Cerebral salt wasting syndrome

Abstract

Traumatic brain injury (TBI) is on the rise, especially in today’s fast-paced world. TBI requires not only neurosurgical expertise but also neurointensivist involvement for a better outcome. Disturbances of sodium balance are common in patients with brain injury, as the central nervous system plays a major role in sodium regulation. Hyponatraemia, defined as serum sodium <135 meq/L is commonly seen and is especially deleterious as it can contribute to cerebral oedema in these patients. Syndrome of inappropriate antidiuretic hormone secretion (SIADH), is the most well-known cause of hyponatraemia in this subset of patients. Cerebral Salt Wasting Syndrome (CSWS), leading to renal sodium loss is an important cause of hyponatraemia in patients with TBI. Although incompletely studied, decreased renal sympathetic responses and cerebral natriuretic factors play a role in the pathogenesis of CSWS. Maintaining a positive sodium balance and adequate hydration can help in the treatment. It is important to differentiate between SIADH and CSWS when trying to ascertain a case for patients with acute brain injury, as the treatment of the two are diametrically opposite.

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© 2016 Journal of Neuroanaesthesiology and Critical Care
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Cerebral salt wasting syndrome
Harshal Dholke, Ann Campos, C Naresh K. Reddy, Manas K. Panigrahi1
Abstract
Traumatic brain injury (TBI) is on the rise, especially in today’s fast‑paced world. TBI requires not only neurosurgical
expertise but also neurointensivist involvement for a better outcome. Disturbances of sodium balance are common in
patients with brain injury, as the central nervous system plays a major role in sodium regulation. Hyponatraemia, dened
as serum sodium <135 meq/L is commonly seen and is especially deleterious as it can contribute to cerebral oedema
in these patients. Syndrome of inappropriate antidiuretic hormone secretion (SIADH), is the most well‑known cause
of hyponatraemia in this subset of patients. Cerebral Salt Wasting Syndrome (CSWS), leading to renal sodium loss is
an important cause of hyponatraemia in patients with TBI. Although incompletely studied, decreased renal sympathetic
responses and cerebral natriuretic factors play a role in the pathogenesis of CSWS. Maintaining a positive sodium balance
and adequate hydration can help in the treatment. It is important to differentiate between SIADH and CSWS when
trying to ascertain a case for patients with acute brain injury, as the treatment of the two are diametrically opposite.
Key words: Brain natriuretic peptide, cerebral salt wasting, conivaptan, udrocortisone, hypertonic saline,
hyponatraemia
Glomerular ltration rate
About 70% of filtered sodium is reabsorbed in the
proximal tubules with <5% being excreted. Any fall in
glomerular ltration rate (GFR) would, therefore, mean
less ltration and excretion of sodium and vice versa.
Renin‑angiotensin‑aldosterone system
Sympathetic stimulation decreases in mean arterial
pressure or decreases in distal tubular sodium levels, all
activate renin-angiotensin-aldosterone system (RAAS)
which results in sodium reabsorption secondary to
aldosterone release.[1]
Natriuretic peptides (atrial natriuretic peptide
and brain natriuretic peptide)
These are produced in the atria and brain and cause
reduction of sympathetic outow from the brainstem as
well as induce natriuresis by increasing the GFR, and by
inhibiting renin and aldosterone release.[2]
INTRODUCTION
Sodium is the most important osmotically active solute
in the extracellular uid. It is the major determinant of
serum osmolality, which in turn plays a major role in the
regulation of body water. Increased serum osmolality,
triggers the release of anti-diuretic hormone (ADH) from
the posterior pituitary. Hypovolaemia and hypotension
results in baroreceptor stimulation which reexly causes
ADH release.[1,2]
Sodium balance in the body is maintained via regulation
of its renal excretion which is affected by:
Departments of Neuroanaesthesia and Critical Care and
1Neurosurgery, Krishna Institute of Medical Sciences,
Secunderabad, Telangana, India
Address for correspondence:
Dr.Harshal Dholke, Department of Neuroanaesthesia and
Critical Care, Krishna Institute of Medical Sciences,
Secunderabad, Telangana, India.
E‑mail:haarshal_21@yahoo.co.in
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DOI:
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How to cite this article: Dholke H, Campos A, Reddy CN,
Panigrahi MK. Cerebral salt wasting syndrome. J Neuroanaesthesiol
Crit Care 2016;3:205-10.
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Dholke, et al.: Cerebral salt wasting syndrome: A review
206 Journal of Neuroanaesthesiology and Critical Care
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In traumatic brain injury (TBI), hyponatraemia can
occur due to a variety of causes, such as syndrome of
inappropriate antidiuretic hormone secretion (SIADH),
CSWS, Anterior hypopituitarism, and drugs such
as oxcarbazepine used for seizure prophylaxis. The
incidence of hyponatraemia in head injury patients
commonly linked to CSWS and SIADH is 5–10%.[3,4] While
SIADH is the cause of hyponatraemia in the majority of
cases, in a small subset of patients, the diagnosis of
CSWS is often missed as it appears to be very similar to
SIADH and is therefore often confused with it. This can
have disastrous consequences as the treatment of the two
conditions is diametrically opposite. In SIADH, despite a
low serum osmolality, there is an inappropriate secretion
of ADH in response to hyponatraemia, leading to water
retention and hypervolaemia.[3] CSWS mimics SIADH
except for the fact that salt wasting is the primary defect
causing volume depletion.[4,5]
First described by Peters et al. in 1950, cerebral salt
wasting (CSW) is a clinical condition characterised
by renal loss of sodium causing dehydration and
hyponatraemia in patients with intracranial neurological
disorders.[6] In 1953, Leaf et al.[7] demonstrated that
exogenous administration of the ADH (vasopressin)
resulted in hyponatraemia, water retention and weight
gain. The increase in the intravascular volume resulted
in a decrease in sodium and chloride levels. This was
not ‘salt wasting’; but was a physiologic response to
an expanded intravascular volume. Four years later,
Schwartz et al.[8] published their landmark paper on
SIADH. A subsequent paper from the group at Yale
attributed hyponatraemia in neurologic disease to
SIADH.[7] For over 20 years, the term CSWS virtually
vanished from literature. In 1981, Nelson et al.[9] studied
hyponatraemia in neurosurgical patients, primarily
subarachnoid haemorrhage, and found that isotopically
measured blood volumes were contracted; he attributed
this nding to CSWS [Figures 1 and 2].
PATHOPHYSIOLOGY OF CEREBRAL
SALT WASTING SYNDROME
In TBI, there can be disruption of hypothalamo-renal
pathways,[2] imbalance of sympathetic output with
decreased renal sympathetic activity,[10] and also possibly
direct injury to the anterior and posterior pituitary,
all of which can play a role in the pathogenesis of
hyponatraemia in these patients. This can disrupt the
cerebral inuence on renal salt and water balance, and
therefore, disturb the kidneys ability to handle sodium
properly.[6]
It is now believed that natriuretic factors such as an atrial
natriuretic peptide, brain natriuretic peptide (BNP),
C-type natriuretic peptide, and possibly dendroaspis
natriuretic peptide are secreted by the injured brain
and may play a role in CSWS. Of all these factors BNP
might be the main factor in CSWS.[5] These peptides
have potent effects on cardiovascular homeostasis by
dampening the sympathetic response thereby altering
the vascular tone and causing dilatation of arteries
and veins.[11] Natriuretic peptides also induce sodium
loss (natriuresis) by inhibiting renin release from the
renal juxtaglomerular cells and preventing aldosterone
release from the adrenals thus antagonising the RAAS.[1]
This effect on the afferent tubules of nephrons leads to,
dilatation of the afferent arteriole resulting in increased
ltration of water and sodium through the glomerulus.
These molecules also have renal natriuretic and diuretic
effect by inhibiting the angiotensin-induced sodium
reabsorption from collecting ducts and antagonising
the action of vasopressin at the collecting duct,
respectively.[12]
Local production of natriuretic peptides within the
adrenal medulla has been demonstrated, which, might
have paracrine inhibitory effects on mineralocorticoid
synthesis.[13] This paracrine mechanism might explain
why, in patients with CSWS, aldosterone and renin levels
fail to rise despite the presence of hypovolaemia.
Other mechanisms suggest that downregulation of
renal sodium transporters due to extracellular volume
expansion and the adrenergic surge that occurs in
the early phase of brain injury might cause pressure
natriuresis.[14,15]
CLINICAL FEATURES AND DIAGNOSIS
In clinical practice, it is important to distinguish CSWS
from SIADH as they share several diagnostic criteria. The
following laboratory studies may be indicated in patients
with cerebral salt-wasting syndrome:[15]
Serum sodium concentration
Patients with untreated CSWS are often hyponatremic
and signs and symptoms may vary according to the
severity as shown in Table 1.[16] As the decline in serum
sodium concentration reduces serum osmolality, a
tonicity gradient develops across the blood-brain barrier
that causes cerebral oedema. Symptoms include lethargy,
agitation, headache, altered consciousness, seizures and
coma.[17,18]
Serum osmolality
Normal serum osmolality is 285–295 mosmosm/L. This
is found to be decreased in SIADH but is either normal
or decreased in CSWS. If the measured serum osmolality
exceeds twice the serum sodium concentration and
azotaemia is not present, hyperglycaemia or mannitol
should be suspected as the cause of hyponatraemia.[15,18]
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Dholke, et al.: Cerebral salt wasting syndrome: A review
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Journal of Neuroanaesthesiology and Critical Care
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Urinary output
Urine appears relatively dilute and the ow rate is often
high in CSWS. It is concentrated with a low ow rate
in SIADH. However, in CSWS, despite its apparently
diluted appearance, urine osmolality is high due to
increased sodium loss.
Fluid balance
The differentiation of SIADH from CSWS depends
on an accurate estimation of intravascular volume.
Unfortunately, no single physical finding can
accurately and reproducibly measure effective
circulating volume. Commonly used signs of
hypovolaemia include orthostatic tachycardia or
hypotension, increased capillary rell time, increased
skin turgor, dry mucous membranes and a sunken
anterior fontanel. These signs usually appear only
when the degree of dehydration is moderate to
severe. Central venous pressure may be an unreliable
determinant of extracellular volume.[15]
In SIADH, there is generally euvolaemia or hypervolaemia.
As opposed to this the important nding in CSWS is
volume depletion. The daily sodium excretion is also
more than the intake, and the overall sodium balance is
negative in CSWS. Therefore, a daily clinical examination
for signs of hypovolaemia as well as a daily intake and
output charting should be done, which will reveal an
overall negative balance.[2] Sometimes, hypovolaemia has
been identied in patients who fulll all other diagnostic
criteria for SIADH. This occurs because the volume
depletion of CSWS causes a secondary rise in ADH.
However, under such conditions, the correct diagnosis
is CSWS rather than SIADH.[19]
Fractional excretion of uric acid
This is dened as the percentage of urate ltered by
glomeruli that is excreted in urine. It is calculated by
dividing the product of (urinary uric acid [mg/mL] × serum
creatinine [mg/mL]) by the product of (serum uric acid
[mg/mL] × urinary creatinine [mg/mL]) and multiplying
the result by 100. Normal values are <10%.[20]
Patients with either CSWS or SIADH can have
hypouricaemia and elevated fractional excretion
of uric acid (FEUA). However, after correction of
hyponatraemia, the hypouricaemia and elevated FEUA
may normalise in SIADH but persist in CSWS (renal salt
wasting).[15]
Fractional excretion of phosphate
This should be determined when evaluating patients
with hyponatraemia and hypouricaemia. Elevated
fractional excretion of phosphate >20% suggests cerebral
salt-wasting syndrome as opposed to SIADH where it
is <10% [Table 2].[20,21]
TREATMENT
The main-stay of management of CSWS is the replacement
of water and sodium which is lost due to diuresis and
natriuresis, whereas, in SIADH, free water has to be
restricted.[22]
Table 1: Clinical presentation of
hyponatraemia
Plasma concentration
of Na in (mmol/L)
Signs/symptoms
>125 Asymptomatic
120-125 Nausea, malaise, vomiting
120-110 Muscle cramps, weakness,
confusion, agitation, delirium,
lethargy and seizures
<110 Seizures, coma, permanent
brain damage, respiratory
arrest
Table 2: Clinical and biochemical features of
the syndrome of inappropriate antidiuretic
hormone secretion and the cerebral salt wasting
syndrome
Biochemical marker SIADH CSWS
Intravascular volume Normal
to high
Low
Serum sodium Low Low
Urinary sodium level High Very
high
Vasopressin level High Low
Urine output Normal
to low
High
Serum uric acid level Low Low
Initial fractional excretion of urate High High
Fractional excretion of urate after
correction of hyponatraemia
Normal High
Urinary osmolality High High
Serum osmolality Low Low
BUN/creatinine level Low to
normal
High
Serum potassium level Normal Normal
to high
Central venous pressure Normal
to high
Low
Pulmonary capillary wedge
pressure
Normal
to high
Low
Brain natriuretic peptide level Normal High
Fractional phosphate excretion (%) <10 >20
BUN=Blood urea nitrogen, SIADH=Syndrome of inappropriate antidiuretic
hormone secretion, CSWS=Cerebral salt wasting syndrome
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Dholke, et al.: Cerebral salt wasting syndrome: A review
208 Journal of Neuroanaesthesiology and Critical Care
| Vol. 3 • Issue 3 • Sep-Dec 2016 |
Once a diagnosis of CSWS is made, efforts should be
made to address hypovolaemia rst. This can be done
with the use of crystalloids like 0.9% normal saline.
This treatment holds true for those patients with mild
hyponatraemia. By doing this, both hypovolaemia
and hyponatraemia can be addressed.[23,24] When the
patient is severely hyponatraemic and hypovolemic
he will require aggressive resuscitation to rst become
euvolemic, followed by the correction of hyponatraemia,
with the use of 3% saline which should be administered
via a central line. With the use of 3% saline, the sodium
correction should not exceed 12 meq/L for every 24 h.
This is necessary, to avoid complications such as central
pontine myelinolysis, metabolic acidosis, volume
overload and pulmonary oedema.[25,26]
Some clinicians have found it useful to the use of
mineralocorticoids in CSWS. Fludrocortisone is one
such drug, which promotes the increased reabsorption
of sodium and the loss of potassium by the renal distal
tubules. Secondary effects such as hypokalaemia,
pulmonary oedema and hypertension may occur with
prolonged use. Apart from this, the steroid base can cause
hyperglycaemia warranting the periodic monitoring of
serum potassium and blood sugars. Hence, it’s use is only
indicated when salt and uid replacement are unable to
correct the hyponatraemia.[27,28]
Diuretics and uid restriction are the main‑stays of
treatment in SIADH. However, one of the newer drugs
recently approved by the United States-Food and Drug
Administration is worth a mention, Conivaptan, is
a non-selective antagonist at V1 and V2 vasopressin
receptors. It antagonises the action of vasopressin
at the collecting ducts causing electrolyte-free water
excretion, thereby raising serum sodium in patients with
SIADH.[29,30] Most recently, Ghali et al. published results
from their randomised, double-blind, placebo-controlled
Plasma Osmolality = 290 mosm/kg
Lack of water increased osmolality
Osmoreceptors
lat preoptic
neuclei
supraoptic PVN
Thirst ADH release
increase
Drinking Collecting duct more
permeable
H2O retention by Kidneys
More water intake decreased osmolality
Osmoreceptors
lat preoptic supraoptic PVN
neuclei
Thirst depressed
ADH release reduced
Collecting duct less
permeable
water loss by kidneys
Figure 1: Sodium regulation in the body
trial conducted across 21 cities in the United States,
Canada and Israel, involving the efficacy of oral
conivaptan in the treatment of patients with euvolemic
and hypervolaemic hyponatraemia.[31] Based on currently
available studies, conivaptan appears to be effective in
inducing aquaresis to correct hyponatraemia in both
euvolemic and hypervolemic hyponatremic patients.
Although conivaptan has been shown to be an effective
aquaretic with short‑term use, this is not without
limitations. Adverse effects reported with short-term
use are typically minimal, but may include serious
effects such as hypokalaemia, orthostatic hypotension,
and unexpectedly rapid serum sodium correction.
Careful patient selection, avoidance of combined use
with conventional diuretics, and close monitoring may
reduce complication rates with the use of conivaptan.[31,32]
When used in CSWS, conivaptan can cause a negative
uid balance and further worsen the situation. This novel
treatment for SIADH also backs the need for accurate
differentiation between CSWS and SIADH before the
start of hyponatraemia correction in cerebral injuries.[33,34]
Conivaptan should not be administered to patients in
whom CSWS or a high likelihood of cerebral vasospasm
is suspected.[34,35]
PREVENTION OF HYPONATRAEMIA IN
TRAUMATIC BRAIN INJURY
In TBI, the maintenance of intracranial pressure (ICP) is
pivotal and we need to strongly address the changes in
serum osmolality and serum sodium levels. There are
ample data which suggests that maintenance of slight
hypernatraemia is associated with a reduced increase in
ICP.[6] This can be very well achieved with the continuous
infusion of hypertonic saline (3% NaCl) and is found to
be well tolerated in these patients.[26]
Figure 2: Effect of hormones on sodium regulation
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Dholke, et al.: Cerebral salt wasting syndrome: A review
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Journal of Neuroanaesthesiology and Critical Care
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A recent study at the University of California, Los
Angeles used an aggressive sodium correction treatment
regimen as a component of their TBI protocol. The mean
target goal was a serum sodium level of 138 mmol/L or
higher if ICP was 15–20 mm Hg. This was achieved with
the use of 3% NaCl to control serum sodium levels and
prevent hyponatraemia. Using this protocol, there was a
12% incidence of serum sodium levels of <137 mmol/L
and a 1% incidence rate of serum sodium levels of <132
mmol/L. There were no documented cases of central
pontine myelinolysis using this protocol.[5]
Treatment protocol suggested for sodium regulation
in TBI[5]
• Measure serum sodium level twice daily for initial
96 h after TBI
• Establish serum sodium goal of ≥138 mmol/L
• Start continuous infusion of 3% NaCl at 25 mL/h
for Na of ≤138 mmol/L
• Maintain 3% NaCl at 15–25 mL/h if ICP is
15–20 mm Hg
• Add udrocortisone 0.1 mg bid (oral) if Na is
≤138 mmol/L
• Increase 3% NaCl to around 50 mL/h to achieve
Na of >145–155 mmol/L if ICP is >20 mm Hg
despite the use cerebrospinal uid drainage using
ventriculostomy.
CONCLUSION
Hyponatraemia can complicate the clinical outcome in
TBI. CSWS is a syndrome of hypovolemic hyponatraemia
caused by renal natriuresis and diuresis. Brain natriuretic
peptide, secreted by the injured brain plays a crucial
role in the pathogenesis of CSW. Making a distinction
between SIADH and CSWS is important due to
different treatment required for the two conditions. The
maintenance of high normal levels of serum sodium in
patient with TBI may help limit increases in ICP as well
as avoid the detrimental effects of hyponatraemia due
to CSWS or SIADH in these patients.
Financial support and sponsorship
Nil.
Conicts of interest
There are no conicts of interest.
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