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Review Article
H
uman cells dwell in salt water. Their well-being depends on From the University of Rochester School
the ability of the body to regulate the salinity of extracellular fluids. By of Medicine and Dentistry and Rochester
General Hospital, Rochester, NY. Address
controlling water intake and excretion, the osmoregulatory system nor- reprint requests to Dr. Sterns at Roches-
mally prevents the plasma sodium concentration from straying outside its normal ter General Hospital, 1425 Portland Ave.,
range (135 to 142 mmol per liter). Failure of the system to regulate within this range Rochester, NY 14621, or at richard.sterns@
rochesterregional.org.
exposes cells to hypotonic or hypertonic stress. This review considers the causes
and consequences of an abnormal plasma sodium concentration and offers a frame- N Engl J Med 2015;372:55-65.
DOI: 10.1056/NEJMra1404489
work for correcting it. Copyright © 2015 Massachusetts Medical Society.
The plasma sodium concentration affects cell volume. The term “tonicity” describes
the effect of plasma on cells — hypotonicity makes cells swell and hypertonicity
makes them shrink. Hypernatremia always indicates hypertonicity. Hyponatremia
usually indicates hypotonicity, but there are exceptions (e.g., hyperglycemic hypo-
natremia and pseudohyponatremia) that are not covered in this review.
Solute concentrations (osmolalities) must be equal inside and outside of cells be-
cause water channels (aquaporins) make cell membranes permeable to water.1,2
The “sodium pump” (Na+/K+–ATPase) functionally excludes sodium from cells,
exchanging it for potassium by means of active transport. Although sodium is
largely extracellular and potassium is intracellular, body fluids can be considered
as being in a single “tub” containing sodium, potassium, and water, because os-
motic gradients are quickly abolished by water movement across cell membranes.
As such, the concentration of sodium in plasma water should equal the concentra-
tion of sodium plus potassium in total body water. This theoretical relationship was
validated empirically by Edelman et al.,3 who used isotopes to measure exchange-
able body cations and water.
Edelman and colleagues described the relation between these variables with the
following equation:
(Na+e + K+e )
[Na+ ] in plasma H2O = 1.11 × −25.6,
total body H2O
where Na+e is exchangeable sodium, K+e exchangeable potassium, and H20 water.
This equation has an intercept (−25.6); the regression line relating plasma sodium
Internal sodium
balance
Figure 1. Internal and External Solute and Water Balance and the Plasma Sodium Concentration.
The plasma sodium concentration is determined according to the ratio of the content of sodium and potassium in
the body (the numerator of the ratio) to total body water (the denominator of the ratio). This concentration is al-
tered by net external balances (intake minus output) of sodium, potassium, and water and by internal exchange be-
tween sodium that is free in solution and sodium that is bound to polyanionic proteoglycans in bone, cartilage, and
skin.
to the ratio of exchangeable (Na+ + K+) to total who consume high-salt diets, sodium can accumu-
body water does not pass through zero because late in the body, seemingly disappearing without a
not all exchangeable sodium is free in solution.4 change in the plasma sodium concentration,
A substantial amount of sodium is bound to body weight, or extracellular fluid volume.12 So-
large polyanionic macromolecules called proteo- dium, potassium, and water balance do not al-
glycans, which make up the ground substance of ways account for changes in the plasma sodium
bone, connective tissue, and cartilage (Fig. 1).1 concentration during recovery from hyponatre-
The sodium concentration of cartilage is nearly mia.13 Proteoglycans in skin serve as a sodium
twice that of plasma. The osmotic force created reservoir, and the number of negative charges
by the high sodium concentration (about 40 mm available to bind sodium varies in response to the
Hg for every difference in concentration of 1 sodium concentration of interstitial tissue.14-16 In
mmol per liter) maintains the high water con- experiments in rats, chronic hyponatremia has
tent in the tissue, allowing it to withstand pres- been shown to be a more potent cause of osteope-
sures that can exceed 20,000 mm Hg during nia than vitamin D deficiency, and loss of sodi-
exercise.5 um from bone exceeded the loss of calcium from
When it became known that much of the bone. The activity of osteoclasts is increased in
sodium in the body is bound to bone, cartilage, chronic hyponatremia owing to a direct effect of
and connective tissue, it was hypothesized that sodium and possibly vasopressin on these cells.17
these tissues could serve as sodium reservoirs, In humans, chronic hyponatremia is associat-
taking up or releasing sodium in response to the ed with osteoporosis and fractures. During ex-
needs of the body.6 Despite early evidence sup- treme-endurance athletic events lasting several
porting the concept of a sodium reservoir,7-9 this hours, bone density decreases measurably, and
theory lost favor10 and was not pursued for half the decrease in bone density correlates remark-
a century. However, the past decade has seen re- ably closely with changes in the plasma sodium
newed interest in stored sodium.11 In patients concentration.17,18
Neuron
Pericyte
Astrocyte
Astrocyte
Astrocytic foot
Astrocytic foot
process
process
Brain capillary
Aquaporin-4
Tight
Endothelial
junction
cell
H2O
Endothelial cell Na+
per liter. In the absence of vasopressin, urine pressin is usually detectable at a plasma sodium
osmolality decreases to as low as 50 mOsm per concentration above 135 mmol per liter, and
kilogram. In persons who consume a typical levels of vasopressin increase linearly with in-
Western diet, with an output of urinary solute of creasing sodium levels.32 The hormone may also
about 900 mOsm daily, a urinary solute concen- be secreted in response to circulatory inadequa-
tration of 50 mOsm per liter yields 18 liters of cy,33 or it may be secreted “inappropriately,” and
urine (750 ml per hour).20 sometimes ectopically, with no osmotic or he-
Although individual responses vary,31 vaso- modynamic stimulus.34 (Vasopressin secretion
es rapidly if large amounts of concentrated salt sometimes lethal brain injury (Tables 1 and 2 and
are ingested or infused or if there are large, Fig. 3).39,40 If severe hypernatremia develops over
unreplaced losses of electrolyte-free water be- a period of minutes (e.g., after massive ingestion
cause of aquaresis or osmotic diuresis (most com- of salt that may occur in a suicide attempt), vas-
monly due to glycosuria). Loss or gain of ap- cular injury created by a suddenly shrinking brain
proximately 3 ml of water per kilogram of body causes intracranial hemorrhage. Brain swelling
weight will change the plasma sodium concen- from an abrupt onset of hyponatremia results in
tration by approximately 1 mmol per liter.51 Maxi- increased intracranial pressure, impairing cere-
mally dilute urine, whether resulting from un- bral blood flow and sometimes causing hernia-
treated diabetes insipidus, spontaneous recovery tion (Fig. 3). Adaptive changes in brain osmolytes
from hyponatremia, or administration of a vaso- permit survival, but they may also contribute to
pressin antagonist, will increase the plasma so- symptoms.55 For example, in acute hyponatremia,
dium concentration by about 2.5 mmol per liter adaptive release of glutamate, an excitatory neu-
per hour. In the absence of urinary loss of water, rotransmitter, may increase the susceptibility to
1 ml of 3% saline per kilogram of body weight seizures; depletion of the transmitter from nerve
will increase the plasma sodium concentration terminals may account for some of the neuro-
by about 1 mmol per liter.51 Therefore, in a wom- logic symptoms of chronic hyponatremia.55
an with a body weight of 50 kg, the increase in The foot processes of astrocytes, which en-
the plasma sodium level caused by a maximum circle both brain capillaries and neurons, express
water diuresis is similar to the increase caused aquaporins (such as aquaporin-4) that allow water
by infusion of approximately 125 ml of 3% saline to cross the blood–brain barrier.2 Astrocytes pro-
per hour. tect neurons from osmotic stress; in response to
hypotonicity, a cell-to-cell transfer of taurine to
adjacent astrocytes allows neurons to maintain
C onsequence s of a n A bnor m a l
Pl a sm a Sodium C oncen t r at ion their volume while astrocytes swell.56 Within 24
to 48 hours after this transfer, astrocytes restore
Extreme hypotonicity ruptures cell membranes; their volume through loss of organic osmolytes,
extreme hypertonicity damages the cytoskeleton but this makes them vulnerable to injury from
and causes breaks in DNA, ultimately leading to rapid normalization of the plasma sodium con-
apoptosis.52 Given time, cells protect their volume centration. Because of the down-regulation of
and their survival by adjusting intracellular solute transporters, recovery of lost brain osmolytes may
contents.53 take a week or longer.55,56 Therefore, rapid cor-
Organic osmolytes are small intracellular mol- rection of hyponatremia is a hypertonic stress to
ecules (e.g., glutamate, taurine, and myo-inositol) astrocytes that are depleted of osmolytes, trig-
that are found throughout nature; their concen- gering apoptosis, disruption of the blood–brain
trations can vary without perturbing cell func- barrier, and, eventually, brain demyelination57 (see
tions.54 Hypotonicity promotes the release of os- the Supplementary Appendix). In experiments in
molytes from cells through volume-sensitive leak animals, brain demyelination has been prevent-
pathways, while, concurrently, osmolyte-accumu- ed by repletion of myo-inositol,58 by lowering the
lating transporters (e.g., the taurine transporter plasma sodium concentration again promptly
TauT and the myo-inositol transporter SMIT) are (within 12 to 24 hours after rapid correction of
down-regulated. With hypertonicity, TauT and hyponatremia),59 or by administration of minocy-
SMIT are up-regulated.53,54 These adaptations al- cline (which prevents proliferation of glial cells).60
low cells to maintain intracellular solute concen- Brain injury after rapid correction of chronic
trations that are equal to the osmolality of hypo- hyponatremia manifests as a biphasic illness called
tonic or hypertonic plasma, with little change in the osmotic demyelination syndrome: an initial
cell volume.53,54 reduction in symptoms is followed by a gradual
Although osmotic disturbances affect all cells, onset of new neurologic findings (see Case 3 in
clinical manifestations of hyponatremia and hy- the Supplementary Appendix).61 The clinical spec-
pernatremia are primarily neurologic, and rapid trum of the osmotic demyelination syndrome is
changes in plasma sodium concentrations in ei- broad and can include seizures, behavioral abnor-
ther direction can cause severe, permanent, and malities, and movement disorders.62 The most se-
Limit of Correction
Related Behavior and Management
Duration or Condition Clinical Features Initial Therapeutic Goal of Overcorrection
Several hours Self-induced water intoxica- Headache, delirium, vom- 100-ml bolus of 3% saline three Excessive correction not
tion associated with psycho- iting, seizures, coma, neu- times as needed for severe known to be harmful
sis, running in marathons, rogenic pulmonary ede- symptoms; increase plasma
use of 3,4-methylenedioxy- ma, brain swelling with sodium concentration by 4–6
methamphetamine (MDMA, risk of fatal herniation mmol/liter in first 6 hr
or “ecstasy”)
1–2 days Postoperative hyponatremia, Headache, delirium, vom- 100-ml bolus of 3% saline three Avoid increasing plasma
especially in women and chil- iting, seizures, coma, neu- times as needed for severe sodium concentration by
dren; hyponatremia associat- rogenic pulmonary ede- symptoms; increase plasma >10 mmol/liter/day
ed with intracranial disease ma, brain swelling with sodium concentration by 4–6
risk of fatal herniation mmol/liter in first 6 hr
Unknown or Conditions associated with Malaise, fatigue, confu- Extra caution indicated for condi- Avoid increasing plasma
≥2 days high risk of the osmotic de- sion, cramps, falls, 10% tions associated with high risk of sodium concentration by
myelination syndrome (plas- incidence of seizures with osmotic demyelination syndrome; >8 mmol/liter/day; consider
ma sodium concentration, plasma sodium concen- 100- ml bolus of 3% saline if need- lowering again if limit is ex-
105 mmol/liter or less; hypo- tration <110 mmol/liter, ed for seizures; increase plasma ceeded, especially in patients
kalemia, alcoholism, malnu- minimal brain swelling, sodium concentration by 4–6 with high risk of the osmotic
trition, liver disease)† and no risk of herniation mmol/liter in first 24 hr demyelination syndrome
* Severe hyponatremia is defined as a plasma sodium concentration below 120 mmol per liter. In the absence of urinary loss of water, 1 ml of
3% saline per kilogram of body weight will increase the plasma sodium concentration by approximately 1 mmol per liter.
† The osmotic demyelination syndrome may develop when the plasma sodium concentration is increased rapidly in outpatients who became
hyponatremic while drinking normal amounts of water and in hospitalized patients who became hyponatremic over 2 or more days.
verely affected patients become “locked in,” un- longed osmotic disturbances, and observational
able to move, speak, or swallow because of studies have shown decreased mortality among
demyelination of the central pons. Although os- hospitalized patients in whom the plasma sodium
motic demyelination may cause permanent disabil- concentration was corrected.70 Taurine and myo-
ity or death, many patients — even those who inositol, organic osmolytes that are lost from
require ventilator support — have a full func- many cells in the adaptation to hyponatremia,
tional recovery.63 Acute hypernatremia may also are normally protective against oxidative injury.54
cause brain demyelination, without the biphasic An experimental model of chronic SIADH in rats
clinical course of the osmotic demyelination syn- showed that prolonged hyponatremia resulted in
drome (Fig. 3).64,65 hypogonadism, loss of body fat, skeletal-muscle
Chronic hypernatremia, like chronic hypona- sarcopenia, and cardiomyopathy.71
tremia, causes a reversible encephalopathy. Par-
ticularly in infants, organic osmolytes gained in C or r ec t ion of a n A bnor m a l
the adaptation to chronic hypernatremia are lost Pl a sm a Sodium C oncen t r at ion
slowly. Therefore, rehydration resulting in rapid
correction of chronic hypernatremia causes sei- Clinicians who treat patients with hyponatremia
zures and a bulging fontanelle indicating cere- and hypernatremia should respond promptly to
bral edema (Fig. 3).35,66,67 the immediate dangers posed by an acute distur-
A plasma sodium concentration that is even bance, while being mindful of adaptations that
slightly outside the normal range increases the make excessive correction potentially harmful.
risk of death,68 but few deaths associated with Aggressive interventions are indicated when the
abnormalities in the plasma sodium concentra- plasma sodium concentration has decreased or
tion are related to neurologic complications.69 increased rapidly or when an abnormal plasma
The underlying disorders that produce an abnor- sodium concentration is causing severe symptoms.
mal plasma sodium concentration may be re- Therapy should be guided by frequent monitoring
sponsible for excess mortality, but there may also of the plasma sodium concentration and not by
be non-neurologic adverse consequences of pro- formulas alone.43
Rapid onset of acute Rapid correction of Rapid onset of acute Rapid correction of
hypernatremia chronic hyponatremia hyponatremia chronic hypernatremia
Uncal
Extrapontine
herniation
Pontine
Demyelination
Neuron
Fatal brain swelling — a rare complication of achieved with 100-ml bolus infusions of 3% sa-
hyponatremia that clinicians are most con- line (2 ml per kilogram in small patients), ad-
cerned about — has only been reported in hypo- ministered at 10-minute intervals to a total of
natremic patients with intracranial disease and three doses, if necessary, to control symptoms.39
in a few specific conditions that cause the plasma Milder symptoms of acute hyponatremia should
sodium concentration to decrease rapidly, such as be treated with enough 3% saline to avoid a
postoperative hyponatremia and self-induced wa- worsening of hyponatremia because of delayed
ter intoxication that develops over a few hours absorption of ingested water or excretion of hy-
(Table 1). Because the brain cannot swell by pertonic urine.72
much more than 5%, correction of hyponatre- Hyponatremia is usually a chronic condition
mia by this amount would be expected to pre- and it should be presumed to be chronic when the
vent the most serious complications of acute actual duration is unclear; to reduce symptoms
water intoxication; empirical observations sup- and improve potential outcomes, chronic hypona-
port this prediction. An increase in the plasma tremia should be corrected gradually with the use
sodium concentration of 4 to 6 mmol per liter is of fluid restriction, salt tablets, slow infusions of
enough to reverse impending brain herniation or 3% saline, furosemide, urea, or vasopressin an-
stop active seizures in patients with severe acute tagonists, or by treatment of the underlying cause.
hyponatremia. Such an increase can be reliably Severe symptoms of hyponatremia may require
Limit of Correction
Related Behavior and Management
Duration or Condition Clinical Features Initial Therapeutic Goal of Overcorrection
Minutes to Acute salt poisoning associat- Seizures, coma, hypertonia, Rapid infusion of 5% dextrose Excessive correction not
hours ed with accidental salt inges- high fever, intracranial hemor- in water plus emergency he- known to be harmful
tion or salt ingestion in at- rhages, thrombosis of dural modialysis to immediately re-
tempted suicide, use of paren- sinuses store normonatremia
teral hypertonic saline, dialy-
sis errors
1–2 days Unreplaced water from uri- Persistent coma, brain Decrease plasma sodium con- Excessive correction not
nary losses associated with demyelination centration by 2 mmol/liter/hr known to be harmful
glycosuria, neurogenic or until plasma sodium concen-
nephrogenic diabetes insipi- tration is 145 mmol/liter; stop
dus or replace water losses
Unknown or In children: diarrhea, inability Obtundation or coma, rehy- In children: decrease plasma In children: avoid decreasing
≥2 days to breast-feed; in adults: dration-associated seizures sodium concentration by 0.3 plasma sodium concentra-
hypodipsia, impaired mental and cerebral edema as a re- mmol/liter/hr; in adults: de- tion by >0.5 mmol/liter/hr;
status sult of rapid correction in crease plasma sodium con- 3% saline for seizures associ-
children centration by 10 mmol/liter/ ated with rehydration; in
day; replace water losses adults: not known
* Severe hypernatremia is defined as a plasma sodium concentration above 150 mmol per liter. In the absence of urinary loss of water, 3 ml
of electrolyte-free water per kilogram of body weight will decrease the plasma sodium concentration by approximately 1 mmol per liter.
more aggressive initial interventions, but there is losses of water; hyponatremia is corrected with
no need to increase the plasma sodium concen- a slow infusion of 3% saline while the urine is
tration by more than 4 to 6 mmol per liter per kept concentrated with repeated doses of desmo-
day. Regardless of how chronic hyponatremia is pressin.73
treated, inadvertent overcorrection, most com- Limiting correction of chronic hypernatremia
monly caused by excretion of dilute urine, is so that the plasma sodium concentration is de-
common and can be very dangerous (see Case 3 creased by less than 0.5 mmol per liter per hour
in the Supplementary Appendix).42,43 If the plas- reduces the risk of cerebral edema and seizures
ma sodium concentration is less than 120 mmol associated with rehydration.66 However, the fear
per liter, or if there are risk factors for osmotic of these complications, which have been reported
demyelination, correction of the plasma sodium only in young children, should not deter the ag-
concentration by more than 8 mmol per liter per gressive rehydration of adults with acute hyper-
day should be meticulously avoided through re- natremia to avoid brain hemorrhage or osmotic
placement of lost water or prevention of water demyelination (Table 2).76 In contrast to the risk
loss with desmopressin, a synthetic vasopres- of inadvertent overcorrection in patients with hy-
sin.42,73 ponatremia, there is little risk of inadvertent
Repeat therapeutic lowering of the plasma overcorrection in patients with hypernatremia,
sodium concentration is justified if the correc- and adults with hypernatremia are often under-
tion of hyponatremia exceeds 8 mmol per liter treated.77,78
per day and there are risk factors for osmotic de-
myelination or if the correction is 10 to 12 mmol C onclusions
per liter per day without these risk factors (Ta-
ble 1)39,40,74,75 — although the benefit of this Disorders of plasma sodium concentration ex-
strategy has not been confirmed in humans. To pose cells to hypotonic or hypertonic stress.
prevent inadvertent overcorrection (see Case 4 in Although all cells are affected, clinical manifes-
the Supplementary Appendix), desmopressin can tations of hyponatremia and hypernatremia are
be administered preemptively, in anticipation of, primarily neurologic, and rapid changes in plas-
rather than in response to, unwelcome urinary ma sodium concentrations in either direction can
cause severe, permanent, and sometimes lethal No potential conflict of interest relevant to this article was
reported.
brain injury. Because the brain adapts to an ab- Disclosure forms provided by the author are available with the
normal plasma sodium level, excessive correction full text of this article at NEJM.org.
of a chronic disturbance can be injurious and
should be avoided.
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