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1. Cerebral salt wasting
Official reprint from UpToDate www.uptodate.com
©2023 UpToDate
Cerebral salt wasting
Author: Biff F Palmer, MD
Section Editor: Richard H Sterns, MD
Deputy Editor: John P Forman, MD, MSc
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2023. | This topic last updated: Jun 28, 2022.
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 [5]. 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:
®
®
(See "Causes of hypotonic hyponatremia in adults".)
●
(See "Diagnostic evaluation of adults with hyponatremia".)
●
(See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic
hormone secretion (SIADH)".)
●
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2. Cerebral salt wasting
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]:
One report suggested that BNP might be the more probable candidate [11]. 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
(See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone
secretion (SIADH) and reset osmostat".)
●
(See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".)
●
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".)
●
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3. Cerebral salt wasting
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
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4. Cerebral salt wasting
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) [2]. 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 [21].
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 [30]. 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 [31]. While these reports are of
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5. Cerebral salt wasting
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) [22].
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
●
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6. Cerebral salt wasting
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) [5].
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
A low serum uric acid concentration due to urate wasting in the urine
●
(See "Causes of hypotonic hyponatremia in adults".)
●
(See "Diagnostic evaluation of adults with hyponatremia".)
●
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7. Cerebral salt wasting
(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 [39].
In addition to hyponatremia, CSW and SIADH share the following features:
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".)
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 [40].
●
Restoration of euvolemia in CSW should remove the stimulus to ADH release, resulting
in a dilute urine and correction of the hyponatremia [41]. 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
●
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8. Cerebral salt wasting
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 [41]. 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
of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on
'Intravenous hypertonic saline'.)
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9. Cerebral salt wasting
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 [9]. Resolution
usually occurs within three to four weeks.
THERAPY OF SIADH ASSOCIATED WITH SAH
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10. Cerebral salt wasting
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
[49]. 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 [50]. 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
(See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone
secretion (SIADH) and reset osmostat", section on 'Intravenous hypertonic saline'.)
●
(See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone
secretion (SIADH) and reset osmostat", section on 'Subarachnoid hemorrhage'.)
●
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11. Cerebral salt wasting
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
●
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12. Cerebral salt wasting
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