The Curious Story of Cerebral Salt Wasting

The extent to which hyponatremia is a result of natriuresis has remained controversial for many years. Cerebral salt wasting (CSW) was first proposed in 1950 to explain the natriuresis and hyponatremia that sometimes accompany intracranial disease. Following the first clinical description of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in 1957, such patients were assumed to develop hyponatremia from nonosmotic arginine vasopressin (AVP) secretion with secondary natriuresis. However, clinical and experimental data suggested that some patients with intracranial diseases may have a primary natriuresis leading to extracellular fluid (ECF) and/or intravascular fluid (IVF) volume contraction (1,2), with elevated plasma AVP levels that are physiologically appropriate for hypovolemia. What has evolved since the description of CSW over a half-century ago is not as much the clinical definition of this disorder (although some suggest that this syndrome also encompasses patients without cerebral disorders and propose adding “renal salt wasting” [RSW] to the descriptor; i.e., CSW/RSW [3]) but more so the assessment of its clinical frequency.

Table 1 illustrates the widely disparate prevalence rates of CSW reported in subarachnoid hemorrhage (SAH). When the prevalence of a disorder ranges from 94% to 0% in similar patient populations, one must question the validity of the criteria used for the diagnosis. Analysis of these series indicates that the frequency of CSW as a primary cause of hyponatremia is critically dependent on the criteria used to assess the volume status of such patients, which differs substantially across reported series. Early studies documented intravascular volume depletion using radioisotope dilution techniques (1,2), but later studies used less reliable clinical criteria—and all methods of estimating ECF and IVF volumes have significant caveats (Table 1). Opponents argue that there is insufficient evidence of hypovolemia with ongoing natriuresis, whereas proponents argue that measures that have traditionally been used to estimate ECF/IVF volume do support hypovolemia in such cases. Although this constitutes an interesting academic controversy, practical implications of failure to apply rigorous diagnostic criteria for CSW in hyponatremic patients are demonstrated by the following case.

Table 1.

Reported incidences of cerebral salt wasting in patients with subarachnoid hemorrhage

Authors	Publication Date	N, CSW/Total	CSW, %	Assessment of ECF/IVF Volume
Nelson et al. (1)	1981	10/12	81	RBC mass (chromium-51 erythrocytes),a plasma volume (isotope dilution),b and total blood volumea
Wijdicks et al. (2)	1985	6/9	67	>10% decrease in plasma volume (isotope dilution),b increased BUN,c and decreased body weightd
Sivakumar et al. (4)	1994	17/18	94	Decreased hematocrite and total blood volumea and/or low CVPf
Sherlock et al. (5)	2006	4/62	6.5	Low CVPf with ongoing natriuresis and diuresis
Kao et al. (6)	2009	11/48	22.9	Daily fluid balance and response to isotonic NaCl infusiong
Hannon et al. (7)	2014	0/49	0	Daily clinical assessment of ECFV, increased BUN,c and low CVPf

CSW, cerebral salt wasting; ECF, extracellular fluid; IVF, intravascular fluid; RBC, red blood cell; CVP, central venous pressure; ECFV, extracellular fluid volume.

^aDecreased RBC mass and total blood volume are indicators of blood loss but not ECF volume depletion.

^bDecreased plasma volume by isotope dilution may indicate ECF/IVF volume depletion but also can be due to venoconstriction with intact ECF and IVF volumes.

^cBUN may be increased by ECF volume contraction but also by other causes (e.g., gastrointestinal bleeding, glucocorticoid administration, or catabolic state).

^dDecreased body weight is typical in sick hospitalized patients, and it is an unreliable indicator of ECF/IVF volume status.

^eDecreased hematocrit may indicate blood loss or dilution from water retention but not ECF/IVF volume depletion, in which case the hematocrit would be increased.

^fLow CVP may indicate ECF/IVF volume depletion but can be influenced by many other factors, including vasodilation and mode of measurement.

^gIncrease in serum [Na⁺] in response to isotonic saline infusion is generally indicative of ECF volume depletion, but it may also occur in conjunction with spontaneous resolution of transient syndrome of inappropriate antidiuretic hormone secretion.

A 55-year-old man underwent transnasal endoscopic resection of a nonfunctional pituitary adenoma. On postoperative day 2, his serum [Na⁺] decreased to 130 mmol/L, despite continued volume expansion with isotonic NaCl at 75 ml/h and stress-dose glucocorticoids. By postoperative day 3, the serum [Na⁺] was 126 mmol/L, and the patient was somnolent. Urine osmolality was 626 mOsm/kg H₂O, and urine [Na⁺] was 262 mmol/L. The patient was clinically euvolemic with normal BP and BUN/creatinine =12/0.8. CSW was diagnosed on the basis of the high urine [Na⁺], and the patient was started on 3% NaCl at 35 ml/h plus NaCl tablets of 2 g every 6 hours in addition to increased isotonic NaCl to 125 ml/h. Over the next 10 hours, the serum [Na⁺] decreased further to 123 mmol/L, and the patient became poorly responsive, despite having received a total of 26.25 g NaCl (450 mmol Na⁺) during that period. Endocrinology was consulted, and the diagnosis was changed to SIADH. Isotonic NaCl and NaCl tablets were discontinued, and 3% NaCl was increased to 70 ml/h. After 12 hours, the serum [Na⁺] increased to 130, and the 3% NaCl was replaced with a 750-ml/d fluid restriction. By postoperative day 5, serum [Na⁺] normalized to 138 mmol/L, and the patient was alert without neurologic deficits.

In this patient, an incorrect diagnosis of CSW led to therapy that worsened the hyponatremia rather than correcting it because of the mistaken assumption that a high urine [Na⁺] in any hyponatremic patient with a neurologic lesion indicates CSW.

Noticeably lacking from the ongoing debate about the true prevalence of CSW are carefully conducted prospective studies that critically assess the cause of hyponatremia in neurologic diseases. A recent study by Hannon et al. (7) addressed this deficiency by studying 100 consecutive patients with acute nontraumatic aneurysmal SAH with daily assessments of clinical ECF/IVF volume status by a single experienced clinician along with serial measurements of plasma cortisol, AVP, and brain natriuretic peptide (BNP). Their results demonstrated the expected high incidence of hyponatremia in patients with SAH (49%); the cause of the hyponatremia was attributable to SIADH in 71.4% and acute glucocorticoid deficiency in 8.2%, with the remaining cases caused by incorrect intravenous fluid administration or hypovolemia. No cases met historically accepted criteria for a diagnosis of CSW (7). This study indicates that CSW is a rare cause of hyponatremia in SAH and, by analogy, likely with other intracranial disorders as well.

Understanding CSW mandates knowledge of the physiologic basis of natriuresis in different disease states. The abbreviated nature of this editorial precludes comprehensive analysis of this question, but several key points deserve emphasis.

1. Increased kidney sodium excretion is a cardinal manifestation of SIADH, which is embedded in the requirements for the diagnosis. Metabolic balance studies demonstrated that excess urine sodium excretion and a negative sodium balance occurred during the development of hyponatremia in patients with SIADH, but eventually, urinary sodium excretion reflected daily sodium intake. Patients appear to exhibit kidney sodium “wasting” because they continue to excrete sodium despite hyponatremia, but they have simply achieved a new steady state of neutral sodium balance, albeit at a lower serum [Na⁺]. The elevated urine [Na⁺] in most patients with intracranial disorders is usually due to antecedent administration of isotonic saline to prevent vasospasm, such as in this patient. Limiting hypotension in patients at risk for cerebral ischemia has biased treatment regimens toward fluid excess.

2. Experimental studies of long-term antidiuretic hormone-induced hyponatremia have indicated that a significant proportion of the hyponatremia is attributable to secondary sodium losses rather than to water retention. However, in these models, the natriuresis did not worsen the hyponatremia, but rather allowed volume regulation of blood and ECF/IVF volumes (8).

3. Ample precedent exists for hyponatremia due to sodium wasting with secondary antidiuresis in Addison disease, secondary to aldosterone deficiency, as well as diuretic-induced hyponatremia. Characteristic of these disorders, normalization of ECF/IVF volume with isotonic saline infusions restores plasma osmolality to normal ranges by shutting off secondary AVP secretion. If hyponatremia in patients with CSW occurred via a similar mechanism, it should also respond to this therapy; however, studies have indicated that it does not (9), such as was true in this patient. Few reported cases of CSW/RSW have shown correction of hyponatremia via aquaresis following isotonic saline infusion (10), but not to the degree typically seen in patients with Addison disease or diuretic-induced hyponatremia.

4. Proposed mechanisms for the natriuresis in CSW have included increased atrial natriuretic peptide/BNP, decreased kidney sympathetic tone, and suppressed aldosterone despite ECF/IVF volume depletion, but evidence unequivocally implicating any of these mechanisms in CSW has not been demonstrated to date. Notably, patients with SIADH have elevated atrial natriuretic peptide/BNP levels that are equivalent to cases of CSW. Studies showing beneficial effects of fludrocortisone in hyponatremic patients with intracranial disorders are cited in support of suppressed activity of the renin-angiotensin-aldosterone system (11), but pharmacologic doses of mineralocorticoids will predictably cause sodium retention even in the absence of mineralocorticoid deficiency.

5. Recent studies proposed that failure to normalize fractional excretion of urate following correction of hyponatremia identified patients with underlying RSW (12), but this remains a hypothesis until prospective studies in larger groups of patients are performed. Furthermore, this represents a post hoc diagnosis that does not help clinicians determine appropriate treatment for hyponatremic patients.

These considerations raise the possibility that hyponatremia with intracranial diseases might represent a mixed disorder in which some patients have both inappropriate AVP secretion and exaggerated natriuresis; which effect predominates in the clinical presentation depends on their relative intensities and the effects of concomitant therapies.

A complete discussion of the implications of our current knowledge of natriuresis for management of hyponatremia in patients with intracranial diseases is beyond the scope of this editorial. Because the majority of hyponatremia in such cases is due to SIADH, this diagnosis should be fully evaluated and treated as such unless the patient meets accepted criteria for a diagnosis of CSW, importantly including clinical evidence suggesting ECF/IVF volume depletion (e.g., hypotension, unexplained tachycardia, low central venous pressure, prerenal azotemia, hemoconcentration, or metabolic alkalosis) in the presence of ongoing natriuresis. If there is uncertainty about the volume status, a limited therapeutic trial of isotonic NaCl (1–2 L) can help to differentiate volume depletion from SIADH. However, in the absence of an initial positive response, continued infusion of isotonic saline will generally not correct the hyponatremia, and it may worsen the serum [Na⁺] in some patients because the infused water is retained while the sodium is excreted, a process called desalination, as was the case with this patient.

Why is CSW a curious story? Mainly because after 7 decades, there has been no proven pathophysiologic basis for the natriuresis of CSW. What is fact? Some reported cases do seem to fit a diagnosis of CSW, and clinicians who treat patients with hyponatremia occasionally identify such cases. What is fiction? The belief that a high percentage of cases of hyponatremia in patients with neurologic disorders is due to CSW. Existing evidence-based data do not support this belief. Consequently, until more high-quality prospective studies are done similar to that of Hannon et al. (7), CSW should be considered a rare cause of hyponatremia compared with the much more frequent SIADH.

Disclosures

The author reports receiving personal fees from Ferring Pharmaceuticals and Otsuka Pharma and a grant from Corcept Pharmaceuticals, all outside of the submitted work.

Funding

None.