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

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          Abstract

          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 χ2 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.

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          Most cited references27

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          Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes.

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            Oral tolvaptan is safe and effective in chronic hyponatremia.

            Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and hypervolemia with hyponatremia in the short term ( 145 mmol/L) led to discontinuation in one patient. Mean serum sodium increased from 130.8 mmol/L at baseline to >135 mmol/L throughout the observation period (P < 0.001 versus baseline at most points). Responses were comparable between patients with euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion, prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety.
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              Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective.

              Severe, symptomatic hyponatremia is often treated urgently to increase the serum sodium to 120 to 130 mmol/L. Recently, this approach has been challenged by evidence linking "rapid correction" (> 12 mmol/L per day) to demyelinating brain lesions. However, the relative risks of persistent, severe hyponatremia and iatrogenic injury have not been well quantified. Data were sought on patients with serum sodium levels 120 mmol/L. Eleven of these 14 patients (including 3 with documented central pontine myelinolysis) had a biphasic course in which neurologic findings initially improved and then worsened on the second to sixth day. Posttherapeutic complications were not explained by age, sex, alcoholism, presenting symptoms, or hypoxic episodes. Increased chronicity of hyponatremia and a high rate of correction in the first 48 h of treatment were significantly associated with complications. No neurologic complications were observed among patients corrected by < 12 mmol/L per 24 h or by < 18 mmol/L per 48 h or in whom the average rate of correction to a serum sodium of 120 mmol/L was < or = 0.55 mmol/L per hour. It was concluded that patients with severe chronic hyponatremia are most likely to avoid neurologic complications when their electrolyte disturbance is corrected slowly.
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                Author and article information

                Contributors
                Journal
                Kidney Med
                Kidney Med
                Kidney Medicine
                Elsevier
                2590-0595
                26 November 2019
                Jan-Feb 2020
                26 November 2019
                : 2
                : 1
                : 20-28
                Affiliations
                [1 ]Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
                [2 ]Division of Nephrology, Department of Medicine, University of California Irvine School of Medicine, Irvine, CA
                [3 ]Department of Nephrology, Ochsner School of Medicine, New Orleans, LA
                [4 ]Lakewood Regional Medical Center, Lakewood, CA
                [5 ]Division of Nephrology, Department of Medicine, Brigham Women’s and Children’s Hospital, Boston, MA
                [6 ]Division of Nephrology, Department of Medicine, UCLA Brain Research Center, Los Angeles, CA
                Author notes
                [] Address for Correspondence: Ramy M. Hanna, MD, Division of Nephrology, Rm 7-155, Factor Bldg, 700 Tiverton Ave, Los Angeles CA 90095. ramyh1@ 123456hs.uci.edu
                Article
                S2590-0595(19)30165-7
                10.1016/j.xkme.2019.09.004
                7380356
                32734225
                5e586ad0-c32e-4204-83a0-1a638e600ec9
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Original Research

                tolvaptan,siadh,hyponatremia,osmotic demyelination syndrome

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