Med Intensiva.

2015;39(4):234---243

www.elsevier.es/medintensiva

REVIEW

Hyponatremia in the neurocritical care patient:

An approach based on current evidence夽
W. Manzanares a,∗ , I. Aramendi a , P.L. Langlois b , A. Biestro a

a
Cátedra de Medicina Intensiva, Centro de Tratamiento Intensivo, Hospital de Clínicas, Facultad de Medicina, Universidad de la
República (UdeLaR), Montevideo, Uruguay
b
Hôpital Fleurimont, Centre Hospitalier Universitaire de Sherbrooke, Département d’Anesthésie-Réanimation, Faculté
de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, Canada

Received 16 September 2014; accepted 11 November 2014

KEYWORDS Abstract In the neurocritical care setting, hyponatremia is the commonest electrolyte disor-
Hyponatremia; der, which is associated with significant morbimortality. Cerebral salt wasting and syndrome
Neurocritically ill of inappropriate antidiuretic hormone have been classically described as the 2 most frequent
patient; entities responsible of hyponatremia in neurocritical care patients. Nevertheless, to distin-
Cerebral salt wasting; guish between both syndromes is usually difficult and useless as volume status is difficult to
Syndrome of be determined, underlying pathophysiological mechanisms are still not fully understood, fluid
inappropriate restriction is usually contraindicated in these patients, and the first option in the therapeutic
antidiuretic strategy is always the same: 3% hypertonic saline solution. Therefore, we definitively agree
secretion; with the current concept of ‘‘cerebral salt wasting’’, which means that whatever is the etiol-
Hypertonic saline ogy of hyponatremia, initially in neurocritical care patients the treatment will be the same:
solution hypertonic saline solution.
© 2014 Published by Elsevier España, S.L.U.

PALABRAS CLAVE Hiponatremias en el paciente neurocrítico: enfoque terapéutico basado en la

Hiponatremias; evidencia actual
Paciente
neurocrítico; Resumen En el paciente neurocrítico la hiponatremia es la distonía más frecuente, com-
Cerebro perdedor portándose como un predictor pronóstico. Clásicamente, el cerebro perdedor de sal y la
de sal; secreción inadecuada de hormona antidiurética han sido las 2 entidades responsables de explicar

夽 Please cite this article as: Manzanares W, Aramendi I, Langlois PL, Biestro A. Hiponatremias en el paciente neurocrítico: enfoque

terapéutico basado en la evidencia actual. Med Intensiva. 2015;39:234---243

∗ Corresponding author.

E-mail address: [email protected] (W. Manzanares).

2173-5727/© 2014 Published by Elsevier España, S.L.U.

Hyponatremia in the neurocritical care patient 235

la mayor parte de los casos de hiponatremia en estos pacientes. Sin embargo, en virtud de la
Secreción inadecuada dificultad en establecer el estado de la volemia en el paciente crítico, el diagnóstico diferencial
de hormona es con frecuencia difícil de establecer. Por otra parte, en el paciente neurocrítico el diagnóstico
antidiurética; diferencial entre ambos síndromes no ha demostrado ser de utilidad debido a que el cloruro
Cloruro de sodio de sodio hipertónico es la piedra angular en el tratamiento de ambos cuadros, y la restricción
hipertónico hídrica con frecuencia está contraindicada. Es por ello que ha surgido el concepto de «cerebro
falto de sal», lo cual traduce la necesidad del aporte de sodio como estrategia terapéutica en
todos los casos.
© 2014 Publicado por Elsevier España, S.L.U.

Introduction between SIADH and CSW is often difficult to establish, and

both syndromes moreover have been suggested to be part of
one same disease condition---manifesting successively in the
Hyponatremia is defined as a serum sodium concentration of
same patient.10,11
<136 mmol/l, and is the most common electrolyte disorder
Considering the above, the present review was carried
in hospitalized patients (affecting 15---20% of all individu-
out to provide an update on the etiological and phys-
als requiring hospital admission).1,2 Likewise, hyponatremia
iopathological aspects of hyponatremia in the neurocritical
is a mortality predictor in critical patients. In this regard,
patient, placing special emphasis on the treatment strate-
Stelfox et al.3 have shown that hyponatremia acquired in
gies adjusted to current evidence.
the Intensive Care Unit (ICU) increases hospital mortal-
ity by 16---28% (p < 0.001). More recently, Sturdik et al.4
have demonstrated that an age of over 65 years, the Hypoosmolarity and neuronal adaptation
presence of dilutional hyponatremia, and its inadequate mechanisms
correction are three independent risk factors associated
to increased hospital mortality in hyponatremic patients. Hyponatremia/hypoosmolarity is a primary cause of water
Corona et al.,5 in a systematic literature review and entry to the cells, resulting in an increase in cell vol-
metaanalysis including 80 randomized clinical trials (RCTs), ume (volumetric variation secondary to osmotic change).14
showed hyponatremia---even when mild---to be associated to This change in turn triggers a volume-regulating mecha-
a significant increase in mortality in the ICU (RR: 2.60; 95%CI: nism called regulatory volume decrease,15 characterized
2.31---2.93, p < 0.0001).5 Likewise, inadequate treatment of by a rapid potassium, chloride and sodium outflow phase
this electrolyte disorder, failing to observe the required with the purpose of quickly ‘‘buffering’’ the osmotic
correction range (overcorrection), as well as insufficient change, and a second outflow phase of organic osmolytes
treatment, imply added risk that further worsens the prog- (‘‘non-perturbing’’ osmolytes) which accumulate in the
nosis of critical patients with hyponatremia.6,7 neurons without producing deleterious effects upon cell
In neurocritical patients, hyponatremia is also the most structure and function (cytoprotective function). These
common electrolyte disorder, having been reported in up to compensating mechanisms are incomplete in acute hypona-
50% of all cases of serious neurological injury.8 Among the tremia (evolution under 48 h) and complete in chronic
acute brain conditions, severe traumatic brain injury (TBI) hyponatremia (evolution longer than 48 h). In the pres-
and aneurysmal subarachnoid hemorrhage (SAH) are those ence of cell swelling, a first phase (called the rapid
with the highest incidence of hyponatremia. In this regard, phase) is observed, involving osmolyte outflow, followed
Sherlock et al.9 showed hyponatremia to be more frequent by a second phase (or slow phase) characterized by inhi-
in patients with hypophyseal disease (5/81; 6.25%), TBI bition of the synthesis of these osmolytes.16 However,
(44/457; 9.6%) and intracranial tumors (56/355; 15.8%).9 In in acute neurological injury these protective mecha-
their study the authors found that among 316 patients with nisms carried out by the neuroglia in response to plasma
SAH, 179 (56.6%) developed hyponatremia, which proved hypotonicity are altered. Likewise, the increase in cir-
severe (natremia <130 mmol/l) in 62 cases (19.6%). In SAH, culating antidiuretic hormone (ADH) levels observed in
hyponatremia can be due to different causes, including the two characteristic conditions (CSW and SIADH) results
syndrome of inappropriate antidiuretic hormone secretion in action upon the V1a receptors of vascular smooth
(SIADH), so-called cerebral salt wasting (CSW)---also known muscle. The stimulation of these receptors generates vaso-
as renal salt wasting---and pressure natriuresis or acute cor- constriction independent of the endothelium, due to an
ticosteroid deficiency (hypocortisolism).10---13 Up until now, increase in the calcium levels through activation of the
CSW has been regarded as the most frequent cause of phosphatidylinositol-bisphosphonate cascade.17 This cere-
hyponatremia in the evolutive course of aneurysmal SAH, bral vasoconstrictor effect reduces cerebral blood flow,
though recently this has been strongly questioned. However, oxygen supply to the astroglia, and the production of ATP
on the basis of current knowledge, the differential diagnosis and phosphocreatine.17
236 W. Manzanares et al.

involved. Likewise, a noninvasive technique widely used in

Table 1 Conventional schematic representation of cere-
the ICU, such as ultrasound, can prove useful for estimating
bral salt wasting (CSW) and syndrome of inappropriate
volemia in patients of this kind.
antidiuretic hormone secretion (SIADH).
Recently, Gritti et al.24 have evaluated the cumu-
CSW SIADH lative sodium balance with the purpose of diagnosing
Extracellular volume ↓ Normal or ↑
CSW in 35 neurocritical patients. In these individuals,
Water balance Negative Normal or ↑
the authors showed that the risk of developing hypov-
Sodium balance Negative Normal or ↑
olemia is increased 7.1-fold (p < 0.001) in the presence
Natriuresis ↑↑↑ ↑
of a negative sodium balance. Likewise, the multivariate
Body weight = or ↓ = or ↑
analysis identified a negative water balance and a neg-
Dehydration Present Absent
ative sodium balance of >2 mEq/kg as independent risk
PCP ↓ = or ↑
factors for hypovolemia. A negative sodium balance was
CVP ↓ = or ↑
therefore identified as a useful tool for establishing a dif-
Plasma/urine osmolarity ↓ ↑
ferential diagnosis between CSW and SIADH in neurocritical
Hematocrit ↑ = or ↓
patients.24
Albuminemia ↑ = or ↓
Azotemia/creatininemia ↑ Normal Hyponatremia in specific clinical scenarios
Uricemia ↓ ↓
Serum potassium = or ↑ = or ↓ Subarachnoid hemorrhage
CSW: cerebral salt wasting; PCP: pulmonary capillary pressure;
CVP: central venous pressure; SIADH: inappropriate antidiuretic Hyponatremia is highly prevalent in patients with SAH, being
hormone secretion syndrome; ↑: increased; ↓: decreased; =: described in 10---50% of the cases, particularly in high-grade
without changes. SAH, in the presence of anterior circulation aneurysms,
Source: Kirkman et al.,2 Kirkman,8 Yee et al.16 and Hwang and and in hydrocephalia. In 2005, Kao et al.25 found 22.9% of
Hwang.21 the case of hyponatremia to be secondary to CSW, while
35.4% corresponded to SIADH. In an elegant and recent
study, Hannon et al.26 prospectively evaluated the etiology
of hyponatremia in a sample of 100 patients with SAH, based
Etiology and physiopathology on clinical assessment and the determination of serum cor-
tisol, arginine, vasopressin and brain natriuretic peptide. In
their study,26 the authors identified SIADH as the predom-
Cerebral salt wasting and SIADH have been defined as the
inant cause (71.4%), while hypocortisolism accounted for
most common causes of hyponatremia in the neurocritical
8.2% of the cases of hyponatremia. The remaining 20.4% of
patient.18,19 However, there are other less prevalent etiolo-
the cases were in turn attributed to hypovolemia or to the
gies, such as the hypervolemic presentations and pressure
type of fluid administered. However, the most significant
natriuresis, which also must be discarded in order to estab-
finding of the mentioned study was the absence of cases
lish an adequate diagnostic strategy.20
consistent with CSW.26
Likewise, despite the notorious interest in these two syn-
Nakagawa et al.27 have recently demonstrated that
dromes in recent years, the differential diagnosis between
the early administration of fludrocortisone acetate can
CSW and SIADH is often a genuine challenge, since the
reduce the risk of hyponatremia (26% versus 16%) and
clinical manifestations are not always conclusive, and the
of symptomatic vasospasm (18.5% versus 6.1%) in SAH.
laboratory test information is frequently confusing. In this
These data could indicate the existence of an asso-
regard, the current tendency is to classify both conditions
ciation between hyponatremia and the development of
under one same disease entity.16,21
vasospasm, though further studies are needed to clarify this
Table 1 shows the main characteristics allowing us
relationship.27 Likewise, in SAH, triple H therapy (hyperten-
to establish a differential diagnosis between CSW and
sion, hypervolemia and hemodilution) as an anti-vasospasm
SIADH.2,8,12,16
strategy promotes pressure natriuresis and the risk of
Classically, the presence of hypovolemia has been
hyponatremia.
regarded as the distinctive feature of CSW, though it is dif-
ficult to diagnose in the neurocritical patient.
However, a series of methods are now available for Ischemic stroke
assessing volemia and cardiac output in the critical patient.
With the introduction of hemodynamic monitoring devices The presence of hyponatremia in ischemic stroke has been
fundamented upon arterial pulse wave analysis (PiCCO® , proposed as a predictor of poor outcome, though the under-
PulseCO® , FloTrac/Vigileo® and MostCare® , among others), lying etiopathogenesis is not fully clear. Huang et al.,28
it has become simple to estimate these parameters on a con- in 925 patients with a first episode of ischemic stroke,
tinuous basis.22 The use of such invasive techniques provides recorded an incidence of hyponatremia of 11.6%, which
adequate results that are better than static preload values in turn was associated to a significant increase in mor-
such as central venous pressure or pulmonary artery wedge tality after three years (RR: 2.23; 95%CI: 1.30---3.82%).
pressure.23 The use of a device of this kind may be necessary Likewise, Rodrigues et al.29 recently identified the presence
in order to obtain a good evaluation of patient volemia, and of hyponatremia in 16% of 565 stroke patients. In this popu-
therefore an adequate diagnosis of the type of hyponatremia lation, hyponatremia was associated to a significant increase
Hyponatremia in the neurocritical care patient 237

in hospital mortality (p = 0.039) and in mortality after three postoperative period. In turn, 19% of the hyponatremia
months (p = 0.001) and one year (p = 0.001). A surprising episodes were asymptomatic; the mean timing of appear-
observation was a greater incidence of urinary infection ance was day 4; and preoperative hypopituitarism was the
in the patients with hyponatremia. Lastly, hyponatremia only variable associated to an increased risk of postopera-
associated to a first episode of ischemic stroke is an indepen- tive hyponatremia. Likewise, hyponatremia was present in
dent risk factor for the development of seizures, according 15% of the cases requiring hospital admission. Lastly, the
to Wang et al.30 (OR: 2.10) and Roivainen et al.31 (OR: 3.26; authors concluded that SIADH was the predominant syn-
95%CI: 1.41---7.57). drome in this population---CSW being exceptional.36 In turn,
Hussain et al.,37 in 339 neurosurgical patients, recorded a
15% incidence of postoperative hyponatremia in the first 30
Traumatic brain injury
days after surgery. Of these episodes, 50% were regarded as
mild, and hospital readmission proved necessary in 6.4% of
Hyponatremia is highly prevalent in patients with
the patients.
severe TBI, where dysfunction of the hypothalamic---
hypophyseal---adrenal axis is common,32 having been
described in 15---68% of the cases, with an incidence of Treatment of hyponatremia
hypopituitarism of 50%33 in the course of the disorder. In
severe TBI, hypopituitarism is more frequent in younger Independently of the underlying etiology and of the fact
patients, as well as in those administered etomidate, that the physiopathology involved is not always clear, the
propofol or fenobarbital.32 The clinical manifestations presence of hyponatremia in neurocritical patients justi-
include hypocortisolism, hyponatremia, hypoglycemia and fies grouping of the two classical hyponatremia-producing
arterial hypotension.34 In clinical practice the systematic syndromes in one same treatment strategy.
assessment of hypophyseal function has been recommended The treatment of hyponatremia recognizes central
in patients with skull base fractures, diffuse axonal damage, pontine myelinolysis as the most severe and feared compli-
and in cases of prolonged admission to the ICU. However, cation, being related to overcorrection, while insufficient
despite the high incidence of hypocortisolism, the existing replacement may also be a cause of permanent brain
evidence contraindicates the empirical use of corticos- damage.38 For this reason, in neurocritical patients, the
teroids as specific treatment for intracranial hypertension treatment of hyponatremia requires identification of its
in TBI. severity, duration (acute and chronic forms), patient
The analysis of other causes of hyponatremia in TBI volemia status, and the severity of the clinical condi-
shows SIADH to account for 33% of the cases, presenting tion. In these patients, and depending on the evolutive
a particular association to subdural hematoma and focal stage, the appearance of hyponatremia must be regarded
contusions.32---34 Likewise, SIADH often manifests during the as a genuine medical emergency requiring the immediate
second week of admission to the ICU and during the evolu- adoption of adequate treatment measures. The follow-
tion of central or neurogenic diabetes insipidus---this being ing sections analyze the management strategies referred
explained by the release of ADH stored in the axons of the to hyponatremia in different clinical scenarios, including
neurohypophysis.21 hyponatremic encephalopathy and a number of critical neu-
Lastly, it must be mentioned that in patients with rological disorders.
severe TBI, hyponatremia may be secondary to the use
of certain drugs such as 20% mannitol---administered Severe and symptomatic hyponatremia:
as an osmotically active agent for the control
hyponatremic encephalopathy
of intracranial pressure (hypovolemic stimulus
secondary to osmotic diuresis)---carbamazepine
Recently, the European Society of Intensive Care Medicine,
and desmopressin (iatrogenic hyponatremia),
in coordination with the European Society of Endocrinol-
used for the treatment of the central diabetes
ogy and the European Renal Association-European Dialysis
insipidus.32---34
and Transplant Association, represented by the European
Renal Best Practice, have published good clinical practice
Neurosurgery guides on the diagnosis and treatment of hyponatremia in
critical patients.38 In the case of severe and symptomatic
In a retrospective analysis including 291 children subjected hyponatremia (hyponatremic encephalopathy), these guides
to tumor resection published by Hardesty et al.,35 hypona- recommend the intravenous infusion of 150 ml of 3% hyper-
tremia was present in almost 10% of the patients, and 5% tonic saline solution (HSS) over 20 min. This 3% HSS bolus
met the previously established criteria of CSW. is to be repeated in the next 20 min as long as the symp-
Trans-sphenoidal surgery is one of the surgical procedures toms persist or if natremia fails to increase significantly.
most commonly associated to hyponatremia, manifesting In this regard, dosing can be repeat up to two times
between 5 and 9 days after the operation, with a peak inci- or until a natremia increment of 5 mmol/l is achieved.38
dence on day 7. Such hyponatremia may be early (secondary The infusion of 3% HSS is able to increase natremia by
to axonal degeneration and the massive release of ADH) 1---2 mmol/h---reversion of the symptoms of hyponatremic
or late (often secondary to adrenal gland insufficiency).21 encephalopathy (seizures, altered consciousness) requiring
Jahangiri et al.,36 in 1045 consecutive surgeries, recently an increase of 4---6 mmol38 (see Fig. 1).
recorded an incidence of hyponatremia of 3% in the pre- In a way similar to the recommendations of the
operative period---a figure that increased to 16% in the European Society of Intensive Care Medicine/European Soci-
238 W. Manzanares et al.

Hyponatremia
Serum sodium <136 mmol/l

Acute (≤48 h) or chronic (>48 h)

• Symptomatic (seizures, coma): • Asymptomatic

hyponatremic encephalopathy

150 ml (2 ml/kg) 3% HSS as bolus in 3% HSS in continuous i.v. infusion to

20 min, repeated up to 2 times or until increase natremia
to 0.5 mmol/h, maximum:
obtaining a natremia increase of 5 mmol/l.
8-10 mmol/24 h
A correction of 4-6 mmol/l is necessary
to prevent herniation or greater
neurological damage.
Maximum: 8-10 mmol/24 h
Treat the underlying condition
if possible. Other treatments
depend on the etiology and on the
extracellular fluid condition

If stability is obtained, proceed

as in asymptomatic hyponatremia
Define volemia
(invasive and noninvasive methods)

Euvolemic hyponatremia
Hypovolemia hyponatremia (SIADH)
(CSW, pressure natriuresis)
* 3% HSS (maximum: 24 mmol/72 h)
*3% HSS (maximum: 24 mmol/72 h) * Fluid restriction
*Fludrocortisone 0.1-0.2 mg/ (relative contraindication in SAH)
8-12 h (oral or enteral route) * Vaptans (conivaptan: 20-40 mg/day)
*0.9% Isotonic saline solution contraindicated in moderate
(avoid desalination) to severe forms
* In refractory cases, consider:
demeclocycline, lithium, furosemide

Figure 1 Therapeutic algorithm for hyponatremia in the neurocritical patient.

ety of Endocrinology/European Renal Association-European allel to management of hyponatremia per se. In current
Dialysis and Transplant Association, Sterns et al.,20 in the clinical practice in neurological ICUs, establishing a differ-
presence of severe symptoms, recommend the administra- ential diagnosis between CSW and SIADH should no longer be
tion of 100 ml of 3% HSS via the intravenous route during seen as a crucial step for guiding treatment.12,20 It has clas-
10 min, with the possibility of repeating the dose three sically been considered that the treatment of CSW requires
times if needed, in order to control the clinical condition. vigorous sodium administration in the form of 3% HSS, with
Although there are more conservative regimens comprising the purpose of compensating natriuresis. In contrast, SIADH
6 mmol/day, it is important to emphasize that the natremia regards fluid restriction as the cornerstone of treatment,
increment when the starting concentration is ≤120 mmol/l since the renal reabsorption of free water is increased in
should not exceed 10 mmol/l during the first 24 h of 3% HSS SIADH. However, this strategy is relatively contraindicated in
administration---with a maximum increase of 8 mmol/l in the patients with SAH, due to the high risk of vasospasm (level of
24 h after obtaining a natremia level of 130 mmol/l.12,20,38 evidence ii). Likewise, other management measures that can
Thus, the increase in serum sodium should not exceed be adopted in SIADH are the use of lithium, demeclocycline
18 mmol/l in 48 h. Lastly, it must be taken into account that and furosemide (Fig. 1).
the correction of concomitant hypokalemia also favors the In 2008, Sterns and Silver12 introduced the concept of
correction of hyponatremia, with the additional need to cor- cerebral salt wasting, which assumes that in patients with
rect the hypoxemia in order to favor neuronal adaptation to severe brain injury, the presence of hyponatremia requires
the hypotonic damage. the administration of 3% HSS independently of the cause
underlying the sodium disorder.12
On the other hand, in neurocritical patients with high
Treatment of hyponatremia in the neurocritical
ADH and natriuretic peptide levels, the administration of
patient isotonic saline solution generates the so-called desalination
phenomenon,39 which can worsen hyponatremia secondary
The hyponatremia management strategy in neurocritical to natriuresis, with the renal production of electrolyte-free
patients implies treatment of the underlying cause in par- water.
Hyponatremia in the neurocritical care patient 239

3% Hypertonic saline solution HSS and fludrocortisone as a reasonable strategy for the
treatment of hyponatremia and the reduction of effective
To date, and despite the high prevalence of hyponatremia circulating volume in aneurysmal SAH. Likewise, in Octo-
in neurocritical patients, no randomized clinical trials (RCTs) ber 2010, the consensus conference of the Neurocritical
have evaluated different hypertonic fluids in the treatment Care Society on the management of aneurysmal SAH estab-
of hyponatremia. Likewise, the existing evidence on the lished that early treatment with fludrocortisone can be
use of HSS is based on non-randomized trials; as a result, used to limit natriuresis (moderate quality evidence, weak
the posology and duration of treatment cannot be clearly recommendation).50
defined.40,41 However, it is necessary to point out that fludrocorti-
Three percent HSS can safely increase natremia with- sone acetate loses efficacy when hyponatremia is severe.
out causing neurological, cardiac or renal alterations, and In 2009, Nakagawa et al.,51 in a series of 39 patients with
is often administered via a peripheral venous access, with aneurysmal SAH, found high atrial natriuretic peptide values
a low risk of complications.40,41 This solution contains the to be associated to hyponatremia. The authors postulated
minimum sodium concentration capable of exceeding the that early treatment of the latter---including the use of
maximum osmolar concentration of urine. As a result, if fludrocortisone---would be able to inhibit the late ischemic
3% HSS constitutes the only replenishment source, natremia neurological deficit, since the mentioned drug can reduce
will always increase, since the desalination phenomenon is the incidence of symptomatic vasospasm. In this regard,
highly improbable. they suggested that an increase in urine sodium levels is
Current evidence indicates that the continuous infusion a good indicator for starting enteral fludrocortisone in the
of 3% HSS is safe in the presence of strict monitoring of early stages of SAH.51 At present, in neurocritical patients
patient natremia, complying with the correction ranges, with osmotic diuresis and natriuresis (CSW), the recom-
and when the maximum target natremia is 155---160 mmol/l mended daily dose of fludrocortisone is 0.1---0.2 mg via the
(permissive or therapeutic hypernatremia).42 In this regard, oral route, 2---3 times a day. This treatment is to be main-
Aiyagari et al.43 reported a 52% mortality rate in severe tained until the normalization of natremia and volemia
hypernatremia defined as >160 mmol/l (induced or sponta- is---this often being achieved after 3---5 days of treatment.
neous), in a population of neurocritical patients. Likewise, Prolonged fludrocortisone treatment increases the incidence
Froelich et al.44 showed the appearance of hypernatremia of side effects such as hypokalemia, arterial hypertension
>155 mmol/l in neurocritical patients subjected to the and hydrostatic pulmonary edema (Table 2). Likewise, min-
continua perfusion of 3% HSS to be associated to the develop- eralocorticoid escape is a well known phenomenon that
ment of renal dysfunction, with creatininemia >1.50 mg/dl conditions tolerance to its effects and a loss of action of
(p = 0.01). the drug after administration periods of over one week.
Three percent HSS infusion can cause side effects such as On the other hand, hydrocortisone has been shown to be
hypernatremia, hyperchloremia, hyperchloremic metabolic effective for the control of natriuresis in patients with SAH
acidosis, hypokalemia and acute renal failure45 (Table 2). and hyponatremia,50 though the existing data are scarce,
On the other hand, an initial intravenous bolus may cause and further RCTs are needed to adequately assess the use
transient arterial hypotension, as well as hypervolemia and of this strategy in neurocritical patients. Lastly, the com-
hemodynamic pulmonary edema. The administration of a bined use of hydrocortisone and fludrocortisone has not been
solution of sodium lactate 0.5 M (osmolarity 1008 mOsm/l) shown to exert synergic effects in terms of sodium gain in
with the purpose of reducing the episodes of intracranial this group of patients.
hypertension in patients with TBI is able to correct natremia
without producing hyperchloremia or metabolic acidosis, as
recently demonstrated by Ichai et al.46 Vasopressin antagonists (vaptans)

Two drugs of this class, tolvaptan and conivaptan, have

Fludrocortisone acetate been approved to date by the United States Food and Drug
Administration (FDA) for the treatment of normovolemic and
In 2005, the first systematic literature review and meta- hypervolemic hyponatremia.52
analysis on the effects of corticosteroids in aneurysmal SAH Conivaptan, administered via the intravenous route, is
and primary intracerebral hemorrhage, including 8 RCTs a receptor V1a and receptor V2 antagonist, and is the
(n = 256), evidenced no positive effect with the administra- drug of choice in the hospital setting for those patients
tion of fludrocortisone.47 unable to tolerate the oral route. However, its use is
Fludrocortisone acetate is a synthetic mineralocorticoid limited to a maximum of four days,53 and its effect is
that favors the renal tubular reabsorption of sodium. It is greater in the presence of hyponatremia and a high glomeru-
able to reduce the natriuretic response, thereby prevent- lar filtration rate (GFR). Likewise, the administration of
ing the appearance of hyponatremia.48 On the other hand, conivaptan in intermittent doses has been found to be effec-
thanks to its weaker glucocorticoid effect, fludrocortisone tive in increasing the renal excretion of free water---with
is associated to a lesser incidence of side effects compared the consequent correction of hyponatremia in neurocritical
with hydrocortisone. In 2009, a multidisciplinary commit- patients.54 In effect, Murphy et al.54 recorded a minimum
tee recommended the use of fludrocortisone in patients increase in natremia of 6 mmol/l in up to 52% of the patients,
with SAH who develop hyponatremia and are thus at a while 69% of them showed a rise in natremia of 4 mmol/l
high risk of vasospasm. In turn, the Stroke Council of after 72 h. More recently, Human et al.55 conducted a
the American Heart Association49 recommends the use of retrospective evaluation of 124 neurocritical patients, and
240 W. Manzanares et al.

Table 2 Drug intervention in the neurocritical patient with hyponatremia.

Strategy Usual dose Side effects Indications
3% Hypertonic saline The usual doses for Overcorrection, thrombosis, Symptomatic acute or
solution20,38,40---45 : sodium treatment of the phlebitis, hypervolemia, chronic hyponatremia.
513 mmol/l; chloride symptomatic and hyperchloremia, acidosis, Osmotherapy in ICH.
513 mmol/l; osmolarity asymptomatic forms are lung edema Osmotic diuresis due to
1026 mOsm/l shown in Fig. 1 natriuresis and decreasing
natremia. Permissive or
therapeutic hypernatremia
Fludrocortisone38,47---50 0.1---0.2 mg/8---12 h (oral or Hypervolemia, lung edema, Hypovolemic hyponatremia,
enteral route) hypokalemia CSW
Conivaptan38,53,54 20 mg i.v. in 30 min in Overcorrection, Euvolemic and
loading dose, followed by hypokalemia, orthostatic hypervolemic
continuous i.v. perfusion of hypotension, hyperazotemia hyponatremia. SIADH (not in
20---40 mg/day. Duration moderate to severe forms).
under 4 days Contraindicated in CSW,
high risk of vasospasm,
glomerular filtration rate
<30 ml/min or severe liver
dysfunction
Tolvaptan38,59,60 15 mg on day 1, possibility
of adjusting to 30---60 mg
with intervals of 24 h if
natremia is <135 mmol/l or
the increase is <5 mmol/l/d
CSW: cerebral salt wasting; ICH: intracranial hypertension; i.v.: intravenous route; SIADH: syndrome of inappropriate antidiuretic hormone
secretion.

found the administration of an intravenous bolus dose of recommended tolvaptan dose is 15 mg, which can be
conivaptan to be able to produce a mean increase in increased to 30---60 mg a day in cases of hyponatremia
natremia of 4 mmol/l. <135 mmol/l, or if the observed natremia increment is
On the other hand, conivaptan has been shown to reduce <5 mmol/day. Since the vaptans correct hyponatremia
intracranial pressure and increase natremia on a transient by facilitating free water elimination, it is impor-
basis, without adverse effects, in patients with severe TBI.56 tant to evaluate the patient blood volume and avoid
In this sense it reflects the concept of reductive osmother- their use in individuals with hypovolemic hyponatremia.
apy, in which there is no gain in solute but a decrease in These drugs therefore might be indicated in neurocrit-
solvent. On the other hand, this effect could also be related ical patients with hyponatremia, though for the time
to inhibition of the V1a receptor, which intervenes in the being their administration should be limited to patients in
expression of AQP4 aquaporin channels this being of fun- which conventional therapy has failed, or as coadjuvant
damental importance in the development of brain edema treatment.52
in patients with severe TBI and stroke.57,58 However, this The recent European guidelines do not advise the use of
requires confirmation by further studies. The current coni- these drugs in neurocritical patients with SIADH and mod-
vaptan dosage consists of a 20 mg intravenous loading dose erate to severe hyponatremia.38 Lastly, these substances
administered over 30 min, followed by a continuous intra- are contraindicated in patients with a glomerular filtration
venous perfusion of 20---40 mg/day for a period of under four rate of <30 ml/min, and in the presence of previous liver
days. disease.53,54
Tolvaptan in turn is a receptor V2 antagonist59 that
has shown clinical benefits by reducing hospital stay in
patients with SIADH, as evidenced by the SALT-1 and Treatment of hyponatremia overcorrection
SALT-2 trials carried out in North America and Europe,
respectively.60 In case reports, this drug has been found In the case of accidental natremia overcorrection, with
to be safe and effective in the treatment of hyponatremia values of >10 mmol/l during the first 24 h, or of 8 mmol/l
associated to SIADH in severe TBI60 and in patients with during day 2, it is possible to reinduce hyponatremia
non-traumatic neurological damage, where the adminis- (according to the guides of the European Society of
tration of a daily dose of 15 mg of tolvaptan has been Intensive Care Medicine/European Society of Endocrinol-
seen to be as effective as conivaptan.60 The currently ogy/European Renal Association-European Dialysis and
Hyponatremia in the neurocritical care patient 241

Transplant Association)38 with the aim of avoiding central 3. Stelfox HT, Ahmed SB, Khandwala F, Zygun D, Shahpori R,
pontine myelinolysis. The following scheme can be used in Laupland K. The epidemiology of intensive care unit-acquired
cases of natremia overcorrection, particularly when the ini- hyponatraemia and hypernatraemia in medical---surgical inten-
sive care units. Crit Care. 2008;12:R162.
tial serum sodium value is 120 mmol/l11,20,38 :
4. Sturdik I, Adamcova M, Kollerova J, Koller T, Zelinkova
The infusion of 3% HSS and of all treatments tending to Z, Payer J. Hyponatraemia is an independent predic-
reduce natriuresis should be interrupted. tor of in-hospital mortality. Eur J Intern Med. 2014;25:
The infusion of 5% dextrose solution (3 ml/kg/h) as a 379---82.
means for administering electrolyte-free water is a useful 5. Corona G, Giuliani C, Parenti G, Norello D, Verbalis JG, Forti
management option. G, et al. Moderate hyponatremia is associated with increased
The administration of intravenous desmopressin (2---4 ␮g risk of mortality: evidence from a meta-analysis. PLoS ONE.
in 3 daily doses). It is important to mention that this drug 2013;8:e80451.
is not indicated in patients with intracranial hypertension, 6. Saramma PP, Menon RG, Srivastava A, Sarma PS. Hypona-
due to the risk of increasing the brain edema. tremia after aneurysmal subarachnoid hemorrhage: impli-
cations and outcomes. J Neurosci Rural Pract. 2013;4:
Hourly monitoring of natremia with the purpose of
24---8.
avoiding a decrease beyond the predetermined target 7. Bagshaw SM, Townsend DR, McDermid RC. Disorders of sodium
value. and water balance in hospitalized patients. Can J Anaesth.
2009;56:151---67.
8. Kirkman MA. Managing hyponatremia in neurosurgical patients.
Conclusion Minerva Endocrinol. 2014;39:13---26.
9. Sherlock M, O’Sullivan E, Agha A, Behan LA, Owens D,
Hyponatremia is the most frequent electrolytic distur- Finucane F, et al. The incidence and pathophysiology of hypona-
traemia after subarachnoid haemorrhage. Postgrad Med J.
bance in neurocritical patients, and is a leading cause of
2009;85:171---5.
morbidity---mortality if adequate and immediate treatment 10. Verbalis JG. Hyponatremia with intracranial disease: not often
is not provided. The syndrome of inappropriate antidi- cerebral salt wasting. J Clin Endocrinol Metab. 2014;99:
uretic hormone secretion and CSW have been described 59---62.
as the two syndromes that most often explain the pres- 11. Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier
ence of hyponatremia associated to increased natriuresis RW, Sterns RH, et al. Diagnosis, evaluation, and treatment
in neurocritical patients. In these cases the evaluation of hyponatremia: expert panel recommendations. Am J Med.
of volemia allows us to establish a differential diagno- 2013;126 10 Suppl. 1:S5---41.
sis between the two disease conditions---though in many 12. Sterns RH, Silver SM. Cerebral salt wasting versus SIADH: what
patients such differentiation is a genuine challenge. How- difference? J Am Soc Nephrol. 2008;19:194---6.
13. Maesaka JK, Imbriano LJ, Ali NM, Ilamathi E. Is it cerebral or
ever, recent evidence has questioned the existence of CSW
renal salt wasting? Kidney Int. 2009;76:934---8.
as a cause of hyponatremia in aneurysmal SAH. Concep- 14. Pasantes-Morales H, Cruz-Rangel S. Brain volume regula-
tually, the diagnosis of cerebral salt wasting seems more tion: osmolytes and aquaporin perspectives. Neuroscience.
appropriate for defining hyponatremia in the neurocritical 2010;168:871---84.
patient, since the reference treatment is always the same, 15. López-Domínguez A, Ramos-Mandujano G, Vázquez-Juárez E,
regardless on the underlying cause: the administration of Pasantes-Morales H. Regulatory volume decrease after swelling
hypertonic saline solution. Likewise, in the neurocritical induced by urea in fibroblasts: prominent role of organic
ICU, the treatment of hyponatremia depends on a num- osmolytes. Mol Cell Biochem. 2007;306:95---104.
ber of factors such as the underlying disease process, 16. Yee AH, Burns JD, Wijdicks EF. Cerebral salt wasting: patho-
the speed with which the condition develops, and patient physiology, diagnosis, and treatment. Neurosurg Clin N Am.
2010;21:339---52.
volemia. Lastly, some alternative treatments have been
17. Holmes CL, Landry DW, Granton JT. Science review: vasopressin
studied, such as fludrocortisone and the vaptans, though and the cardiovascular system. Part 1----Receptor physiology. Crit
conclusive evidence regarding their use is still lacking, and Care. 2003;7:427---34.
no definitive agreement has been reached regarding their 18. Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in
indications. hyponatremia: role of sex, age, vasopressin, and hypoxia. Am J
Physiol Renal Physiol. 2008;295:F619---24.
19. Brimioulle S, Orellana-Jimenez C, Aminian A, Vincent JL.
Conflicts of interest Hyponatremia in neurological patients: cerebral salt wasting
versus inappropriate antidiuretic hormone secretion. Intensive
Care Med. 2008;34:125---31.
The authors declare that they have no conflicts of interest. 20. Sterns RH, Nigwekar SU, Hix JK. The treatment of hypona-
tremia. Semin Nephrol. 2009;29:282---99.
21. Hwang JJ, Hwang DY. Treatment of endocrine disorders in the
References neuroscience intensive care unit. Curr Treat Options Neurol.
2014;16:271.
1. Funk GC, Lindner G, Druml W, Metnitz B, Schwarz C, Bauer P, 22. Ochagavia A, Baigorri F, Mesquida J, Ayuela JM, Ferrándiz A,
et al. Incidence and prognosis of dysnatremias present on ICU García X, et al. Monitorización hemodinámica en el paciente
admission. Intensive Care Med. 2010;36:304---11. crítico. Recomendaciones del Grupo de Trabajo de Cuidados
2. Kirkman MA, Albert AF, Ibrahim A, Doberenz D. Hyponatremia Intensivos Cardiológicos y RCP de la Sociedad Española de
and brain injury: historical and contemporary perspectives. Medicina Intensiva, Crítica y Unidades Coronarias. Med Inten-
Neurocrit Care. 2013;18:406---16. siva. 2014;38:154---69.
242 W. Manzanares et al.

23. Sabatier C, Monge I, Maynar J, Ochagavia A. Valoración de la 40. Libert N, de Rudnicki S, Cirodde A, Mion G. Sérum salé hyper-
precarga y la respuesta cardiovascular al aporte de volumen. tonique, quoi de neuf? Reanimation. 2010;19:163---70.
Med Intensiva. 2012;36:45---55. 41. Thongrong C, Kong N, Govindarajan B, Allen D, Mendel E,
24. Gritti P, Lanterna LA, Rotasperti L, Filippini M, Cazzaniga Bergese SD. Current purpose and practice of hypertonic
S, Brembilla C, et al. Clinical evaluation of hyponatremia saline in neurosurgery: a review of the literature. World
and hypovolemia in critically ill adult neurologic patients: Neurosurg. 2014;82:1307---18, http://dx.doi.org/10.1016/
contribution of the use of cumulative balance of sodium. j.wneu.2013.02.027.
J Anesth. 2014;28:687---95, http://dx.doi.org/10.1007/s00540- 42. Sterns RH, Hix JK, Silver S. Treating profound hypona-
014-1814-x. tremia: a strategy for controlled correction. Am J Kidney Dis.
25. Kao L, Al-Lawati Z, Vavao J, Steinberg GK, Katznelson L. Preva- 2010;56:774---9.
lence and clinical demographics of cerebral salt wasting in 43. Aiyagari V, Deibert E, Diringer MN. Hypernatremia in the neu-
patients with aneurysmal subarachnoid hemorrhage. Pituitary. rologic intensive care unit: how high is too high? J Crit Care.
2009;12:347---51. 2006;21:163---72.
26. Hannon MJ, Behan LA, O’Brien MM, Tormey W, Javad- 44. Froelich M, Ni Q, Wess C, Ougorets I, Hartl R. Continuous hyper-
pour M, Sherlock M, et al. Hyponatremia following tonic saline therapy and the occurrence of complications in
mild/moderate subarachnoid hemorrhage is due to neurocritically ill patients. Crit Care Med. 2009;37:1433---41.
SIAD and glucocorticoid deficiency and not cere- 45. Diringer MN. New trends in hyperosmolar therapy? Curr Opin
bral salt wasting. J Clin Endocrinol Metab. 2014;99: Crit Care. 2013;19:77---82.
291---8. 46. Ichai C, Payen JF, Orban JC, Quintard H, Roth H, Legrand R,
27. Nakagawa I, Hironaka Y, Nishimura F, Takeshima Y, Matsuda et al. Half-molar sodium lactate infusion to prevent intracra-
R, Yamada S, et al. Early inhibition of natriuresis suppresses nial hypertensive episodes in severe traumatic brain injured
symptomatic cerebral vasospasm in patients with aneurysmal patients: a randomized controlled trial. Intensive Care Med.
subarachnoid hemorrhage. Cerebrovasc Dis. 2013;35:131---7. 2013;39:1413---22.
28. Huang WY, Weng WC, Peng TI, Chien YY, Wu CL, Lee M, 47. Feigin VL, Anderson N, Rinkel GJ, Algra A, van Gijn J, Bennett
et al. Association of hyponatremia in acute stroke stage with DA. Corticosteroids for aneurysmal subarachnoid haemorrhage
three-year mortality in patients with first-ever ischemic stroke. and primary intracerebral haemorrhage. Cochrane Database
Cerebrovasc Dis. 2012;34:55---62. Syst Rev. 2005;20:CD004583.
29. Rodrigues B, Staff I, Fortunato G, McCullough LD. Hypona- 48. Katayama Y, Haraoka J, Hirabayashi H, Kawamata T,
tremia in the prognosis of acute ischemic stroke. J Stroke Kawamoto K, Kitahara T, et al. A randomized controlled
Cerebrovasc Dis. 2013;23:850---4, http://dx.doi.org/10.1016/ trial of hydrocortisone against hyponatremia in patients
j.jstrokecerebrovasdis.2013.07.011. with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:
30. Wang G, Jia H, Chen C, Lang S, Liu X, Xia C, et al. Analysis of risk 2373---5.
factors for first seizure after stroke in Chinese patients. Biomed 49. Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion
Res Int. 2013;2013:702871. JE, Diringer MN, et al. Guidelines for the management
31. Roivainen R, Haapaniemi E, Putaala J, Kaste M, Tatlisumak T. of aneurysmal subarachnoid hemorrhage: a statement for
Young adult ischaemic stroke related acute symptomatic and healthcare professionals from a special writing group of the
late seizures: risk factors. Eur J Neurol. 2013;20:1247---55. stroke council, American Heart Association. Stroke. 2009;40:
32. Moro N, Katayama Y, Igarashi T, Mori T, Kawamata T, Kojima 994---1025.
J. Hyponatremia in patients with traumatic brain injury: 50. Diringer MN, Bleck TP, Claude Hemphill J 3rd, Menon D, Shutter
incidence, mechanism, and response to sodium supplementa- L, Vespa P, et al. Critical care management of patients follow-
tion or retention therapy with hydrocortisone. Surg Neurol. ing aneurysmal subarachnoid hemorrhage: recommendations
2007;68:387---93. from the Neurocritical Care Society’s Multidisciplinary Consen-
33. Agha A, Rogers B, Mylotte D, Taleb F, Tormey W, Phillips J, et al. sus Conference. Neurocrit Care. 2011;15:211---40.
Neuroendocrine dysfunction in the acute phase of traumatic 51. Nakagawa I, Kurokawa S, Nakase H. Hyponatremia is predictable
brain injury. Clin Endocrinol (Oxf). 2004;60:584---91. in patients with aneurysmal subarachnoid hemorrhage----Clinical
34. Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, significance of serum atrial natriuretic peptide. Acta Neurochir
Agha A. Hypothalamopituitary dysfunction following traumatic (Wien). 2010;152:2147---52.
brain injury and aneurysmal subarachnoid hemorrhage: a sys- 52. Aditya S, Rattan A. Vaptans: a new option in the management
tematic review. JAMA. 2007;298:1429---38. of hyponatremia. Int J Appl Basic Med Res. 2012;2:77---83.
35. Hardesty DA, Kilbaugh TJ, Storm PB. Cerebral salt wasting 53. Wright WL, Asbury WH, Gilmore JL, Samuels OB. Conivaptan
syndrome in post-operative pediatric brain tumor patients. Neu- for hyponatremia in the neurocritical care unit. Neurocrit Care.
rocrit Care. 2012;17:382---7. 2009;11:6---13.
36. Jahangiri A, Wagner J, Tran MT, Miller LM, Tom MW, Kunwar S, 54. Murphy T, Dhar R, Diringer M. Conivaptan bolus dosing for the
et al. Factors predicting postoperative hyponatremia and effi- correction of hyponatremia in the neurointensive care unit.
cacy of hyponatremia management strategies after more than Neurocrit Care. 2009;11:14---9.
1000 pituitary operations. J Neurosurg. 2013;11:1478---83. 55. Human T, Onuoha A, Diringer M, Dhar R. Response to a bolus
37. Hussain NS, Piper M, Ludlam WG, Ludlam WH, Fuller CJ, Mayberg of conivaptan in patients with acute hyponatremia after brain
MR. Delayed postoperative hyponatremia after transsphe- injury. J Crit Care. 2012;27:e1---5.
noidal surgery: prevalence and associated factors. J Neurosurg. 56. Galton C, Deem S, Yanez ND, Souter M, Chesnut R, Dagal A,
2013;119:1453---60. et al. Open-label randomized trial of the safety and efficacy of
38. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, a single dose conivaptan to raise serum sodium in patients with
et al. Clinical practice guideline on diagnosis and treatment of traumatic brain injury. Neurocrit Care. 2011;14:354---60.
hyponatraemia. Intensive Care Med. 2014;40:320---31. 57. Liu X, Nakayama S, Amiry-Moghaddam M, Ottersen OP, Bhard-
39. Steele A, Gowrishankar M, Abrahamson S, Mazer CD, Feldman waj A. Arginine-vasopressin V1 but not V2 receptor antagonism
RD, Halperin ML. Postoperative hyponatremia despite near- modulates infarct volume, brain water content, and aquaporin-
isotonic saline infusion: a phenomenon of desalination. Ann 4 expression following experimental stroke. Neurocrit Care.
Intern Med. 1997;126:20---5. 2010;12:124---31.
Hyponatremia in the neurocritical care patient 243

58. Trabold R, Krieg S, Schöller K, Plesnila N. Role of vasopressin vasopressin V2-receptor antagonist tolvaptan. J Crit Care.
V(1a) and V2 receptors for the development of secondary brain 2013;28, 219.e1---e12.
damage after traumatic brain injury in mice. J Neurotrauma. 60. Verbalis JG, Adler S, Schrier RW, SALT Investigators. Efficacy and
2008;25:1459---65. safety of oral tolvaptan therapy in patients with the syndrome of
59. Friedman B, Cirulli J. Hyponatremia in critical care patients: inappropriate antidiuretic hormone secretion. Eur J Endocrinol.
frequency, outcome, characteristics, and treatment with the 2011;164:725---32.