Increasing plasma sodium with Tolvaptan under regulated water intake: comparison with hypertonic saline

In the treatment of hyponatremia, there is a potential risk of osmotic demyelination due to an excessively rapid rise in plasma sodium. We reasoned that a controlled rate of sodium increase could be achieved using a vasopressin antagonist like Tolvaptan while regulating water intake by under-replacing urine output by a constant amount relative to body weight. Studies were conducted in healthy male subjects in a clinical research unit to determine the effect of either 60 mg (n = 6) or 30 mg (n = 6) of Tolvaptan on plasma sodium, osmolality, plasma arginine vasopressin, thirst, and urine volume and osmolality. To regulate water intake, each subject ingested a volume of water equal to his urine output minus 5 mL/kg of his basal body weight every hour. Ten to 14 days later, the same subjects underwent a 6-h infusion of 3% saline, and the data were compared with the results with Tolvaptan. Both doses of Tolvaptan lowered urine osmolality and markedly increased free water clearance and urine output. Plasma sodium increased from 138 ± 0.6 to 144 ± 2.0 mEq/L and from 139 ± 0.8 to 144 ± 2.2 with Tolvaptan 60 and 30 mg, respectively, over 6 h of regulated water intake. When the same subjects were infused with hypertonic saline, the rise in plasma sodium and osmolality was nearly identical to that produced by Tolvaptan under regulated water intake. Tolvaptan can be used to achieve a controlled rise in plasma sodium by regulating water intake. Subjects with hyponatremia may benefit from this approach, which reduces their excess body water and is therefore a more physiologic way to correct hyponatremia.NEW & NOTEWORTHY This study shows that the rise in plasma sodium induced by the vasopressin V2-receptor antagonist Tolvaptan can be controlled by regulating water intake to under-replace urine output by a fixed amount per kilogram body weight in healthy subjects. This approach produced increases in plasma sodium that were comparable to hypertonic saline and provides a means to prevent rapid rises in plasma sodium beyond the target rate.