INTRODUCTION — Hyponatremia is a common electrolyte disorder in the setting of central nervous system (CNS) disease. This is usually attributed to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) [1-4].
Cerebral salt wasting (CSW) is another potential cause of hyponatremia in those with CNS disease, particularly patients with subarachnoid hemorrhage. CSW is characterized by hyponatremia and extracellular fluid depletion due to inappropriate sodium wasting in the urine . However, some authorities contend that CSW does not really exist and is only a misnomer for what is actually SIADH, with the putative salt wasting being due to unappreciated volume expansion [6,7].
Issues related to CSW, including the differentiation from SIADH, will be reviewed here. The causes and diagnosis of hyponatremia, causes and treatment of SIADH, and the general management of patients with subarachnoid hemorrhage are presented separately:
PATHOPHYSIOLOGY — With respect to pathophysiology, two issues need to be addressed: the mechanism of salt wasting and the mechanism of hyponatremia.
The mechanism by which cerebral disease might lead to renal salt wasting is poorly understood. Two putative mechanisms are disruption of neural input to the kidney and central elaboration of a circulating natriuretic factor [8,9]:
●The sympathetic nervous system promotes sodium, uric acid, and water reabsorption in the proximal tubule, as well as renin release. Thus, impaired sympathetic neural input could explain the reductions in proximal sodium and urate reabsorption as well as the impaired release of renin and aldosterone. The failure of serum aldosterone to rise in response to volume depletion would explain the absence of potassium wasting despite the increase in distal sodium delivery.
●The second theory is that a circulating factor that impairs renal tubular sodium reabsorption is released in patients with brain injury [6,10-13]. The primary candidate is brain natriuretic peptide (BNP), which decreases sodium reabsorption and inhibits renin release [11,12,14]. BNP may also decrease autonomic outflow via effects at the level of the brainstem [14,15]. A discussion of the various actions of these hormones is available in a separate topic review. (See "Natriuretic peptide measurement in heart failure".)
One report suggested that BNP might be the more probable candidate . In this prospective observational study, 10 patients with subarachnoid hemorrhage were compared with a control group of 10 patients who underwent craniotomy for resection of cerebral tumors and 40 controls. The patients with subarachnoid hemorrhage had increases in urine volume and sodium excretion that correlated with a marked significant increase in mean plasma BNP (15.1 versus 1.6 pmol/L in the other two groups) and with the increase in intracranial pressure. The concentration of ANP was normal, while that of aldosterone was reduced, an effect that may be mediated in part by BNP.
It was suggested that BNP was released from hormone-producing neurons in the brain in response to increased intracranial pressure. Some have speculated that renal salt wasting and the resultant volume depletion is a protective measure, limiting extreme rises in intracranial pressure. In addition, the vasodilatory properties of BNP might decrease the tendency for vasospasm in subarachnoid hemorrhage.
With respect to the mechanism of hyponatremia, renal salt wasting leads to volume depletion, which provides a baroreceptor stimulus for the release of ADH, thereby impairing the ability of the kidney to elaborate a dilute urine and leading to hyponatremia. (See "Causes of hypotonic hyponatremia in adults" and "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)".)
Is cerebral salt wasting real? — Some authors have suggested that CSW may not exist [6,7]. They contend that most patients who are given a diagnosis of CSW may be excreting excess sodium physiologically, either because of reduced venous capacitance caused by catecholamine-induced vasoconstriction or because of volume expansion with intravenous fluids. As an example, patients with subarachnoid hemorrhage are at risk for cerebral vasospasm that is thought to be precipitated by reduced cerebral blood flow. As a result, they are typically given large volumes of isotonic saline. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".)
If volume expansion were induced by saline administration, a high rate of sodium excretion would not be an indicator of salt wasting. In a survey of patients admitted to a neurosurgical unit, a positive balance for sodium could be documented in over 90 percent of those believed to have CSW when calculations included all infusions from the time of first contact with medical or paramedical personnel [6,7].
However, many authorities feel that CSW is a distinct entity. In the setting of CNS disease, patients with CSW meet the traditional laboratory criteria for the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but clearly have decreased extracellular volume due to excessive urinary sodium excretion [16-20]. By comparison, SIADH is associated with a slightly increased or normal extracellular volume.
EPIDEMIOLOGY AND CAUSES — The incidence of CSW is unclear, particularly given that its existence is disputed [6,7]. Among patients with CNS disease, CSW is a much less common cause of hyponatremia than the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
Although CSW has been most often described in patients with subarachnoid hemorrhage, it accounts for only a small proportion of cases of hyponatremia in these patients (7 percent in one series compared to 69 percent due to SIADH) . Furthermore, the frequency of CSW as a cause of hyponatremia in this setting may be diminishing since the usual management of patients with subarachnoid hemorrhage consists of providing large volumes of isotonic saline. In another prospective cohort of 100 patients with acute nontraumatic aneurysmal subarachnoid hemorrhage, hyponatremia developed in 49 percent of subjects . Hyponatremia was attributable to SIADH in 71 percent of patients and to glucocorticoid deficiency in 8 percent. Incorrect choice or insufficient use of fluids or hypovolemia accounted for the remainder of the cases. There were no cases that met the accepted criteria for CSW. This study is noteworthy in that all patients underwent serial assessment of volume status by an experienced clinician along with measurement of plasma cortisol, arginine vasopressin, and brain natriuretic peptide. (See 'Diagnosis' below and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Hyponatremia'.)
CSW has also been reported in patients with carcinomatous or infectious meningitis, encephalitis, poliomyelitis, and central nervous system tumors, as well as following CNS surgery [5,22-26]. Rare cases have been described in children [27-29].
Some investigators who use the fractional excretion of urate following correction of hyponatremia as an indicator of salt wasting have identified this phenotype in patients both with and without neurologic disease, leading them to suggest the terminology should be changed from CSW to renal salt wasting . In addition, these authors have identified a protein, haptoglobin-related protein without signal peptide, in salt-wasting patients that possesses characteristics of a proximally acting diuretic . While these reports are of interest, better characterization of these patients is needed.
CLINICAL FEATURES — Patients with CSW may have moderate or severe hyponatremia and polyuria [32,33]. The typical onset of hyponatremia due to CSW is within the first 10 days following a neurosurgical procedure or event. However, case reports have described later onset (eg, one month after transsphenoidal surgery for treatment of a pituitary macroadenoma) .
CSW is associated with extracellular fluid depletion. As a result, hypotension, decreased skin turgor, and/or an elevated hematocrit may be observed.
Theoretically, the volume depletion seen with CSW may worsen cerebral perfusion directly, and the associated hypotension may precipitate vasospasm in those with subarachnoid hemorrhage [34,35]. Whether hyponatremia itself potentiates vasospasm is uncertain, but it may worsen cerebral edema and therefore contribute to mental status decline. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Hyponatremia'.)
DIAGNOSIS — CSW should be considered in any patient with CNS disease and hyponatremia. A directed history and physical examination and appropriate laboratory tests are essential. The general approach to the diagnosis of hyponatremia is discussed separately. (See "Diagnostic evaluation of adults with hyponatremia".)
In the setting of CNS disease, CSW is diagnosed in the patient with clinical evidence of hypovolemia who has the following characteristics:
●Hyponatremia (less than 135 mEq/L) with a low plasma osmolality
●An inappropriately elevated urine osmolality (above 100 mosmol/kg and usually above 300 mosmol/kg)
●A urine sodium concentration usually above 40 mEq/L
●A low serum uric acid concentration due to urate wasting in the urine
Clinical evidence of hypovolemia is crucial since all of these laboratory findings are also seen in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
Given the overlap and the frequent difficulty in determining whether a patient has mild hypovolemia, the diagnosis of CSW should require that volume repletion leads to a dilute urine, which would be due to the removal of the hypovolemic stimulus to ADH release. Excretion of a dilute urine would lead to correction of the hyponatremia.
Although difficult to perform accurately, evidence of net negative sodium balance prior to therapy is also consistent with the diagnosis of CSW [6,29]. Calculation of the sodium intake includes that obtained via intravenous and oral routes (including sodium supplements and food), while sodium excretion involves frequent measurement of urine sodium concentrations combined with knowledge of urine volumes.
Formation of a dilute urine with volume repletion has not been demonstrated, and, in many if not most reported cases, clear evidence of hypovolemia has not been present [6,7].
DIFFERENTIAL DIAGNOSIS — In the setting of CNS injury, CSW must be distinguished from other causes of hyponatremia, principally the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) . Glucocorticoid deficiency as a cause of increased vasopressin should be excluded in patients with sellar or suprasellar disease [36,37]. General discussions concerning the causes and diagnosis of hyponatremia are presented separately:
CSW versus SIADH — Some authorities suggest that the distinction between CSW and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is critically important, with possible adverse consequences if the incorrect therapeutic strategy is administered [5,38]. Others suggest that the distinction is less important since all hyponatremic patients (where due to CSW or SIADH) who have active intracranial pathology (eg, recent intracranial surgery or subarachnoid hemorrhage) should be treated with 3 percent (hypertonic) saline to ensure a prompt increase in the serum sodium concentration and to avoid a decrease in extracellular fluid volume .
In addition to hyponatremia, CSW and SIADH share the following features:
●The urine osmolality is inappropriately high in the presence of hyponatremia (which normally suppresses ADH release) due to increased release of ADH. This response is appropriate in CSW, due to the volume depletion, but inappropriate in SIADH.
●The urine sodium is usually >40 mEq/L due to volume expansion in SIADH and putative salt wasting in CSW.
●The serum uric acid concentration is typically reduced due to urinary losses, perhaps due to a putative hormone such as BNP in CSW and to volume expansion and a direct effect of ADH on the V1 receptor in SIADH .
It is only the presence of clear evidence of volume depletion (eg, hypotension, decreased skin turgor, elevated hematocrit, possibly increased BUN/serum creatinine ratio) despite a urine sodium concentration that is not low that suggests that CSW might be present rather than SIADH [6,8]. By comparison, extracellular fluid volume is normal or slightly increased with SIADH. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)
Theoretically, evaluation of the response to isotonic saline would help distinguish between CSW and SIADH. (See "Diagnostic evaluation of adults with hyponatremia".)
●Restoration of euvolemia in CSW should remove the stimulus to ADH release, resulting in a dilute urine and correction of the hyponatremia . As mentioned above, this has not been documented in CSW. Lack of urinary dilution does not necessarily preclude CSW since it might be expected that patients with subarachnoid hemorrhage would also have SIADH.
●By contrast, isotonic saline often worsens the hyponatremia in SIADH as the salt is excreted and some of the water is retained. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Intravenous hypertonic saline'.)
However, we discourage treatment of hyponatremia with isotonic saline in patients with cerebral disease because of the dangers of a further fall in serum sodium concentration.
Calculation of the fractional excretion of uric acid (FEUA) before and after correction of hyponatremia has been proposed as an alternative way of distinguishing SIADH from cerebral salt wasting . According to this theory, before correction of hyponatremia, FEUA is >11 percent in both SIADH and salt wasting. Conversely, after correction of hyponatremia, a FEUA that remains >11 percent is said to indicate salt wasting, caused by impaired proximal tubule sodium reabsorption, whereas a FEUA <11 percent identifies patients with SIADH. However, serial measurements of FEUA have not been validated with a consistent, rigorous, and convincing gold standard for identifying salt wasting [42-44] . For this reason, the diagnostic validity of these measurements is unproven.
Although unlikely, it is also possible that some patients have preexisting hyponatremia due to some other disorder that is associated with a urine sodium that is not low (eg, thiazide diuretics and hypoaldosteronism). (See "Causes of hypotonic hyponatremia in adults".)
Hyponatremia and hyperkalemia are the two major manifestations of adrenal insufficiency. The hyponatremia is mediated by increased release of ADH, which can be due to any cause of cortisol deficiency or hypoaldosteronism, while hyperkalemia only occurs with primary adrenal disease. The diagnosis of adrenal insufficiency is discussed separately. (See "Hyponatremia and hyperkalemia in adrenal insufficiency" and "Determining the etiology of adrenal insufficiency in adults".)
TREATMENT — Fluid restriction, the usual first-line therapy for the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), is not advised in hyponatremic patients with subarachnoid hemorrhage. In such patients, fluid restriction may increase the risk of cerebral infarction among patients who actually have CSW because ongoing salt losses may worsen the volume depletion and lower the blood pressure. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)
Instead, we treat with 3 percent (hypertonic) saline to raise the serum sodium (algorithm 1). All patients with active intracranial pathology (eg, recent intracranial surgery or subarachnoid hemorrhage) should have a prompt increase in the serum sodium concentration and should avoid a decrease in extracellular fluid volume. (See "Overview of the treatment of hyponatremia in adults".)
Some authorities suggest that isotonic saline be used as initial therapy in patients with CSW since, theoretically, it will suppress the release of ADH, thereby permitting excretion of the excess water and correction of the hyponatremia. However, if CSW is the sole cause of the hyponatremia, volume repletion would reduce the urine osmolality to below 100 mosmol/kg. However, dilution of the urine in response to isotonic saline is rare in patients with hyponatremia caused by subarachnoid hemorrhage or other intracranial disorders. (See "Overview of the treatment of hyponatremia in adults", section on 'Isotonic saline in true volume depletion'.)
Lack of urinary dilution does not necessarily preclude CSW since it might be expected that patients with subarachnoid hemorrhage would also have SIADH. Volume repletion would have little effect on urine osmolality in SIADH since ADH secretion in this disorder is not mediated by hypovolemia [8,9,45]. Hypertonic saline will increase the serum sodium concentration in patients with both CSW and SIADH.
For patients with documented CSW, salt tablets can be administered once the patients are able to take oral medications. Salt tablets may also be effective in patients with SIADH. Administration of a mineralocorticoid, such as fludrocortisone, can also be used [29,46-48].
Long-term therapy of CSW is not necessary since CSW tends to be transient . Resolution usually occurs within three to four weeks.
THERAPY OF SIADH ASSOCIATED WITH SAH — The optimal therapy for hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in patients with subarachnoid hemorrhage (SAH) is not clear since the standard initial therapy, fluid restriction, may increase the risk of cerebral infarction . We generally prefer the administration of 3 percent (ie, hypertonic) saline in such patients. (See "Overview of the treatment of hyponatremia in adults".)
Although isotonic saline can also be given, particularly if the serum sodium is normal, careful monitoring is required since isotonic saline can lower the serum sodium in patients with SIADH. The administered sodium will be excreted (there is no defect in sodium handling in SIADH), but some of the water will be retained if the urine osmolality is substantially higher than 300 mosmol/kg (the osmolality of isotonic saline). Such patients should be treated with hypertonic saline. How this occurs is discussed elsewhere:
In patients with subarachnoid hemorrhage, a separate issue is the possible administration of a mineralocorticoid, such as fludrocortisone, to prevent volume depletion and delayed cerebral ischemia [29,50,51]. The potential efficacy of this approach was examined in a trial of 91 patients with newly diagnosed subarachnoid hemorrhage who were randomly assigned to fludrocortisone (0.2 mg twice daily) or control therapy for a maximum of 12 days . Plasma volume was measured by the isotope dilution technique during the first day as well as days 6 and 12, and sodium balance was ascertained using estimates of intake and measurement of urinary sodium excretion. Significantly fewer patients in the treatment group developed negative sodium balance (38 versus 63 percent in the control group at 6 days, 29 versus 70 percent at 12 days). There was a suggestion that fludrocortisone might reduce cerebral ischemia (22 versus 31 percent).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia" and "Society guideline links: Fluid and electrolyte disorders in adults".)
SUMMARY AND RECOMMENDATIONS
●Cerebral salt wasting (CSW) is characterized by hyponatremia and extracellular fluid depletion due to inappropriate sodium wasting in the urine in the setting of acute disease in central nervous system (CNS), usually subarachnoid hemorrhage. CSW is a much less common cause of hyponatremia in patients with cerebral injury than the syndrome of inappropriate ADH secretion (SIADH). (See 'Introduction' above and 'Epidemiology and causes' above.)
●The pathophysiology of CSW is related to impaired sodium reabsorption, possibly due to the release of brain natriuretic peptide and/or diminished central sympathetic activity. Regardless of the mechanism, sodium wasting can lead sequentially to volume depletion, increased ADH release, hyponatremia due to the associated water retention, and possibly increased neurologic injury. (See 'Pathophysiology' above.)
●Some authorities contend that CSW does not exist and that the laboratory findings are due to SIADH. However, we feel that CSW is a distinct entity. (See 'Is cerebral salt wasting real?' above.)
●Specific laboratory findings include hyponatremia with a low plasma osmolality, an inappropriately elevated urine osmolality (above 100 mosmol/kg and usually above 300 mosmol/kg), a urine sodium concentration above 40 mEq/L, and a low serum uric acid concentration due to urate wasting in the urine. Since CSW is associated with extracellular fluid depletion, hypotension and decreased skin turgor may also be observed. (See 'Clinical features' above.)
●CSW mimics all of the laboratory findings in the SIADH. The only clue to the presence of CSW rather than SIADH is clinical evidence of extracellular volume depletion, such as hypotension and decreased skin turgor, and/or increased hematocrit, in a patient with a urine sodium concentration above 40 mEq/L. Unlike SIADH, volume repletion in CSW leads to a dilute urine, due to removal of the hypovolemic stimulus to ADH release, and subsequent correction of the hyponatremia. This finding has not been convincingly demonstrated, which could reflect concurrent SIADH due to the CNS disease. (See 'Differential diagnosis' above.)
●Regardless of whether hyponatremia is caused by CSW or SIADH, hyponatremic patients who have active intracranial pathology (eg, recent intracranial surgery or subarachnoid hemorrhage) should be treated with 3 percent (hypertonic) saline to ensure a prompt increase in the serum sodium concentration and to avoid a decrease in extracellular fluid volume. (See 'Treatment' above.)
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