Tolvaptan Versus Fluid Restriction in SIADH
Tolvaptan Versus Fluid Restriction in SIADH
Context. The relevance of hyponatremia has been acknowledged by guidelines from the United
 States of America (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 - the investigators compared fluid
 restriction with the pharmacological increase of water excretion by blocking the vasopressin
 2 receptors with tolvaptan at a low and moderate dose.

 Design. Prospective observational study.

 Setting. Neurosurgical Department of a University hospital with more 200 pituitary procedures
 per year.

 Patients. Participants undergoing surgery for sellar lesions and developing a serum sodium
 below 135 mmol/L. The diagnosis of SIADH was established by eu- or hypervolemia (daily
 measurement of body weight and fluid balance daily), an inappropriately concentrated urine
 (specific gravity) and exclusion of a cortico- and thyreotropic insufficiency.

 Intervention. Participants were treated with fluid restriction (n=38) or tolvaptan at 3.75
 (n=38) or 7.5 mg (n=48) orally.

 Main Outcome Measures. Treatment efficacy was assessed by the duration of hyponatremia,
 sodium nadir and length of hospitalization. Safety was established by an increment serum
 sodium below 10 mmol/L per day and exclusion of side effects.
Patients of the Department of Neurosurgery, University of Erlangen-Nuremberg, undergoing
 surgery for sellar lesions were prospectively included. The study protocol was approved by
 the local Ethical Committee (Re.-No. 103_12 BC). Informed written consent was given by the
 participants or the next-of-kin in each case. Exclusion criteria comprised of those below 18
 years of age, pregnancy and a drug intolerance.

 Patients Baseline information included age, gender, BMI and the clinical presentation. The
 pre-operative work-up included an opthalmological examination, a 1.5 Tesla magnetic resonance
 imaging (MRI) with 2mm axial, coronal and sagittal sections revealing the tumor localization,
 extension, and its invasive behavior. Microsurgery was always performed by the same surgeon.
 The macroscopic delineation and invasiveness, the surgical manipulation of the pituitary
 stalk and extend of tumor resection, surgical complications, as well as an intraoperative
 cerebrospinal fluid (CSF) leak were documented. The tumor and the dura of the floor of the
 sella were examined histo-pathologically including the proliferation rate, regressive
 changes, atypical findings, and the existence of Crooke cells and periodic acid-Schiff (PAS)
 expression. Routine laboratory work-up included creatinine, urea, and alanine
 aminotransferase (ALT).

 The pre- and postoperative endocrine testing of the pituitary function comprised the basal
 values of cortisol (CORT), growth hormone (GH), insulin-like growth factor (IGF) 1, thyroid
 stimulating hormone (TSH), free thyroxine (fT4), total triiodothyronine (tT3), luteinizing
 hormone (LH), follicle stimulating hormone (FSH), testosterone (TES), estradiol (E2), and
 prolactin (PRL). Insufficiency of the corticotropic axis was determined by a short synacthen
 test (adreno-corticotropic hormone; ACTH)-test stimulating with 0.25 mg Syntropin (Synacthen,
 Novartis Pharma, Nuremberg, Germany) intra-venously and serum cortisol measurement at 0 and
 30 minutes.

 Surveillance Post-operatively, participants were transferred to the general floor. For a
 minimum of 10 days, fluid intake, body weight, and urine volume with specific gravidity are
 documented daily, along with blood pressure and heart rate three-times daily, blood samples
 for the assessment of electrolytes are taken on day 1, 2, 3, 5, 7, and 9. An endocrine
 dynamic testing was performed on day 7.

 Analytical methods Venous blood samples were drawn in the morning between 7:00 and 9:00 am
 into pre-cooled tubes. Clotted samples were promptly centrifuged at 3,000 X g for 15 min at 4
 degree Celsius, and then the plasma was frozen at -80 degree Celsius until analysis.

 An automated system (Immulite®2000, Diagnostic Products Corporation) was used for the
 following serum hormone measurements: Serum cortisol levels > 10.5 µg/dL, with an assay
 sensitivity of 0.20 µg/dL, was considered normal; a cortisol response peak to the ACTH-test
 higher than 18 µg/dl was considered adequate; for IGF-1 of 135-485 ng/mL (18-30 years),
 120-397 ng/mL (31-40 years), 113-306 ng/mL (41-50 years), 100-250 ng/mL (51-60 years), and
 92-229 ng/mL (>60 years) (assay sensitivity of 20 ng/mL); LH > 0.25 U/L (follicular phase)
 and > 20 U/L (menopausal) in women, and > 1 international units (IU)/L in men (assay
 sensitivity of 0.05 mIU/mL); FSH > 0.25 U/L (follicular phase) and > 30 U/L (menopausal) in
 women, and > 1 IU/L in men (assay sensitivity of 0.1 mIU/mL); TES > 90 ng/dL in men (assay
 sensitivity of 15 ng/dL); E2 > 60 pg/mL (follicular phase) and > 10 pg/mL (menopausal) in
 women (assay sensitivity of 15 pg/mL); PRL < 500 micro international units (µIU)/L (assay
 sensitivity of 0.16 µU/L); PRL serum concentrations were considered normal < 360 ng/ml in men
 and < 530 ng/mL in women. TSH serum concentrations were considered normal > 0.45 µU/mL, fT4 >
 0.77 ng/dL, and tT3 > 0.8 ng/mL.

 Study design Treatment of hyponatremia was initiated as soon as a SIADH was confirmed by eu-
 or hypervolemia (daily measurement of body weight and fluid balance), an inappropriately
 concentrated urine (measurement of specific gravity), and exclusion of a cortico- and
 thyreotropic insufficiency. The established treatment regime consisted of a restriction of
 fluid intake < 1 L whenever the serum sodium dropped below 135 mmol/L or the body weight
 gained more than 1 kg (fluid restriction). In a second cohort of patients, the fluid
 restriction was replaced by a low dosage of tolvaptan (tolvaptan 3.75 mg), and in a third
 cohort by a medium dosage (tolvaptan 7.5 mg). Since a rapid correction of hyponatremia is
 hazardous and leaves the patient vulnerable to the risk of osmotic demyelination, we not only
 started the cohort study with a very low concentration of 3.75 mg tolvaptan, but also
 established a tight follow-up regime after medication. The serum sodium concentration was
 controlled at 6:00 pm. Those participants, whose serum sodium concentration further dropped
 below 132 mmol/L, were treated with a second tablet of tolvaptan and the serum sodium was
 measured the next day at 8:00 am. Those participants, whose serum sodium was increased by not
 more than 5 mmol/L underwent the next blood check on the next day at 8:00 am. Those
 participants, whose serum sodium increased by more than 5 mmol/L were treated by 1L tea/water
 or a 500 mL 5% glucose infusion.

 Statistical analysis SPSS statistical software (SPSS Inc., Chicago, Illinois, USA) was used
 for all statistical analyses. Analyses were performed using the Chi-squared test and
 Mann-Whitney U tests where appropriate. Significance was accepted at p < 0.05.
Inclusion Criteria:

 Informed written consent was given by the participant or the next-of-kin.

 Exclusion Criteria:

 Age below 18 years Pregnancy Tolvaptan intolerance.