The Journal of Clinical Endocrinology & Metabolism, 2022, 00, 1–11 https://doi.org/10.1210/clinem/dgac622 Advance access publication 27 October 2022 Approach to the Patient Disorders of Salt and Water Balance After Pituitary Surgery 1 2 Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane 4102, Australia Faculty of Medicine, University of Queensland, Brisbane 4072, Australia Correspondence: Warrick Inder MD, FRACP, Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia. E-mail: warrick.inder@health.qld.gov.au. Abstract Transsphenoidal surgery is the first-line treatment for many clinically significant pituitary tumors and sellar lesions. Although complication rates are low when performed at high-volume centers, disorders of salt and water balance are relatively common postoperatively. Both, or either, central diabetes insipidus (recently renamed arginine vasopressin deficiency - AVP-D), caused by a deficiency in production and/or secretion of arginine vasopressin, and hyponatremia, most commonly secondary to the syndrome of inappropriate antidiuresis, may occur. These conditions can extend hospital stay and increase the risk of readmission. This article discusses common presentations of salt and water balance disorders following pituitary surgery, the pathophysiology of these conditions, and their diagnosis and management. Key Words: pituitary surgery, water balance disorders, arginine vasopressin deficiency, hyponatremia Abbreviations: AVP, arginine vasopressin; AVP-D, arginine vasopressin deficiency; CSWS, cerebral salt-wasting syndrome; SIAD, syndrome of inappropriate antidiuresis; TSS, transsphenoidal surgery. Case 1: Triphasic Response A 42-year-old female was diagnosed with a nonfunctioning pituitary tumor after presenting with bitemporal hemianopia and fatigue. She had secondary adrenal insufficiency, secondary hypothyroidism, hypogonadotropic hypogonadism, and mild hyperprolactinemia. Magnetic resonance imaging demonstrated a 33×22×22 mm pituitary tumor with suprasellar extension and compression of the optic chiasm. Hydrocortisone and thyroxine replacement were commenced, and she underwent transsphenoidal pituitary surgery. On day 1 postoperatively, she developed increased polydipsia and polyuria. Urine output exceeded 400 mL/hour and the fluid balance record showed a 24-hour intake of 4390 mL and urine output of 5685 mL. Urine specific gravity was 1.005, urine osmolality 210 mOsmol/kg, plasma osmolality 304 mOsmol/kg, and plasma sodium 142 mmol/L (reference 136-145 mmol/L). Postoperative arginine vasopressin deficiency (AVP-D) previously known as central or cranial diabetes insipidus (1) was diagnosed and desmopressin 1 μg was administered subcutaneously, with a reduction in urine output to 40 to 70 mL/ hour. One further dose of desmopressin was required 12 hours later when polyuria returned, with no further recurrence thereafter during her admission. Early recovery of her hypothalamic–pituitary–adrenal axis occurred postoperatively and hydrocortisone was ceased. On day 4 postoperatively, she developed mild hyponatremia with a plasma sodium nadir of 130 mmol/L. A fluid restriction of 1 L/24 hours was instituted for the syndrome of inappropriate antidiuresis (SIAD), with normalization of plasma sodium by day 6 postoperatively, when the patient was discharged home and advised to drink to thirst. Two days later, she represented with polyuria and biochemistry consistent with AVP-D and commenced desmopressin tablets 100 μg orally twice daily. Case 2: Delayed SIAD An 82-year-old female underwent transsphenoidal surgery (TSS) for a nonfunctioning pituitary tumor measuring 14×12×15 mm and compressing the optic chiasm, causing visual field compromise. The inpatient postoperative course was uncomplicated, and she was discharged home 6 days after surgery. Plasma sodium on the day of discharge was 135 mmol/L and she was advised to drink to thirst and avoid excessive fluid intake. The patient represented 2 days later with nausea. On readmission, she had euvolemic hyponatremia, with plasma sodium 120 mmol/L, urine osmolality 528 mOsmol/kg, and urine sodium 59 mmol/L. Morning cortisol was 360 nmol/L (reference >330 nmol/L) and free thyroxine was 18.2 pmol/L (reference 11.5-22.7 pmol/L), indicating normal adrenal and thyroid function. She was diagnosed with delayed postoperative hyponatremia secondary to SIAD, readmitted, and commenced on fluid restriction of 500 mL/day and urea 30 g orally twice daily. Case 3: Polyuria in Acromegaly A 23-year-old male presented with headaches and bitemporal hemianopia. He had signs of active acromegaly, and elevated growth hormone of 142 µg/L (reference 0.05-3.0) and insulin-like growth factor 1 of 150 nmol/L (reference 15-41). The remainder of his pituitary profile showed mild Received: 5 June 2022. Editorial Decision: 19 October 2022. Corrected and Typeset: 14 November 2022 © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons. org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac622/6775276 by guest on 17 November 2022 Emily K. Brooks1,2 and Warrick J. Inder1,2 2 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 Introduction TSS is the first-line treatment for many clinically significant pituitary tumors and sellar lesions, including craniopharyngiomas, Rathke’s cleft cysts, and, in some cases, meningiomas (2–4). Traditionally, TSS was performed via a microscopic approach; however, endoscopic TSS offers improved visualization and has been adopted by many as the preferred method (2,5–8). TSS performed in high-volume pituitary centers offers good tumor outcomes and low rates of complications (9). Craniotomy is now rarely performed (3). The posterior pituitary has a major role in water homeostasis and patients are vulnerable to sodium and water imbalances in the early postoperative period due to manipulation of the pituitary and infundibulum during surgery (10,11). Overview of Normal Water Balance Water homeostasis is predominantly controlled by arginine vasopressin (AVP) (12). AVP is a 9 amino acid peptide derived from pro-AVP, a 164 amino acid precursor protein consisting of a signal peptide, the AVP moiety, neurophysin 2, and copeptin, a 39 amino acid glycopeptide (13). Pro-AVP is synthesized in the paraventricular and supraoptic nuclei of magnocellular neurons in the hypothalamus (12). Posttranslational processing separates AVP, copeptin, and neurophysin 2 during transport down the infundibulum to axon terminals in the posterior pituitary, where AVP is stored in neurosecretory granules until specific osmotic and nonosmotic stimuli cause secretion into the circulation (12,14). Increasing plasma osmolality is the principal stimulus for AVP release. Changes in extracellular fluid osmolality are detected by osmoreceptors, the main site of which is the organum vasculosum lamina terminalis (15). Osmoreceptors project to magnocellular neurons to stimulate release of AVP. The concentration of circulating AVP is directly related to serum osmolality, and a rise in plasma osmolality above a threshold of approximately 280 mOsmol/kg results in a linear increase (16). The actions of AVP are mediated by binding to 1 of 3 receptors (V1-V3) on target cells (12). Regulation of water balance is mediated via AVP binding to V2 receptors on renal collecting tubular cells, leading to increased tubular fluid permeability via aquaporin-2 water channels, water retention, and urinary concentration (12). AVP also has a key role in regulation of the hypothalamic– pituitary–adrenal axis stress response (13,17). A second neurosecretory pathway transports high concentrations of AVP from parvocellular neurons to the pituitary hypophyseal portal system, where it has a neuroregulatory role in adrenocorticotropic hormone release from the anterior pituitary (13). In turn, AVP is suppressed by glucocorticoids (18), which increase the osmotic threshold for AVP release (19), while glucocorticoid deficiency increases AVP synthesis and secretion (20). Pathophysiology of Water Balance Disorders After Pituitary Surgery Water balance disorders following pituitary surgery are well recognized (10,21). AVP-D or SIAD can occur in isolation, with incidences up to 45% (22–25) and 28% (10,21,22,26– 30), respectively. Less commonly, a biphasic phenomenon, where an initial polyuric phase is followed by an antidiuretic phase, or a triphasic phenomenon, where a second final polyuric phase follows hyponatremia, can occur, with reported incidences of 1.1% and 3.4% (10). Figure 1 outlines the pathophysiology of water balance disorders after pituitary surgery. In the immediate postoperative period (within 24 to 48 hours), AVP-D may develop due to partial or complete pituitary stalk section, which severs the connections between the AVP neuronal bodies in the hypothalamic magnocellular neurons and the nerve terminals in the posterior pituitary, preventing stimulated AVP secretion (10,31). Delayed SIAD can follow early AVP-D or occur in isolation, secondary to uncontrolled release of stored AVP by degenerating nerve terminals in the posterior pituitary (32). SIAD may or may not be followed by further AVP-D, which can recur after stored AVP in the posterior pituitary has been released if greater than 80% to 90% of AVP neuronal bodies in the hypothalamus have undergone retrograde degeneration (31). Isolated SIAD occurs following partial pituitary stalk injury, where sufficient nerve fibers connecting the AVP neuronal cell bodies in the hypothalamus to the posterior pituitary nerve terminals are left intact to prevent AVP-D, but degeneration of injured nerve terminals still results in uncontrolled AVP release (10,31). Early Arginine Vasopressin Deficiency Acute AVP-D after pituitary surgery is relatively common, although the reported incidence is variable, ranging from 0.3% to 45% (22–25,33). Risk factors for development of transient AVP-D vary between studies and have included tumor size >1 cm (23), craniopharyngioma (34), Rathke’s cleft cyst (34,35), intraoperative cerebrospinal fluid leak (35), Cushing disease (10), visual abnormalities on presentation, suprasellar tumor extension, previous nonendoscopic lesion resection (35), gross total resection (23), and craniotomy (25). AVP-D may be less common after endoscopic TSS compared with the microscopic approach (8,9,36), although this was not found in all studies (24,37). High perioperative doses of glucocorticoids are also associated with an increased incidence of early AVP-D (38, 39), likely resulting from glucocorticoid-induced AVP suppression in people with reduced AVP reserve. Given glucocorticoid deficiency increases AVP secretion (20), administration of physiological doses of glucocorticoids in the setting of adrenal insufficiency can also unmask AVP-D (18). AVP-D can be partial or complete, depending on the extent of hypothalamic magnocellular neuronal damage (40). The onset of polyuria is usually abrupt and generally occurs within 12 to 27 hours postoperatively (22,25,41). Most Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac622/6775276 by guest on 17 November 2022 hyperprolactinemia, hypogonadotropic hypogonadism, and normal adrenal and thyroid function. Magnetic resonance imaging demonstrated a large pituitary tumor measuring 37×25×21 mm with suprasellar extension and optic chiasm compression. TSS was performed. The patient had significant polyuria on the first postoperative day, with urine output exceeding 500 mL/hour. Urine output measured 6300 mL and fluid intake measured 3500 mL within the first 24 hours postoperatively. The patient was not thirsty, and biochemistry was not consistent with AVP-D, with urine osmolality 243 mOsmol/kg, plasma osmolality 285 mOsmol/kg, and plasma sodium 137 mmol/L. The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 3 cases of early AVP-D are transient and resolve within 3 to 5 days postoperatively (11,23). Patients who develop early AVP-D may have an extended hospital stay, with Ajlan et al reporting a mean length of stay of 4 days for those who experienced AVP-D postoperatively compared with 3 days for those without AVP-D (23). Monitoring All patients who have undergone pituitary surgery should have close monitoring postoperatively, including fluid intake and urine output, thirst, and daily electrolyte monitoring (42–44 ). If polyuria occurs, clinical review of symptomatic thirst, hydration status, and fluid balance, and biochemical investigation with urine specific gravity, plasma sodium, and paired serum and urine osmolality should be performed. For patients who develop AVP-D, electrolytes should be monitored twice daily until resolution or stabilization (42,44). Patients with adipsic AVP-D, reduced consciousness, or impaired thirst require closer monitoring, and plasma Table 1. Criteria for diagnosis of early arginine vasopressin deficiency following pituitary surgery Parameter Description Polyuria >300 mL/hour for at least 2-3 consecutive hours Fluid balance Negative Urine specific gravity <1.005 Plasma sodium Often >140-145 mmol/L Can be normal if free access to fluids and intact thirst mechanism Serum osmolality Often >300 mOsmol/kg Can be normal if free access to fluids and intact thirst mechanism Urine osmolality <300 mOsmol/kg Exclude other causes of polyuria Intraoperative or postoperative fluids, hyperglycemia, diuretic therapy, rapid decrease in growth hormone in patients with acromegaly electrolytes should be performed more frequently (eg, every 6 hours) (45,46). Diagnosis of Early Postoperative Arginine Vasopressin Deficiency AVP-D should be suspected in the presence of polyuria greater than 300 mL/hour for at least 2 to 3 consecutive hours within 24 to 48 hours of surgery (21,31–33,40) accompanied by thirst. The diagnostic criteria for AVP-D are in Table 1. Other causes of an increased urine output should be excluded, including the administration of intraoperative or perioperative intravenous fluids, osmotic diuresis secondary to hyperglycemia, diuretic medications or mannitol, and diuresis secondary to a sudden reduction in growth hormone levels in acromegaly. Soft tissue swelling and increased extracellular volume are features of acromegaly (44, 47), owing to the antinatriuretic effects of growth hormone (48). Rapid diuresis of excess free fluid is often seen within 48 hours following successful resection of growth hormone–secreting tumors (49). In the absence of other causes of diuresis, polyuria associated with low urine specific gravity (<1.005), excessive thirst, plasma sodium >145 mmol/L, plasma osmolality >300 mmol/L, and urine osmolality <300 mOsmol/kg is consistent with AVP-D (46). However, plasma osmolality and sodium may remain normal in patients with free access to fluids and an intact thirst mechanism. There has not been a uniform definition for postoperative AVP-D; however, De Vries et al recently proposed diagnostic criteria to include the presence of hypotonic polyuria, defined by urine output >300 mL/hours for 3 consecutive hours and urine specific gravity of <1.005; and at least 1 of excessive thirst, serum osmolality >300 mOsmol/ kg, or plasma sodium >145 mmol/L (46). Management of Early Postoperative Arginine Vasopressin Deficiency Patients should have free access to fluids and be encouraged to drink to thirst as water balance may be maintained in some patients with increased fluid intake alone (46). If urine output is excessive, and especially if hypernatremia is developing, the patient is sedated or unable to maintain adequate oral fluid Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac622/6775276 by guest on 17 November 2022 Figure 1. Pathophysiology of water balance disorders following pituitary surgery. 4 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 Permanent Arginine Vasopressin Deficiency In most patients, endogenous AVP secretion recovers. However prolonged AVP-D, present for 2 weeks to 6 months, or chronic (persistent) AVP-D, present for more than 6 months following surgery (46), can occur in 0.9% to 10.1% of patients (10,22,23,33). The risk of persistent AVP-D is increased if proximal sectioning above the median eminence has occurred, as the probability of Wallerian degeneration of the magnocellular neurons increases (57). Risk factors for developing permanent AVP-D are also inconsistent between studies and have included age younger than 50 years (23), large intrasellar masses, intraoperative cerebrospinal fluid leak (23,33), elevated plasma sodium >145 mmol/L within 5 days postoperatively (35), Rathke’s cleft cyst (33,35), craniopharyngioma (33,58), and development of early AVP-D within 24 to 48 hours postoperatively (22). Patients with AVP-D at discharge should be managed with oral formulations of desmopressin and educated on the treatment of AVP-D and symptoms of hyponatremia. Among those with AVP-D on discharge, 80% have resolution within 3 months postoperatively (22), and although recovery from AVP-D persisting for more than 1 year following surgery is uncommon, long-term recovery has also been reported (10,22,45). Patients should be advised to delay a dose of desmopressin weekly to allow a period of breakthrough polyuria to monitor for possible resolution of symptoms, and to avoid water retention and hyponatremia. If the diagnosis of persistent AVP-D postoperatively is unclear, further confirmatory testing should be performed with either a hypertonic saline or arginine stimulated copeptin (59,60), or a formal water deprivation test if copeptin measurement is not available (61). Adipsic Arginine Vasopressin Deficiency Adipsic AVP-D is characterized by absence of a thirst response to hypernatremia. Loss of thirst, which is the key homeostatic mechanism, predisposes to significant hypernatremia and volume depletion (62). The risk of adipsic AVP-D is increased following resection of craniopharyngioma and suprasellar pituitary tumors, where there has been damage to the circumventricular organs (58,62–64). Smith et al reported postoperative AVP-D in 96% of patients with craniopharyngiomas, compared with 30% with suprasellar pituitary tumors and 14% with intrasellar pituitary tumors (58). Thirty-one percent of patients with a craniopharyngioma had an altered thirst mechanism (58). Management of adipsic AVP-D can be challenging, as it is difficult to reproduce the tight control of sodium and water homeostasis maintained by physiological osmoregulation (62,64). Perioperative management should include close monitoring of fluid intake and output, daily weighs, and titration of fluid intake and desmopressin dose to achieve eunatremia. Hyponatremia The incidence of delayed hyponatremia, the majority of which is secondary to SIAD, varies between 1.7% and 28% (10,21,22,26–30,65). It occurs as early as day 4 to as late as day 14 postoperatively (22,66), with a nadir around 7 days (32,67). Fortunately, hyponatremia is most often mild, asymptomatic, and self-limiting, resolving within around 5 days (66). A recent metanalysis reported the rate of symptomatic delayed hyponatremia to be 5.6%, with a range of 0 to 19.7% (60). Moderate or severe hyponatremia is the most common cause of readmission following pituitary surgery (11,27,68,69). Up to 7.6% of patients are readmitted following TSS for delayed hyponatremia, which generally occurs between postoperative days 4 and 17 (average: days 8-9) (67–71 ), with plasma sodium ranging from 111 to 129 mmol/L (average: 119-120 mmol/L) (68,71). Predictive factors for the development of postoperative hyponatremia are inconsistent between studies, however include Cushing disease (10,22), female sex (27,29,66,72), low body mass index (27,72), younger (67) or older age (>60 years) (65), preoperative hyponatremia, cardiac, renal, and/or thyroid disease (66), postoperative cerebrospinal fluid drainage (66), preoperative hypopituitarism (26), optic chiasm compression (70), fall in plasma sodium on first postoperative day (70), operative time (65), and postoperative early AVPD (29). Monitoring Patients are usually discharged from hospital within a few days of pituitary surgery, and development of hyponatremia typically occurs in the outpatient setting. All patients should be advised of the risk of delayed hyponatremia and associated symptoms with a recommendation to represent if these occur. Symptoms may include nausea, headache, anorexia, Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac622/6775276 by guest on 17 November 2022 intake, desmopressin (1-deamino-8-D-arginine vasopressin; dDAVP) should be administered (46). Desmopressin is a synthetic analogue of AVP, with higher antidiuretic potency, longer duration of action, and less vasopressor activity (50), which can be administered by oral, intranasal, subcutaneous, and intravenous routes (46). In the early postoperative period, desmopressin should be administered on an “as required” basis via subcutaneous or intravenous injection. There is no apparent difference in antidiuretic effect between the intravenous or subcutaneous routes (51). Administration of 1 μg of desmopressin via intravenous push increases urine osmolality to 700 to 800 mOsmol/kg (52) and suppresses diuresis to <1 mL/minute within 15 to 30 minutes of administration for 5 to 12 hours (53). Further increases in desmopressin dose result in prolongation of the duration of action rather than a greater reduction in urine output (52,53). There is large interindividual variability in the antidiuretic effect and duration of desmopressin (54). Following desmopressin administration, monitoring of urine output should continue, and a further dose administered if polyuria recurs. Postoperative AVP-D is usually transient, and generally 1 to 2 doses of desmopressin are sufficient (10). Overtreatment of AVP-D increases the risk of precipitating hyponatremia, particularly if the second SIAD phase occurs. If AVP-D persists beyond 48 hours, regular desmopressin is prescribed. Oral administration of desmopressin tablets has been associated with a lower incidence of hyponatremia than nasal formulations (55) and is now the preferred option for many patients (56). Furthermore, nasal administration should be avoided in the postoperative period due to impaired absorption secondary to nasal congestion (46). Ongoing monitoring of plasma sodium and urine output should be performed and withholding of desmopressin attempted prior to hospital discharge to identify possible recovery from AVP-D. The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 Table 2. Criteria for diagnosis of delayed hyponatremia secondary to SIAD postoperatively Parameter Description Plasma sodium <135 mmol/L Plasma osmolality <275 mOsmol/kg Euvolemia Urine osmolality >100 mOsmol/kg Urine sodium >30 mmol/L Exclude other causes of hyponatremia Exclude adrenal insufficiency and hypothyroidism, SIAD secondary to infection, desmopressin and other medications Abbreviations: SIAD, syndrome of inappropriate antidiuresis. confusion, and, rarely, decreased level of consciousness and seizures (22). Monitoring of plasma sodium approximately 7 days after surgery has been recommended for recognition and early management of delayed hyponatremia (29,73). Although a reduction in readmission for delayed hyponatremia following implementation of a screening protocol was not demonstrated in a study by Bohl et al, this may have been limited by missed or early screening of plasma sodium on postoperative days 5 to 6, prior to the development of hyponatremia (74). Diagnosis SIAD accounts for the majority of hyponatremia in the early postoperative period. However differential diagnoses includes adrenal insufficiency, hypothyroidism, SIAD in the setting of infection, hypotonic fluid or desmopressin administration, and cerebral salt wasting (29,66). A plasma sodium <135 mmol/L with plasma osmolality <275 mOsmol/kg, urine osmolality >100 mOsmol/kg and urine sodium >30 mmol/L, in the presence of euvolemia and absence of other causes is consistent with SIAD (Table 2) (75). Management SIAD after pituitary surgery should be managed similarly to that from other causes. Management options include fluid restriction, oral urea, oral tolvaptan, and administration of 3% hypertonic saline in severely symptomatic cases. Patients with acute hyponatremia of <48 hours duration are often severely symptomatic if the plasma sodium falls to <120 mmol/L and benefit from a prompt increase in plasma sodium to reduce cerebral edema. In comparison, those with hyponatremia of >48 hours duration with minimal neurological symptoms require a slower correction, to avoid the risk of osmotic demyelination. A correction rate of no more than 10 mmol/L during the first 24 hours and 18 mmol/L during the first 48 hours is recommended in this cohort (75,76). Fluid restriction is often first-line therapy for mild to moderate hyponatremia where the plasma sodium is 125 to 135 mmol/L. Although there are no randomized controlled trials proving the efficacy and safety of fluid restriction in the postpituitary surgery setting, clinical experience supports its continuing use. However, fluid restriction alone is often ineffective or slow at correcting hyponatremia (66,67,77,78). A recent randomized controlled trial in people with chronic SIAD demonstrated a median rise in plasma sodium by 3 mmol/L after 3 days of fluid restriction (1000 mL/day) compared with 1 mmol/L without any specific treatment. Thereafter, minimal increase in plasma sodium occurred, with the rise from baseline being 4 mmol/L vs 1 mmol/L after 30 days in the fluid restriction and no intervention groups, respectively (78). Similarly, another randomized controlled trial showed a rise in plasma sodium of 4.9 mmol/L after 4 days of fluid restriction (500-1000 mL/day), and by 5.7 mmol/L after 28 days (79). Data from a hyponatremia registry of over 3000 patients also showed only a very modest rise in plasma sodium of 2 mmol/L over the initial day of fluid restriction monotherapy (75). In a review of SIAD following pituitary surgery, monotherapy with fluid restriction achieved a mean rise in plasma sodium of 3.3 mmol/L over 72 hours and 32% of patients did not achieve any increase in plasma sodium (67). Predictors of failure of fluid restriction include urine osmolality >500 mOsmol/kg, sum of the urine sodium and potassium exceeding plasma sodium, 24-hour urine volume <1500 mL, and increase in plasma sodium <2 mmol/L within the initial 24 to 48 hours of fluid restriction <1000 mL/day (76). Fluid restriction should be at least 500 mL less than the estimated 24-hour urine output (76). Urea induces mild osmotic diuresis (77) and progressive rise in plasma sodium in patients with SIAD, with a low risk of overcorrection or serious adverse effects (80–82 ). A dose of 7.5 to 90 g/day results in a mean rise in plasma sodium of 2.5 to 5 mmol/L over the first 24 hours (80,82). Urea is an effective and safe treatment for acute hyponatremia in neurosurgical patients (83,84), including after pituitary surgery (21). Experimental data suggest that urea is protective against osmotic demyelination (85); however, overcorrection of plasma sodium in chronic hyponatremia should still be avoided. Recommended dosing of urea is 30 to 60 g daily in 2 divided doses. Urea has a bitter taste, and tolerability can be improved by combination with sweet-tasting substances such as orange juice (76). Tolvaptan is an orally administered selective vasopressin receptor (V2) antagonist effective in the management of euvolemic and hypervolemic hyponatremia (86,87), although it is limited by concerns of plasma sodium overcorrection (87,88). Baseline plasma sodium ≤121 mmol/L and blood urea nitrogen ≤10 mg/dL (plasma urea of ≤3.7 mmol/L) are associated with a significantly greater rise in plasma sodium following tolvaptan (89). The use of tolvaptan for SIAD in the postoperative pituitary surgery setting is mostly limited to retrospective studies and case reports or series (90–93). In postoperative pituitary patients, a single-dose of tolvaptan is effective in normalizing plasma sodium and reducing the duration of hospital admission (90); however, it is associated with a risk of overcorrection. In a retrospective study, Indirli et al found higher correction rates of plasma sodium with tolvaptan (median dose 15 mg) than standard treatment which included fluid restriction and/or hypertonic saline (12 mmol/L/24 hour vs 1.8 mmol/L/24 hours). However overcorrection of plasma sodium of >10 mmol/L/24 hour occurred in 64% of patients treated with tolvaptan (90). A similar effect on plasma sodium was observed between doses of 7.5 mg and 15 mg tolvaptan (90). Similarly, in a prospective observational study, Kleindienst et al reported a dose of tolvaptan 7.5 mg was more effective than fluid restriction in correction of SIAD Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac622/6775276 by guest on 17 November 2022 Volume status 5 6 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 however, often the duration of hyponatremia is uncertain, and overcorrection should be avoided. Plasma sodium should be closely monitored, and where the rate of correction exceeds thresholds, particularly when the initial sodium was <120 mmol/L, strategies to prevent overcorrection should be instituted. Urine output should be replaced with free water (orally or in the form of 5% dextrose) with or without the addition of desmopressin to prevent further urinary losses (75,76). Prevention Many centers recommend patients drink to thirst on hospital discharge and emphasize avoidance of overdrinking to help prevent delayed hyponatremia. Several retrospective studies have shown reduced postoperative hyponatremia and associated readmission rates with implementation of a mandatory prophylactic fluid restriction, except in patients who have developed AVP-D (98–102 ). Fluid restriction volume and duration have varied between these studies, ranging between 1000 and 2500 mL/day and from 1 to 2 weeks postoperatively. Matsuyama et al reported a reduction in SIAD after pituitary surgery from 38% to 14% following the introduction of fluid restriction of 1800 mL/day in selected patients with 2 or more of plasma sodium <140 mmol/L, daily urine output <1000 mL, or body weight gain compared with preoperative weight on day 6 postoperatively (101). Deaver et al showed a reduction in hospital readmission rates after TSS from 7.6% to 2.4% after implementation of a 1500 mL/day fluid restriction from day 1 to 15 post-TSS (98). It is likely that more rigorous fluid restriction of 1000 mL/day is needed to prevent hyponatremia. Snyder et al demonstrated a reduction in delayed hyponatremia from 5% to 1%, but not readmission rates (7% vs 4%), following implementation of a 1000 mL fluid restriction for 7 days following hospital discharge (72). Burke et al showed a reduction in readmission with hyponatremia from 3.41% to 0% after implementing a mandatory 1000 mL/day fluid restriction for 7 days after discharge (99). Similarly, Winograd et al implemented a 1000 mL/ day fluid restriction on days 4 to 8 postoperatively and demonstrated no hyponatremia among patients on fluid restriction compared with a rate of 12.3% for hyponatremia and 7% for hospitalization among patients not fluid restricted (100). No fluid balance complications occurred in patients following the fluid restriction protocol (99). A recent metaanalysis of 4 of these studies (98–100,102) consisting of 852 patients included prior to and 530 patients included following implementation of a fluid restriction protocol showed an odds ratio of 5.02 (95% CI 2.16-11.65), favoring fluid restriction (103). Further prospective studies are needed to confirm the efficacy of prophylactic fluid restriction, and the optimal volume, duration, and postoperative day start of fluid restriction. In the meantime, fluid restriction of approximately 1000 mL per day from around days 4 to 9 postoperatively appears efficacious and safe for many patients, except those with AVP-D. Patients should be advised to drink to thirst if symptoms of AVP-D develop. Cerebral Salt Wasting Very rarely, hyponatremia can result from cerebral saltwasting syndrome (CSWS). CSWS is characterized by Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac622/6775276 by guest on 17 November 2022 following pituitary surgery (sodium increase 7.8 mmol/L/24 hour vs 3.5 mmol/L/24 hour). However, overcorrection occurred in 30% of patients in the 7.5 mg tolvaptan group (94). Despite the higher rates of overcorrection, no side effects, importantly osmotic demyelination, occurred in either study (90,94). Hyponatremia following TSS develops acutely, and many patients do not have significant risk factors for osmotic demyelination, such as hyponatremia duration >48 hours or plasma sodium <120 mmol/L (76). Hypertonic saline (3%) is indicated in severe symptomatic hyponatremia to rapidly increase plasma sodium with the aim of decreasing brain edema (75,76). Rapid intermittent bolus therapy is recommended over continuous infusions (75,76). Two studies by Baek et al and Garrahy et al demonstrated faster initial elevation in plasma sodium with bolus therapy (95,96). Garrahy et al included more participants with severe symptomatic hyponatremia and also showed faster improvement of neurological symptoms with bolus therapy (96). Baek et al reported a higher incidence of overcorrection, with 41.4% and 57.1% in the bolus and continuous infusions groups respectively receiving relowering treatment compared with 22.7% and 0% for the bolus and continuous infusion groups in the study by Garrahy et al. Of note, Baek et al used 150-mL boluses and Garrahy et al used 100-mL boluses of 3% hypertonic saline (95,96). The risk of overcorrection using 150-mL boluses is increased in severely symptomatic patients and where the baseline plasma sodium is <120 mmol/L (97). We recommend administering hypertonic saline as per the American guidelines for the management of severe symptomatic hyponatremia, which recommend up to 3 boluses of 100 mL 3% hypertonic saline in patients with severe symptomatic hyponatremia (76) compared with the European guidelines which recommend up to 2 boluses of 150 mL (75). Using 100-mL boluses may allow for a more controlled and safe increase in plasma sodium (97). We propose an algorithm for the management of delayed hyponatremia after pituitary surgery (Fig. 2). Asymptomatic mild to moderate hyponatremia (sodium ≥125 mmol/L) can often be managed as an outpatient, with strict fluid restriction of 500 to 1000 mL/24 hours and close monitoring of plasma sodium until improvement is seen. In patients who have symptomatic or profound hyponatremia (sodium <125 mmol/L), hospitalization is recommended. Patients with moderate asymptomatic hyponatremia (sodium 125-129 mmol/L) can be managed with aggressive fluid restriction (500 mL/24 hours) initially, with or without the addition of oral urea therapy, if available. In those with inadequate improvement on fluid restriction alone, or with profound hyponatremia (sodium <125 mmol/L) who remain asymptomatic or have mild symptoms, combined treatment with fluid restriction and urea remains appropriate (81). Fluid restriction and urea can be relaxed once the plasma sodium exceeds 132 mmol/L, or if there are signs of DI developing. Patients with plasma sodium <120 mmol/L or neurological symptoms should be managed with hypertonic saline with the aim to raise the plasma sodium promptly and improve symptoms (75). Thereafter, fluid restriction and urea may be sufficient as continuing therapy. Tolvaptan may also be considered for moderate hyponatremia depending on availability. If tolvaptan is administered, the patient should be encouraged to drink to thirst to limit overcorrection from induced aquaresis. Most hyponatremia occurring following pituitary surgery is acute and the risk of complications from overcorrection low; The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 7 Management of delayed hyponatremia post-pituitary surgerya,b Asymptomatic mild-moderate hyponatremia (plasma sodium ≥ 125 mmol/L) Symptomatic or profound hyponatremia (plasma sodium <125 mmol/L) Outpatient management likely appropriate Inpatient management Plasma sodium 125–129 mmol/L Fluid restriction 500 –1000 mL/dayc Fluid restriction 500 mL/day +/–oral uread,e if available Plasma sodium 120–125 mmol/L and asymptomatic or mild symptoms Combined treatment with fluid restriction 500 mL/day + oral uread,e if available Consider tolvaptan if availablef Consider tolvaptan if availablef Monitor plasma sodium daily until improvement Monitor plasma sodium daily until improvement Readmission if inadequate improvement or symptomatic Readmission if plasma sodium decreasing and/or symptomatic If inadequate improvement on fluid restriction alone, add oral urea Plasma sodium <120 mmol/L or neurological symptoms Initial treatment with 3% hypertonic salineg Fluid restriction and oral urea may be appropriate continuing therapy Figure 2. Proposed algorithm for the management of delayed hyponatremia secondary to SIAD following pituitary surgery. aSecondary to postoperative SIAD, exclude other causes first, including adrenal insufficiency, hypothyroidism, infection, exogenous desmopressin administration, or other medications. bIf chronic hyponatremia (>48 hours duration, or unknown duration), avoid overcorrection and aim increase in plasma sodium by <10 mmol/L over the initial 24 hours, and <18 mmol/L over the initial 48 hours. cWhen used in combination with frusemide, fluid restriction <1000 mL/ day has been associated with acute kidney injury (79). dUrea 30 to 60 g daily in divided doses. eMonitor kidney function (using creatinine, not urea) in patients taking urea. fTolvaptan 7.5 mg as single dose (can be repeated if required) if low risk of complications from overcorrection of plasma sodium (including acute hyponatremia of known <48 hours duration, plasma sodium >120 mmol/L). gHypertonic saline recommended as per guidelines (76). excessive natriuresis associated with intracranial disease (104–108 ). Only very few cases of purported CSWS have been reported following pituitary surgery (109–112 ), and care should be taken to avoid erroneously diagnosing this condition. CSWS and SIAD can appear similar biochemically and the most defining differentiating feature is the presence of volume expansion in SIAD and volume depletion in CSWS (113). Treatment of CSWS is directed at replacing volume and salt deficits (114). Fludrocortisone can also be beneficial in counteracting excessive natriuresis (108,114). Postoperative Copeptin Direct measurement of AVP is technically challenging for multiple reasons and not used routinely (13,115–118). However, copeptin is easily measured and correlates well with plasma AVP (119,120). Given AVP has a role in the endocrine stress response and is stimulated by physiological stress (13), several studies have investigated the utility of measuring plasma copeptin postoperatively to predict the development of AVP-D (121,122). Winzeler et al demonstrated plasma copeptin <2.5 pmol/L measured within 12 hours postoperatively was a risk factor for AVP-D (sensitivity 81%, specificity 97%) (121). Similarly, Berton et al found the absence of a peak in plasma copeptin 1 hour postoperatively was predictive of postoperative AVP-D (sensitivity 87.5%, specificity 76%) (122). However, the time delay in obtaining copeptin results in clinical practice and the ease of monitoring patients in the immediate postoperative period questions the current clinical usefulness of immediate postoperative copeptin measurements for prediction of early AVP-D. Conclusion Disorders of water and salt balance are common following pituitary surgery and are associated with increased morbidity, prolongation of hospital stay, and readmission. AVP-D and SIAD can occur in isolation or, less commonly, as part of a biphasic or triphasic response. While numerous predictive factors have been reported, it is difficult to reliably predict which patients will develop AVP-D and/or SIAD, and monitoring is necessary for all patients following pituitary surgery to allow for early detection, timely initiation of appropriate management, and reduction of associated complications. Prophylactic fluid restriction may be a safe, cost-effective, and efficacious method to reduce the incidence of delayed hyponatremia. Back to the Cases Case 1: Triphasic Response This patient demonstrated a triphasic phenomenon after pituitary surgery, with early AVP-D followed by delayed hyponatremia, and finally developing permanent AVP-D. She maintained symptomatic control of polyuria with uptitration of desmopressin tablets to 200 μg in the morning, and 300 μg at night. Delaying 1 desmopressin dose each week was recommended, both to assess for ongoing need of desmopressin and prevent hyponatremia. Two years later, she remains on desmopressin for permanent AVP-D but has had full recovery of her anterior pituitary function. Case 2: Delayed SIAD This patient had delayed hyponatremia postoperatively secondary to SIAD. Fluid restriction and urea treatment Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac622/6775276 by guest on 17 November 2022 Plasma sodium >130 mmol/L 8 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 00, No. 0 improved her plasma sodium from 120 mmol/L to 125 mmol/ L by the following day, and to 130 mmol/L 3 days later. She was discharged home on 750 mL/day fluid restriction that was further relaxed and ceased as her sodium normalized. Three months postoperatively, she has normal anterior and posterior pituitary function. Case 3: Polyuria in Acromegaly Data Availability Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. 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