Risk of Serum Sodium Overcorrection with V2 Antagonists in SIADH and Other High Risk Patients

Abstract

Hyponatremia is a complex process caused by dysregulation of total body sodium and total body water that can be seen in hypovolemic, euvolemic, and hypervolemic states. Rapid correction of hyponatremia can also lead to serious complications. The development of V2 antagonists, such as tolvaptan, has changed and simplified the management of dilutional hyponatremia by allowing the targeting of antidiuretic hormone (ADH) action and blocking its effect on the V2 receptor. This will decrease the synthesis and relocation of aquaporin 2 to the cortical collecting duct apical membrane. Tolvaptan is approved to be used in euvolemic and hypervolemic hyponatremia, specifically in the syndrome of inappropriate antidiuretic hormone secretion and heart failure. The SALT-1 and SALT-2 studies suggested a starting dose of 15 mg of tolvaptan based on pharmacokinetic data, and while this is an effective dose, multiple studies have shown that patients can overcorrect with this starting dose. At least 1 case of osmotic demyelination-the dreaded complication of overly rapid hyponatremia correction-has been observed with tolvaptan use. While strategies for rapid attenuation of this overcorrection exist, and are discussed, starting tolvaptan at a lower dose of 7.5 mg initially and up-titrating even within the first day is another strategy that can avoid overcorrection. This was noted to be especially important in cases of hyponatremia due to the syndrome of inappropriate ADH secretion. We note that this approach can more slowly correct the hyponatremia with less attendant neurological risks than the currently recommended minimum starting dose of tolvaptan.

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

“…Accordingly, the authors recommended the use of tolvaptan, 7.5 mg, in patients with SIADH to avoid overcorrection. 22 These findings are in contrast to data in the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 (SALT-1), SALT-2, and SALT-3 trials, which included mostly hypervolemic patients receiving 15 mg of tolvaptan who had a low probability of overcorrection. [23][24][25] Morris et al 20 showed that patients with SIADH who received tolvaptan responded differently than volumeoverloaded patients with congestive heart failure and hyponatremia.…”

“…In low-risk cases, every 8 to 12 hours is generally acceptable, more frequently in cases at higher risk for osmotic demyelination syndrome or overcorrection with vaptan therapy. 22 We have previously recommended that patients who receive 7.5 mg of tolvaptan should have urine osmolality and serum [Na + ] checked. 22 If a sufficient response is noted, laboratory test results should be monitored.…”

“…22 We have previously recommended that patients who receive 7.5 mg of tolvaptan should have urine osmolality and serum [Na + ] checked. 22 If a sufficient response is noted, laboratory test results should be monitored. If an insufficient response is noted with urine osmolality remaining >300 mOsm, a repeat dosing of 7.5 mg of tolvaptan can be used.…”

“…If an insufficient response is noted with urine osmolality remaining >300 mOsm, a repeat dosing of 7.5 mg of tolvaptan can be used. 22 It is our recommendation that in patients with SIADH, 7.5 mg of tolvaptan should be used as the starting dose for therapy with V2 antagonists, particularly in patients with high risk factors for osmotic demyelination syndrome and/or rapid overcorrection.…”

“…[17][18][19] Instances of overcorrection were reported particularly in elderly female malnourished patients and patients who had SIADH, 12,20 increasing their risk for osmotic demyelination syndrome. 15,21 In 2017, Kamgar et al 22 suggested evidence of the risk for hyponatremia overcorrection in patients with SIADH on the lowest recommended dose of tolvaptan (15 mg). Accordingly, the authors recommended the use of tolvaptan, 7.5 mg, in patients with SIADH to avoid overcorrection.…”