ENDOCRINE AND METABOLIC DYSFUNCTION

SYNDROMES IN THE CRITICALLY ILL 0749-0704/01 $15.00 + .OO

CEREBRAL SALT WASTING

SYNDROME
Mark R. Harrigan, MD

Hyponatremia is a common complication of intracranial disease and

is associated with a number of disorders, including head injury, tumors,
intracranial infections, and stroke. Hyponatremia occurs in as many as
30% of patients with subarachnoid hemorrhage (SAH)lSand is associated
with extracellular volume depletion and cerebral ischemia.63Neurologic
dysfunction, which is thought to result from cerebral edema, is the
principal manifestation of hyponatremia and can exacerbate underlying
intracranial disorders. Severe hyponatremia, or a rapidly falling serum
sodium level, can lead to confusion, lethargy, seizures, and coma. When
severe hyponatremia is overcorrected or corrected too rapidly, pontine
myelinolysis and death can result. Therefore, early diagnosis and effec-
tive treatment of hyponatremia are critical for hyponatremic patients
with intracranial disease.
'

The term cerebral salt wasting (CSW) was introduced by Peters and
colleagues in 1950.45They hypothesized that cerebral disorders can cause
the kidneys to be unable to conserve salt, leading to salt depletion and
concomitant extracellular fluid loss. Although this phenomenon was
supported by other reports,7." it was eclipsed by identification of the
syndrome of inappropriate antidiuretic hormone secretion (SIADH) in
1957. In SIADH, physiologically inappropriate secretion of antidiuretic
hormone (ADH) or increased renal sensitivity to ADH leads to renal
conservation of water and dilutional hyponatremia. This syndrome has
been well documented in association with a number of neurologic disor-
ders. The primary treatment for SIADH is water restriction. Evidence
has accumulated to indicate that many patients with intracranial disease

From the Department of Surgery, Section of Neurosurgery, University of Michigan, Ann

Arbor, Michigan

CRITICAL CARE CLINICS

VOLUME 17 * NUMBER 1 *JANUARY 2001 125
126 HARRIGAN

actually experience CSW as it was originally described. This occurrence

has important clinical implications, because the appropriate treatment of
hyponatremia caused by CSW, salt and water supplementation, is the
opposite of the accepted treatment for SIADH. The objectives of this
article are to examine the evidence in favor of the CSW syndrome,
explore the possible mechanisms behind CSW, and discuss the diagnosis
and management of the patient with CSW.

DEFINITION OF CEREBRAL SALT WASTING

Cerebral salt wasting is defined as the renal loss of sodium during

intracranial disease leading to hyponatremia and a decrease in extracel-
lular fluid volume.

EVIDENCE IN FAVOR OF CEREBRAL SALT WASTING

In the original report of CSW in 1950, Peters and coworkersfi de-

scribed three patients with intracranial disease (encephalitis,intracranial
hemorrhage, and bulbar poliomyelitis). Each patient had hyponatremia
(serum sodium <120 mEq/L) and an inability to prevent loss of sodium
in the urine. The patients demonstrated salt depletion and responded
well to salt replacement. The authors speculated that renal salt wasting
may occur in brain disease when adrenocorticotropichormone secretion
is disrupted, leading to a decrease in adrenal mineralocorticoid secretion,
or may occur by way of an alteration of direct neuronal control over the
kidneys. Two years later, Welt and reported that the pitu-
itary-adrenal axis was intact in two patients with intracranial disease,
hyponatremia, and renal salt wasting. Copt7 also found no evidence of
pituitary or adrenal deficiency in a case report of a patient with a
thalamic tumor, dehydration, severe hyponatremia, and renal salt wast-
ing. These authors hypothesized that CSW was caused by a defect in
the direct neural regulation of renal tubular activity.
After the identification of SIADH in 1957,47hyponatremia in patients
with central nervous system disease was almost exclusively ascribed to
SIADH. The concept of hyponatremia caused by renal salt wasting fell
from favor, and many authors even equated the term CSW with SIADH.6,
67 The finding that 14% of patients with SIADH have no detectable
abnormalities in ADH secretion” suggested that a mechanism other than
excessive levels of ADH can lead to a clinical picture somewhat similar
to SIADH. Subsequently, some patients who met the traditional labora-
tory criteria for SIADH were noted to be volume depleted rather than
euvolemic or hypervolemic. In 1981, Nelson and colleagues42reported a
study of 12 patients with intracranial disease (SAH, head injury, or
craniotomy for unruptured aneurysm) who met the traditional labora-
tory criteria for SIADH. Blood volume analyses demonstrated significant
decreases in red blood cell mass, plasma volume, and total blood volume
 CEREBRAL SALT WASTING SYNDROME 127

in 10 of the 12 patients. These findings were consistent with the original

concept of CSW, whereby an inability of the kidneys to conserve sodium
leads to progressive salt wasting and volume depletion. The authors
theorized that volume depletion stimulates ADH release, leading to
water retention and, along with concomitant salt loss, hyponatremia.
Additional evidence in favor of CSW was gathered in a monkey
model of SAH.43Seven of nine monkeys became natriuretic and hypona-
tremic after experimental SAH. The natriuretic period lasted an average
of 4.4days, and the average lowest serum sodium level was 125.7 mEq/L.
Although the sodium balance was negative after SAH, the plasma vol-
ume was not significantly decreased. Plasma ADH levels were usually
elevated for a day after surgery but were comparable to preoperative
values during the period of natriuresis. In this model, hyponatremia
seemed more likely to result from natriuresis and a negative salt balance
than an excess of ADH.
Further support for CSW came in a study of sodium balance and
volume status in 21 patients after aneurysmal SAH." Plasma volume
decreased by more than 10% in 11 of the 21 patients. Ten of the 11
patients with decreased volumes had negative sodium balances: six also
had hyponatremia. Decreased plasma volume was accompanied by an
increase in blood urea nitrogen and a decrease in body weight. This
demonstration of hyponatremia, natriuresis, and volume depletion was
incompatible with true SIADH.
In a study of 256 patients with severe brain injury, six patients met
the criteria for SIADH: three in the first 3 days after injury and three
after more than a week.59Plasma ADH levels were measured and found
to be elevated only in the group with early hyponatremia. In the patients
with late hyponatremia, plasma ADH levels were appropriate for serum
osmolality. Moreover, two of the patients with late hyponatremia did
not respond to fluid restriction. The authors theorized that elevated
levels of ADH can occur after brain injury because of a number of
factors that promote ADH release, such as hypovolemia caused by
fluid or blood loss, stress, pain, medications and increased intracranial
pressure. This hypersecretion of ADH, although not physiologically
inappropriate, may lead to hyponatremia. Hyponatremia in the second
week after brain injury, however, is more likely to be caused by CSW
than SIADH.
More evidence in favor of CSW was provided by a series of 21
neurosurgical patients with hyponatremia who met the criteria for
SIADH.49The patients had a variety of intracranial disorders. Volume
status was assessed by measuring central venous pressure (CVP) and
total blood volume; hematocrit was observed. All 21 patients were
hypovolemic, with or without anemia. Hyponatremia was corrected in
all patients after administration of isotonic saline and oral salt (and
whole blood if anemic). The presence of volume depletion and the
response to volume supplementation rather than restriction are more
compatible with CSW than SIADH.
A succession of case reports has provided additional evidence for
128 HARRIGAN

the existence of CSW and a demonstration of the variety of intracranial

disorders that are associated with CSW. CSW, as diagnosed by hypona-
tremia, volume depletion, and clinical response to volume and salt
replacement, has been described in patients with tuberculous meningi-
tis,4I, 46, 56 metastatic adenocarcinoma of the lung and carcinomatous
meningitis,44pituitary exploration and biopsy,' pilocytic astrocytoma
involving the third ventricle and pituitary region,6O parietal glioma13and
transsphenoidal surgery for pituitary aden0rna,6~in elderly patients after
head and in two pediatric patients with central nervous system
disease (closed head trauma in one and seizure disorder, spastic diplegia,
mental retardation, and hydrocephalus in the other).19
To investigate the possibility that fluid restriction may actually
harm patients with hyponatremia, Wijdicks and performed
a retrospective study of 134 patients after aneurysmal SAH. Forty-four
patients were hyponatremic, and 25 of these met the criteria for SIADH.
Twenty-six patients were treated with fluid restriction, and cerebral
infarctions developed in 21 (81%). The rate of cerebral infarction was
significantly higher among the patients with hyponatremia versus the
patients with normal serum sodium levels. These findings provided
indirect evidence that hyponatremia in patients with SAH is more likely
to be the result of CSW, in which case fluid restriction exacerbates
underlying volume depletion, leading to an increased risk of cerebral
infarction.
In summary, the evidence in favor of CSW converges on the three
following points: (1) a negative salt balance precedes or accompanies
the development of hyponatremia in many patients with intracranial
disease; (2) these patients are volume contracted, a state that is incompat-
ible with SIADH; and (3) these patients respond to salt and volume
replacement rather than fluid restriction. The available studies indicate
that CSW occurs as frequently ass9 or more frequently34,42, 49, than@

SIADH in neurosurgical patients.

POSSIBLE MECHANISMS

The mechanism by which intracranial disease leads to renal salt

wasting is not understood. The brain can influence renal sodium reab-
sorption by both humoral and neural mechanisms, and a derangement
of either system, or both, may lead to CSW.

Natriuretic Factors

Infusion of hypertonic saline into the cerebral ventricles of the rat

causes a natriuresis that persists after renal denervation? 58 suggesting
the existence of a blood-borne natriuretic factor capable of mediating
CSW. Smithsofirst proposed the existence of a blood-borne natriuretic
hormone; several natriuretic peptides have been identified since, the best
 CEREBRAL SALT WASTING SYNDROME 129

known of which is atrial natriuretic peptide (ANP). ANP, a 28-amino

acid polypeptide, was first identified in rat atrial muscle when infusions
of extracts of atrial muscle were found to cause more than a 30-fold
increase in urinary sodium and chloride excretion and a 10-fold increase
in urinary volume.10 The biologic effects of ANP include natriuresis
and diuresis, vasodilation, and suppression of renin and aldosterone
secretion.16ANP is released from the heart in response to atrial stretch,
circulates in the plasma with a half-life of about 3 minutes, and is cleared
by receptor and enzymatic mechanisms. ANP-containing neurons have
been identified in the rat hypothalamus and lamina terminalis30,53; how-
ever, the concentration of ANP in the brain is 10,000 times less than in
the making it unlikely that brain secretion of ANP is responsible
for CSW. Although atrial stretch is thought to be the principal mecha-
nism for cardiac ANP release, there is evidence that the central nervous
system modulates cardiac ANP secretion. Adrenergic and cholinergic
agents cause ANP release, and lesions of specific areas in the hypothala-
mus, intracerebroventricular injections of ANP immune serum, and deaf-
ferentation of baroreceptor input to the hypothalamus all reduce cardiac
secretion of ANP in response to acute volume expansion. Thus, intra-
cranial disease may lead to a disturbance of the brain's control over
ANP secretion and, under certain conditions, excessive ANP secretion.
Measurement of ANP levels during intracranial disease implies a
role for ANP in hyponatremia, although the picture is complex. Serum
ANP levels were elevated above the normal range in six of eight neuro-
surgical patients with a variety of neurologic disorders, and a near-
linear relationship was observed between serum ANP levels and urine
sodium.61In a study of plasma ANP levels in 25 patients with intracran-
ial aneurysms, ANP levels were significantly elevated in 21 patients
with SAH, compared with 4 patients with unruptured aneurysms, and
returned to normal over 2 weeks.14 There was no correlation between
ANP levels and serum sodium levels, and the ANP levels in two patients
with SAH who had hyponatremia were not significantly different from
those in the other patients with SAH. Thus, elevated levels of ANP
alone do not account for hyponatremia observed after SAH.
In a report of a patient with hyponatremia after SAH, both plasma
ADH and ANP levels were elevated above the normal range for 5 days
after hemorrhage, but only ANP remained elevated at 13 and 28 days,
associated with a prolonged period of h y p ~ n a t r e m i a .These
~ ~ results
suggest that SIADH may immediately occur after an acute intracranial
insult, but prolonged hyponatremia is associated with persistent eleva-
tion of plasma ANP. This conclusion was supported by a study of 11
patients with hyponatremic SAH.26Both ADH and ANP concentrations
were significantly elevated on days 0 to 2 after onset of SAH. ANP
levels remained high in patients with hyponatremia on days 6 to 14
after SAH, whereas ADH levels became significantly lower during the
second week.
Several observations oppose the idea that ANP is the primary
natriuretic factor hypothesized to exist in CSW. Plasma ANP levels
130 HARRIGAN

actually were found to decrease during experimental natriuresis induced

by intracerebroventricular administration of hypertonic saline." In the
same model, the dopamine antagonist haloperidol, which attenuates
the natriuretic effect of exogenous ANP, failed to impair brain-induced
natriuresis.21,23 Two clinical series have failed to find an increase in
plasma ANP levels after SAH, although one study did not consider
serum sodium statusI5 and the other included only one patient with
hyp~natremia.~~ Normal levels of ANP have been found in patients with
CSW associated with parietal glioma13 and intracerebral hemorrhage61
and after surgery for pituitary aden0ma.6~In a case of SIADH associated
with carcinoma of the lung, plasma ANP levels were elevated above the
normal range, suggesting that high plasma levels of ANP may actually
be a feature of SIADH rather than CSW.5
A regression analysis of 15 patients with CSW secondary to tubercu-
lous meningitis found that alterations in plasma ANP levels accounted
for only 65% of the variation in plasma sodium levels, implying that
other factors are involved in CSW.4I Two other natriuretic factors may
have a role. Brain natriuretic peptide (BNP), originally found in porcine
brain, is largely of cardiac ventricular origin and shares considerable
sequence identity with ANP. It is secreted by the cardiac ventricles in
response to increased pressure or stretch of the ventricles and has bio-
logic effects similar to those of ANP. Plasma BNP levels are elevated in
patients with SAH and are associated with hyponatremia.4,26, 57 Elevated
plasma BNP levels also are associated with cerebral vasospasm.HCircu-
lating BNP may be involved in CSW in several ways. Sympathetic
stimulation during acute intracranial disease may cause release of car-
diac BNP, which may suppress aldosterone secretion and act directly on
renal f~nction.~,57 Brain natriuretic peptide ,also has been localized to the
hypothalam~s~~ and may be released when this part of the brain is
damaged.4Another protein, termed plasma natriuretic factor, was identi-
fied when rats treated with intraperitoneal infusion of plasma from
neurosurgical patients developed natri~resis.~~ This factor awaits further
characterization.
In summary, circulating natriuretic factors probably are involved in
CSW. However, the presence of multiple natriuretic factors, possibly in
combination with other factors or direct neural effects on the kidneys,
are likely to be necessary for the development of CSW.

Ouabain-like Compound

The natriuretic response of the rat brain to intracerebroventricular

infusion of hypertonic saline is blocked by the infusion of digoxin-
specific antibodies into the cerebral ventricles.68This finding suggests
that an ouabain-like compound (OLC) in the brain is involved in CSW.
OLC immunoreactivity has been found in the hypothalamus and me-
dulla of rat.72Plasma OLC immunoreactivity was identified in 18 of 25
patients with aneurysmal SAH.65The presence of OLC correlated with
 CEREBRAL SALT WASTING SYNDROME 131

the amount of subarachnoid bleeding, and the data implied that a

negative sodium balance and volume depletion occurred more often in
patients who were positive for OLC, a trend that did not reach statistical
significance. Thus, OLC appears to be released into the plasma in re-
sponse to SAH, possibly as a result of hypothalamic damage. However,
the potential for crossreactivity of antiglycoside antibodies with nongly-
coside substances makes these results less certain.27In addition, ouabain,
an inhibitor of Na /K+-adenosinetriphosphatase, does not cause sig-
+

nificant diuresis, except in toxic d0ses.l' In the model of CSW induced

by intraventricular administration of hypertonic saline, intravenous ad-
ministration of large doses of digoxin-specific antibodies do not block
central nervous system-induced natriuresis.68Taken together, these re-
sults suggest that brain OLC has a role in CSW but that it is unlikely
that circulating OLC alone is the blood-borne natriuretic factor that is
hypothesized to mediate CSW.

Direct Neural Effects

Generalized hyperactivity of the sympathetic nervous system occurs

after SAH,52and sustained sympathetic stimulation leads to a decrease
in plasma volume and total blood volume.37This occurrence may ac-
count for some of the volume loss seen in SAH and other acute intracran-
ial disorders; however, decreases in renal sympathetic nerve activity lead
to natriuresis and diuresis because of an increase in renal blood flow
and glomerular filtration, a decrease in renin release, and a decrease in
renal tubular sodium reabsorption.12,31 It is possible that acute brain
injury ultimately leads to an interruption in sympathetic output to the
kidneys that is analogous to spinal shock, whereby an acute spinal
cord injury results in a transient inhibition of sympathetic activity. A
combination of circulating natriuretic factors and direct neural involve-
ment may be required for the development of CSW.14

Anatomic Correlations

A comparison of the anatomy of intracranial lesions with the occur-

rence of CSW might be useful in identifying parts of the central nervous
system involved in CSW. CSW has been documented in patients with
tumors in the right posterior thalamus7 and the right parietal 10be.l~
Specific brain lesions are associated with natriuresis. An experimentally
induced lesion in the medulla leads to natriuresis and polyuria.28Most
reports of CSW concern patients with aneurysmal SAH, especially in-
volving the anterior cerebral artery complex, which is frequently associ-
ated with damage to the hypothalamus.8 Several reports of CSW associ-
ated with tuberculous meningitis also implicate the hyp~thalamus.~~, 46, 56
Tuberculous meningitis is typically localized to the basal cisterns, with
associated endarteritis affecting the perforating vessels to the hypothala-
132 HARRIGAN

mus and basal ganglia, and potential ischemia or infarction of those

regions.41

DIFFERENTIAL DIAGNOSIS

Causes of hyponatremia to consider in patients with intracranial

disease include iatrogenic fluid overloading or diuresis, congestive heart
failure, renal or liver disease, hypothyroidism, and adrenal insufficiency.
Artifactual hyponatremia can be seen with hyperglycemia and hypertri-
glyceridemia. A less well-established cause of hyponatremia is sodium-
potassium shift, in which sodium is shifted from the extra- to the
intracellular compartment.2, This phenomenon has not been investi-
gated in the setting of intracranial Because most patients with
CSW seem to meet the general criteria for SIADH, a thorough examina-
tion and laboratory evaluation are necessary to distinguish between the
two (Table 1). Attention to volume status is critical. A decrease in
extracellular fluid volume and a negative salt balance are the most
important features of CSW that set it apart from SIADH. Symptoms of
diminished fluid volume include anorexia, nausea, vomiting, apathy,
weakness, orthostatic light-headedness, and syncope. Physical findings
include orthostatic hypotension, poor skin turgor, sunken eyes, dry
mucous membranes, absence of axillary perspiration, and tachycardia.
Weight loss is a signal of volume loss. A water input:output ratio <1
shows a negative water balance. For patients with invasive hemody-
namic monitoring, a low pulmonary capillary wedge pressure (<8
mm Hg) or a low CVP (<6 mrn Hg) implies volume contraction. A
negative water clinical dehydrati~n?~weight loss? 25, 69 or-

Table 1. DIFFERENTIAL DIAGNOSIS OF CEREBRAL SALT WASTING VERSUS THE

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION*
csw SIADH
Plasma volume .1 T
Salt balance Negative Variable
Water balance Negative t or no change
Signs and symptoms of dehydration Present Absent
Weight 1 t or no change
Pulmonary capillary wedge pressure 1 t or normal
Central venous pressure 1 t or normal
Hematocrit t 1 ornochange
Osmolality t or normal 1
Blood urea nitrogen: creatinine ratio t Normal
Serum protein concentration t Normal
Urine sodium concentration tt T
Serum potassium concentration t or no change 1 or no change
Serum uric acid concentration Normal 1
‘CSW, cerebral salt wasting; SIADH, syndrome of inappropriate antidiuretic hormone secretion; l ,
decrease; t ,increase; t t ,significant increase. (From Harrigan MR Cerebral salt wasting syndrome: A
review. Neurosurgery 38152-160,1996; with permission)
 CEREBRAL SALT WASTING SYNDROME 133

thostatic hypotension,' and a CVP <6 mm Hg44, 49 are documented

features of CSW.
Several laboratory tests are useful in evaluating volume status and
salt balance. Elevations in the hematocrit, the blood urea nitrogen:creati-
nine ratio, and the serum protein concentration suggest dehydration and
argue against the presence of SIADH. Urine sodium concentration
should be markedly elevated in CSW, whereas it is variable in SIADH.
An elevated serum potassium level during hyponatremia is incompatible
with SIADH and suggests CSW.= Serum uric acid is decreased in SIADH
but is usually normal in CSW.44Derived parameters of sodium and
water homeostasis, obtained from timed urinary collections and match-
ing plasma samples, can help distinguish CSW from SIADH.% Creati-
nine, osmotic and free-water clearances, reabsorbed tubular water, and
fractional water and sodium excretions, considered in the context of
spot plasma and urinary electrolyte measurements, provide additional
evidence for diagnosis when the clinical picture is unclear.
Studies of volume status, using isotope-dilution techniques, can be
performed at the bedside. Diminished plasma volume (<35 mL/kg) is
a central feature of CSW. Hyponatremic patients with intracranial dis-
ease were found to have an average plasma volume of 30.3 mL per
kilogram, which is 26% less than that for normonatremic control pa-
tients." A decrease in total blood volume (<60 mL/ kg) is also associated
with CSW.49
Serum ADH and ANP levels are not helpful in distinguishing be-
tween CSW and SIADH. Although elevated ADH levels can be diagnos-
tic of SIADH and ADH is usually depressed in CSW, ADH levels can
be misleading. Stress, pain, and increased intracranial pressure, common
features of acute intracranial disease, can promote secretion of ADH.
SIADH and CSW have been reported to occur successively in the same
patient, particularly after SAH.59Cerebral salt wasting may occur after
SIADH; the reverse situation may also occur: ADH secretion may appro-
priately increase, despite the presence of hyponatremia, in response to
volume dep1eti0n.l~. ANP levels have been observed to be elevated14,
19,61,71 or normal13,6L 69 in CSW.

MANAGEMENT

The management of CSW begins with treatment of the underlying

neurologic process. In particular, CSW related to acute hydrocephalus
or elevated intracranial pressure may respond promptly to cerebrospinal
fluid drainage."
The cornerstones of the treatment of CSW are volume replacement
and maintenance of a positive salt balance. Water and salt supplementation
is the most common method. Intravenous hydration with normal saline
(0.9% sodium chloride [NaCl]),1.13, 19r4, 49 hypertonic saline (3% NaC1),'3, 19,
or oral salt1,13,19, 49, 69 may be used alone or in combination, depending on
the severity of hyponatremia and the ability of the patient to tolerate enteral
administration. Enteral administration of salt may be preferable, because
134 HARRIGAN

intravenous administration of hypertonic saline may cause volume

expansion and successive loss in the urine.24Blood products are useful
for volume expansion if anemia is also present.49Colloids are effective
as volume expanders by absorbing interstitial and third-space fluid.17
The goal of water replacement is to match urine losses; the amount of
sodium required may be estimated by multiplying the deficit in serum
-
sodium concentration by total body water (50% 60% of body
Rapid correction of hyponatremia has been associated with pontine
myelinolysis, but the optimal rate of correction is unclear. A cautious
approach is to raise serum sodium no faster than 0.7 mEq per liter per
hour, for a maximum total daily change not to exceed 20 mEq per liter.
Overcorrection should be avoided.
A decrease in plasma volume of >lo% occurs in some 50% of
patients with aneurysmal SAH.64An added benefit of volume expansion
for these patients is an improvement in cerebral perfusion and a reduc-
tion in risk of cerebral ischemia and infar~tion.~~,51, 52, 63
In CSW, sodium administration corrects both volume contraction
and hyponatremia, whereas in SIADH, it tends to be of only temporary
and limited benefit. This response to saline infusion can help distinguish
SIADH from sodium depletion.MAn increase in salt intake during CSW
may only further enhance sodium excretion.66Prevention of volume
depletion by reducing renal sodium excretion is an alternative to volume
replacement. The mineralocorticoid fludrocortisone acetate directly acts
on the renal tubule to enhance sodium reabsorption. Adverse effects of
fludrocortisone can include hypokalemia, pulmonary edema and hyper-
tension. Prompt resolution of hyponatremia was reported after adminis-
tration of fludrocortisone in three elderly patients with CSW after head
A randomized, controlled trial in patients with aneurysmal SAH
found that 0.1 mg of fludrocortisone, given orally three times a day for
8 days, significantly reduced water and sodium excretion and the fre-
quency of hyp~natremia.~~ Hyponatremia occurred in 6.6% of patients
receiving fludrocortisone, compared with 33.3%of control patients. Tran-
sient hypokalemia, but not pulmonary edema, was observed in patients
treated with fludrocortisone. All patients received therapeutic hyperten-
sion to maximize cerebral perfusion; fludrocortisone tended to reduce
the need for dobutamine.
Serum sodium levels and volume status should be monitored
closely during treatment of CSW. Fluid intake and output data and daily
weights are easy to obtain and provide important information about
volume status. Central venous pressure closely correlates with changes
in total blood volume in patients with normal cardiac and pulmonary
function and also can help guide management of hyponatremia in pa-
tients meeting these ~riteria.4~

SUMMARY
There is significant evidence to show that many patients with hypo-
natremia and intracranial disease who were previously diagnosed with
 CEREBRAL SALT WASTING SYNDROME 135

SIADH actually have CSW. The critical difference between SIADH and
CSW is that CSW involves renal salt loss leading to hyponatremia and
volume loss, whereas SIADH is a euvolemic or hypervolemic condition.
Attention to volume status in patients with hyponatremia is essential.
The primary treatment for CSW is water and salt replacement. The
mechanisms underlying CSW are not understood but may involve ANP
or other natriuretic factors and direct neural influence on renal function.
Future investigation is needed to better define the incidence of CSW in
patients with intracranial disease, identify other disorders that can lead
to CSW, and elucidate the mechanisms underlying this syndrome.

References

1. Andrews BT, Fitzgerald PA, Tyrell JB, et a 1 Cerebral salt wasting after pituitary
exploration and biopsy: Case report. Neurosurgery 18:469-471, 1986
2. Astrup J, Prytz H, Thomsen AC, et al: Red cell sodium and potassium contents in
liver cirrhosis. Gastroenterology 78530-534,1980
3. Beasley D, Malvin RL, Mouw DR CNS-induced natriuresis and renal hemodynamics
in conscious rats. Am J Physiol 245:F763-F771, 1983
4. Berendes E, Walter M, Cullen P, et al: Secretion of brain natriuretic peptide in patients
with aneurysmal subarachnoid haemorrhage. Lancet 349:245-249, 1997
5. Cogan E, Debieve MF, Philipart I, et a1 High plasma levels of atrial natriuretic factor
in SIADH. New Engl J Med 314:1258-1259,1986
6. Cooper WC, Green IJ, Wang S Cerebral salt-wasting associated with Gullain-Barre
syndrome. Arch Intern Med 116113-119, 1965
7. Cort JH: Cerebral salt wasting. Lancet 1:752-754, 1954
8. Crompton MR Hypothalamic lesions following the rupture of cerebral berry aneu-
rysms. Brain 86:301-314,1963
9. Czaczkes JW, Aviram A, Keynan A, et al: Red blood cell content of water, sodium and
, potassium in body fluid disturbances. Isr J Med Sci 3:137-142, 1967
10. DeBold AJ, Borenstein HB, Veress AT, et al: A rapid and potent natriuretic response to
intravenous injection of atrial myocardial extract in rats. Life Sci 28:89-94, 1981
11. DeWardener HE, Clarkson E M Concept of natriuretic hormone. Physiol Rev 65:658-
759,1985
12. DiBona G F Neural control of renal function in health and disease. Clin Auton Res
469-74, 1994
13. Diringer M, Ladenson PW, Bore1 C, et al: Sodium and water regulation in a patient
with cerebral salt wasting. Archi Neurol46:928-930, 1989
14. Diringer M, Ladenson PW, Stern BJ, et al: Plasma atrial natriuretic factor and subarach-
noid hemorrhage. Stroke 19:1119-1124, 1988
15. Doczi T, Joo F, Vecerneyes M, et al: Increased concentration of atrial natriuretic factor
in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage and
raised intracranial pressure. Neurosurgery 23:16-19, 1988
16. Espiner E A Physiology of natriuretic peptides. J Intern Med 235:527-541,1994
17. Fosset D Management of Aneurysmal Subarachnoid Hemorrhage. Essential Medical
Information Systems, Durant, pp 136-143, 1993
18. Fox JL, Falik JL, Shalhoub RJ: Neurosurgical hyponatremia: The role of inappropriate
antidiuresis. J Neurosurg 34:50&514, 1971
19. Ganong CA, Kappy M S Cerebral salt wasting in children: The need for recognition
and treatment [published erratum appears in Am J Dis Child 147369, 19931. Am J Dis
Child 147167-169, 1993
20. Goldberg M, Handler J S Hyponatremia and renal wasting of sodium in patients with
malfunction of the central nervous system. New Engl J Med 263:1037-1043, 1960
21. Hansel1 P, Anden NE, Grabowska-Anden M, et al: Atrial natriuretic factor, urinary
136 HARRIGAN

catechol compounds and electrolyte excretion in rats during normal hydration and
isotonic volume expansion: Influence of dopamine receptor blockade. Acta Physiol
Scand 134421428, 1988
22. Hansell P, Goransson A, Leppaluoto J, et al: CNS-induced natriuresis is not mediated
by the atrial natriuretic factor. Acta Physiol Scand 129:221-227, 1987
23. Hansell P, Sjoquist M, Fasching A, et al: CNS-induced natriuresis during dopamine
receptor blockade: Further support for the existence of at least two separate natriuretic
hormonal systems. Acta Physiol Scand 133:373-380, 1988
24. Ishiguro S, Kimura A, Munemoto S, et al: Hyponatremia due to excess natriuresis. No
Shinkei Geka 16:707-711, 1988
25. Ishikawa S, Saito T, Kaneko K, et al: Hyponatremia responsive to fludrocortisone
acetate in elderly patients after head injury. Ann Intern Med 106:187-191, 1987
26. Isotani E, Suzuki R, Tomita K, et a 1 Alterations in plasma concentrations of natriuretic
peptides and antidiuretic hormone after subarachnoid hemorrhage. Stroke 25:2198-
2203, 1994
27. Jackowski A: Disordered sodium and water in neurosurgery. Br J Neurosurg 6:173-
176, 1992
28. Jungmann P, Meyer E: Experimentelle Untersuchungen uber die Abhangigkeit der
Nierenfunktion vom Nervensystem. Arch Exp Pathol Pharmakol7349-70,1913
29. Juul R, Edvinsson L, Ekman R, et a1 Atrial natriuretic peptide-LI following subarach-
noid hemorrhage. Acta Neurochir (Wien) 10618-23, 1990
30. Kawata M, Ueda S, Nakao K, et al: Immunohistochemical demonstration of alpha-atrial
natriuretic polypeptide-containing neurons in the rat brain. Histochemistry 83:l-3,1985
31. Kopp UC, DiBona G F The neural control of renal function. In Seldin D, Giebisch G,
(eds): The Kidney: Physiology and Pathophysiology, New York, Raven Press, 1992,
pp 1157-1204
32. Kroll M, Juhler M, Lindholm J: Hyponatraemia in acute brain disease. J Intern Med
232291-297,1992
33. Levinsky NG: Fluids and electrolytes. In Isselbacher K, Brawnwald E, Wilson J, et
al: (eds): Harrison’s Principles of Internal Medicine, New York, McGraw-Hill, 1994,
pp 242-253
34. Lolin Y, Jackowski A: Hyponatremia in neurosurgical patients: Diagnosis using derived
parameters of sodium and water hemostasis. Br T Neurosura 6:457-466,1992
35. Maesaka JK, Venkatesan J, Piccione JM, et al: Plasma natrGretic factor(s) in patients
with intracranial disease, renal salt wasting and hypouricosuria. Life Sci 52:1875-
1882, 1993
36. Maroon JC, Nelson PB: Hypovolemia in patients with subarachnoid hemorrhage:
Therapeutic implications. Neurosurgery 4223-226, 1979
37. Mason DT, Bartter FC: Autonomic regulation of blood volume. Anesthesiology 29:681-
692,1968
38. Minamino M, Makino Y, Tateyamo H, et al: Characterization of immunoreactive
human C-type natriuretic peptide in brain and heart. Biochem Biophys Res Commun
179~535-542,1991
39. Mori T, Katayama Y, Kawamata T, et al: Improved effect of hypervolemic therapy with
inhibition of natriuresis by fludrocortisone in patients with aneurysmal subarachnoid
hemorrhage. J Neurosurg 91:947-952, 1999
40. Mulleners WM, Verhagen WI, Bartels RH: Cerebral salt wasting syndrome [letter]. J
Neurol Neurosurg Psychiatr 603234-235,1996
41. Narotam PK, Kemp M, Buck R, et a1 Hyponatremic natriuretic syndrome in tubercu-
lous meningitis: The probable role of atrial natriuretic peptide. Neurosurgery 34982-
988, 1994
42. Nelson PB, Seif SM, Maroon JC, et al: Hyponatremia in intracranial disease: Perhaps
not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Neuro-
surg 55:938-941, 1981
43. Nelson PB, Seif S, Gutai J, et al: Hyponatremia and natriuresis following subarachnoid
hemorrhage in a monkey model. J Neurosurg 60:233-237,1984
44. Oster JR, Perez GO, Larios 0, et al: Cerebral salt wasting in a man with carcinomatous
meningitis. Archi Intern Med 143:2187-2188, 1983
 CEREBRAL SALT WASTING SYNDROME 137

45. Peters JP, Welt LG, Sims EAH, et al: A salt wasting syndrome associated with cerebral
disease. Trans Assoc Am Physicians 63:57-64, 1950
46. Sakarcan A, Bocchini J Jr: The role of fludrocortisone in a child with cerebral salt
wasting. Pediatr Nephrol 12769-771,1998
47. Schwartz WB, Bennet W, Curelop S, et al: A syndrome of renal sodium loss and
hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone.
Am J Med 23:529-542, 1957
48. Shimoda M, Yamada SH, Yamamoto I, et a1 Atrial natriuretic polypeptide in patients
with subarachnoid haemorrhage due to aneurysmal rupture. Acta Neurochir (Wien)
9753-61,1989
49. Sivakumar V, Rajshekhar V, Chandy MJ: Management of neurosurgical patients with
hyponatremia and natriuresis. Neurosurgery 34:269-274,1994
50. Smith Hw: Salt and water volume receptors: An exercise in physiologic apologetics.
Am J Med 23:623-652,1957
51. Solomon RA, Fink ME, Lennihan L Prophylactic volume expansion therapy for the
prevention of delayed cerebral ischemia after early aneurysm surgery: Results of a
preliminary trial. Arch Neurol45:325-332, 1988
52. Solomon RA, Post KD, McMurty J I Depression of circulating blood volume in patients
after subarachnoid hemorrhage: Implications for the management of symptomatic
vasospasm. Neurosurgery 15:354-361,1984
53. Standaert DG, Needleman P, Saper CB: Organization of atriopeptin-like immunoreac-
tive neurons in the central nervous system of the rat. J Comp Neurol253:315-341,1986
54. Sviri GE, Feinsod M, Soustiel J F Brain natriuretic peptide and cerebral vasospasm in
subarachnoid hemorrhage. Clinical and TCD correlations. Stroke 31:118-122,2000
55. Takahashi K, Totsune K, Sone M, et al: Human brain natriuretic peptide-like immunore-
activity in human brain. Peptides 13:121-123, 1992
56. Ti LK, Kang SC, Cheong KF: Acute hyponatraemia secondary to cerebral salt wasting
syndrome in a patient with tuberculous meningitis. Anaesthes Intensive Care 26420-
423, 1998
57. Tomida M, Muraki M, Uemura K, et al: Plasma concentrations of brain natriuretic
peptide in patients with subarachnoid hemorrhage. Stroke 2931584-1587,1998
58. Ulfendahl HR, Goransson A, Hansel1 P, et al: Natriuresis obtained by stimulation of
the cerebroventricular system with sodium ions indicates a blood-borne natriuretic
factor. Acta Physiol Scand 127269-271, 1986
59. Vingerhoets F, de Tribolet N: Hyponatremia hypo-osmolarity in neurosurgical patients.
”Appropriate secretion of A D H and ”cerebral salt wasting syndrome.” Acta Neu-
rochir (wien) 91:50-54,1988
60. Walter M, Berendes E, Claviez A, et a1 Inappropriate secretion of natriuretic peptides
in a patient with a cerebral tumor [letter]. JAh4A 282:27-28, 1999
61. Weinand ME, OBoynick PL, Goetz KL A study of serum antidiuretic hormone and
atrial natriuretic peptide levels in a series of patients with intracranial disease and
hyponatremia. Neurosurgery 25:781-785,1989
62. Welt LG, Selden DW, Nelson WI, et al: Role of the central nervous system in metabo-
lism of electrolytes and water. Arch Intern Med 90:355-378, 1952
63. Wijdicks EFM, Vermeulen M, Hijdra A, et a1 Hyponatremia and cerebral infarction in
patients with a ruptured intracranial aneurysms: Is fluid restriction harmful? Ann
Neurol 17137-140, 1985
64. Wijdicks EFM, Vermeulen M, ten Haaf J, et al: Volume depletion and natriuresis in
patients with a ruptured intracranial aneurysm. Ann Neurol 18:211-216,1985
65. Wijdicks EFM, Vermeulen M, van Brummelen P, et al: Digoxin-like immunoreactive
substance in patients with aneurysmal subarachnoid hemorrhage. Br Med J 294:729-
732, 1987
66. Wijdicks EFM, Vermeulen M, van Brummelen P, et al: The effect of fludrocortisone
acetate on plasma volume and natriuresis in patients with aneurysmal subarachnoid
hemorrhage. Clin Neurol Neurosurg 90209-214, 1988
67. Wise BL: Inappropriate secretion of ADH caused by obstruction of ventriculoatrial
shunts. J Neurosurg 28429433,1968
138 HARRIGAN

68. Yamada K, Goto A, Nagoshi H, et a l Role of brain ouabain-like compound in central

nervous system-mediated natriuresis in rats. Hypertension 23:1027-1031, 1994
69. Yamaki T, Tano-oka A, Takahashi A, et al: Cerebral salt wasting syndrome distinct
from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Acta
Neurochirur 115:156-162, 1992
70. Yamamoto N, Kuwayama A, Miyamoto N, et a1 Elevation of plasma atrial natriuretic
peptide in a neurosurgical patient with the syndrome of inappropriate secretion of
antidiuretic hormone: Case report. Neurol Med Chir (Tokyo) 29:255-258, 1989
71. Yamamoto N, Miyamoto N, Seo H, et al: Hyponatremia with high plasm ANP level:
Report of two cases with emphasis on the pathophysiology of cerebral salt wasting [in
Japanese]. No Shinkei Geka 15:1019-1023, 1987
72. Yamamato M, Zukeran C, Teruya H, et a1 Ouabain-like immunoreactivity in the
medulla oblongata of rats. Arch Histol Cytol 61:317-326, 1998
73. Zerbe R, Stropes L, Robertson G: Vasopressin function in the syndrome of inappropri-
ate antidiuresis. AM Rev Med 31:315-327, 1980

Address reprint requests to

Mark R. Harrigan, MD
Taubman Center Room 2128, Box 0338
1500 E. Medical Center Drive
Ann Arbor, MI 48109

e-mail [email protected]