Hyponatremia in Neurotrauma - The Role of Vasopressin

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This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Hyponatremia in Neurotrauma - The Role of Vasopressin
1
Andrea Kleindienst, M.D., Ph.D, 2Mark J. Hannon, M.D. 1Michael Buchfelder, M.D., PhD.,
3
Joseph G. Verbalis, M.D.
Hyponatremia in Neurotrauma - The Role of Vasopressin (doi: 10.1089/neu.2015.3981)
1
Dept. of Neurosurgery, Friedrich-Alexander-University of Nürnberg-Erlangen, Erlangen, Germany
2
Consulting Endocrinologist, Bantry General Hospital, Bantry, Co. Cork, Ireland
3
Dept. of Medicine, Georgetown University, Washington, D.C., USA
Journal of Neurotrauma
Running title: Hyponatremia in Neurotrauma
Table of Contents title: Hyponatremia in Neurotrauma – Role of Vasopressin
Corresponding author: Andrea Kleindienst, M.D., Ph.D.
Dept. of Neurosurgery, Friedrich-Alexander-University Erlangen-Nuremberg
Schwabachanlage 6, D-91054 Erlangen, Germany
Phone +49 9131 85 34577, Fax +49 9131 85 34551
Email: andrea.kleindienst@uk-erlangen.de
2
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Mark J. Hannon, M.D.
Consultant Endocrinologist and Physician
Bantry General Hospital, Bantry, Co. Cork, Ireland
Phone: +353 27 50133
Email: mark.hannon@hse.ie
Michael Buchfelder, M.D., Ph.D.
Dept. of Neurosurgery, Friedrich-Alexander-University Erlangen-Nuremberg
Schwabachanlage 6, D-91054 Erlangen, Germany

Phone +49 9131 85 34566, Fax +49 9131 85 34476
Email: michael.buchfelder@uk-erlangen.de
Joseph G. Verbalis, M.D.
Dept. of Endocrinology, Georgetown University Medical Center,
Suite 232 Building D, 4000 Reservoir Rd NW, Washington, DC 20007, USA.
Phone +1 202 687 2818
Email: verbalis@georgetown.edu
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Abstract
Hyponatremia is frequent in patients suffering from traumatic brain injury, subarachnoid hemorrhage
or following intracranial procedures, with approximately 20% having a decreased serum sodium
concentration to <125 mmol/L. The pathophysiology of hyponatremia in neurotrauma is not
completely understood, but in large part is explained by the syndrome of inappropriate secretion of
antidiuretic hormone (SIADH). The abnormal water and/or sodium handling creates an osmotic
gradient promoting the shift of water into brain cells, thereby worsening cerebral edema and
precipitating neurological deterioration. Unless hyponatremia is corrected promptly and effectively,
morbidity and mortality increases through seizures, elevations in intracranial pressure, and/or
herniation. The excess mortality in patients with severe hyponatremia (<125 mmol/L) extends beyond
the time frame of hospital admission, with a reported mortality of 20% in hospital and 45% within 6
months of follow-up. Current options for the management of hyponatremia include fluid restriction,
hypertonic saline, mineralocorticoids and osmotic diuretics. However, the recent development of
vasopressin receptor antagonists provides a more physiological tool for the management of excess
water retention and consequent hyponatremia, such as occurs in SIADH. This review summarizes the
existing literature on the pathophysiology, clinical features, and management of hyponatremia in the
setting of neurotrauma.
Key-words: hyponatremia, vasopressin, anti-diuretic hormone, acute brain injury, body fluid volume
regulation
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Introduction
Hyponatremia is the most frequent electrolyte imbalance encountered in hospital inpatients and is
especially frequent in patients suffering from any type of neurotrauma, including traumatic brain injury
(TBI), subarachnoid hemorrhage (SAH) and following intracranial procedures. Up to 20% of patients
admitted for TBI and over 50% of patients admitted for SAH develop hyponatremia, with about 20%
of them experiencing a decrease in serum sodium concentration to <125 mmol/L 1, 2.
Although acute severe hyponatremia has long been known to increase inpatient mortality, recent data
suggest that even mild degrees of hyponatremia may confer an adverse prognosis on diverse patient
groups 3-7.
Given the frequent occurrence of hyponatremia in patients with neurotrauma, prompt and correct
management of hyponatremia is essential in this patient group. However, the causes of hyponatremia in
neurotrauma are diverse, and may only in part be explained by the syndrome of inappropriate secretion
8, 9
of antidiuretic hormone (SIADH) . The abnormal water and/or sodium handling creates an osmotic
10
gradient promoting the shift of water into brain cells , thereby worsening cerebral edema and
precipitating neurological deterioration. Unless hyponatremia is corrected promptly and effectively,
morbidity and mortality increases through seizures, elevations in intracranial pressure, and/or cerebral
herniation 11.
In this review we will explore the pathophysiology of disorders of salt and water balance in
neurotrauma with particular reference to the role of arginine vasopressin (AVP, also known as
antidiuretic hormone, ADH), and provide a brief summary of our recommended management
strategies.
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The Clinical Importance of Hyponatremia
In a prospective study of hospital admissions, the overall mortality was 28% in hyponatremic patients
(<125 mmol/L) as compared to 9% in normonatremic controls, and increased up to 50% in patients

12
with serum sodium concentrations <115 mmol/L . In an animal study, even asymptomatic subjects
13
had a subclinical brain edema when the serum sodium was <125 mmol/L . The excess mortality in
patients with severe hyponatremia (<125 mmol/L) extends beyond the time frame of hospital
admission, with a mortality of 20% in hospital and 45% within 6 months of follow-up 14. Interestingly,
recently published data suggest that the excess mortality is not confined to patients with severe
hyponatremia. In a prospective cohort study on 8142 patients, hyponatremia (<135 mmol/L) was
present in 15% of the patients on admission, with an increased risk of mortality even in those with mild
hyponatremia (130–134 mmol/L, hazard ratio 1.38) 15.
The above data documenting the higher mortality seen in patients with various degrees of
hyponatremia is particularly concerning when considering patients with neurotrauma. This is because
hyponatremia is the commonest electrolyte abnormality in neurosurgical patients, occurring in up to

16, 17
50% of cases depending on the underlying diagnosis (Table 1) . Furthermore, patients with an
intracranial pathology are more likely to develop complications, such as hyponatremic seizures, even at
higher serum sodium concentrations than usual 2. Although hyponatremia is an important determinant
of outcomes, its importance is often overlooked 18.
Neurological symptoms in patients with acute hyponatremia occur as a result of cerebral edema, as
water moves from the hypotonic plasma across the blood brain barrier (BBB) resulting in progressive
brain edema. The clinical manifestations of the accompanying increased intracranial pressure vary from
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nausea and malaise, which may be seen when the serum sodium concentration falls below 125-130
mmol/L. Headache, lethargy, obtundation and eventually seizures, coma, and respiratory arrest can
occur as the serum sodium concentration progressively falls below 115-120 mmol/L. However, the
degree of cerebral edema produced is also dependent upon the rapidity of the fall in serum sodium
concentrations, and deaths from acute hyponatremia during endurance exercise events has been
19
documented with sodium levels in the 120-125 mmol/L range . Brain herniation ultimately remains
20
the greatest risk in acute severe hyponatremia and in patients with intracranial pathology .
Noncardiogenic pulmonary edema has also been described 21, 22.
Pathophysiology of Hyponatremia in Neurotrauma

The pathophysiology of hyponatremia following brain injury may involve excess secretion of AVP,
adrenocorticotropic hormone (ACTH) insufficiency, or the hypothesized cerebral salt wasting (see
Table 2) 8, 9. Symptoms appear to correlate best with the interplay between a net increase in brain water
versus a loss of brain solutes 23. The differential diagnosis of hyponatremia is broad, and is summarised
in Table 3.
Syndrome of inappropriate antidiuretic hormone secretion
Frederic Bartter and William Schwartz first described SIADH in a presentation to the American
Society for Clinical Investigation in 1956 24, detailing two patients with lung carcinoma who developed
severe hyponatremia. Once radioimmunoassays for the measurement of arginine AVP became
available, their index clinical description and pathophysiological hypothesis was substantiated by
25
papers which reported elevated plasma AVP concentrations in the syndrome . However, the
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differentiation of SIADH from other causes of hyponatremia remains important in order for the correct
treatment to be instigated. Our understanding of the regulation of water metabolism has been greatly
26, 27
advanced to the cellular level by the discovery of aquaporin (AQP) water channels . AQP channels
have been localized to several organs in the body, including kidney and brain. Experimental data
demonstrate that AVP regulates AQP2 activity and expression with subsequent water reabsorption at
28, 29
the kidney . Prolonged excessive AVP release is associated with an “escape” from antidiuresis,
with down-regulation of AQP2 mRNA and protein expression. In the brain parenchyma, AVP
30
stabilizes fluid osmolality at the cellular level , most likely through a vasopressin V1A receptor-
31
mediated regulation of AQP4 expression . The pathological event of acute brain injury, ischemia or
hypoxia results in an energy deficit for membrane stabilizing ion pumps creating an osmotic imbalance
between the intra and extracellular compartments, which challenge the AQP and AVP regulatory
systems. Additional systemic hypotension due to cardiovascular regulatory compromise activates the
release of vasopressor hormones, among them AVP, leading to hyponatremia due to SIADH.
The diagnostic criteria for SIADH are outlined in Table 4. The supplementary criteria are of minimal
clinical utility. Plasma AVP concentrations are elevated in many conditions that cause hyponatremia
and therefore results are hard to interpret. Furthermore, the nonapeptide AVP is subject to proteolysis
making it unstable, and radioimmunassays with sufficiently reliable AVP antibodies to provide
meaningful results are not available in a time frame that would benefit patient care. Copeptin is a stable
byproduct of AVP synthesis which is secreted in equimolar concentrations with AVP - measurement of
this peptide may in future serve as a surrogate of AVP secretion 32.

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Vasopressin receptors and specific antagonists
Three AVP receptors are known to differ in localization and in signal transduction mechanisms 33. The
AVP V1a and V1b receptors activate phospholipase C and increase cytosolic free calcium. They
mediate vasoconstriction, platelet aggregation, ionotropic stimulation, and myocardial protein synthesis
(all V1a) and pituitary ACTH secretion (V1b). Vasopressin V2 receptors are found predominantly in
the principal cells of the renal collecting duct, act through activating protein kinase A and AQP2 water
channels to mediate the antidiuretic effects of AVP 34. The increased urine output produced by the V2
receptor antagonists is quantitatively equivalent to that of diuretics such as furosemide but the
excretion of urinary solutes is not augmented, i.e. they are aquaretic 35.
The development of these specific AVP receptor antagonists represents a novel therapeutic option in
SIADH. Four V2 receptor antagonists have been studied in clinical trials. Conivaptan is a combined
V1a and V2 receptor antagonist, while lixivaptan, satavaptan and tolvaptan are selective V2 receptor
antagonists. At present in the US, tolvaptan and conivaptan are approved for clinical use. In Europe,
just tolvaptan is approved. There is a growing database of randomised prospective trials showing a
predictable and consistent benefit over placebo in patients with euvolemic or hypervolemic
36-38
hyponatremia caused by chronic heart failure, cirrhosis, or SIADH . However, patients with acute
hyponatremia, including head trauma and postoperative conditions, were ineligible for these studies,
which limits the evidence base in neurotrauma.
The V2 receptor antagonists have the potential to replace water restriction as first-line therapy in
SIADH (Table 5), but their current use is limited by cost considerations. Reported side effects are
uncommon and although the literature documents the potential for overly rapid correction, there have
been no documented cases of osmotic demyelination syndrome (ODS) in patients in whom the vaptans
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10
have been used appropriately, within clinical guidelines. A recent multicenter trial (TEMPO3:4)
investigating the usefulness of tolvaptan in polycystic kidney disease 39 raised concerns with regard to
liver function - an increase in liver enzymes was more common among patients who received tolvaptan
when compared with placebo. The US FDA has issued safety warnings that tolvaptan should not be
used for longer than 30 days and should not be used in patients with liver disease, based on the data
above. However, this warning is not effective in Europe.

40, 41
Data on the specific use of this class of medications in patients with neurotrauma is limited .
Nevertheless, given that treatment options in this situation are limited and treatment duration would be
for a relatively short period, the appeal of a physiologic AVP antagonist is obvious.
Adrenocorticotropic hormone deficiency
In patients with hyponatremia following neurotrauma, it is important to distinguish euvolemic
hyponatremia due to ACTH deficiency from SIADH. The biochemical presentation of acute
adrenocorticotropic insufficiency is almost identical to that of SIADH. Although apparently
euvolemic, ACTH deficient patients may have a subtle degree of volume contraction leading to
42
baroregulated AVP secretion . The elevated plasma AVP concentrations in patients with ACTH
43
deficiency and hyponatremia are independent of whether they have a secondary glucocorticoid
44
deficiency with preserved mineralocorticoid secretion or Addison’s disease . Vice versa,
glucocorticoids exhibit a functional AVP antagonism and normalize low serum sodium concentrations
45
. In a rat model of adrenal insufficiency, high plasma AVP concentrations are reported, even after
46
water loading . However, in rats with adrenal insufficiency and central diabetes insipidus, urinary
output did not rise in response to a free water load, indicating that both AVP and cortisol are necessary
47
to enable maximal water excretion . Considering the high prevalence of anterior pituitary
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11
insufficiency following brain injury 48, an acute glucocorticoid deficiency should be considered as the
potential cause of hyponatremia in any patient with neurotrauma.
The diagnosis of ACTH deficiency in the acute care setting is often particularly difficult. A review
advocated a random plasma cortisol cut-off of approximately 15 μg/dL (414 nmol/L) for the diagnosis
49
of ACTH deficiency in intensive care patients (with normal plasma binding proteins) . The Critical
Care Medicine Taskforce has recommended a very conservative random total plasma cortisol cut-off of
< 10 μg/dL (276 nmol/L), or a delta total plasma cortisol of <9 μg/dL (248 nmol/L) after
50
adrenocorticotrophic hormone (250 μg) administration, to make the diagnosis . However, this
recommendation is intended to cover all intensive care patients, and there is a lack of normative data in
neurotrauma patients upon which to base an appropriate cut-off.

Cerebral salt wasting syndrome
Another potential cause of hyponatremia in the setting of neurotrauma is the cerebral salt wasting
syndrome (CSWS). This clinical syndrome was first described in 1950 by Peters et al 51 and it has since
been described in association with a spectrum of intracranial pathologies, including SAH 52, clipping of
intracranial aneurysms 53, and TBI 54. The original researchers hypothesised that the cerebral pathology
directly attenuated renal sympathetic innervation, causing natriuresis and diuresis, with resultant
hyponatremia and blood volume depletion. The possibility of a potential condition separate from
SIADH that could cause hyponatremia in neurotrauma was revisited in 1981 after a report of 12
52
unselected patients, who had developed hyponatremia following SAH and TBI . Hyponatremia
developed in association with natriuresis and inappropriate urine concentration in 10 patients with good
evidence of a reduction in plasma volume and total blood volume. The authors concluded that there
was clear evidence that hypovolemia precluded the diagnosis of SIADH by standard criteria, and raised
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12
the possibility of CSWS. Two subsequent studies further stressed the possibility of CSWS. Wijdicks
and colleagues found only 25 out of 134 SAH patients to meet diagnostic criteria for SIADH, whereas
55, 56
97 patients were felt to be suspicious of CSWS . The evidence to support a syndrome of cerebral
salt wasting has not been universally accepted, however, with speculation that the diuresis and
natriuresis simply represents an escape from SIADH-induced antidiuresis 57.

A microdialysis study determined the local AVP release in the hypothalamic region around the third
ventricle – in the supraoptic (SON) and paraventricular (PVN) nucleus where AVP is synthetized –
58
following experimental SAH . This study found a dissociated AVP release into blood, and into the
extracellular fluid of the SON and PVN. This release occurred specific to SAH without a contribution
of baroreceptor activation. A sustained AVP release was especially generated within the PVN known to
have descendent projections to the sympathetic nervous system, including a renal-hypothalamic reflex-
loop promoting urinary sodium excretion after activation. A proof of concept study, showing that renal
sympathetic innervation causing natriuresis and diuresis, with resultant hyponatremia and blood
volume depletion is the pathophysiological cause of CSWS, has yet to be performed. One reason is that
the sodium excretion following experimental SAH was not robust enough to investigate the additional
effect of renal denervation 59.
Hyponatremia following Traumatic Brain Injury
Following TBI, approximately 15% of patients develop hyponatremia, usually within the first 5 days
after the injury 1. This development is almost always transient and self-resolving 54, 60
. Assessing the
AVP pro-hormone fragment copeptin (cut-off 15 pmol/L) early after TBI, 45% of patients
demonstrated an increased release on day 1 32, thereby supporting the idea that hyponatremia following
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13
TBI is primarily due to SIADH. However, this study found that the strong correlation between serum
sodium and urine excretion (p=0.003) on admission no longer existed on days 3 and 7. Furthermore,
copeptin levels did not reflect the individual 24 hr urine excretion or serum sodium levels, suggesting
32
an uncoupling of copeptin/AVP release and renal water excretion . Hence, SIADH may not be the
exclusive cause of hyponatremia following TBI.

The existence of an ACTH deficiency following TBI in general, and as a reason of hyponatremia in
particular, is still a matter of debate. Almost all previous studies on a corticotropic insufficiency relied
on the assessment of cortisol at a single time point, providing only a “snapshot” of the patients’
61-67
pituitary function . Since plasma cortisol levels are highly dynamic in the days following TBI,
protocols with only a single time point for testing may underestimate the true incidence of injury-
induced pituitary dysfunction 62, 63. Following repetitive assessment for a corticotropic insufficiency in
the acute phase following TBI, an incidence of up to 78% was suggested, and 15% of this cohort
60
developed transient hyponatremia . On the other hand, a very high urinary excretion of cortisol
metabolites early after TBI is not consistent with such a high incidence of corticotropic dysfunction 48,
and some doubt in the relevance of post-TBI hypopituitarism has recently been raised 68. Nonetheless,
the presence of hyponatremia, hypotension and hypoglycaemia might indicate the presence of an acute
69 65
ACTH insufficiency in TBI victims and, if present, should be further investigated . Chronic
hyponatremia is rare following TBI, and if present another cause should be sought 54, 60.
Hyponatremia following Subarachnoid Hemorrhage
Hyponatremia is far more common following SAH than TBI. The aetiology of hyponatremia following
70
SAH is diverse and includes SIADH, CSWS, and acute ACTH deficiency, as well as the more
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14
general causes of hyponatremia outlined in Table 2. However, there is a considerable dispute as to
which of these diverse aetiologies most commonly cause hyponatremia following SAH. A number of
56, 71-73
small studies have suggested that CSWS is the most common cause , due to the finding that
71, 72 74
plasma atrial natriuretic peptide (ANP) and brain natriuretic peptic (BNP) concentrations both
rise following SAH. However, SIADH also has been associated with elevated ANP levels as a result of
water retention 75, and recent data suggested that the presence of elevated plasma BNP concentrations
could not be regarded as a reliable predictor of either blood volume status or the development of
76
hyponatremia . Elevated plasma BNP concentrations may therefore not necessarily mediate the
development of hyponatremia. Some recent retrospective studies 2, 17 have failed to substantiate CSWS
as a cause for anything more than a minority of cases of hyponatremia following SAH, and strongly
support SIADH as the predominant cause of hyponatremia. Another retrospective study found that only
35% of severe hyponatremia (<130 mmol/L) was considered to be due to SIADH, with a substantial
77
proportion of 23% considered to be secondary to CSWS . However, this patient cohort had more
severe SAH and only those patients with serum sodium <130 mmol/L were analyzed in detail.
A weakness in all of the retrospective studies is that there was no routine assessment of cortisol levels,
so the authors were unable to comment on how many patients with apparent SIADH had their
electrolyte abnormalities as a manifestation of glucocorticoid deficiency. It is now apparent that acute
ACTH deficiency may be more common than previously recognised following brain injury 78. Recent
studies by Klose et al 79 and Parenti et al 80 reported that between 7% and 12% were cortisol deficient
immediately following SAH, and studies involving repeated measurement of plasma cortisol have
found far higher rates of ACTH insufficiency 81. In a recent prospective study that involved repeated
assessments of both serum sodium and plasma cortisol levels, hyponatremia occurred in 50% of SAH
patients, and the commonest cause of hyponatremia was SIADH (71%), followed by corticotropic
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15
82
deficiency (14%), and 29% of these had steroid-remedial hyponatremia . However, another
prospective study utilizing a ghrelin test estimated only a 2% incidence of ACTH insufficiency in the
acute phase of SAH 83.
These data have to be appraised carefully, as the assessment of a corticotropic deficiency in the acute
phase following neurotrauma is difficult. First, basal cortisol levels are inconclusive, and the methods
of dynamic testing are either contraindicated following SAH (e.g., insulin tolerance test as the gold
standard), have a high rate of falsely normal results in the acute setting (e.g., glucagon stimulation test,
short synacthen test) or are primarily indicated for evaluation of growth hormone deficiencies (e.g.,
84
ghrelin test) . Second, in the acute phase after SAH, there is a discordance of total and free plasma
85
cortisol with a five-fold greater increase of free versus total cortisol . Hence, the prevalence of true
adrenal insufficiency may be small, and caution is advocated in assessing adrenal function by total
cortisol measurements in this population.
In aggregate, the data to date strongly suggest that SIADH is the most common cause of hyponatremia
following SAH, with acute corticotropic insufficiency also playing a role. Although CSWS does occur,
it is a relatively rare event following SAH. None of the studies summarized above demonstrated any
significant occurrence of long-term hyponatremia following SAH. Like TBI, this appears to be a
transient and self-resolving phenomenon.
Management of Hyponatremia
Despite ongoing controversy in some areas, what is clear from the prevalence data on neurotrauma is
that hyponatremia is common, the commonest cause of hyponatremia is SIADH, and hyponatremia due
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16
to all causes increases mortality. Currently, water restriction (0.5-1.0 L/day) is the treatment of choice
86-88
for the management of hyponatremia . However, directly counteracting the effects of excessive
AVP release utilizing AVP receptor antagonists has emerged as another therapeutic option.
In order to provide appropriate management, a distinction must be made between the severity of
hyponatremia based on serum sodium levels versus neurological symptoms. Many patients with
chronic hyponatremia are able to tolerate substantial lowering of serum sodium to “severe” levels (i.e.,
serum sodium <120 mmol/L) because adaptive volume regulatory mechanisms prevent cerebral edema
23
. On the other hand, a rapid drop in serum sodium concentration – such as seen in patients with
neurotrauma - may produce seizures and diminished consciousness at more moderate serum sodium
concentrations (120-129 mmol/L) that generally present little neurological threat in chronic
hyponatremia. Therefore, for the purpose of management, severe hyponatremia refers to hyponatremia
associated with severe neurological symptoms, regardless of the serum sodium concentration, which is
almost always due to an acute (< 48 hr) decrease in serum sodium concentration.
Treatment of symptomatic hyponatremia is difficult. Untreated severe hyponatremia, especially when

13, 89
associated with evidence of cerebral irritation, such as seizures, is potentially fatal , and recovery
may occur with permanent brain damage. On the other hand, treatment itself is hazardous under some
conditions, since overly rapid correction of hyponatremia leaves the patient vulnerable to the risk of
ODS (also known as central pontine myelinolysis), which is characterized by spastic tetraparesis,
cranial nerve palsies, pseudobulbar palsy, potentially resulting in a “locked in syndrome”. Osmotic
demyelination predominantly affects the pontine area, but up to 10% of cases also involve the
90
cerebellum, thalamus, midbrain and lateral geniculate body . The risk is highest when chronic
hyponatremia is corrected overly rapidly, particularly in patients with other risk factors for ODS (serum
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17
sodium ≤105 mmol/L, hypokalemia, alcoholism, malnutrition, liver failure 88). It has traditionally been
advised not to correct the serum sodium by more than 0.5 mmol/L/hr 91 – in other words, not more than
92
12 mmol/L over twelve hours . If serum sodium is corrected more rapidly, intracellular sodium and
potassium concentrations are restored immediately, but organic solutes may take 5-7 days to normalize
93
. This results in a hypertonic extracellular compartment that causes movement of water to the myelin
sheath outside the neuron with subsequent intramyeline edema, osmotic endothelial injury and local
94
release of myelinotoxic factors, precipitating oligodendrocyte failure and death . An additional
mechanism is osmotic disruption of the blood-brain barrier 95, which allows an influx into the brain of
96
complement and other immune factors that are toxic to oligodendrocytes . These changes generally
occur over 2-3 days, but symptoms of ODS can begin within hours of an overly rapid correction of
hyponatremia. The mainstay of diagnosis of ODS is clinical suspicion and examination, aided by T1
weighted magnetic resonance imaging (MRI) that may have the classic appearance of a hypointense
pons on sagittal imaging but a hyperintense pons on coronal sections. Prognosis is variable, but often is
poor with persistent neurological deficit 21.
Recently, expert panel recommendations on the management of hyponatremia have been updated 88. In
contrast to traditional guidelines, they do not recommend that the correction in serum sodium be evenly
distributed across the first 24 hours. In fact, as severely symptomatic hyponatremia is a medical
emergency with significant associated morbidity and mortality, there is a need for a rapid initial
correction to reduce cerebral edema. Published experience with hypertonic saline to treat symptomatic
acute hyponatremia has shown that a 5 mmol/L increase in serum sodium can reduce intracranial
97
pressure and resolve the neurological symptoms of herniation by nearly 50% within an hour .
Therefore the suggested approach to hyponatremia with severe neurological symptoms is to elevate
serum sodium initially by 3-5 mmol/L over 2-4 hours. This will reverse cerebral edema, reduce
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18
intracranial pressure and prevent seizures. For severe symptoms, a 100 mL bolus of 3% saline should
be given over 10 minutes, repeated three times if no clinical improvement. This regimen has been
successful in a small cohort of runners with acute symptomatic exercise-induced hyponatremia 98. The
remainder of the targeted increase in serum sodium can then be distributed over 24 hours. For mild to
moderate symptoms with a low risk of cerebral herniation, 3% saline infusion is again recommended
but at a slower rate of 0.5-2mL/kg/hr. These treatment recommendations are summarized in Table 5.
The second recommendation of the expert panel is a change in the targeted increase in serum sodium
concentration. There have been reported cases of ODS with increases in serum sodium between 8-12
mmol/L 99. Although these cases are rare, it is now recommended that the targeted increase in serum
sodium concentration is ≤8 mmol/L over the first 24 hours of therapy. Recognition of the difficulty in
avoiding overshooting this tight target however, a 12 mmol/L increase was retained as the maximum
rise in serum sodium that should be accepted. The target in groups with associated risk factors for
88
ODS is recommended to be ≤6mmol/L with a maximum of 8 mmol/L . Overcorrection of
hyponatremia can be reversed by the administration of intravenous dextrose, parenteral desmopressin,
or both. Although there is little evidence to determine which of these is preferable, re-induction of
hyponatremia in animals with rapid overcorrection of hyponatremia has been shown to reduce
mortality 100.
In patients without acute severe hyponatremia, the key to management is an accurate diagnosis of the
underlying cause, as outlined in Table 3. However, this may not be easy in clinical practice. The
diagnosis of ACTH deficiency is often particularly difficult, especially in the acute setting of SAH or
TBI since normative data are missing. Whenever a corticotropic deficiency has been documented
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19
unequivocally, treatment with parenteral glucocorticoids usually leads to a rapid resolution of
hyponatremia due to ACTH deficiency.
Treatment with sodium chloride solution either orally or intravenously is the specific therapy for
101
CSWS . It is often necessary to give large volumes to keep up with urinary losses. As CSWS is
invariably self-limiting, aggressive treatment with intravenous fluids is usually only required for a few
days 102.
The first line management for chronic SIADH (> 48 hour duration) is generally fluid restriction.
However, in the management of many cases of neurotrauma, patients are often aggressively hydrated to
decrease the risk of cerebral vasospasm. Therefore, it is very often impossible to implement an
adequate degree of fluid restriction. Hypertonic saline can be used as described for acute symptomatic
hyponatremia, but requires prolonged intravenous administration. Demeclocycline, a tetracycline
antibiotic that reduces the responsiveness of the collecting tubule cells to AVP, can be used in the
management of SIADH, but has an unpredictable response rate and a slow onset of action. It can also
lead to nephrotoxicity and a photosensitive skin rash. Lithium is an even more problematic treatment
for SIADH, with very erratic response rates and a wide range of side effects. Urea has been shown to
103
be effective but is not widely available and is very unpalatable. Sodium chloride tablets,
fludrocortisone and loop diuretics have all been used for treatment of SIADH in this setting but there is
no physiological rationale for their use. Consequentially, all conventional treatments for chronic
hyponatremia are suboptimal in patients with SIADH due to neurotrauma.
Vasopressin V2 receptor antagonists, also known as “vaptans”, show a predictable and consistent
benefit over placebo in non-neurotrauma populations 36-38, though a recent review emphasized the need
for head-to-head trials with other established, though less well validated, treatments for hyponatremia
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20
104
. Vaptans have the potential to replace fluid restriction as first-line therapy in SIADH (Table 5).
Although the literature documents the clear potential for over-correction using these agents to correct
hyponatremia, there have been no documented cases of ODS in patients in whom the vaptans have
been used appropriately and within clinical guidelines. An additional benefit of using vaptans is that
they enable use of other necessary therapies. An example of this is that when patients with neurological
disorders are volume expanded with isotonic saline to prevent vasospasm, any underlying SIADH
causes retention of the water component of the isotonic saline with resultant worsening hyponatremia.
Vaptans prevent the water retention, thereby enabling use of high volumes of isotonic saline without
the complication of hyponatremia. Whenever vaptans are used, they should not be combined with
either fluid restriction or hypertonic saline, to decrease the risk of overly rapid correction 88. Given that
treatment would be of a relatively short duration in most cases of neurotrauma, the appeal of an
effective and safe AVP antagonist is obvious.
Based on currently available literature and clinical guidelines, the following points can be proposed for
management of hyponatremia in neurotrauma patients.
The treatment of acute symptomatic hyponatremia is indicated if:
 The duration of hyponatremia is less than 24 to 48 hours; or
 An intracranial pathology or an increased intracranial pressure exists; or
 Seizures, obtundation or coma are evident despite the duration of hyponatremia.
The goal of the management of acute symptomatic hyponatremia is:

Page 21 of 41
21
 Urgent correction of serum sodium by 4-6 mmol/L to prevent brain herniation and
neurological damage from cerebral ischemia.
Sodium deficit can be calculated as:
 Sodium deficit = sex * normal weight (desired serum sodium – serum sodium).
 Male = factor 0.6, female = factor 0.5.

 Patients with SIADH have a dilutional hyponatremia from water retention, and therefore
do not have a sodium deficit as the cause of their low serum sodium level.
The recommended treatment for hyponatremia due to SIADH is:

For severe symptoms, 100 mL of 3% NaCl infused intravenously over 10 minutes x 3 as
needed;
 For mild to moderate symptoms with a low risk of herniation, 3% NaCl infused at 0.5-2
mL/kg/hr;
 The rate of correction need not be restricted in patients with true acute hyponatremia, nor
is re-lowering of excessive corrections indicated (Figure); however, if there is any
uncertainty as to whether the hyponatremia is chronic versus acute, then the limits for
correction of chronic hyponatremia should be followed;
 Alternatively, an AVP receptor antagonist can be given without any fluid restriction:
tolvaptan 7.5 – 15 mg po 88; or, in the U.S. only, conivaptan, 20 mg iv bolus infusion over
30 min 105;
Page 22 of 41
22
 With any active therapy of hyponatremia, serum sodium levels should be monitored at
least every 6 hours during the first 24-48 hrs of therapy, and even more frequently (every
1-2 hrs) with use of hypertonic saline solutions 88.
Conclusion
The frequent occurrence of hyponatremia following TBI, SAH, and pituitary surgery, and the
associated increased morbidity and mortality, requires the involved physicians to be familiar with the
pathophysiology, differential diagnosis and treatment options for hyponatremia. At the moment, fluid
restriction is the treatment of choice for treating hyponatremia due to SIADH. However, directly
counteracting the effects of the excessive AVP secretion by utilizing vasopressin V2 receptor
antagonists offers a novel new and mechanistically appealing approach to the management of SIADH,
which offers some distinct advantages in the management of patients whose hyponatremia is due to
neurotrauma.
Disclosure
AK received a grant by Otsuka Pharma. JGV is a consultant to Otsuka Pharma and has received a
research grant from Otsuka Pharma.

Page 23 of 41
23
Tables and Figure Legends
Table 1. Incidence of significant hyponatremia (serum sodium <130 mmol/L) in patients admitted to
the neurosurgical unit in Beaumont Hospital, Dublin between January 2002 – September 2003 (adapted
from 17 with permission).

Table 2. Etiology of 187 cases of hyponatremia (serum sodium <130 mmol/L) documented in 1,698
admissions to the Irish National Neurosciences Centre at Beaumont Hospital, Dublin between January
17
2002 and September 2003 (adapted from with permission). SIADH, syndrome of inappropriate
antidiuretic hormone secretion; CSWS, cerebral salt-wasting syndrome.
106
Table 3. Causes of hyponatremia. Adapted from , with permission. SIADH, syndrome of
inappropriate antidiuretic hormone secretion; ACTH, adrenocorticotropic hormone.
Table 4. Diagnostic criteria for the diagnosis of syndrome of inappropriate antidiuretic hormone
secretion.
Table 5. Treatment of symptomatic hyponatremia (adapted from 88).
Figure. Recommendations for relowering of serum sodium concentration ([Na+]) to goals (green) for
patients presenting with serum [Na+] <120 mmol/L who exceed the recommended limits of correction
(red) in the first 24 hours. With permission from Verbalis, Goldsmith et al. 2013.
Page 24 of 41
24
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TBI
Page 33 of 41
SAH
Spinal
Tumour
Diagnosis
All Patients
Pituitary surgery
4
5
44
56
62
187
sodium <130mmol/L
No. of patients with plasma
81
489
457
355
316
1698
Total
11
%
6.2
9.6
0.81
15.8
19.6
33
Page 34 of 41
34
Pathophysiology Number of patients %
(Total = 187)
SIADH 116/187 62
Previously on carbamazepine 7/116

Subgroups of Previously on desmopressin 10/116
SIADH
Previously on selective 14/116
patients
serotonin-specific re-uptake
inhibitors
Neurotrauma 85/116
Hypovolaemia 50/187 26.7
Inappropriate intravenous fluids 9/187 4.8
CSWS 7/187 3.7
Mixed SIADH/ CSWS 5/187 2.7

Page 35 of 41
35
Clinical Signs Urinary Na+ < 20 mmol/L Urinary Na+ > 40 mmol/L
Hypovolemic Dry mucous Gastrointestinal losses Diuretics
membranes
Mucosal losses Addison’s disease
Decreased turgor
Pancreatitis Cerebral salt wasting
Tachycardia
Sodium depletion post Salt wasting nephropathy
Hypotension diuretics
(orthostatic)
Raised urea, renin

Euvolemic Underlying illness Hypothyroidism SIADH
SIADH with ongoing fluid ACTH deficiency
restriction
Hypervolemic Peripheral edema Cirrhosis Cardiac failure with diuretic
therapy
Ascites Cardiac failure
Raised venous Nephrotic syndrome
pressure
Primary polydipsia
Pulmonary edema
Underlying illness
36
Page 36 of 41
Page 37 of 41
37
Essential Criteria Supplemental Criteria
1. Hyposomolality; plasma osmolality < 280 Abnormal water load test
mOsm/kg
2. Inappropriate urinary concentration (Uosm >
100 mOsm/kg)
3. Patient is clinically euvolemic Plasma vasopressin concentration
4. Elevated urinary sodium (> 40 mmol/L),
with normal salt and water intake
5. Exclude hypothyroidism and glucocorticoid

deficiency – particularly in patients with
neurosurgical conditions
Page 38 of 41
38
Goal Urgent correction by 4-6 mmol/L to prevent
brain herniation and neurological damage from
cerebral ischemia
Recommended Treatment
 Severe Symptoms 100 mL of 3% NaCl infused intravenously

over 10 minutes x 3 as needed
 Mild to Moderate Symptoms 3% NaCl infused at 0.5-2 mL/kg/h
with a low risk of herniation
 SIADH Fluid restriction or vaptans

Rate of Correction
 True Acute Hyponatremia Not restricted, nor is relowering of excessive
corrections indicated
 Uncertainty Whether the Hyponatremia Increment of serum sodium 4-6 mmol/L within
is Chronic 24h, relowering of excessive corrections
recommended
Page 39 of 41
39
ABBREVIATIONS
ACTH adrenocorticotropic hormone
ADH antidiuretic hormone
ANP atrial natriuretic peptide

AQP aquaporin
AVP arginine vasopressin
BBB blood brain barrier

BNP brain natriuretic peptide
CSWS cerebral salt wasting syndrome
L liter
mmol millimole
MRI magnetic resonance imaging
ODS osmotic demyelination syndrome
SAH subarachnoid hemorrhage
SIADH syndrome of inappropriate antidiuretic hormone excretion
TBI traumatic brain injury
V1 vasopressin 1 (receptor)
V2 vasopressin 2 (receptor)
40
Page 40 of 41
Page 41 of 41
41

Hyponatremia in Neurotrauma - The Role of Vasopressin

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Hyponatremia in Neurotrauma - The Role of Vasopressin

Running title: Hyponatremia in Neurotrauma

Table of Contents title: Hyponatremia in Neurotrauma – Role of Vasopressin

Corresponding author: Andrea Kleindienst, M.D., Ph.D.

Dept. of Neurosurgery, Friedrich-Alexander-University Erlangen-Nuremberg

Schwabachanlage 6, D-91054 Erlangen, Germany

Phone +49 9131 85 34577, Fax +49 9131 85 34551

Mark J. Hannon, M.D.

Consultant Endocrinologist and Physician

Bantry General Hospital, Bantry, Co. Cork, Ireland

Phone: +353 27 50133

Michael Buchfelder, M.D., Ph.D.

Dept. of Neurosurgery, Friedrich-Alexander-University Erlangen-Nuremberg

Schwabachanlage 6, D-91054 Erlangen, Germany

Phone +49 9131 85 34566, Fax +49 9131 85 34476

Joseph G. Verbalis, M.D.

Dept. of Endocrinology, Georgetown University Medical Center,

Suite 232 Building D, 4000 Reservoir Rd NW, Washington, DC 20007, USA.

Phone +1 202 687 2818

concentration to <125 mmol/L. The pathophysiology of hyponatremia in neurotrauma is not

precipitating neurological deterioration. Unless hyponatremia is corrected promptly and effectively,

of them experiencing a decrease in serum sodium concentration to <125 mmol/L 1, 2.

precipitating neurological deterioration. Unless hyponatremia is corrected promptly and effectively,

The Clinical Importance of Hyponatremia

(<125 mmol/L) as compared to 9% in normonatremic controls, and increased up to 50% in patients

hyponatremia (130–134 mmol/L, hazard ratio 1.38) 15.

hyponatremia is the commonest electrolyte abnormality in neurosurgical patients, occurring in up to

of outcomes, its importance is often overlooked 18.

Noncardiogenic pulmonary edema has also been described 21, 22.

Pathophysiology of Hyponatremia in Neurotrauma

Syndrome of inappropriate antidiuretic hormone secretion

this peptide may in future serve as a surrogate of AVP secretion 32.

Vasopressin receptors and specific antagonists

which limits the evidence base in neurotrauma.

above. However, this warning is not effective in Europe.

Adrenocorticotropic hormone deficiency

In patients with hyponatremia following neurotrauma, it is important to distinguish euvolemic

adrenocorticotropic insufficiency is almost identical to that of SIADH. Although apparently

potential cause of hyponatremia in any patient with neurotrauma.

neurotrauma patients upon which to base an appropriate cut-off.

Cerebral salt wasting syndrome

natriuresis simply represents an escape from SIADH-induced antidiuresis 57.

effect of renal denervation 59.

Hyponatremia following Traumatic Brain Injury

exclusive cause of hyponatremia following TBI.

Hyponatremia following Subarachnoid Hemorrhage

general causes of hyponatremia outlined in Table 2. However, there is a considerable dispute as to

electrolyte abnormalities as a manifestation of glucocorticoid deficiency. It is now apparent that acute

acute phase of SAH 83.

cortisol measurements in this population.

transient and self-resolving phenomenon.

Treatment of symptomatic hyponatremia is difficult. Untreated severe hyponatremia, especially when

poor with persistent neurological deficit 21.

hyponatremia can be reversed by the administration of intravenous dextrose, parenteral desmopressin,

unequivocally, treatment with parenteral glucocorticoids usually leads to a rapid resolution of

hyponatremia due to ACTH deficiency.

hyponatremia, but requires prolonged intravenous administration. Demeclocycline, a tetracycline

hyponatremia are suboptimal in patients with SIADH due to neurotrauma.

effective and safe AVP antagonist is obvious.

management of hyponatremia in neurotrauma patients.

The treatment of acute symptomatic hyponatremia is indicated if: