia were reviewed. Demographic and clinical data including age, sex, weight, height, comorbidity, cause of hyponatremia, hypertonic saline use, and comedication were collected. Baseline laboratory parameters measured included serum sodium, serum potassium, serum creatinine, blood urea nitrogen, serum tonicity, ALT, AST, and urine osmolality. The primary outcome was the overcorrection of serum sodium, which was defined as an increase in serum sodium by more than 10mmol/L in 24h. From a total of 77 patients included in the analysis, 24 (31.2%) showed sodium overcorrection (> 10mmol/L/24h); 2 (2.6%) in heart failure cohort, 17 (22.1%) in SIADH cohort, and 5 (6.5%) in unknown cause cohort. More than half of patients (51.9%) were administered hypertonic saline prior to tolvaptan. Hypertension, cancer, diuretics, baseline serum sodium, and SIADH were associated with the risk of overcorrection in the univariable analysis. Significant factors for the overcorrection from multivariable analysis were lower body mass index, presence of cancer (adjusted odds ratio, 10.87; 95% CI, 1.23-96.44), and lower serum sodium at baseline (adjusted odds ratio, 0.76 for every 1mEq/L increase; 95% CI, 0.61-0.94). The overcorrection of hyponatremia in non-hypovolemic patients treated with tolvaptan was significantly associated with lower body mass index, presence of cancer, and lower serum sodium at baseline. In subgroup analysis using SIADH patients, baseline sodium and cancer were found to be significant factors of overcorrection.

Hyponatremia in Cirrhosis: Implications for Liver Transplantation.

Hyponatremia in cirrhosis is defined as a serum sodium level ≤130 mEq/L and occurs in approximately 22% of patients with cirrhosis. The appearance of hyponatremia in patients with cirrhosis portends a poor prognosis before liver transplantation (LT), independent of the Model for End-Stage Liver Disease (MELD) score. With the development of the MELD-sodium score, the management of hyponatremia has become more relevant than ever before. Overcorrection of hyponatremia before LT or perioperatively can lead to the devastating neurologic condition known as osmotic demyelination syndrome, which is often irreversible and fatal. Therefore, the most important tenet of hyponatremia is to avoid correcting the serum sodium by ≥8 mEq/L in a 24-hour period. Treatment of hyponatremia is highly challenging. The vast majority of patients with cirrhosis have chronic hypervolemic hyponatremia. Fluid restriction increases serum sodium levels, but tolerance and compliance are significant barriers. Diuretic withdrawal is helpful but contributes to worsening fluid overload. There are limited data to support use of intravenous concentrated albumin solutions. The use of the arginine vasopressin antagonists ("vaptans") is contentious; however, they may have a limited role. Risk factors for intraoperative overcorrection of serum sodium include increased utilization of packed red blood cell and fresh frozen plasma transfusions, which are often unavoidable. Intraoperative management is evolving, and more data are needed in regard to the use of sodium-reduced continuous venovenous hemofiltration and the use of trishydroxymethylaminomethane (Tris) to avoid excess sodium rebound. A thorough discussion of the current treatment options before and during LT is given in this review.

A Multidisciplinary Approach for the Management of Severe Hyponatremia in Patients Requiring Continuous Renal Replacement Therapy

IntroductionHyponatremia is a common electrolyte disorder in critically ill patients. Rapid correction of chronic hyponatremia may lead to osmotic demyelination syndrome. Management of severe hyponatremia in patients with acute or chronic kidney disease who require continuous renal replacement therapy (CRRT) is limited by the lack of commercially available hypotonic dialysate or replacement fluid solutions.MethodsThis was a single-center quality improvement project that consisted of the development and implementation of a multidisciplinary protocol for gradual correction of severe hyponatremia in patients who were admitted to the intensive care unit (ICU) and required CRRT. The protocol utilized a simplified method based on single-pool urea kinetic modeling and a hybrid technique of volume exchange, and addition of sterile water for sodium dilution of commercially available dialysate and replacement fluid solutions.ResultsWe report data of the first 3 ICU patients who required CRRT for acute kidney injury management, had severe hyponatremia (serum sodium <120 mEq/l), and were treated under the protocol. Targeted and gradual hyponatremia correction was achieved in all 3 patients. The observed versus the predicted serum sodium correction in each patient was concordant. No complications related to the protocol were reported. We detailed facilitators of and hindrances to the development and successful implementation of our multidisciplinary protocol.ConclusionWe demonstrated gradual and individualized rates of severe hyponatremia correction utilizing customized (sodium dilution) dialysate/replacement fluid solutions in ICU patients who required CRRT. It is not known whether the use of customized solutions to prevent hyponatremia overcorrection has a significant impact on patient outcomes. Further research in this susceptible population is needed.

Kinetic Sodium Equation with Built-In Rate of Correction: Aid to Prescribing Therapy for Hyponatremia or Hypernatremia

Purpose Both hyponatremia and hypernatremia occur frequently in patients with cancer. To understand these disorders, investigators have mathematically modeled the serum sodium concentration in humans. Methods We expanded the model to incorporate time, in a “kinetic sodium” equation, and then a term explicitly appears for the rate of sodium correction, a key consideration to avoid treatment complications. The equation is solved for the fluid administration rate to assist the clinician with the hospital order in the management of dysnatremia. Results With baseline data on the input and output rates of Na/K/water along with the patient's body weight, a clinician can use the kinetic equation to aim for a desired [sodium] over a safe timeframe. The formula returns the infusion rate for any treatment fluid, such as normal saline, hypertonic saline, or 5% dextrose in water. The formula can also calculate treatment in terms of the dosage of salt tablets. If an abrupt water diuresis is anticipated, the equation should be entered with the predicted urine [Na+K] and flow rate to avoid overcorrection of hyponatremia. To demonstrate efficacy, we applied the kinetic equation to real-life cases of hypo- and hypernatremia. Conclusions The kinetic equation improves upon existing sodium equations by potentially accounting for all inputs and outputs, if known, and incorporating a rate of correction. The quantitative approach provides a basis for prescribing intravenous fluids and salt tablets.

Does Accidental Overcorrection of Symptomatic Hyponatremia in Chronic Heart Failure Require Specific Therapeutic Adjustments for Preventing Central Pontine Myelinolysis?

This review aims at summarizing essential aspects of epidemiology and pathophysiology of hyponatremia in chronic heart failure (CHF), to set the ground for a practical as well as evidence-based approach to treatment. As a guide through the discussion of the available evidence, a clinical case of hyponatremia associated with CHF is presented. For this case, the severe neurological signs at presentation justified an emergency treatment with hypertonic saline plus furosemide, as indicated. Subsequently, as the neurological emergency began to subside, the reversion of the trend toward hyponatremia overcorrection was realized by continuous infusion of hypotonic solutions, and administration of desmopressin, so as to prevent the very feared risk of an osmotic demyelination syndrome. This very disabling complication of the hyponatremia correction is then briefly outlined. Moreover, the possible advantages related to systematic correction of the hyponatremia that occurs in the course of CHF are mentioned. Additionally, the case of tolvaptan, a vasopressin receptor antagonist, is concisely presented in order to underline the different views that have led to different norms in Europe with respect to the USA or Japan as regards the use of this drug as a therapeutic resource against the hyponatremia.

The Effects of Pre-Existing Hyponatremia and Subsequent-Developing Acute Kidney Injury on In-Hospital Mortality: A Retrospective Cohort Study.

Background and ObjectivesBoth hyponatremia and acute kidney injury (AKI) are common and harmful in hospitalized patients. However, their combined effects on patient mortality have been little studied.MethodsWe retrospectively enrolled 19191 adult patients who were admitted for 1 year. Pre-existing hyponatremia was defined as a serum sodium level < 135 mmol/L on the first measurement of their admission. AKI was defined as a rise in serum creatinine by ≥ 26.5 μmol/L or ≥ 1.5 times of the baseline value of creatinine during the hospital stay.ResultsThe prevalence of pre-existing hyponatremia was 8.2%. During a median 6.0 days of hospital stay, the incidence rates of AKI and in-hospital patient mortality were 5.1% and 0.9%, respectively. Pre-existing hyponatremia independently predicted AKI development and in-hospital mortality (adjusted hazard ratio [HR] 1.300, P = 0.004; HR 2.481, P = 0.002, respectively). Pre-existing hyponatremia and subsequent development of AKI increased in-hospital mortality by 85 times, compared to the patients with normonatremia and no AKI. In subgroup analysis, the AKI group showed higher rates of de novo hypernatremia than the non-AKI group during the admission. De novo hypernatremia, which might be associated with over-correction of hyponatremia, increased in-hospital mortality (HR 3.297, P <0.001), and patients with AKI showed significantly higher rates of de novo hypernatremia than patients without AKI (16.2% vs. 1.4%, P < 0.001, respectively).ConclusionPre-existing hyponatremia may be associated with the development of AKI in hospitalized patients, and both hyponatremia and hospital-acquired AKI could have a detrimental effect on short term patient mortality, which might be related to the inappropriate correction of hyponatremia in AKI patients.

Complications and management of hyponatremia.

Hyponatremia causes significant morbidity, mortality, and disability. This review considers the literature of the past 18 months to improve understanding of these complications and to identify therapeutic strategies to prevent them. Acute hyponatremia causes serious brain swelling that can lead to permanent disability or death. A 4-6 mEq/l increase in serum sodium is sufficient to reverse impending herniation. Brain swelling is minimal in chronic hyponatremia, and to avoid osmotic demyelination, correction should not exceed 8 mEq/l/day. In high-risk patients, correction should not exceed 4-6 mEq/l/day. Inadvertent overcorrection of hyponatremia is common and preventable by controlling unwanted urinary water losses with desmopressin. Even mild chronic hyponatremia is associated with increased mortality, attention deficit, gait instability, osteoporosis, and fractures, but it is not known if the correction of mild hyponatremia improves outcomes. Controlled trials are needed to identify affordable treatments for hyponatremia that reduce the need for hospitalization, decrease hospital length of stay, and decrease morbidity. Such trials could also help answer the question of whether hyponatremia causes excess mortality or whether it is simply a marker for severe, lethal, underlying disease.

Hyponatremia in the intensive care unit: How to avoid a Zugzwang situation?

Hyponatremia is a common electrolyte derangement in the setting of the intensive care unit. Life-threatening neurological complications may arise not only in case of a severe (<120 mmol/L) and acute fall of plasma sodium levels, but may also stem from overly rapid correction of hyponatremia. Additionally, even mild hyponatremia carries a poor short-term and long-term prognosis across a wide range of conditions. Its multifaceted and intricate physiopathology may seem deterring at first glance, yet a careful multi-step diagnostic approach may easily unravel the underlying mechanisms and enable physicians to adopt the adequate measures at the patient’s bedside. Unless hyponatremia is associated with obvious extracellular fluid volume increase such as in heart failure or cirrhosis, hypertonic saline therapy is the cornerstone of the therapeutic of profound or severely symptomatic hyponatremia. When overcorrection of hyponatremia occurs, recent data indicate that re-lowering of plasma sodium levels through the infusion of hypotonic fluids and the cautious use of desmopressin acetate represent a reasonable strategy. New therapeutic options have recently emerged, foremost among these being vaptans, but their use in the setting of the intensive care unit remains to be clarified.

Urea minimizes brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline

Hyponatremia is a common electrolyte disorder that carries significant morbidity and mortality. However, severe chronic hyponatremia should not be corrected rapidly to avoid brain demyelination. Vasopressin receptor antagonists (vaptans) are now being widely used for the treatment of hyponatremia along with other alternatives like hypertonic saline. Previous reports have suggested that, in some cases, urea can also be used to correct hyponatremia. Correction of severe hyponatremia with urea has never been compared to treatment with a vaptan or hypertonic saline with regard to the risk of brain complications in the event of a too rapid rise in serum sodium. Here, we compared the neurological outcome of hyponatremic rats corrected rapidly with urea, lixivaptan, and hypertonic saline. Despite similar increase in serum sodium obtained by the three drugs, treatment with lixivaptan or hypertonic saline resulted in a higher mortality than treatment with urea. Histological analysis showed that treatment with urea resulted in less pathological change of experimental osmotic demyelination than was induced by hypertonic saline or lixivaptan. This included breakdown of the blood-brain barrier, microglial activation, astrocyte demise, and demyelination. Thus, overcorrection of hyponatremia with urea resulted in significantly lower mortality and neurological impairment than the overcorrection caused by lixivaptan or hypertonic saline.

A Rare Case of Central Pontine Myelinolysis in Overcorrection of Hyponatremia with Total Parenteral Nutrition in Pregnancy.

A 42-year-old high risk pregnant female presented with hyponatremia from multiple causes and was treated with total parenteral nutrition. She developed acute hypernatremia due to the stage of pregnancy and other comorbidities. All the mechanisms of hyponatremia and hypernatremia were summarized here in our case report. This case has picture (graph) representation of parameters that led to changes in serum sodium and radiological findings of central pontine myelinolysis on MRI. In conclusion we present a complicated case serum sodium changes during pregnancy and pathophysiological effects on serum sodium changes during pregnancy.

Use of Desmopressin Acetate in Severe Hyponatremia in the Intensive Care Unit

Excessive correction of chronic and profound hyponatremia may result in central pontine myelinolysis and cause permanent brain damage. In the case of foreseeable or established hyponatremia overcorrection, slowing down the correction rate of sodium plasma levels (PNa) or reinducing mild hyponatremia may prevent this neurologic complication. This retrospective and observational study was performed with 20 consecutive patients admitted to two intensive care units for severe hyponatremia, defined by PNa <120 mmol/L and/or neurologic complications ascribable to hyponatremia and subsequently treated by desmopressin acetate (DDAVP) during correction of hyponatremia when the rate of correction was overtly or predictably excessive. The primary endpoint was the effectiveness of DDAVP on PNa control. DDAVP dramatically decreased the rate of PNa correction (median 0.81 mmol/L per hour [interquartile range, 0.46, 1.48] versus -0.02 mmol/L per hour [-0.16, 0.22] before and after DDAVP, respectively; P<0.001) along with a concurrent decrease in urine output (650 ml/h [214, 1200] versus 93.5 ml/h [43, 143]; P=0.003), and a rise in urine osmolarity (86 mmol/L [66, 180] versus 209 mmol/L [149, 318]; P=0.002). The maximal magnitude of PNa variations was also markedly reduced after DDAVP administration (11.5 mmol/L [8.25, 14.5] versus 5 mmol/L [4, 6.75]; P<0.001). No patient developed seizures after DDAVP or after subsequent relowering of PNa that occurred in 11 patients. Desmopressin acetate is effective in curbing the rise of PNa in patients admitted in the intensive care unit for severe hyponatremia, when the initial rate of correction is excessive.

Desmopression is an effective adjunct treatment for reversing excessive hyponatremia overcorrection

We report a case of a 50-year-old malnourished African American male with hiccups, nausea and vomiting who was brought to the Emergency Department after repeated seizures at home. Laboratory evaluations revealed sodium (Na(+)) 107 mmol/L, unmeasurably low potassium, chloride < 60 mmol/L, bicarbonate of 38 mmol/L and serum osmolality 217 mOsm/kg. Seizures were controlled with 3% saline IV. Once nausea was controlled with iv antiemetics, he developed large volume free water diuresis with 6 L of dilute urine in 8 h (urine osmolality 40-60 mOsm/kg) and serum sodium rapidly rose to 126 mmol/L in 12 h. Both intravenous desmopressin and 5% dextrose in water was given to achieve a concentrated urine and to temporarily reverse the acute rise of sodium, respectively. Serum Na(+) was gradually re-corrected in 2-3 mmol/L daily increments from 118 mmol/L until 130 mmol/L. Hypokalemia was slowly corrected with resultant auto-correction of metabolic alkalosis. The patient discharged home with no neurologic sequaele on the 11(th) hospital day. In euvolemic hyponatremic patients, controlling nausea may contribute to unpredictable free water diuresis. The addition of an antidiuretic hormone analog, such as desmopressin can limit urine output and prevent an unpredictable rise of the serum sodium.

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