Severe refractory hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone secretion treated with Tolvaptan

M Kostoula, V Bravis, S Robinson, J Cox

Introduction: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for approximately 30% hyponatraemia cases. Therapeutic modalities include nonspecific measures (fluid restriction, hypertonic saline, demeclocycline). Recently, vasopressin receptor antagonists have been introduced as specific, direct therapy of SIADH.

Case: A 53-year-old female with a history of non-small cell lung cancer and multiple brain metastases was admitted unresponsive with [Na+] 114 mmol/L. Clinical and biochemical assessment led to a diagnosis of SIADH and she was treated with a combination of fluid restriction, hypertonic saline and demeclocycline. She was discharged with [Na+] 129 mmol/L, on demeclocycline therapy. She subsequently represented with impaired level of consciousness (GCS 9/15) and [Na+] 110 mmol/L. The diagnosis was again SIADH. After 24-hour treatment with hypertonic saline and 1L/day fluid restriction, she improved to GCS 11/15 and [Na+] 113 mmol/L. The trial of demeclocycline was deemed unsuccessful and the drug was stopped, whilst hypertonic saline with fluid restriction were continued. 48 hours later [Na+] was 115 mmol/L, so the fluid restriction changed to 500mls/day. By day 8 of admission [Na+] reached 130 mmol/L. In view of the background of metastatic malignancy, the recurrent severe hyponatraemia and the severity of the clinical presentations, the decision was made to initiate low dose Tolvaptan therapy, in order to facilitate her discharge and decrease the risk of recurrence. 8 hours after the first 15mg dose, the patient developed a headache, complained of thirst and became polyuric. Her [Na+] had increased to 142 mmol/L and her urinary [Na+] had dropped to <20 mmol/L, with urine osmolality of 81 mOsm/kg, in the context of clinical hypovolaemia. The Tolvaptan-induced aquaresis was reversed with oral and intravenous rehydration and the drug was withheld for 24 hours. A further 24 hours later, the patient was euvolaemic with [Na+] 137 mmol/L. A 7.5mg dose of Tolvaptan was re-trialled and 24 hours later the [Na+] was 131 mmol/L. She was discharged on that dose with close and frequent metabolic day ward reviews and strict instructions for home fluid balance monitoring. She currently remains normonatraemic and undergoing palliative chemotherapy.

Discussion: Tolvaptan is a competitive vasopressin receptor antagonist and has some evidence-base for the treatment of refractory SIADH. Hypersensitivity to Tolvaptan leading to excessive aquaresis is rare, but can occur. Vaptans can be considered in patients with refractory SIADH-induced hyponatraemia, in the context of chronic illness, to facilitate outpatient management, particularly when other drug therapies have failed and unsustainable fluid restriction remains unrealistic in the community setting.