Treatment of Hyponatremic Encephalopathy in the

Critically Ill
Steven G. Achinger, MD, FASN1; Juan Carlos Ayus, MD, FACP, FASN2–5

Objectives: Hyponatremic encephalopathy, symptomatic cerebral 100 mL per hour can be given safely. It is critical to recognize the
edema due to a low osmolar state, is a medical emergency and early signs of cerebral edema (nausea, vomiting, and headache)
often encountered in the ICU setting. This article provides a criti- and intervene with IV 3% sodium chloride as this is the time to
cal appraisal and review of the literature on identification of high- intervene rather than waiting until more severe symptoms develop.
risk patients and the treatment of this life-threatening disorder. Cerebral demyelination is a rare complication of overly rapid cor-
Data Sources, Study Selection, and Data Extraction: Online rection of hyponatremia. The principal risk factors for cerebral
search of the PubMed database and manual review of articles demyelination are correction of the serum sodium more than 25
involving risk factors for hyponatremic encephalopathy and treat- mEq/L in the first 48 hours of therapy, correction past the point
ment of hyponatremic encephalopathy in critical illness. of 140 mEq/L, chronic liver disease, and hypoxic/anoxic episode.
Data Synthesis: Hyponatremic encephalopathy is a frequently (Crit Care Med 2017; XX:00–00)
encountered problem in the ICU. Prompt recognition of hypona- Key Words: central pontine myelinolysis; DDAVP; hypertonic
tremic encephalopathy and early treatment with hypertonic saline saline; hyponatremia
are critical for successful outcomes. Manifestations are varied,
depending on the extent of CNS’s adaptation to the hypoosmo-
lar state. The absolute change in serum sodium alone is a poor

H
predictor of clinical symptoms. However, certain patient specific yponatremia is a frequently encountered problem in
risks factors are predictive of a poor outcome and are important to the ICU. Hyponatremic encephalopathy, which can
identify. Gender (premenopausal and postmenopausal females), occur in either acute or chronic hyponatremia, is
age (prepubertal children), and the presence of hypoxia are the defined as neurologic symptoms due to hypoosmolar-induced
three main clinical risk factors and are more predictive of poor cerebral edema (1, 2). The presenting symptoms may range
outcomes than the rate of development of hyponatremia or the from minimal to severe. This is a medical emergency that
absolute decrease in the serum sodium. must be recognized promptly, and treatment initiated expedi-
Conclusions: In patients with hyponatremic encephalopathy exhib- tiously to avoid devastating neurologic complications, which
iting neurologic manifestations, a bolus of 100 mL of 3% saline, may ultimately result in death (3). Although the chronicity
given over 10 minutes, should be promptly administered. The of the illness (the duration of time between a normal serum
goal of this initial bolus is to quickly treat cerebral edema. If signs sodium and the presentation to the ICU) can affect the clinical
persist, the bolus should be repeated in order to achieve clinical presentation and the risks of treatment-related injury due to
remission. However, the total change in serum sodium should not overcorrection, the decision to treat with hypertonic saline is
exceed 5 mEq/L in the initial 1–2 hours and 15–20 mEq/L in the determined by clinical symptoms not the duration of hypo-
first 48 hours of treatment. It has recently been demonstrated in a natremia or the absolute decrease in the serum sodium (1,
prospective fashion that 500 mL of 3% saline at an infusion rate of 2). This is in recognition that chronic hyponatremia of even
modest degrees can lead to poor outcomes (2). This review
1
Department of Nephrology, Watson Clinic LLP, Lakeland, FL. will focus on the treatment of hyponatremic encephalopathy
2
Renal Consultants of Houston, Department of Research, Houston, TX. in the ICU setting and not on hyponatremia without symp-
3
Department of Nephrology, Hospital Italiano, Buenos Aires, Argentina. toms of cerebral edema.
4
Department of Nephrology, Hospital Austral, Austral University, Buenos
Argentina, Argentina.
5
Department of Nephrology, University of California, Irvine, CA.
PATHOGENESIS OF HYPONATREMIA
Dr. Ayus received funding from OTSUKA Laboratories. Dr. Achinger has
disclosed that he does not have any potential conflicts of interest. Hyponatremia, a serum sodium of less than 135 mEq/L, is a
For information regarding this article, E-mail: carlosayus@yahoo.com reflection of a systemic hypoosmolar state and develops when
Copyright © 2017 by the Society of Critical Care Medicine and Wolters water intake exceeds water excretion. This typically occurs in
Kluwer Health, Inc. All Rights Reserved. the setting of impaired free water excretion by the kidneys or
DOI: 10.1097/CCM.0000000000002595 less commonly psychogenic polydipsia resulting in an excess of

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Achinger and Ayus

total body water relative to total body sodium and potassium solutes from the neuroglial cell via the Na+/K+ ATPase pump
(Fig. 1). Conditions that impair free water excretion are associ- (8). By reducing the neuroglial cell’s intracellular osmolality,
ated with both physiologic and pathologic release of antidi- water leaves the cell down the osmotic gradient resulting in an
uretic hormone (ADH) (4) and have been well established overall reduction in brain volume, a process known as “regu-
(5) (Table 1). These conditions impair the kidneys’ primary latory brain volume decrease” (9). Neurologic injury occurs
defense against the development of hyponatremia, the urinary when these mechanisms are unable to fully compensate for the
diluting capacity. increased intracranial pressure due to the cerebral edema (10).
During hyponatremic states, an osmotic gradient devel- Several clinical factors have been shown to impair the neuro-
ops between the circulation and the brain, resulting in water glial cell’s adaptive responses, and these clinical factors predict
movement into the brain through aquaporin-4 channels poor patient outcomes (1).
located in astrocytes, one of the types of neuroglial cells (6).
Astrocytes, located on the brain side of the microcirculation,
help to regulate the movement of fluids and molecules across CLINICAL MANIFESTATIONS
the blood brain barrier by the cells’ foot processes that contact Manifestations are varied, depending on the extent of CNS’s
brain capillaries. This fluid movement results in cell expan- adaptation to the hypoosmolar state. The absolute change in
sion and an increase in brain volume. The resultant increase serum sodium alone is a poor predictor of clinical symptoms
in intraparenchymal brain volume is immediately offset by (11). On a practical level, clinical presentations can be classi-
the shunting of cerebrospinal fluid from the intracranial vault, fied as acute (where the duration of hyponatremia is known
which accommodates some of the volume perturbation, but to be < 48 hr). When this occurs, it is often hospital acquired
this mechanism has limited capacitance (7). The main accom- (postoperative or due to inappropriate use of hypotonic flu-
modation comes through energy-dependent extrusion of ids in other settings). Acute hyponatremia does also occur in
settings such as exercise-induced hyponatremia or methylene-
dioxymethamphetamine-associated hyponatremia. Chronicity
uncertain is the most common presentation and includes most
ICU hyponatremia admissions where the time development
is uncertain (diuretic related, antidepressant related, hypo-
volemia, syndrome of inappropriate ADH (SIADH), adre-
nal insufficiency, etc,). Chronic hyponatremia occurs where
the duration of hyponatremia is known to be greater than
48 hours (e.g., a patient with recurrent congestive heart fail-
ure admissions and documented laboratory studies showing
hyponatremia). Although the chronicity can affect the degree
of symptoms (a patient who develops a serum sodium of 122
in 48 hr following surgery is far more likely to develop hypo-
natremic encephalopathy than a patient who develops a serum
Figure 1. Mechanisms for the maintenance of water balance. sodium of 122 3 wk after initiation of a thiazide diuretic), it is
ADH = antidiuretic hormone. important to understand that all patients with hyponatremia,

TABLE 1. Major Etiologies of Hyponatremia in the ICU

Hypovolemic Hyponatremia Euvolemic Hyponatremia Hypervolemic Hyponatremia

Renal losses Postoperative state Congestive heart failure

  Diuretics (especially thiazide type) Exercise-induced hyponatremia Cirrhosis
  Mineralocorticoid deficiency Drugs Acute and chronic renal failure
  Renal tubular acidosis
 Ecstasy (methylenedioxymethamphetamine)
  Cerebral salt wasting
 Anticonvulsants
Polydipsia
Extrarenal losses Syndrome of inappropriate antidiuretic
hormone secretion
 Vomiting
Hypothyroidism
 Diarrhea
Glucocorticoid deficiency
 Pancreatitis
 Burns

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 Concise Definitive Review

regardless of the chronicity of the development of hyponatre- had normal troponin levels, normal echocardiograms, and
mia, can develop hyponatremic encephalopathy, especially in normal pulmonary artery occlusion pressures demonstrating
high-risk groups such as premenopausal and postmenopausal that the pulmonary edema seen in these cases was not due to a
females and when hypoxia is present (1, 2). Early signs of cere- cardiogenic etiology (14, 16). Hyponatremia produces cerebral
bral edema such as nausea, vomiting, and headaches often edema, which in turn leads to neurogenic pulmonary edema
go unrecognized (12). As intracranial pressure continues to (14). Pulmonary edema then leads to hypoxia which impairs
increase, brain dysfunction, exhibited as altered mentation and brain volume regulation (6, 17, 18), resulting in a vicious cycle
seizures, occurs. If left uncorrected, hypercapnic respiratory of worsening cerebral edema and hypoxia. This syndrome is
failure, a sign of brainstem involvement with the possibility of treated with a bolus of hypertonic saline (14).
herniation, and death may follow (1, 2, 12, 13). Cerebral/renal salt wasting occurs most commonly in neu-
Although there are many causes of hyponatremia in the ICU, rosurgical patients (19). This condition is characterized by a
there are two entities that deserve special attention, noncardio- neurogenic natriuresis by an unknown mechanism that leads
genic pulmonary edema and hyponatremia as well as cerebral/ to volume depletion and secondary ADH secretion from the
renal salt wasting. Noncardiogenic pulmonary edema associ- pituitary that results in hyponatremia. In this way, the cardinal
ated with the presence of cerebral edema (also known as “the distinguishing factor between the SIADH, where nonosmotic
Ayus-Arieff syndrome”) (Fig. 2) could be the initial presenta- ADH secretion is the key pathologic feature, and cerebral salt
tion of a patient with hyponatremic encephalopathy (14). The wasting is the presence or absence of a low circulating effective
two most common causes of hyponatremia and pulmonary arterial blood volume (Table 2). In the past, this differentiation
edema are exercise-induced hyponatremia and hyponatremia was difficult as the effective arterial blood volume could not be
due to ingestion of the recreational drug methylenedioxy- measured directly; however, pulmonary artery occlusion pres-
methamphetamine, commonly known as “ecstasy” (14, 15) but sure (20, 21) (in the absence of diastolic cardiac dysfunction) or
can be seen in any cause of hyponatremia. The main mecha- right atrial pressure (22) (in the absence of pulmonary hyper-
nism for hyponatremic encephalopathy to produce neurogenic tension) could be used to estimate this. Natriuretic peptides (23)
pulmonary edema is the increase in intracranial pressure due hold promise as a tool to estimate effective arterial blood vol-
to hyponatremia (16). The patients described in these reports ume as they are directly related to vascular blood volume and
can help in determining the vascular status of patient. An addi-
tional tool in differentiating SIADH and cerebral/renal salt wast-
ing is the fractional excretion of urate as the excretion of urate
is usually reduced in patients with hypovolemia (24). In many
cases, patients who have SIADH due to the cerebral trauma dur-
ing neurosurgery are misclassified as having cerebral salt wast-
ing. This distinction is important to make as the treatment of
cerebral salt wasting, when hyponatremic encephalopathy is
not present, is volume expanded with 0.9% saline, whereas in a
patient with SIADH, 0.9% saline is futile therapy and can lead
to iatrogenic fluid overload. When a patient with cerebral salt
wasting is aggressively volume expanded with 0.9% saline and
there is no improvement in the condition, the diagnosis of needs
to be revisited. Following serum sodium, urine osmolality, and
serum brain, natriuretic peptide can be helpful in assessing such
patients.

RISK FACTORS FOR HYPONATREMIC

ENCEPHALOPATHY
Gender (1), age (25), and the presence of hypoxia (1, 14, 16)
are the three main clinical risk factors and are more predic-
tive of poor outcomes than the rate of development of hypo-
natremia or the absolute decrease in the serum sodium (13)
(Table 3). These are equivalent risk factors with summative
effects (except that in children where gender does not play a
Figure 2. A depiction of the Ayus-Arieff syndrome (used with permission role). Children are at increased risk due to a high brain-to-
from Moritz et al [15]). Hyponatremia produces cytotoxic cerebral edema, cranial vault size ratio as there is less space for accommodation
which in turn leads to neurogenic pulmonary edema. Pulmonary edema as brain volume increases (25). Among postsurgical patients
leads to hypoxia, which impairs brain cell volume regulation resulting in
a vicious cycle of worsening cerebral edema and pulmonary edema. This who develop hyponatremia, females of premenopausal age are
syndrome can be reversed by the prompt administration of 3% NaCl. also at increased risk for development of cerebral edema (1).

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Achinger and Ayus

TABLE 2. Comparison of Syndrome of Inappropriate Antidiuretic Hormone and Cerebral

Salt Wasting
Syndrome of Inappropriate Antidiuretic
Attribute Hormone Cerebral Salt Wasting

Osmolality
 Urine High High
 Serum Low Low
Urine sodium level > 40 mEq/L > 40 mEq/L
  Volume status Euvolemia to mild hypervolemia Hypovolemia
  Central venous pressure Normal to high Low
  Pulmonary artery occlusion pressure Normal to high Low
  Brain natriuretic peptide level Normal High
  Blood urea nitrogen/creatinine ratio Low to normal High
Serum uric acid level Low Low
Serum potassium level Normal Normal to high
Fractional excretion of urate
  During hyponatremic phase High High
  Following correction of hyponatremia Normal High

TABLE 3. Risk Factors for Hyponatremic Encephalopathy

Risk Factors Mechanism

Postsurgical females of Impaired regulatory brain volume decreaseb: Estrogens decrease the catalytic activity of astrocyte
premenopausal agea (1) Na+/K+, ATPase preventing solute extrusion
Age < 16 (25) High brain volume-to-cranial vault size ratio resulting in less space to accommodate brain volume
increases
Hypoxia (1, 14, 16) Impaired regulatory brain volume decrease: Hypoxia decreases the catalytic activity of astrocyte Na+/
K+, ATPase preventing solute extrusion
Brain injury Vasogenic cerebral edema
Cytotoxic cerebral edema
Acute hyponatremia Decreased time for brain adaptation
When compared with postsurgical males, this subgroup is 25 times more likely to develop permanent brain damage or death (1).
a

Regulatory brain volume decrease is the extrusion of solutes out of the neuroglia cell via the Na+/K+ ATPase resulting in a reduction in brain volume (6).
b

This increased risk of premenopausal females has been seen PREVENTION OF ICU-ACQUIRED
in several clinical scenarios associated with hyponatremia: the HYPONATREMIA
use of ecstasy (15, 26), use of diuretics (13), exercise (14), and Until proven otherwise, a patient in a critical care setting
use of desmopressin (DDAVP; Ferring Pharmaceuticals, Saint- should be assumed to have an impairment in free water excre-
Prex, Switzerland) (27). Estrogens are believed to inhibit the tion. In patients with intact kidney function, ADH levels are
catalytic activity of the astrocyte’s Na+/K+ ATPase resulting likely to be high. In patients with renal failure, free water excre-
in impairment of regulatory volume decrease. This has been tion is also impaired. Common situations where water balance
demonstrated in rat astrocytes treated in vitro (28). Finally, is impaired include the following: cases of effective circulating
hypoxia has been shown to predict poor outcomes in patients volume depletion (cirrhosis, heart failure, and third spacing
with hyponatremic encephalopathy (1), as it also impairs the of fluid), gastrointestinal fluid losses, diuretic use (especially
Na+/K+ ATPase from extruding solutes (17, 18). Hypoxia can thiazides), renal failure (acute and chronic), SIADH, corti-
develop in encephalopathic hyponatremic patients through sol deficiency, and hypothyroidism (Fig. 3). As noted above,
two mechanisms: hypercapnic respiratory failure (16) and hypotonic IV fluids should not be used except in the setting of
neurogenic pulmonary edema (14). replacement of a water deficit (i.e., hypernatremia). Isotonic

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 Concise Definitive Review

clinical settings characterized

by impaired free water excre-
tion (29) can have disastrous
consequences (1). The use of
hypotonic fluids is reserved for
treatment of a free water defi-
cit, such as exists in the setting
of hypernatremia (29).

THE HYPERTONIC
SALINE BOLUS: A
SAFE AND EFFECTIVE
APPROACH TO TREAT
HYPONATREMIC
ENCEPHALOPATHY
Hypertonic saline is the treat-
ment of choice for hypona-
tremic encephalopathy (2,
11, 30). Our group has used
hypertonic saline to treat
over 150 patients (2, 11, 14,
25, 27, 30–33) with hypona-
tremic encephalopathy. We
have used this in both children
and adults, in patients with
acute and chronic hyponatre-
mia, in patients presenting at
a medical tent or emergency
department, and in patients
with hospital-acquired hypo-
natremia. In these groups of
patients, brain imaging and
long-term neurologic follow-
Figure 3. Nonosmotic and osmotic causes of hyponatremia in the ICU. Used with permission from Moritz and up was performed, and we
Ayus (29).
have not encountered cerebral
demyelination as a complica-
normal saline (0.9% NaCl) containing 154 mEq/L of Na+ and tion of hypertonic saline in any of these cases. Our findings of
Cl- is the most appropriate parenteral fluid when IV fluids the efficacy of hypertonic saline in the treatment of hypona-
are indicated for the maintenance of intravascular volume in tremic encephalopathy have been confirmed by other investi-
the postoperative period (29). Also, in the ICU setting, it is gators (34–36).
the most appropriate fluid choice in almost all circumstances However, despite the efficacy of this therapeutic approach,
unless replacing a water deficit and hypotonic fluids are clearly we recognize that the indiscriminate use of prolonged infu-
needed (29). Also, any patient receiving fluid therapy should sions of hypertonic saline without appropriate monitoring
have the serum sodium measured at least daily (29). can produce neurologic injury from an excessive correction
Hospital-acquired hyponatremic encephalopathy occurs of hyponatremia. Because of this concern, and to minimize
most commonly when hypotonic fluids are administered to the risk of hypertonic saline therapy, in 2005, we introduced a
a patient with an impairment of free water excretion (29). A simple approach of using small repeated intermittent boluses
clinical setting that merits specific discussion is the postopera- of hypertonic saline (37) in order to achieve a rapid and
tive state (1). Approximately 1% of patients develop a serum controlled increase in serum sodium to treat hyponatremic
sodium of less than 130 mEq/L following surgery, and clinically encephalopathy, that conformed to the various opinions on the
important hyponatremia complicates 20% of these cases (1). safe limits of correcting hyponatremia (38).
The postoperative state commonly includes multiple stimuli Our approach is to treat any patient with suspected hypo-
for ADH release including pain, stress, nausea, vomiting, nar- natremic encephalopathy (whether acute or chronic), with
cotic medications, and volume depletion (29). Administration either early (nausea, vomiting, headache) or advanced symp-
of a hypotonic IV fluid in the postoperative state or in other toms (seizures, respiratory arrest), child or adult, and with a

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Achinger and Ayus

2 mL/kg bolus of 3% NaCl. The time course over which the mortality (either death or neurologic injury leading to perma-
hyponatremia has developed is not a determinant of who nent institutionalization) (2). We advocate for earlier inter-
should receive therapy for suspected hyponatremic encepha- vention, rather than waiting for more catastrophic symptoms
lopathy, this is because chronicity is not always known and to develop prior to initiating therapy. As long as precautions
hypertonic saline therapy is known to be safe, even when the regarding hypertonic saline therapy we discuss elsewhere are
duration of hyponatremia is clearly chronic (known to be > adhered to, concerns about osmotic demyelination syndrome
48 hr in duration). Early symptoms (nausea, vomiting, head- should not prevent appropriate treatment of patients with
ache, and ataxia) while they are milder in severity should still chronic hyponatremic encephalopathy with hypertonic saline.
be treated with hypertonic saline as they may be a precursor The bolus could be repeated 1–2 times in sequential fashion
to more severe manifestations (such as seizures and respira- if symptoms persisted. A single bolus would result in, at most,
tory arrest). Even though the risk of imminent decompensa- a 2 mEq/L acute rise in serum sodium, which could quickly
tion may be low in many cases (e.g., a patient with cirrhosis, reduce brain edema. In most cases, a 4–6 mEq/L acute rise
ataxia, and a serum sodium of 115), given the safety of hyper- in plasma sodium will begin to reverse the neurologic symp-
tonic saline when used appropriately (30) and the superiority toms, and failure to show some clinical improvement follow-
of hypertonic saline over fluid restriction alone in manage- ing an acute elevation in serum sodium would suggest that the
ment of chronic hyponatremic encephalopathy (2), we feel patient is not suffering from hyponatremic encephalopathy.
that the use of hypertonic saline, especially in an ICU setting, The bolus approach can be given safely through a peripheral
rather than fluid restriction alone is warranted. Early IV saline IV and can be used in a non-ICU setting (30). It would be
therapy in symptomatic patients with chronic hyponatremic effective regardless of the etiology of hyponatremia, serving as
encephalopathy is associated with 0% morbidity and mortal- a volume expander in hypovolemic hyponatremia and is suffi-
ity, whereas delay of therapy with IV saline until respiratory ciently hypertonic to increase the serum sodium in euvolemic
insufficiency develops is associated with 64% morbidity and hyponatremia from SIADH. It also does not require the use
of complicated formulas, which
have been demonstrated to
be inaccurate as they assume
a closed system and do not
account for the renal response
to therapy (39). Other therapies
such as 0.9% NaCl, 1.8% NaCl,
mannitol, urea, oral sodium,
and vaptans cannot be recom-
mended as first-line therapies
to treat hyponatremic encepha-
lopathy as they do not reliably
increase the serum sodium or
reverse the neurologic symp-
toms (38).
This approach has already
been successfully used in critical
care patients (36) and has been
adopted as the standard of care
by the European Societies of
Nephrology, Endocrinology and
Critical Care (38) and sport med-
icines societies (40). The goal of
this initial bolus is to quickly
treat severe cerebral edema. The
sodium should not be corrected
more than 5 mEq/L in the first
1–2 hours of treatment and not
to exceed 15–20 mEq in the first
48 hours of treatment. Prompt
recognition of the problem and
early initiation of therapy are the
most important factors associ-
Figure 4. Treatment of hyponatremic encephalopathy. DDAVP by Ferring Pharmaceuticals, Saint-Prex, Switzerland. ated with successful intervention

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 Concise Definitive Review

and good neurologic outcomes. It is critical to recognize the stabilized. The rationale for close monitoring is that ongoing
early signs of cerebral edema (nausea, vomiting, and head- water losses cannot always be predicted. Therefore, urine out-
ache) and intervene with IV 3% sodium chloride as this is the put should be followed closely to assess for a water diuresis that
time to intervene rather than waiting until more severe symp- is indicative of free water losses that can cause correction of the
toms develop (2, 41). When therapy is delayed until after late sodium in addition to the increase in serum sodium provided
symptoms (altered sensorium, seizure, and respiratory arrest) by hypertonic saline. Finally, the serum sodium should not be
develop, the prognosis is much worse (41). The goals of ther- corrected past normonatremic levels during the first 48 hours
apy with hypertonic saline (Fig. 4) can be summarized as fol- of therapy as this is a further risk factor for the development of
lows: 1) remove patients with severe manifestations of cerebral cerebral demyelination (11).
edema from immediate danger; 2) correct serum sodium to a No head-to-head studies of continuous IV infusion of 3%
mildly hyponatremic levels; and 3) maintain this level of serum saline versus bolus IV infusion have been performed, so this
sodium to allow for the brain to adapt to the change in serum must appropriately temper our conclusions, but given the
osmolality. observation studies demonstrating the efficacy and safety of
A recent case series has demonstrated that 500 mL of a bolus approach and the potential for overcorrection with
3% saline over 6 hours can be given safely (30). Any patient a longer, continuous infusion, we feel that bolus IV infusion
receiving bolus therapy of 3% saline should have the serum therapy is a viable and safer alternative to continuous IV infu-
sodium checked every 1–2 hours until the patient has clinically sion of 3% saline and may be the preferred approach.

RISK FACTORS FOR

THE DEVELOPMENT
OF CEREBRAL
DEMYELINATION
Cerebral demyelination is a
potential complication from
the overcorrection of severe
and chronic hyponatremia. It is
primarily seen in patients with
hyponatremia of greater than
48 hours duration and a plasma
sodium less than 115 mEq/L (38,
42–45). It is infrequently seen in
patients with acute hyponatre-
mia or plasma sodium values
greater than 120 mEq/L (34, 35,
38, 45, 46). Although there are
multiple isolated reports of cere-
bral demyelination occurring in
patients with hyponatremia (38)
when examined in large series of
patients with severe hyponatre-
mia, cerebral demyelination is
extremely rare (46–48). Animal
studies and clinical observations
in humans have demonstrated
that cerebral demyelination is
a complication from an exces-
sive magnitude of correction of
hyponatremia of greater than
25 mEq/L over a 24–48 hours
period (11, 49, 50). Cerebral
demyelination does not appear
to be related to an excessive
hourly rate of correction as long
Figure 5. Clinical use of desmopressin to prevent overcorrection of severe hyponatremia in a patient thiazide-
associated hyponatremia with 3% IV saline and subsequent use of (DDAVP; Ferring Pharmaceuticals, Saint- as the overall magnitude is kept
Prex, Switzerland) to therapeutically slow the rate of water diuresis and ultimately rate of sodium correction. less than 20 mEq/L in the first

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Achinger and Ayus

48 hours of therapy (11). The main risk for an overcorrection of of hyponatremia in cases that involve a risk of water diuresis
hyponatremia is not from the use of hypertonic saline but rather (caused by a drop in urine osmolality termed a “reverse urine
from renal response to fluid therapy and a spontaneous free water osmolality”), for example, compulsive water drinking, cor-
diuresis that occur when the stimulus for arginine vasopressin tisol deficiency, thyroid deficiency, and medication-induced
release abates. The primary conditions where a brisk free water hyponatremia (e.g., thiazide diuretics) (52). This concept has
diuresis can occur are thiazide-induced hyponatremia, water been validated by other groups, showing the clinical usage of
intoxication, volume depletion, adrenal insufficiency following this therapeutic maneuver (53–58). During the treatment of
replacement therapy, and DDAVP-induced hyponatremia fol- hyponatremia, the clinician needs to be vigilant to be sure
lowing DDAVP withdrawal (13, 27). Cerebral demyelination can that a free water diuresis does not occur. In order to prevent
occur with any therapy used to correct severe and chronic hypo- ongoing water losses in the urine and “autocorrection” of the
natremia, including normal saline and V2 antagonists, if there is serum sodium, DDAVP can be given to increase urinary con-
an excessive correction of hyponatremia (13). centration and reduce free water losses. However, this must
There are risk factors other than hyponatremia that can be done carefully, with the patient strictly fluid restricted or
place a patient at risk for developing cerebral demyelination kept with no enteral intake in an ICU setting. If unrestricted
such as severe liver disease (11), hypokalemia (44), thiazide fluid intake occurs during DDAVP administration, signifi-
diuretic use (13), alcoholism (11, 13), malnutrition (51), hypo- cant hyponatremia can develop. An increase in urine output
phosphatemia (13), and hypoxia (13). Most reported patient is the first sign that a water diuresis is ensuing, and therefore
with cerebral demyelination have had one or more of these risk hourly urine output needs to be followed in all patients with
factors. Patients with these risk factors have been reported to hyponatremic encephalopathy, especially those with drug-
have cerebral demyelination in the absence of hyponatremia induced hyponatremia. DDAVP administration leads to a
(13). When symptoms of cerebral demyelination manifest, it prompt reduction in urine and increase in urine osmolality
is typically a delayed phenomenon, occurring days to weeks as seen in (Fig. 5), where a representative case is presented
following the correction of hyponatremia (11). Patients may of a patient with alcoholism and thiazide-induced hypona-
present with a continuum of symptoms, ranging from asymp- tremia presents with seizures and an initial serum sodium
tomatic to those with extremely altered mentation, which may of 103 mEq/L who developed a water diuresis following cor-
manifest as a pseudocoma with a locked-in stare (11). MRI of rection of her hyponatremia with IV 3% sodium chloride.
the brain, which is sensitive for the detection of demyelinating Keeping the serum sodium from increasing by more than 15
lesions, is often necessary to establish the diagnosis (11). mEq/L in the first 48 hours is the goal during the treatment
of hyponatremic encephalopathy. Use of DDAVP during this
PREVENTION OF OVERCORRECTION initial period may require the patient to stay in the ICU in
OF HYPONATREMIA WITH USE OF order to monitor intake and output strictly. After 48 hours,
DESMOPRESSIN (DDAVP) the DDAVP can usually be stopped and the patient observed
Our group in 1993 (52) advanced the concept that DDAVP while the sodium continues to correct. This general approach
could be used to minimize water excretion during correction is outlined in Figure 6.

Figure 6. Use of desmopressin to prevent overcorrection of the serum sodium while treating hyponatremic encephalopathy. DDAVP by Ferring Pharma-
ceuticals, Saint-Prex, Switzerland. SIADH = syndrome of inappropriate antidiuretic hormone.

8 www.ccmjournal.org xxx 2017 • Volume XX • Number XXX

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 Concise Definitive Review

SUMMARY 16. Ayus JC, Arieff AI: Pulmonary complications of hyponatremic enceph-
alopathy. Noncardiogenic pulmonary edema and hypercapnic respira-
Hyponatremia is a common clinical disorder in the ICU set- tory failure. Chest 1995; 107:517–521
ting, and when it is complicated by hyponatremic encephalop- 17. Vexler ZS, Ayus JC, Roberts TP, et al: Hypoxic and ischemic hypoxia
athy, it is associated with poor outcomes. Prompt recognition exacerbate brain injury associated with metabolic encephalopathy in
of patients with hyponatremic encephalopathy is critical in laboratory animals. J Clin Invest 1994; 93:256–264
18. Ayus JC, Armstrong D, Arieff AI: Hyponatremia with hypoxia: Effects
order to provide immediate therapy. Treatment with bolus on brain adaptation, perfusion, and histology in rodents. Kidney Int
therapy of 3% IV sodium chloride is recommended when 2006; 69:1319–1325
early symptoms occur rather than waiting until late symptoms 19. Bitew S, Imbriano L, Miyawaki N, et al: More on renal salt wasting
develop as delay in therapy is associated with poor neurologic without cerebral disease: Response to saline infusion. Clin J Am Soc
Nephrol 2009; 4:309–315
outcomes. We recommend patients be treated by correcting
20. Palmer BF: Hyponatremia in patients with central nervous system
the serum sodium with hypertonic saline beginning with an IV disease: SIADH versus CSW. Trends Endocrinol Metab 2003;
bolus of 100 mL of 3% saline, which may be repeated if needed. 14:182–187
The goal of therapy is to adequately treat cerebral edema while 21. Yee AH, Burns JD, Wijdicks EF: Cerebral salt wasting:
Pathophysiology, diagnosis, and treatment. Neurosurg Clin N Am
avoiding correction of the serum sodium by more than 15–20 2010; 21:339–352
mEq/L in the first 48 hours of therapy, thereby preventing the 22. Damaraju SC, Rajshekhar V, Chandy MJ: Validation study of a central
development of cerebral demyelination. venous pressure-based protocol for the management of neurosurgi-
cal patients with hyponatremia and natriuresis. Neurosurgery 1997;
40:312–316; discussion 316–317
ACKNOWLEDGMENT 23. Marin-Grez M, Fleming JT, Steinhausen M: Atrial natriuretic peptide
causes pre-glomerular vasodilatation and post-glomerular vasocon-
We like to acknowledge Elizabeth Ziner, MD, for her assistance striction in rat kidney. Nature 1986; 324:473–476
in article preparation and preparation of figures. 24. Maesaka JK, Miyawaki N, Palaia T, et al: Renal salt wasting without
cerebral disease: Diagnostic value of urate determinations in hypona-
tremia. Kidney Int 2007; 71:822–826
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