Management of Hyponatremia and Volume Contraction
Alejandro A. Rabinstein • Nicolas Bruder
Published online: 12 July 2011Ó Springer Science+Business Media, LLC 2011
Hyponatremia is the most common electrolyte
imbalance seen in patients with aneurysmal subarachnoid
Hydrocortisone Á Saline Á Sodium Á Vasopressin
hemorrhage, occurring in one-third to one-half of patients. Hyponatremia may be caused by cerebral salt wasting andby the syndrome of inappropriate secretion of antidiuretichormone or a combination of both. Limited data are avail-
able describing hyponatremia treatment in subarachnoidhemorrhage patients. A Medline search was performed for
Hyponatremia is the most common electrolyte imbalance in
English-language manuscripts describing original research
patients with aneurysmal subarachnoid hemorrhage (SAH),
in the treatment for hyponatremia in patients with aneu-
occurring in 30-50% of cases Hyponatremia is typ-
ically defined as a serum sodium concentration < 135
articles were identified as followed: three testing fludro-
mmol/L; some studies require these values to be present
cortisone, two hydrocortisone, and one each for hypertonic
over two consecutive days to satisfy the definition. Hypo-
saline and 5% albumin. Data quality for treatment efficacy
natremia typically occurs between days 3 and 14 after
and safety were moderate for corticosteroid studies and low
aneurysm rupture, but some series have noted that it usually
or very low for hypertonic saline and 5% albumin. Avail-
presents before the onset of vasospasm in patients who
able data, although limited, support early treatment with
corticosteroids to limit hyponatremia, with fludrocortisone
The mechanisms that likely mediate the development of
hyponatremia in SAH are cerebral salt wasting (CSW) andthe syndrome of inappropriate secretion of antidiuretichormone (SIADH) These two processes are dif-ficult to discriminate in clinical practice. Both CSW and
Participants: Michael N. Diringer, Thomas P. Bleck, Nicolas Bruder,
SIADH are associated with hypotonic hyponatremia and
E. Sander Connolly, Jr., Giuseppe Citerio, Daryl Gress, Daniel
inappropriately high urinary sodium content; however, they
Hanggi, J. Claude Hemphill, III, MAS, Brian Hoh, Giuseppe Lanzino,
are fundamentally different in their pathogenesis. CSW is
Peter Le Roux, David Menon, Alejandro Rabinstein, Erich
thought to be caused by increased secretion of natriuretic
Schmutzhard, Lori Shutter, Nino Stocchetti, Jose Suarez, MiriamTreggiari, MY Tseng, Mervyn Vergouwen, Paul Vespa, Stephan
peptides (likely mediated by activation of the sympathetic
nervous system) leading to excessive excretion of sodiumin the urine. High intratubular sodium content secondarily
provokes an osmotic gradient that drags water into the
Department of Neurology, Mayo Clinic, 200 First Street,SW-Mayo W8B, Rochester, MN 55905, USA
urine. Consequently, CSW is associated with intravascular
volume contraction. Conversely, SIADH is caused byexcessive secretion of antidiuretic hormone leading to free
water retention. As a result, SIADH is associated with
Department of Anesthesiology and Intensive Care,Universite' de la Me'diterrane'e, Marseille, France
normal or slightly expanded intravascular volume. Hence,
assessment of intravascular volume is the best measure to
This review was designed to explore evidence in the
differentiate CSW and SIADH at the bedside [, ].
published literature for the treatment for hyponatremia in
Discriminating between CSW and SIADH is important
patients with aneurysmal SAH. Original research studies
as they require different treatments. Fluid restriction, as
were evaluated for treatment outcome and safety, with
usually recommended in cases of pure SIADH, is danger-
study design and quality of evidence assessed for each
ous in patients with SAH and vasospasm ,
Therefore, in practice, this management strategy is dis-couraged. Furthermore, as CSW and SIADH may coexistin the same patient low circulating blood volume is
quite prevalent in hyponatremic patients . Carefulrepletion of volume losses and assessment of circulating
A comprehensive electronic Medline literature search
evaluating the role and treatment for hyponatremia in
The most feared complication of hypotonic hyponatremia
aneurysmal SAH was conducted to include English-lan-
is cerebral edema. Seizures can occur in severe cases (usu-
guage articles published through October 2010. Candidate
ally with serum sodium concentrations < 125-120 mmol/
articles were identified by searching for papers that inclu-
L). It is, however, difficult to determine the contribution of
ded the key words subarachnoid hemorrhage and sodium.
hyponatremia to complications in individual patients. Fur-
A separate search was performed using the key word
thermore, the relationship between cerebral edema and brain
subarachnoid hemorrhage and at least one of the following
water content is complex and multiple factors, such as reg-
additional key words: fludrocortisone, hydrocortisone,
ulation of aquaporin-4 channels, may have a more
mineralocorticosteroids, hypertonic saline, 3% sodium
determinant role than serum sodium concentration and
chloride, 3% sodium acetate, albumin, vasopressin antag-
onists, and conivaptan. Titles and abstracts from candidate
There is no conclusive evidence that hyponatremia
articles were reviewed to select studies focused on man-
influences the prognosis in patients with SAH. In a series of
agement of hyponatremia in aneurysmal SAH. Among
298 patients, Qureshi et al.  found that hypernatremia,
these articles, selected articles were included if they
but not the more common hyponatremia, was independently
described original research treatment studies that provided
associated with poor outcomes at 3 months. It is unclear
information to address at least one of the following
whether the association between poor prognosis and
hypernatremia is related to a direct detrimental effect of
What is the best time for initiation of treatment for
hypernatremia or hypernatremia is a surrogate marker of
hyponatremia (before hyponatremia occurs or once it
other potentially causative or contributory factors (e.g.,
is established and, if the latter, using what sodium
greater hypothalamic damage from the hemorrhage or more
frequent use of osmotherapy). Similarly, in their analysis of
What are the best treatment alternatives?
580 patients, Wartenberg et al. ] found that hypernatre-
mia (defined as serum sodium concentration > 150 mmol/
What are the complications from treatment?
L) had a greater prognostic impact than hyponatremia
What are the complications from hyponatremia?
(defined as serum sodium concentration < 130 mmol/L),although the association between hypernatremia and poor
Selected studies were evaluated using the GRADE
outcome was not independent and appeared related to the
presence of intracranial hypertension. In these studies,hyponatremia was not associated with symptomatic vaso-spasm or delayed cerebral ischemia. The difference with
older studies reporting an association between hyponatre-mia and higher risk of cerebral infarctions  may be
A total of 315 articles were identified using the key words
explained by the past practice of fluid restriction and the
subarachnoid hemorrhage and sodium, with 52 potentially
more aggressive fluid replacement protocols used in the
pertinent articles for the management of hyponatremia in
more contemporary series. A recent study confirmed that
aneurysmal SAH identified. The second search using the
hyponatremia is not associated with poor outcome in most
broader range of key words identified no additional
patients with aneurysmal SAH, although an association was
potentially pertinent articles that had not been found using
found between late-onset hyponatremia (developing after
the key word sodium. Among these studies, 8 studies were
day 3 post-SAH) in poor-grade cases and higher risk of
found to address at least one of the required questions listed
cerebral infarction, probably indicating a greater vulnera-
above [-One study focused predominantly on
bility to volume depletion in these patients [
pathophysiology rather than on treatment and was therefore
not included . Among the remaining 7 studies, the
Selected studies did not report evidence about compli-
majority tested a corticosteroid (5 studies, 3 fludrocorti-
sone, and 2 hydrocortisone), with one study testing
aneurysmal SAH. The literature, however, suggests that
hypertonic saline infusion and one 5% albumin.
hyponatremia is not associated with worse outcome in
No studies were included among the selected articles
patients with SAH who receive adequate volume and
describing vasopressin receptor antagonists in SAH. Vaso-
pressin receptor antagonists, such as conivaptan, have beenshown to be effective for the treatment of hyponatremia
associated with euvolemic or hypervolemic conditions. Because vasopressin receptor antagonists increase
Interpretations about prevention or correction of hypona-
urine output and hypovolemia is common in hyponatremic
tremia and natriuresis that can be made based on the
patients with SAH, there is a concern that these drugs could
available literature are limited by problems with the quality
aggravate cerebral ischemia in these patients. The safety
of the evidence reviewed. The quality of the evidence for
and efficacy of these medications have not been properly
the end point of prevention or correction of hyponatremia
evaluated in clinical studies of SAH patients.
and natriuresis is summarized in Table. Table sum-marizes the quality of the evidence regarding the safety of
tested therapies. Overall, the quality of the evidence ismoderate for corticosteroids with mineralocorticoid action
Most studies evaluated preventive strategies and aimed for
such that further research is likely to have an important
maintenance of normal serum sodium concentration
impact on our confidence in the estimate of the effect and
(i.e., 135-145 mmol/L). Overall, corticosteroids with
may change the estimate. Evidence quality is very low to
mineralocorticoid action were found to be consistently
low for hypertonic saline and albumin; thus, the estimate of
effective in preventing excessive natriuresis and hypona-
the effect is very uncertain at present and further research is
tremia when started early after SAH onset. Side effects
very likely to have an important impact on this estimate.
were infrequent and not severe. There was no evidence of
Safety data are likewise limited but reassuring, espe-
mineralocorticoid escape effect after administration of the
cially for corticosteroids with mineralocorticoid action, for
corticosteroid for a few days in the studies reviewed.
which more data are available. The number of patients
Data were too scant to assess the value of hypertonic
included in the available studies, however, is low, and
saline or 5% albumin in the management of hyponatremia.
patients deemed to be at high risk of complications fromfluid retention were often excluded from published studies.
Therefore, further research is needed to establish clearsafety.
Corticosteroids with mineralocorticosteroid action areassociated with increased incidence of hyperglycemia(hydrocortisone), hypokalemia (hydrocortisone and flu-
which are readily treatable. The incidence of congestive
Hyponatremia and volume contraction are common after
heart failure/pulmonary edema does not appear to be sig-
aneurysmal SAH. Treatment is generally focused on
nificantly increased. In some cases, hydrocortisone was
maintaining normal serum sodium concentration and
selected instead of fludrocortisone because fludrocortisone
intravascular volume. Studies show that early treatment
has a longer half-life, which could increase the risk of
with mineralocorticoids can ameliorate natriuresis and
congestive heart failure. The studies testing fludrocorti-
hyponatremia, with a better side effect profile seen with
sone, however, did not appear to substantiate this concern.
fludrocortisone compared with hydrocortisone, due to
Safety data for hypertonic saline and 5% albumin were
greater glucocorticoid action with hydrocortisone. Only
limited from the selected studies. In general, the literature
early institution of these drugs (i.e., within a couple of days
suggests that continuous infusion of 3% saline (up to a
of aneurysm rupture) has been tested, and the value of
serum sodium concentration of 160 mmol/L) can be per-
starting a mineralocorticoid once a patient has become
formed safely when adequately monitored [
polyuric or hyponatremic is unknown.
Frequent boluses of 5% albumin may also be associated
While hypertonic saline may be used to treat severe
with low risk of complications [Although these
hyponatremia, it is unclear whether this treatment will be
data are encouraging, data about the safety of hypertonic
helpful for preventing or improving symptomatic vaso-
saline and albumin derive mostly from studies not designed
spasm. Albumin can ameliorate excessive fluid and sodium
to evaluate the management of hyponatremia.
losses in the urine; however, its impact on functional
outcome is uncertain. Vasopressin receptor antagonists are
aquaporin-4 mediates the effect of osmotherapy in postischemic
effective for the treatment for hyponatremia in patients
cerebral edema. Crit Care Med. 2008;36:2634-40.
14. Wartenberg KE, Schmidt JM, Claassen J, Temes RE, Frontera
with SIADH, but they have not been tested in aneurysmal
JA, Ostapkovich N, Parra A, Connolly ES, Mayer SA. Impact of
SAH patients in whom they could be dangerous by exac-
medical complications on outcome after subarachnoid hemor-
rhage. Crit Care Med. 2006;34:617-23.
15. Hasan D, Wijdicks EF, Vermeulen M. Hyponatremia is associ-
ated with cerebral ischemia in patients with aneurysmalsubarachnoid hemorrhage. Ann Neurol. 1990;27:106-8.
16. Zheng B, Qiu Y, Jin H, Wang L, Chen X, Shi C, Zhao S. A
predictive value of hyponatremia for poor outcome and cerebral
1. Qureshi AI, Suri MF, Sung GY, et al. Prognostic significance of
infarction in high-grade aneurysmal subarachnoid haemorrhage
hyperatremia and hyponatremia among patients with aneurysmal
patients. J Neurol Neurosurg Psychiatry. 2011;82:213-7.
subarachnoid hemorrhage. Neurosurgery. 2002;50:749-55.
17. Atkins D, Best D, Briss PA, et al. Grading quality of evidence
2. Audibert G, Steinmann G, de Talance' N, et al. Endocrine
and strength of recommendations. BMJ. 2004;328:1490.
response after severe subarachnoid hemorrhage related to sodium
18. Wijdicks EF, Vermeulen M, van Brummelen P, van Gijn J. The
and blood volume regulation. Anesth Analg. 2009;108:1922-8.
effect of fludrocortisone acetate on plasma volume and natriuresis
3. Suarez JI, Qureshi AI, Parekh PD, et al. Administration of
in patients with aneurysmal subarachnoid hemorrhage. Clin Neu-
hypertonic (3%) sodium chloride/acetate in hyponatremic patients
with symptomatic vasospasm following subarachnoid hemor-
19. Hasan D, Lindsay KW, Wijdicks EF, et al. Effect of fludrocor-
rhage. J Neurosurg Anesthesiol. 1999;11:178-84.
tisone acetate in patients with subarachnoid hemorrhage. Stroke.
4. Okuchi K, Fujioka M, Fujikawa A, et al. Rapid natriuresis and
preventive hypervolaemia for symptomatic vasospasm after
20. Mori T, Katayama Y, Kawamata T, Hirayama T. Improved
subarachnoid haemorrhage. Acta Neurochir (Wien). 1996;138:
efficiency of hypervolemic therapy with inhibition of natriuresis
by fludrocortisone in patients with aneurysmal subarachnoid
5. Diringer MN, Wu KC, Verbalis JG, Hanley DF. Hypervolemic
hemorrhage. J Neurosurg. 1999;91:947-52.
therapy prevents volume contraction but not hyponatremia fol-
21. Moro N, Katayama Y, Kojima J, Mori T, Kawamata T. Prophy-
lowing subarachnoid hemorrhage. Ann Neurol. 1992;31:543-50.
lactic management of excessive natriuresis with hydrocortisone
6. Rabinstein AA, Wijdicks EF. Hyponatremia in critically ill
for efficient hypervolemic therapy after subarachnoid hemor-
neurological patients. Neurologist. 2003;9:290-300.
7. Palmer BF. Hyponatraemia in a neurosurgical patient: syndrome
22. Katayama Y, Haraoka J, Hirabayashi H, et al. A randomized
of inappropriate antidiuretic hormone secretion versus cerebral
controlled trial of hydrocortisone against hyponatremia in patients
salt wasting. Nephrol Dial Transplant. 2000;15:262-8.
with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:
8. Brimioulle S, Orellana-Jimenez C, Aminian A, Vincent JL.
Hyponatremia in neurological patients: cerebral salt wasting ver-
23. Suarez JI, Shannon L, Zaidat OO, et al. Effect of human albumin
sus inappropriate antidiuretic hormone secretion. Intensive Care
administration on clinical outcome and hospital cost in patients
with subarachnoid hemorrhage. J Neurosurg. 2004;100:585-90.
9. Diringer MN. Neuroendocrine regulation of sodium and volume
24. Mayer SA, Solomon RA, Fink ME, et al. Effect of 5% albumin
following subarachnoid hemorrhage. Clin Neuropharmacol.
solution on sodium balance and blood volume after subarachnoid
hemorrhage. Neurosurgery. 1998;42:759-67.
10. Bruder N, Ichai C, Gelb AW. Hyponatremia and subarachnoid
25. Bhardwaj A. Neurological impact of vasopressin dysregulation
hemorrhage: will that be one pinch or two of salt? Anesth Analg.
and hyponatremia. Ann Neurol. 2006;59:229-36.
26. Rabinstein AA. Vasopressin antagonism: potential impact on
11. Wijdicks EF, Vermeulen M, Hijdra A, van Gijn J. Hyponatremia
neurologic disease. Clin Neuropharmacol. 2006;29:87-93.
and cerebral infarction in patients with ruptured intracranial
27. Froelich M, Ni Q, Wess C, Ougorets I, Ha¨rtl R. Continuous
aneurysms: is fluid restriction harmful? Ann Neurol. 1985;17:
hypertonic saline therapy and the occurrence of complications in
neurocritically ill patients. Crit Care Med. 2009;37:1433-41.
12. Wijdicks EF, Vermeulen M, ten Haaf JA, Hijdra A, Bakker WH,
28. Woo CH, Rao VA, Sheridan W, Flint AC. Performance charac-
van Gijn J. Volume depletion and natriuresis in patients with a
teristics of a sliding-scale hypertonic saline infusion protocol for
ruptured intracranial aneurysm. Ann Neurol. 1985;18:211-6.
the treatment of acute neurologic hyponatremia. Neurocrit Care.
13. Zeynalov E, Chen CH, Froehner SC, Adams ME, Ottersen OP,
Amiry-Moghaddam M, Bhardwaj A. The perivascular pool of
OPTIMAL MEDICAL THERAPY FOR THE DYSVASCULAR PATIENT : UNDERSTANDING ATHEROSCLEROSIS AND THE ‘BIG PICTURE’ From the Division of Vascular & Endovascular Surgery, University of South Florida Health, Tampa, Florida Correspondence : Martin Back, MD USF Vascular 2A Columbia Dr Tampa, FL 33606 Phone 813-259-0956 Fax 813-259-0606 Ema Peripheral arterial disease (PAD) describes the manifes
The METEX study ( Met hotrexate versus Ex pectant management) Methotrexate versus expectant management in women with ectopic pregnancy Background The incidence of ectopic pregnancy (EP) is approximately 1-2 % of all pregnancies. An early diagnosis is possible by transvaginal sonography (TVS) in combination with serum hCG measurements. As a consequence, the clinical presentation