Euvolemic hyponatremia in cancer patients. Report of the Hyponatremia Registry: an observational multicenter international study.
ABSTRACT: Hyponatremia secondary to SIADH is frequent in cancer patients and potentially deleterious. The aim of this sub-analysis of the Hyponatremia Registry database is to analyze current diagnostic and therapeutic management practices in cancer patients with SIADH.We analyzed 358 cancer patients who had serum sodium concentration ([Na+]) ? 130 mEq/L and a clinical diagnosis of SIADH from 225 sites in the USA and EU.Precise diagnostic testing was performed in only 46%. Almost 12% of all patients did not receive any hyponatremia treatment. The most frequent therapies were fluid restriction (20%), isotonic saline (14%), fluid restriction/isotonic saline (7%), tolvaptan (8%), and salt tablets (7%). Hypertonic saline was used in less than 3%. Tolvaptan produced the greatest median rate of [Na+] change (IQR) (3.0 (4.7) mEq/L/day), followed by hypertonic saline (2.0(7.0) mEq/L/day), and fluid restriction/isotonic saline (1.9(3.2) mEq/L/day). Both fluid restriction and isotonic saline monotherapies were significantly less effective (0.8(2.0) mEq/L/day and 1.3(3.0) mEq/L/day, respectively) and were associated with clinically relevant rates of treatment failure. Only 46% of patients were discharged with [Na+] ? 130 mEq/L. Overly rapid correction of hyponatremia occurred in 11.7%.Although essential for successful hyponatremia management, appropriate diagnostic testing is not routinely performed in current practice. The most frequently employed monotherapies were often ineffective and sometimes even aggravated hyponatremia. Tolvaptan was used less often but showed significantly greater effectiveness. Despite clear evidence that hyponatremia is associated with poor outcome in oncology patients, most patients were discharged still hyponatremic. Further studies are needed to assess the beneficial impact of hyponatremia correction with effective therapies.
Project description:<h4>Background</h4>Hyponatremia is a frequent and potentially life-threatening adverse side effect of thiazide diuretics. This sub-analysis of the Hyponatremia Registry database focuses on current management practices of thiazide-associated hyponatremia (TAH) and compares differences between TAH and syndrome of inappropriate antidiuretic hormone secretion (SIADH).<h4>Methods</h4>We analyzed 477 patients from 225 US and EU sites with euvolemic hyponatremia ([Na+] ?130 mEq/L) who were receiving a thiazide diuretic. Of these, 118 met criteria for true thiazide-induced hyponatremia (TIH).<h4>Results</h4>Thiazide was withdrawn immediately after hyponatremia was diagnosed only in 57% of TAH; in these patients, the median rate of [Na+] change (?daily[Na+]) was significantly higher than those with continued thiazide treatment (3.8 [interquartile range: 4.0] vs. 1.7 [3.8] mEq/L/day). The most frequently employed therapies were isotonic saline (29.6%), fluid restriction (19.9%), the combination of these two (8.2%), and hypertonic saline (5.2%). Hypertonic saline produced the greatest ?daily[Na+] (8.0[6.4] mEq/L/day) followed by a combination of fluid restriction and normal saline (4.5 [3.8] mEq/L/day) and normal saline alone (3.6 [3.5] mEq/L/day). Fluid restriction was markedly less effective (2.7 [2.7] mEq/L/day). Overly rapid correction of hyponatremia occurred in 3.1% overall, but in up to 21.4% given hypertonic saline. Although there are highly significant differences in the biochemical profiles between TIH and SIADH, no predictive diagnostic test could be derived.<h4>Conclusions</h4>Despite its high incidence and potential risks, the management of TAH is often poor. Immediate withdrawal of the thiazide is crucial for treatment success. Hypertonic saline is most effective in correcting hyponatremia but associated with a high rate of overly rapid correction. We could not establish a diagnostic laboratory-based test to differentiate TIH from SIADH.
Project description:Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130?mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0-4.0); fluid restriction, 2.0 (0.0-4.0); isotonic saline, 3.0 (0.0-5.0); hypertonic saline, 5.0 (1.0-9.0); and tolvaptan, 4.0 (2.0-9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5?mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135?mEq/l in 78% of patients and 130?mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.
Project description:Hyponatremia is a common electrolyte disorder in cancer patients and has been associated with poor prognosis. A frequent cause of cancer-related hyponatremia is the syndrome of inappropriate antidiuretic hormone (SIADH). This study was a post hoc subgroup analysis of the SALT-1 (Study of Ascending Levels of Tolvaptan in Hyponatremia) and SALT-2 clinical trials. Hyponatremic subjects with SIADH and cancer received the oral selective vasopressin V2-receptor antagonist tolvaptan (n = 12) or matching placebo (n = 16) once-daily for 30 days. The initial tolvaptan dose (15 mg) was titrated over 4 days to 30 or 60 mg per day, as needed, according to serum sodium level and tolerability. Baseline serum sodium levels in the SIADH/cancer cohort of the SALT trials was 130 and 128 mEq/L for tolvaptan and placebo, respectively. Mean change from baseline in average daily serum sodium AUC for tolvaptan relative to placebo was 5.0 versus -0.3 mEq/L (P < 0.0001) at day 4, and 6.9 versus 1.0 mEq/L (P < 0.0001) at day 30; the observed treatment effects were similar to those in the overall SIADH population (i.e., with and without cancer) at both time points. Serum sodium normalization was observed in 6/12 and 0/13 subjects at day 4 and 7/8 and 2/6 subjects at day 30 in the tolvaptan and placebo groups, respectively (P < 0.05 for both). Common treatment-emergent AEs for tolvaptan were consistent with previously reported results. In this post hoc study of the SALT trial population, oral tolvaptan was an effective and safe therapy for the treatment of hyponatremia in subjects with SIADH and cancer.
Project description:Hyponatremia is the most common electrolyte disorder in lung cancer patients. This condition may be related to many causes including incidental medications, concurrent diseases and side effects of antineoplastic treatments or the disease itself. Although not frequently life-threatening, it is usually associated with prolonged hospitalization, delays in scheduled chemotherapy, worsening of patient performance status and quality of life and may also negatively affect treatment response and survival. Most of the available data focus on thoracic tumors, especially small-cell lung cancer (SCLC), where hyponatremia is frequently related to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Few studies specifically focus on non-small cell lung cancer (NSCLC) patients. Hyponatremia treatment needs to be personalized based on severity and duration of sodium serum reduction, extracellular fluid volume and etiology. However, literature data highlight the importance of early correction of the serum concentration levels. To achieve this the main options are fluid restriction, hypertonic saline, loop diuretics, isotonic saline, tolvaptan and urea. The aim of this review is to analyze the role of hyponatremia in lung cancer patients, evaluating causes, diagnosis, management and clinical implications.
Project description:Context:The relevance of hyponatremia has been acknowledged by guidelines from the United States (2013) and Europe (2014). However, treatment recommendations differ due to limited evidence. Objective:In hyponatremia following pituitary surgery-caused by the syndrome of inappropriate antidiuretic hormone (SIADH) secretion-we compared fluid restriction with the pharmacological increase of water excretion by blocking the vasopressin 2 receptors with tolvaptan at a low and a moderate dose. Design:Prospective observational study. Setting:Neurosurgical Department of a University hospital with more than 200 surgical pituitary procedures per year. Patients:Patients undergoing pituitary surgery and developing serum sodium below 136 mmol/L. The diagnosis of SIADH was established by euvolemia (daily measurement of body weight and fluid balance), inappropriately concentrated urine (specific gravity), and exclusion of adrenocorticotropic and thyroid-stimulating hormone deficiency. Intervention:Patients were treated with fluid restriction (n?=?40) or tolvaptan at 3.75 (n?=?38) or 7.5 mg (n?=?48). Main Outcome Measures:Treatment efficacy was assessed by the duration of hyponatremia, sodium nadir, and length of hospitalization. Safety was established by a sodium increment below 10 mmol/L per day and exclusion of side effects. Results:Treatment with 7.5 mg of tolvaptan resulted in a significant attenuation of hyponatremia and in a significant overcorrection of serum sodium in 30% of patients. The duration of hospitalization did not differ between treatment groups. Conclusions:Tolvaptan at a moderate dose is more effective than fluid restriction in the treatment of SIADH. Overcorrection of serum sodium may be a side effect of tolvaptan even at low doses.
Project description:BACKGROUND:Tolvaptan effectively corrects hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but undesired overcorrection can occur. We hypothesized that pretherapy parameters can predict the rapidity of response to tolvaptan in SIADH. STUDY DESIGN:Multicenter historical cohort study. SETTING & PARTICIPANTS:Adults with SIADH or congestive heart failure (CHF) treated with tolvaptan for a serum sodium concentration ? 130 mEq/L at 5 US hospitals. PREDICTORS:Demographic and laboratory parameters. OUTCOMES:Rate of change in serum sodium concentration. MEASUREMENTS:Spearman correlations, analysis of variance, and multivariable linear mixed-effects models. RESULTS:28 patients with SIADH and 39 patients with CHF treated with tolvaptan (mean baseline serum sodium, 120.6 and 122.4 mEq/L, respectively) were studied. Correction of serum sodium concentration > 12 mEq/L/d occurred in 25% of patients with SIADH compared to 3% of those with CHF (P<0.001). Among patients with SIADH, the increase in serum sodium over 24 hours was correlated with baseline serum sodium concentration (r=-0.78; P<0.001), serum urea nitrogen concentration (SUN; r=-0.76; P<0.001), and estimated glomerular filtration rate (r=0.58; P=0.01). Baseline serum sodium and SUN concentrations were identified as independent predictors of change in serum sodium concentration in multivariable analyses. When patients were grouped into 4 categories according to baseline serum sodium and SUN median values, those with both low baseline serum sodium (?121 mEq/L) and low baseline SUN concentrations (?10mg/dL) exhibited a significantly greater rate of increase in serum sodium concentration (mean 24-hour increase of 15.4 mEq/L) than the other 3 categories (P<0.05). Among patients with CHF, only baseline SUN concentration was identified as an independent predictor of change in serum sodium concentration over time. LIMITATIONS:Lack of uniformity in serial serum sodium concentration determinations and documentation of water intake. CONCLUSIONS:Baseline serum sodium and SUN values are predictive of the rapidity of hyponatremia correction following tolvaptan use in SIADH. We advise caution when dosing tolvaptan in patients with both low serum sodium and SUN concentrations.
Project description:Rationale & Objective:Euvolemic 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 Design:A retrospective chart review study comparing outcomes in patients with SIADH treated with 15 versus 7.5 mg of tolvaptan. Settings & Participants:Patients 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. Predictors:Tolvaptan dose of 7.5 versus 15 mg daily. Outcomes:Appropriate 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 Approach:Descriptive study with additional outcomes compared using t tests and F-tests (Fischer's Exact ?2 Test). Results:Among 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). Limitations:Small sample size, retrospective, and nonrandomized. Conclusions:Tolvaptan, 7.5 mg, daily corrects hyponatremia with similar efficacy and less risk for overcorrection in patients with SIADH versus 15 mg of tolvaptan.
Project description:Hyponatremia is a frequent complication following pituitary surgery. We report a case with hyponatremia after surgery of a pituitary adenoma that was successfully treated with tolvaptan. A 68-year-old man with a pituitary tumor presented with mild hyponatremia (133 mEq/L) before surgery. The patient developed hyponatremia (125 mEq) 4 days postsurgery, and 10% sodium chloride was infused. Seven 7 days postsurgery, hyponatremia was improved (132 mEq/L), and tolvaptan 15 mg was given orally as a single dose instead of the 10% sodium chloride infusion. His serum sodium remained within normal limits. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) after pituitary surgery most probably led to the hyponatremia, and tolvaptan was effective because it is an oral vasopressin receptor antagonist.
Project description:Aim:Treatment practices and effectiveness in cirrhotic patients with hyponatremia (HN) in the HN Registry were assessed. Methods:Characteristics, treatments, and outcomes were compared between patients with HN at admission and during hospitalization. For HN at admission, serum sodium concentration [Na] response was analyzed until correction to > 130?mmol/L, switch to secondary therapy, or discharge or death with sodium ? 130?mmol/L. Results:Patients with HN at admission had a lower [Na] and shorter length of stay (LOS) than those who developed HN (P < 0.001). Most common initial treatments were isotonic saline (NS, 36%), fluid restriction (FR, 33%), and no specific therapy (NST, 20%). Baseline [Na] was higher in patients treated with NST, FR, or NS versus hypertonic saline (HS) and tolvaptan (Tol) (P < 0.05). Treatment success occurred in 39%, 39%, 52%, 78%, and 81% of patients with NST, FR, NS, HS, and Tol, respectively. Relapse occurred in 55% after correction and was associated with increased LOS (9 versus 6 days, P < 0.001). 34% admitted with HN were discharged with HN corrected. Conclusions:Treatment approaches for HN were variable and frequently ineffective. Success was greatest with HS and Tol. Relapse of HN is associated with increased LOS.
Project description:Hyponatremia defined as a plasma sodium concentration of less than 135?mmol/L is a very common disorder, occurring in hospitalized patients. Hyponatremia often results from an increase in circulating arginine vasopressin (AVP) levels and/or increased renal sensitivity to AVP, combined with an increased intake of free water. Hyponatremia is subdivided into three groups, depending on clinical history and volume status: hypovolemic, euvolemic, and hypervolemic. Acute symptomatic hyponatremia is usually treated with hypertonic (3%) saline. Syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) and hypervolemic hyponatremia caused by heart failure or cirrhosis are treated with vasopressin antagonists (vaptans) since they increase plasma sodium (Na(2+)) concentration via their aquaretic effects (augmentation of free-water clearance). The role of tolvaptan in the treatment of acute hyponatremia and conversion of oliguric to nonoliguric phase of acute tubular necrosis has not been previously described.