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Efficacy and safety of two different tolvaptan doses in the treatment of hyponatremia in the Emergency Department

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Abstract

Hyponatremia (plasma sodium concentration or P[Na+] <136 mEq/L) is the most common electrolyte unbalance in clinical practice. Although it constitutes a negative prognostic factor, it frequently remains underdiagnosed and undertreated. Tolvaptan is an oral V2-receptor antagonist which produces aquaresis. Given its emerging role in the treatment of dilutional hyponatremia, we aimed to compare the efficacy and safety of two different doses of this drug in an Emergency Department (ED) setting. Consecutive patients with moderate–severe euvolemic or hypervolemic hyponatremia were sequentially assigned to the 15 mg Group and to the 7.5 mg Group, and were revaluated at 6, 12 and 24 h. Further evaluations and administrations were scheduled daily until P[Na+] correction was achieved or the maximum period of 72 h was exceeded. A 1-month follow-up was performed. Twenty-three patients were enrolled: 12 were included in the 15 mg Group, 11 in the 7.5 mg Group. Both doses significantly elevated the P[Na+] over 24 h, although the 15 mg Group showed faster corrections than the 7.5 mg Group (12 vs 6 mEq/L/24 h; P = 0.025). An optimal correction rate (within 4–8 mEq/L/24 h) was observed in 45.4 % of the 7.5 mg Group against 25.0 % (P n.s.). The standard dose led to dangerous overcorrections (>12 mEq/L/24 h) in 41.7 % of the patients, while the low dose did not cause any (P = 0.037). No osmotic demyelination syndrome was observed. A 7.5 mg tolvaptan dose can be considered both effective and safe in treating hyponatremia in the ED, while a 15 mg dose implicates too high risk of overcorrection.

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References

  1. Adrogué HJ, Madias NE (2000) Hyponatremia. N Engl J Med 342(21):1581–1589

    Article  PubMed  Google Scholar 

  2. Upadhyay A, Jaber BL, Madias NE (2006) Incidence and prevalence of hyponatremia. Am J Med 119(7):S30–S35

    Article  CAS  PubMed  Google Scholar 

  3. Hoorn EJ, Lindemans J, Zietse R (2006) Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol Dial Transplant 21(1):70–76

    Article  PubMed  Google Scholar 

  4. Hawkins RC (2003) Age and gender as risk factors for hyponatremia and hypernatremia. Clin Chim Acta 337(1–2):169–172

    Article  CAS  PubMed  Google Scholar 

  5. Bartoli E, Castello L, Fumo E, Pirisi M (2002) Electrolyte derangements and diuretic misuse in the elderly. Arch Gerontol Geriatr Suppl 8:43–52

    Article  CAS  PubMed  Google Scholar 

  6. Hannon MJ, Thompson CJ (2010) The syndrome of inappropriate antidiuretic hormone: prevalence, causes and consequences. Eur J Endocrinol 162(1):S5–S12

    Article  CAS  PubMed  Google Scholar 

  7. Greenberg A, Verbalis JG, Amin A et al (2015) Current treatment practice and outcomes. Report of the hyponatremia registry. Kidney Int 88(1):167–177

    Article  PubMed  PubMed Central  Google Scholar 

  8. Verbalis JG (2010) Brain volume regulation in response to changes in osmolality. Neuroscience 168(4):862–870

    Article  CAS  PubMed  Google Scholar 

  9. Corona G, Giuliani C, Parenti G et al (2013) Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PLoS One 8(12):e80451

    Article  PubMed  PubMed Central  Google Scholar 

  10. Amin A, Deitelzweig S, Christian R et al (2012) Evaluation of incremental healthcare resource burden and readmission rates associated with hospitalized hyponatremic patients in the US. J Hosp Med 7(8):634–639

    Article  PubMed  Google Scholar 

  11. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G (2006) Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 119(1):71.e1–8

  12. Upadhyay A, Jaber BL, Madias NE (2009) Epidemiology of hyponatremia. Semin Nephrol 29(3):227–238

    Article  CAS  PubMed  Google Scholar 

  13. Spasovski G, Vanholder R, Allolio B et al (2014) Clinical practice guideline on diagnosis and treatment of hyponatremia. Nephrol Dial Transplant 29(2):i1–i39

    Article  PubMed  Google Scholar 

  14. Castello L, Pirisi M, Sainaghi PP, Bartoli E (2005) Hyponatremia in liver cirrhosis: pathophysiological principles of management. Dig Liver Dis 37(2):73–81

    Article  CAS  PubMed  Google Scholar 

  15. Huda MS, Boyd A, Skagen K et al (2006) Investigation and management of severe hyponatraemia in a hospital setting. Postgrad Med J 82:216–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fenske W, Maier SK, Blechschmidt A, Allolio B, Störk S (2010) Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med 123(7):652–657

    Article  PubMed  Google Scholar 

  17. Bartoli E, Castello L, Sainaghi PP (2003) Diagnosis and therapy of hyponatremia. Ann Ital Med Int 18(4):193–203

  18. Riegger GA, Liebau G, Kochsiek K (1982) Antidiuretic hormone in congestive heart failure. Am J Med 72(1):49–52

    Article  CAS  PubMed  Google Scholar 

  19. Schrier RW (2006) Water and sodium retention in edematous disorders: role of vasopressin and aldosterone. Am J Med 119(7):S47–S53

    Article  CAS  PubMed  Google Scholar 

  20. Schrier RW, Gross P, Gheorghiade M et al (2006) Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355(20):2099–2112

    Article  CAS  PubMed  Google Scholar 

  21. Berl T, Quittnatt-Pelletier F, Verbalis JG et al (2010) Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 21(4):705–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rossi J, Bayram M, Udelson JE et al (2007) Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial. Acute Card Care 9(2):82–86

    Article  PubMed  Google Scholar 

  23. Konstam MA, Gheorghiade M, Burnett JC Jr et al (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 297(12):1319–1331

    Article  CAS  PubMed  Google Scholar 

  24. Gheorghiade M, Gattis WA, O’Connor CM et al (2004) Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA 291(16):1963–1971

    Article  CAS  PubMed  Google Scholar 

  25. Rajendran R, Grossman A, Kar P (2012) Vasopressin receptor antagonist in the treatment of the syndrome of inappropriate antidiuretic hormone in general hospital practice. Endocr J 59(10):903–909

    Article  CAS  PubMed  Google Scholar 

  26. Torres VE, Chapman AB, Devuyst O et al (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367(25):2407–2418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Verbalis JG, Grossman AB, Höybye C, Runkle I (2014) Review and analysis of differing regulatory indications and expert panel guidelines for the treatment of hyponatremia. Curr Med Res Opin 30(7):1201–1207

    Article  PubMed  Google Scholar 

  28. Verbalis JG, Goldsmith SR, Greenberg G et al (2013) Diagnosis, evaluation and treatment of hyponatremia: expert panel recommendations. Am J Med 126(10):S1–S42

    Article  PubMed  Google Scholar 

  29. Sterns RH, Nigwekar SU, Hix JK (2009) The treatment of hyponatremia. Semin Nephrol 29(3):282–299

    Article  CAS  PubMed  Google Scholar 

  30. Inomata T, Izumi T, Matsuzaki M, Hori M, Hirayama A, Investigators Tolvaptan (2011) Phase III clinical pharmacology study of tolvaptan. Cardiovasc Drugs Ther 25(1):S57–S65

    Article  PubMed  Google Scholar 

  31. Sakaida I, Yanase M, Kobayashi Y et al (2012) The pharmacokinetics and pharmacodynamics of tolvaptan in patients with liver cirrhosis with insufficient response to conventional diuretics: a multicentre, double-blind, parallel-group, phase III study. J Int Med Res 40(6):2381–2393

    Article  CAS  PubMed  Google Scholar 

  32. Kenz S, Haas CS, Werth SC, Bohnet S, Brabant G (2011) High sensitivity to tolvaptan in paraneoplastic syndrome of inappropriate ADH secretion (SIADH). Ann Oncol 22(12):2696

    Article  CAS  PubMed  Google Scholar 

  33. Bartoli E, Castello L, Bergamasco L, Sainaghi PP (2007) A new method to distinguish the hyponatremia of electrolyte loss from that due to pure solvent changes. Eur J Appl Physiol 101(1):133–142

    Article  CAS  PubMed  Google Scholar 

  34. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N, Conivaptan Study Group (2007) Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 27(5):447–457

  35. Gerbes AL, Gulberg V, Ginès P et al (2003) Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Gastroenterology 124(4):933–939

    Article  CAS  PubMed  Google Scholar 

  36. Abraham WT, Hensen J, Gross P et al (2012) Lixivaptan safely and effectively corrects serum sodium concentrations in hospitalized patients with euvolemic hyponatremia. Kidney Int 82(11):1223–1230

    Article  CAS  PubMed  Google Scholar 

  37. Aronson D, Verbalis JG, Mueller M, Krum H, Investigators DILIPO (2011) Short- and long-term treatment of dilutional hyponatraemia with satavaptan, a selective arginine vasopressin V2-receptor antagonist: the DILIPO study. Eur J Heart Fail 13(3):327–336

    Article  CAS  PubMed  Google Scholar 

  38. Rozen-Zvi B, Yahav D, Gheorghiade M, Korzets A, Leibovici L, Gafter U (2010) Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis. Am J Kidney Dis 56(2):325–337

    Article  CAS  PubMed  Google Scholar 

  39. Jaber BL, Almarzouqi L, Borgi L, Seabra VF, Balk EM, Madias NE (2011) Short-term efficacy and safety of vasopressin receptor antagonists for treatment of hyponatremia. Am J Med 124(10):977.e1–9

  40. Tzoulis P, Waung JA, Bagkeris E et al (2015) Real-life experience of tolvaptan use in the treatment of severe hyponatraemia due to syndrome of inappropriate antidiuretic hormone secretion. Clin Endocrinol. doi:10.1111/cen.12943

    Google Scholar 

  41. Verbalis JG, Martinez AJ (1991) Determinants of brain myelinolysis following correction of chronic hyponatremia in rats. In: Jard S, Jamison RL (ed) Vasopressin, Vol 208. Colloque INSERM/John Libbey Eurotext Ltd, Paris, France, pp 539–547

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Authors and Affiliations

  1. Maggiore della Carità University Hospital, Novara, Italy

    Luigi Mario Castello, Alice Panizza, Ettore Bartoli & Gian Carlo Avanzi

  2. Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy

    Luigi Mario Castello, Marco Baldrighi, Alice Panizza, Ettore Bartoli & Gian Carlo Avanzi

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  1. Luigi Mario Castello
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  2. Marco Baldrighi
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  3. Alice Panizza
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  4. Ettore Bartoli
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Correspondence to Luigi Mario Castello.

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Statement of human and animal rights

The study protocol was approved by the local Ethics Committee of the Maggiore della Carità University Hospital in Novara (CE 125/10, October 22nd, 2010). The study was designed in accordance with the Delaration of Helsinki and with the privacy laws.

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All eligible patients were asked to give their written informed consent after reading a brief description of the study.

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Castello, L.M., Baldrighi, M., Panizza, A. et al. Efficacy and safety of two different tolvaptan doses in the treatment of hyponatremia in the Emergency Department. Intern Emerg Med 12, 993–1001 (2017). https://doi.org/10.1007/s11739-016-1508-5

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  • DOI: https://doi.org/10.1007/s11739-016-1508-5

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