Tolvaptan Versus Fluid Restriction in the Treatment of Hyponatremia Resulting From SIADH Following Pituitary Surgery

Andrea Kleindienst; Simeon Georgiev; Sven Martin Schlaffer; Michael Buchfelder


J Endo Soc. 2020;4(7) 

In This Article

Abstract and Introduction


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.


Hyponatremia of any cause represents the most common electrolyte disturbance of hospitalized patients, affecting up to 30%.[1,2] To date, diagnosis and treatment of hyponatremia are not considered ideal,[3,4] and the respective guidelines established in the United States[5] and Europe[6] document existing controversies resulting from the lack of evidence.

In at least 30% of cases, hyponatremia is a result of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH),[7] first described by Bartter and Schwartz.[8] Antidiuretic hormone (ADH) also known as arginine vasopressin (AVP) is released from the posterior pituitary and responds to increased serum osmolality to retain water in the nephrons. In SIADH, unregulated AVP secretion either from the posterior pituitary gland or an abnormal nonpituitary source results in antidiuresis, eventually resulting in hyponatremia.

Disorders affecting the pituitary and/or the hypothalamus are known to be associated with dysregulation of AVP/ADH secretion, such as SIADH.[9,10] Adenomas are the most common pituitary tumors, with an overall estimated prevalence of 14% in autopsy studies and 22% in radiological studies.[11] Complications of pituitary surgery comprise anterior pituitary insufficiency of 5% to 19%[12,13] and, due to the inevitable manipulation of the neurohypophysis, disturbances of water, electrolytes, and osmoregulation, including 18% to 23% presenting with hyponatremia.[14–16] Available data on the pathogenesis of hyponatremia after pituitary surgery point towards a bi- or triphasic release pattern of AVP/ADH. Following an early secretional arrest, an unregulated AVP release from the affected posterior pituitary or from degenerating magnocellular neurons may occur some days after surgery, finally returning to a residual AVP secretion.[17] The timing of delayed hyponatremia is similar to the interphase that is seen after experimentally induced[18] or clinically observed diabetes insipidus.[19] Hyponatremia resulting from impaired aquaresis[20] may be further amplified, since water intake in man is not appropriately reduced, unlike in animals.[21]

Abnormal water and electrolyte handling in hyponatremia creates an osmotic gradient promoting the shift of water into brain cells,[22] potentially causing cerebral edema.[23] Even in asymptomatic patients, hyponatremia may be responsible for adverse effects like gait instability.[24] Unless hyponatremia is corrected promptly and effectively, morbidity and mortality increase through seizures or elevation in intracranial pressure.[25]

Current treatment recommendations for the management of hyponatremia are based on the differentiation of acute and chronic hyponatremia, the underlying etiology, and the existence of symptoms,[5] while historically treatment was targeted at relief of symptoms and consisted of fluid restriction.[26,27] In a single-center study, following pituitary surgery, a universal 1 L per day of fluid restriction for 1 week postoperatively was used quite successfully to prevent hospital readmission due to hyponatremia following early discharge.[28] However, AVP receptor antagonists (vaptans) have been assessed to treat SIADH after surgery for Cushing disease.[29] Given the lack of evidence-based postoperative practices in pituitary surgery regarding SIADH treatment, a recent audit revealed that fluid restriction is used most often (46/74, 62.2%), while a minority of physicians apply additional therapies such as NaCl tablets (25.7%), hypertonic saline (6.7%), or vaptans (17.6%).[30]

Vaptans, the specific AVP receptor antagonists, represent a novel therapeutic option in SIADH. In the kidney, ADH/AVP acts on vasopressin V2 receptors of the principal cells of the cortical and medullary collecting tubules to increase water permeability, thereby mediating an antidiuretic response. While randomized prospective trials show a consistent benefit of vaptans over placebo,[31,32] there exists no head to head trial with fluid restriction.[33] In neurosurgery, and specifically following pituitary surgery, as yet only case reports on the use of vaptans for hyponatremia have been published.[16,34–36]

The purpose of this prospective study was to evaluate the efficacy of fluid restriction versus tolvaptan at a low (3.75 mg) and a moderate (7.5 mg) dose in the treatment of hyponatremia due to SIADH following pituitary surgery with regard to the interval to re-establish normonatremia. While a rapid correction of chronic hyponatremia leaves the patient vulnerable to the risk of osmotic demyelination syndrome (ODS),[37] case reports demonstrate that even a careful correction protocol in hyponatremia following pituitary surgery can be associated with severe neurological deficits due to ODS.[38–40] Hence, safety was assessed by the occurrence of serum sodium overcorrection (>10 mmol/L per 24 hours).