SPECIAL

ARTICLE

JIACM 2006; 7(2): 91-103

Clinical Approach to Altered Serum Sodium levels

Ashish K Duggal*, Pushpa Yadav**, AK Agarwal***, BB Rewari****
Disorders of sodium and water balance are very common
and are seen in the emergency department almost every
day worldwide. Sodium is the principal solute in the extra cellular compartment and hence the plasma osmolality
largely depends on the serum sodium concentration. Plasma
osmolality in turn is regulated tightly within a narrow range
of 275 - 290 mosm/kg by various mechanisms. A decrease
or increase in the serum sodium level will have an effect
on the plasma osmolality and this can have deleterious
effects on the whole body in particular, the central nervous
system. Severe hypo- and hypernatraemia are associated
with significantly high mortality and morbidity. Moreover,
inappropriate treatment may result in treatment related
complications such as osmotic demyelination syndrome.
This article discusses the pathophysiology and management
of both hyponatraemia and hypernatraemia with special
emphasis on preventing treatment related complications.

Hyponatraemia
Hyponatraemia is defined as a decrease in the serum
sodium concentration to a level below 136 mmol/l.
Although plasma osmolality is closely related to serum
sodium concentration, hyponatraemia can be associated
with low, normal, or high osmolality1. Osmolality or tonicity
refers to the contribution to osmolality of solutes such as
sodium, glucose, and urea that cannot freely move across
the cell membrane thereby reducing transcellular shifts in
water2. Plasma osmolality can be measured by osmometry,
or can be calculated by the following formula3:

in the otherwise relatively impermeable section of the

nephron5. Thirst is another crucial but less sensitive
mechanism for maintaining plasma osmolality. Furthermore,
because the cell membranes are freely permeable to water,
all body fluids are in osmotic equilibrium. As a result, plasma
sodium concentration not only reflects the plasma
osmolality but also the intracellular osmolality. Any change
in the serum sodium concentration not only changes the
tonicity of the extracellular fluid, but also causes water to
shift into or out of cells as the tonicity of the two
compartments equilibrates. This shift has important
implications because the CNS manifestations of hypo- and
hypernatraemia are the result of these water fluxes3.
Hyponatraemia is the most common electrolyte abnormality
found in hospitalised patients3. It has an incidence of around
1% and the frequency increases with increasing age6. In acute
(< 48 hrs) and symptomatic hyponatraemia, the mortality
rates may be as high as 17.9%7-9. Hyponatraemia is more
commonly caused by an excess free water rather than
sodium depletion. There is convincing evidence that
hyponatraemia is not only a marker of serious underlying
disease, but when severe, can itself be the cause of major
neurologic damage and death7, 10.

Classification of hyponatraemia
Hyponatraemia can be classified according to the plasma
osmolality into hyperosmolar, iso-osmolar and hypoosmolar states. Table I lists the various causes of
hyponatraemia according to the classification3, 11.

Posm = 2 [Na](meq/l)+ [glucose] (mg/dl) + BUN (mg/dl)

18
2.8

Table I: Causes of Hyponatraemia

Plasma osmolality is preserved within the normal range by

the hormone arginine vasopressin, also known as the antidiuretic hormone (ADH). Osmoreceptors near the
hypothalamus sense plasma osmolality and modulate
vasopressin release4. Vasopressin functions at the distal
collecting duct of the kidney to increase water reabsorption

Hyperosmolar Hyponatraemia
Hyperglycemia
Hypertonic mannitol
Iso-osmolar Hyponatraemia
Pseudohyponatraemia
Post-TURP
Hypo-osmolar Hyponatraemia

* Medical Officer, ** Senior Physician and Associate Professor, *** Consultant, Professor and Head,
**** Senior Physician and Assistant Professor, Department of Medicine, Dr RML Hospital, New Delhi - 110 001.

Hypovolaemic Hyponatraemia
Renal sodium loss
Diuretic agents
Osmotic diuresis (glucose, urea, mannitol)
Adrenal insufficiency
Salt-wasting nephropathy
Bicarbonaturia (renal tubular acidosis,
disequilibrium stage of vomiting)
Ketonuria
Extra-renal sodium loss
Diarrhoea
Vomiting
Blood loss
Excessive sweating (e.g., in marathon runners)
Fluid sequestration in third space, i.e.,
Bowel obstruction
Peritonitis
Pancreatitis
Muscle trauma
Burns
Hypervolaemic Hyponatraemia
Congestive heart failure
Cirrhosis
Nephrotic syndrome
Renal failure (acute or chronic)
Pregnancy
Euvolaemic Hyponatraemia
Thiazide diuretics
Hypothyroidism
Adrenal insufficiency
Syndrome of inappropriate secretion of antidiuretic
hormone
Cancer
Pulmonary tumors
Mediastinal tumors
Extrathoracic tumors
Central nervous system disorders
Acute psychosis
Mass lesions
Inflammatory and demyelinating diseases
Stroke
Haemorrhage
Trauma
Drugs
Desmopressin, oxytocin, prostaglandin-synthesis
inhibitors, nicotine, phenothiazines, tricyclics,
serotonin-reuptake inhibitors, opiate derivatives,
chlorpropamide, clofibrate, carbamazepine,
cyclophosphamide, vincristine
Pulmonary conditions
Infections
92

Acute respiratory failure

Positive-pressure ventilation
Miscellaneous
Post-operative state
Pain
Severe nausea
Infection with the human immunodeficiency virus
Decreased intake of solutes
Beer potomania
Tea-and-toast diet
Excessive water intake
Primary polydipsia
Dilute infant formula

Hyperosmolar hyponatraemia
Hyponatraemia can occur with increased plasma osmolality
(> 290 mosm/kg) as a result of increased concentration of
an effective solute in the extra-cellular fluid compartment.
This creates an osmotic gradient that drives water from the
cells into the extra cellular space leading to a lower, diluted
sodium concentration. This can be seen in severe
hyperglycaemia during uncontrolled diabetes. Quantitatively,
the measured sodium decreases approximately 1.5 meq/l
for every 100 mg/dl rise in serum glucose concentration12.
This formula is based on the presumption that the volume
of distribution of glucose is 45% of the total body water. But
in many patients admitted in the hospital, the body
composition may be altered and this formula cannot be
used. The following formula is a more generalised formula
to predict changes in serum sodium12:
Change in sodium = 5.5 (1 - V)/2 C change in glucose
where V is the volume of distribution of glucose as a fraction
of total body water.
Less common causes of hyperosmolar hyponatraemia
include hypertonic mannitol, sorbitol, maltose and
radiocontrast administration13, 14. This is also known as
translocational hyponatraemia.

Iso-osmolar hyponatraemia
Hyponatraemia can occur with a normal plasma osmolality
(275 - 290 mosm/kg). This occurs as a result of either
pseudohyponatraemia, by massive absorption of irrigant
solutions that do not contain sodium, as during transurethral
resection of the prostate, and by accumulation of cations in
the extracellular space other than sodium.

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Pseudohyponatraemia is a laboratory artefact and occurs with

severe hypertriglyceridaemia and paraproteinaemia. It occurs
because the large non-aqueous molecules such as lipids or
proteins occupy a greater proportion of the serum and there
is a corresponding decrease in total sodium content per unit
volume of serum. This is a laboratory artefact, which is now
fairly obsolete with the use of modern instruments that use
sodium ion specific electrodes15.
Irrigating fluids used during TURP and endoscopic
hysterectomies are hypotonic or isotonic glycine, mannitol,
or sorbitol16, 17. Hyponatraemia is caused primarily by
retention of near-isotonic fluid in the extracellular space.
The plasma osmolality may be normal in case of isotonic
solutions such as 5% mannitol, or hypo-osmolar if the
solution used is hypotonic such as 1.5 percent glycine or
3.3% sorbitol11. Whether the symptoms derive from the
presence of retained solutes, the metabolic products of
such solutes, hypotonicity, or the low serum sodium
concentration remains unclear17.

Hypo-osmolar hyponatraemia
Most cases of hyponatraemia are associated with a low
plasma osmolality (< 275 mosm/kg) reflecting a net gain of
free water3. Patients can be classified according to the total
body volume state of the patient.
Hypovolaemic hyponatraemia occurs when there is loss
of both water and sodium, but sodium loss exceeds that of
water. As a result of hypovolaemia, vasopressin release and
the thirst mechanism are activated leading to increased
water retention, thus further aggravating the hypo-osmolar
state. Causes of water and sodium loss could be:

with diuretic use, but does not require a change in

therapy. Few patients, particularly elderly females
who are volume depleted are at greater risk of
developing severe hyponatraemia20, 21. It typically
develops within three days to three weeks of
initiation of therapy22. Multiple mechanisms are
involved in the pathogenesis of diuretic-induced
hyponatraemia. Diuretic-induced volume
depletion impairs renal diluting capacity and
diuretics block reabsorption in the thick ascending
limb in the loop of Henle21. Diuretic-induced
hypokalaemia and hypomagnesaemia may also
contribute to hyponatraemia23.
2. Extra-renal causes include: loss of sodium and water
from the gut as in diarrhoea and vomiting, or third space
collection as in severe burns, pancreatitis, and peritonitis.
In this case, sodium and water loss causes both water
and sodium reabsorption by the kidneys, but the
amount of water reabsorbed is more than the amount
of sodium reabsorbed because of the baroreceptormediated ADH release and decreased GFR, and
increased proximal tubular reabsorption because of
hypovolaemia. So there is a relative deficiency of
sodium24.
Euvolaemic hyponatraemia occurs when there is free
water gain and negligible sodium loss. These individuals
make up the largest single group of hospitalised
hyponatraemic patients7. In these cases, there is either
decreased water excretion or increased water intake.
Causes include:

b. Hypoaldosteronism.

1. Adrenal insufficiency. Hyponatraemia in primary adrenal

deficiency is related both to hypocortism and
hypoaldosteronism. The water retention is primarily
ADH dependent which is related to reduction in blood
pressure and cardiac output. ADH secretion may also
be directly increased by CRH secretion, which is also
increased in primary adrenal insufficiency25, 26.

c.

2. Hypothyroidism27.

1. Renal causes, which include:

a.

Salt wasting nephropathies such as polycystic

kidney disease and chronic pyelonephritis in which
there is loss of sodium in excess of water.

Use of thiazide diuretics. Although thiazide

diuretics are not the most common cause of
hyponatraemia7, 18, 19, they are the most common
causes of severe symptomatic hyponatraemia
causing neurological sequelae 20, 21. Mild
asymptomatic hyponatraemia frequently occurs

Journal, Indian Academy of Clinical Medicine

3. Syndrome of inappropriate ADH secretion (SIADH), the

most common cause of hyponatraemia in hospitalised
patients7. Vasopressin is released from the posterior
pituitary or an ectopic site inappropriately resulting in
decreased free water excretion. In SIADH, there is no

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93

overt hypervolaemia inspite of water retention because

only one-third of the water is distributed in the
extracellular space. However, there is a modest
expansion of the intravascular volume, which results in
an increased RPF and GFR. It also results in reduced
proximal tubular absorption of sodium, which further
contributes to hyponatraemia. Once a steady state is
reached, urinary sodium excretion becomes equal to
dietary sodium intake28. Diagnostic criteria of SIADH
are3:
a.

Hypo-osmolar hyponatraemia

b. Clinical euvolaemia
c.

Inappropriately concentrated urine > 100 mosm/kg

d. Normal adrenal, cardiac, thyroid, hepatic and renal

functions.
Causes of SIADH can be categorised into four major
groups: malignancy, pulmonary disease, CNS disease
and pharmacological use (Table I) 3,11.
4. Psychogenic polydipsia or compulsive water drinking
is found predominantly in the psychiatric population,
particularly in individuals with schizophrenia. These
patients often drink over 15 lit of water a day,
overwhelming their kidneys maximum capacity to
excrete free water. This leads to dilutional hyponatraemia
with urine osmolality less than 100 mosm/l29.
5. Reset osmostat is a chronic condition where vasopressin
osmoreceptors have a lower threshold to trigger
vasopressin release. This has been associated with
quadriplegia, psychosis, tuberculosis, and chronic
malnutrition30.
6. Beer potomania is seen in chronic alcoholism. Chronic
alcoholics, who already have low dietary sodium and
nutritional stores, ingest large quantities (4 - 5 l) of low
sodium beer with minimal food intake, can have
hyponatraemia. Although the kidneys produce
maximally dilute urine, the amount of daily dietary
solute intake is so low that the kidneys are unable to
maintain isoosmolality leading to water retention and
hyponatraemia31.
Hypervolaemic hyponatraemia: Here free water gain
exceeds sodium gain, resulting in hyponatraemia. This is

94

seen mainly in the setting of increased total body water as

occurs in oedematous states such as CHF, hepatic cirrhosis,
nephrotic syndrome, and renal failure. In these conditions,
although the total body water is increased, the effective
arterial volume is decreased. Intravascular volume depletion
triggers secretion of ADH, renin-angiotensin,
norepinephrine, and thirst. So the intake and retention of
water exceeds the intake of sodium leading to dilutional
hyponatraemia3.

Clinical features
The signs and symptoms of hyponatraemia depend not
only on the absolute serum sodium levels but also on the
rate of serum sodium decline 32. While chronic
hyponatraemia defined as hyponatraemia for more than
48 hrs may be asymptomatic, acute hyponatraemia of
duration < 48 hrs, may result in severe neurological
dysfunction28. Those at extremes of age are less tolerant to
hyponatraemia.
Symptoms of hyponatraemia are listed in Table II32, 33.
Table II: Clinical features of hyponatraemia.
Serum sodium > 125 mmol/l:
Usually asymptomatic
Serum sodium 120 - 125 mmol/l:
Gastrointestinal:
Anorexia
Nausea
Vomiting
Serum sodium < 120 mmol/l:
Neuromuscular:
Muscle cramps
Generalised weakness
Seizures
Neurologic:
Confusion
Disorientation
Agitation
Delirium
Lethargy
Stupor
Serum sodium < 110 mmol/l:
Seizures
Coma
The neurological manifestations are most likely related to

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diffuse cerebral oedema, which results from movement of

water from extracellular fluid into brain cells. In severe cases,
death can result from tentorial herniation and brain stem
compression32.

Brain adaptation to hyponatraemia

During hyponatraemia, the brain cells exposed to hypotonic
plasma swell because fluid shifts into the brain cells resulting
in cellular swelling. The swelling occurs within the confines
of the rigid skull leading to reduction in cerebral blood
flow. The early adaptation of the brain cells to
hyponatraemia is by loss of water into the CSF. This is
followed by extrusion of sodium and potassium from the
brain cells. This constitutes the early adaptive response34, 35.
The late adaptive response occurs with the extrusion of
organic osmolytes such as myoinositol, glycerophosphatylcholine, glutamate, glutamine, creatinine, and taurine35, 36.
Organic osmolytes account for approximately one-third of
the solute loss in chronic hyponatraemia36. If adaptation of
the brain is incomplete, raised intracranial tension develops
which may eventually lead to death.
Risk factors for developing acute cerebral oedema during
hyponatraemia are mentioned in Table III28.

result, water is drawn from the brain cells and brain volume
shrinks. Since there is a delay in the reaccumulation of
organic osmolytes, there is a higher concentration of
inorganic ions as compared to the organic osmolytes. This
probably has a role in the pathogenesis of myelinolysis35.
Table III enlists the various risk factors for development of
ODS28, 41. The clinical manifestations of ODS may be delayed
for 2 - 6 days after the elevation of serum sodium and
include dysarthria, dysphagia, paraparesis or quadriparesis,
and rarely even seizures or coma37, 42, 43. Demyelinating
lesions can be detected by MRI and appear as areas of
increased signal activity on T2-weighted images and as
areas of decreased signal intensity on T1-weighted MRI
scans28. ODS is associated with a very poor prognosis and
there is no effective therapy, although plasmapheresis and
IV immunoglobulins have been tried with variable success44.

Management of hyponatraemia
The treatement of hyponatraemia requires a proper
assessment of the patient so as to determine the cause of
hyponatraemia. The two primary goals of therapy are to
initiate the treatment of the underlying condition and to
restore the normal serum osmolality without causing an
iatrogenic complication. Mild asymptomatic hyponatraemia

Table III: Risk factors for developing acute cerebral oedema during hyponatraemia.
Acute cerebral oedema

Osmotic demyelination syndrome

Young menstruating women

Alcoholics

Elderly women on thiazides

Malnourished patients

Children

Hypokalaemic patients

Psychiatric polydipsic patients

Burn victims

Hypoxaemic patients

Elderly women on thiazide diuretics

Liver transplant patients

Osmotic demyelination syndrome (ODS) is associated

with rapid correction of hyponatraemia37-39. The adaptive
response of the brain creates a potential problem for
therapy. A rapid increase in the plasma sodium
concentration can lead to osmotic demyelination syndrome,
previously known as central pontine myelinolysis. This rapid
cellular dehydration originally was identified in the pons,
but now has been identified in other areas of the brain40.
Because of the organic solute loss that occurs during
adaptation, the brain cells become hypotonic to the
extracellular fluid during correction of hyponatraemia. As a

Journal, Indian Academy of Clinical Medicine

does not require specific therapy. The management of

severe symptomatic hyponatraemia is controversial.
Although a number of questions remain unanswered, the
current evidence is in favour of the following points:
a.

Early recognition and correction of severe hyponatraemia

is beneficial because, it itself is associated with
significant morbidity and mortality32, 45, 46.

b. ODS occurs because of rapid correction of

hyponatraemia, and is not due to hyponatraemia itself38.
c.

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If correction of severe hyponatraemia is carried out

April-June, 2006

95

slowly these patients fare better32.

d. Chronic hyponatraemia alongwith associated risk
factors is associated with permanent neurologic
sequelae than acute hyponatraemia32, 45,46.
e. Patients with chronic hyponatraemia are more likely to
develop ODS as compared to those with acute
hyponatraemia28.
Based on these evidences, certain guidelines can be
made for treatment of severe hyponatraemia. Hypertonic
saline is clearly indicated in patients who are both
severely symptomatic and their serum sodium
concentration is less than 120 meq/l. Patients with milder
symptoms and serum sodium < 105 meq/l may also be
given hypertonic saline22.

Figure 1 shows a suggested algorithm for the diagnosis

and management of hyponatraemia.
Hyperosmolar and iso-osmolar hyponatraemia patients do
not require immediate correction of hyponatraemia; instead,
reversal of the underlying disorder, such as hyperglycaemia
is sufficient3.
Hypo-osmolar hyponatraemia: Treatment of hypoosmolar hyponatraemia depends on the volume status of
the patient, severity of hyponatraemia, and the duration of
hyponatraemia.
In patients with severe symptomatic hyponatraemia, urgent
treatment is necessary to prevent the complication of
cerebral oedema46.

Hyponatraemia < 135 meq/l

Plasma osmolality Normal = 275 - 290

Isoosmolar

Isoosmolar

Hypoosmolar
(most common)

Pseudohyponatraemia
Lipid
Protein
Bladder irrigation

Glucose

Hypervolaemic

Volume status
assessment

Rx accordingly

Euvolaemic

Hypovolaemic

Uosm

Cirrhosis
CHF
Nephrotic syndrome
Renal failure

< 100 mosm/l

Fluid restriction
+
Diuretics

1 polydipsia
Reset osmostat
Beer potomania

Urinary Na+
> 100 mosm/l

< 20
meq/l

SIADH
Hyothyroidism
Adrenal insufficiency
Diuretic use

Extrarenal
Na+ loss

> 20
meq/l
Renal
Na+ loss

Isotonic IVF
Fluid restriction
Isotonic IVF for
Beer potomania

Treat underlying disease

Fluid restriction
Hypertonic IVF for severe cases

Fig. 1: Algorithm for management of Hyponatraemia.

96

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In hypervolaemic patients, water and sodium restriction

are usually enough but in some very severe cases
(presence of seizures or coma) hypertonic (3%) saline
alongwith a loop diuretic may be used47. This helps in
removing the excess of free water. These patients are
however usually chronically hyponatraemic and care
should be taken so as to avoid rapid or over-correction48.
Euvolaemic patients can be subdivided into 2 groups:
those with concentrated urine (Uosm > 100 mosm/kg),
and those with a dilute urine (Uosm < 100 mosm/kg).
The first group includes mainly patients with SIADH.
These patients need to be treated according to the
severity and duration of their symptoms. In severely
symptomatic patients, particularly those with Na+ < 120
meq/l, hypertonic saline should be used3. The second
group includes psychogenic polydipsia and reset
osmostat where simple water restriction is enough3. In
beer potomania, patients should be treated with isotonic
saline to replenish low sodium stores3.
Hypovolaemic patients with hyponatraemia initially require
isotonic saline for concurrent salt and water repletion.
Once the patient has reached a clinically euvolaemic state,
there is no longer a stimulus for vasopressin release
allowing self-correction of hyponatraemia. Therefore, once
euvolaemia is achieved, hypotonic saline should be used
instead of isotonic saline3. This will prevent a rapid
correction of the sodium levels.

hyponatraemia is the cessation of life-threatening

manifestations, moderation of other symptoms, or the
achievement of a serum sodium concentration of 125 to
130 mmol/l49, 50.
In asymptomatic patients, the rate of correction should be
not more than 0.5 to 1.0 mmol/l and less than 8 - 10
mmol/l in 24 hours38, 43. It is important to note that these
asymptomatic patients are more likely to develop ODS
with higher infusion rates as the brain in such patients has
undergone adaptation.
The rate of infusion of the selected solution can be
determined by the following formula3, 11:
Serum Na+ change with 1 l of IVF =
Na+ content in IVF- Measured Serum Na+
[Correction factor * weight (kg)] +1
The correction factor is actually the total body water as a
fraction of the total body weight. The correction factor
varies according to age and sex as shown in Table IV. The
amount of fluid to be infused in l/hr can be calculated as
follows:
Amount of fluid (l/hr) =
(total body water +1)* rate of correction (meq/l/hr)
Infusate Na+ measured Na+
Table IV: Correction factor for calculation of amount
of sodium to be infused.
Patient

Fluid resuscitation rate

There is no consensus about the optimal treatment of
symptomatic hyponatraemia. Nevertheless, correction
should be made of a sufficient pace and magnitude to
reverse the manifestations of hypotonicity, but not be so
rapid and large as to pose a risk of ODS. Most reported cases
of ODS have occurred when the rate of correction exceeded
12 mmol/l/day, but isolated cases have been reported with
corrections of 9 - 10 mmol/l/ day37, 38, 41, 49. So the current
consensus is that the rate of correction should not be more
than 8 mmol on any day3, 11. Initially, the rate of correction
may be rapid, but this also should not be more than 1 - 2
mmol/per hour for 3 - 4 hours, or even briefly if the
symptoms improve11. Recommended indications for
stopping the rapid correction of symptomatic

Journal, Indian Academy of Clinical Medicine

Paediatric
Male, non-elderly
Female, non-elderly
Male, elderly
Female, elderly

Correction factor
0.6
0.6
0.5
0.5
0.45

For example, in a 60 kg elderly woman who presents with

a significant altered mental status and a sodium
concentration of 110 meq/l, hypertonic saline should be
instituted immediately. The rate of correction in this case
should initially be 2 meq/l/hr for the first two to three hours.
The amount of fluid required is [(0.45*60 = 27) +1]*2/513110 = 0.139 l or 139 ml in the first hour.
The sodium concentration of various commonly used
solutions is shown in Table V.

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97

Table V: Various IV fluids used in the treatment of hyponatraemia and hypernatraemia and the amount of
sodium in the fluid.
Infusate

Infusate Na+
(mmol per litre)

Extracellular fluid distribution

(%)

855
513
154
130
77

100
100
100
97
73

34
0

55
40

5% Sodium chloride in water

3% Sodium chloride in water
0.9% Sodium chloride in water
Ringers lactate solution
0.45% Sodium chloride in water
0.2% Sodium chloride in
5% dextrose in water
5% Dextrose in water
Other therapeutic options include:

Classification of Hypernatraemia

1. Urea: it induces water loss by providing an osmotic load.

Moreover, urea diffuses into the brain and its
accumulation prevents excessive brain dehydration. It
could also trigger the accumulation of organic
osmolytes in brain51.

Hypernatraemia is always associated with hypertonicity of

the plasma. It can therefore be classified according to the
volume status of the patient into the following categories:

2. Demeclocycline and lithium: these act on the collecting

tubule, reducing its responsiveness to ADH. They can
be considered for patients with persistent
hyponatraemia unresponsive to water restriction, high
salt intake, and a loop diuretic52.
3. Vasopressin receptor antagonists selective for the
V2 receptor may be beneficial in patients with SIADH
and in hyponatraemic patients with CHF and
cirrhosis53.

Hypernatraemia
Hypernatraemia is defined as serum or plasma sodium
concentration > 145 meq/l. Hypernatraemia represents a
deficit of water in relation to the bodys sodium stores. It
can result from net water loss or hypertonic sodium gain.
Sustained hypernatraemia can occur only when thirst or
access to water is impaired1. Those at highest risk are
patients with altered mental status, intubated patients,
infants, and elderly patients 1, 3. The incidence of
hypernatraemia ranges from 0.3% to 1%54. In adults, acute
hypernatraemia has been associated with a mortality rate
as high as 75% and chronic hypernatraemia is associated
with a mortality rate of around 60%55. Even in survivors,
severe morbidity in the form of permanent neurological
sequelae is quite common.

98

1. Hypovolaemic hypernatraemia: Here the fluid lost is

hypotonic, so free water loss exceeds sodium loss,
resulting in hypernatraemia. Water loss can be extrarenal or renal, and these patients display signs of
hypovolaemia such as tachycardia, poor skin turgor,
orthostatic hypotension, and dry mucous membranes.
a.

Extra-renal loss can occur through the skin, as with

profuse sweating. Sweat is hypotonic and patients
who have fever, or who are exposed to very high
temperatures and have limited access to water or
decreased thirst, can become hypernatraemic.
Similarly, patients with burns or skin diseases such
as pemphigus vulgaris can also have
hypernatraemia. Alternatively, extra-renal loss can
occur through the GIT as in diarrhoea (especially if
hypertonic fluid is used for volume replacement,
or there is inadequate volume replacement), nasogastric suctioning, vomiting, and third space
collection (pancreatitis or bowel obstruction). In
all these cases, the urinary sodium concentration
is low (< 10 meq/l) and the urine osmolality is high
(> 700 mosm/kg)3, 22.

b. Renal loss can occur with diuretic use and severe

osmotic diuresis resulting from hypertonic
mannitol administration, severe glycosuria in
diabetics, or elevated urea in the setting of post-

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obstructive diuresis. In these cases, urinary Na+ is

elevated (> 20 meq/l) and urine is isotonic or
hypotonic (< 700 mosm/kg)3.
2. Euvolaemic hypernatraemia: In this case, there is pure
water loss without the signs of hypovolaemia.
Patients appear euvolaemic despite free water loss
because most of the water is lost from intracellular
space. The water loss can result from extra-renal or
renal causes.
a.

Extra-renal causes: Extra-renal loss of water can

occur through skin or respiratory tract. Healthy
adults average 500 ml/day insensible loss of water
through the skin even in the absence of
discernible sweating22. The normal insensible
respiratory loss is also 500 ml/day22. This can
increase greatly in the presence of fever,
respiratory infection, high altitude, or
hyperventilation during mechanical ventilation.
Skin and respiratory losses may reach upto several
litres/day, but this is easily replaced by most
people. Hypernatraemia results when people do
not have access to water or fail to drink. Relative
hypodipsia is common in elderly patients with
normal mental functions and neurological status.
Primary hypodipsia is another cause of extra-renal
loss of free water, which results from destruction
of thirst centres in the hypothalamus, caused by
multiple disorders such as hypothalamic tumours,
granulomatous diseases, vascular abnormalities,
and trauma56. Essential hypernatraemia is a variant
of primary hypodipsia in which there is an upward
resetting of the osmotic thresholds for thirst and
vasopressin release, but their response to
haemodynamic stimuli remains normal57.

b. Renal causes: Renal loss of free water is due to

diabetes insipidus (DI). DI is a disorder characterised
by either an absence of ADH secretion (central or
neurogenic DI) or a failure of the kidney to respond
to ADH (nephrogenic DI)58. In diabetes insipidus,
lack of ADH or its effect results in loss of large
volumes of dilute urine and a consequent rise in
plasma osmolality and serum Na+ concentration.
Thirst is stimulated and alert patients are able to
maintain their plasma osmolality within the normal

Journal, Indian Academy of Clinical Medicine

range. Hypernatraemia does not occur unless there

is a concomitant defect in the thirst mechanism or
restricted access to water. These patients are
euvolaemic because water is lost both from the
extracellular as well as intracellular space. Causes
of DI are enlisted in Table VI3, 58, 59.
2. Hypervolaemic hypernatraemia: It results from pure Na+
overload. It is rare and frequently iatrogenic. This is seen
in excessive sodium bicarbonate administration during
cardio-pulmonary resuscitation, over-correction of
hyponatraemia, hypertonic dialysate in peritoneal and
haemodialysis, and hypertonic enteral and parenteral
hyperalimentation. Non-iatrogenic causes include
mineralocorticoid deficiency and near drowning in salty
water.
Causes of hypernatraemia are enlisted in Table VI3, 59.
Table VI: Causes of hypernatraemia.
Hypernatraemia due to net water loss
Pure water (euvolaemic)
Unreplaced insensible losses (dermal and
respiratory)
Hypodipsia
Neurogenic (central) diabetes insipidus
Post-traumatic
Tumours, cysts, histiocytosis, tuberculosis,
sarcoidosis
Idiopathic
Aneurysms, meningitis, encephalitis,
GuillainBarr syndrome
Ethanol ingestion (transient)
Nephrogenic diabetes insipidus
Congenital nephrogenic diabetes insipidus
Acquired nephrogenic diabetes insipidus
Renal disease (e.g., medullary cystic disease)
Hypercalcaemia or Hypokalaemia
Drugs (lithium, demeclocycline, foscarnet,
methoxyflurane, amphotericin B, vasopressin
V2receptor antagonists)
Hypotonic fluid (hypovolaemic)
Renal causes
Loop diuretics
Osmotic diuresis (glucose, urea, mannitol)
Post-obstructive diuresis
Polyuric phase of acute tubular necrosis
Intrinsic renal disease
Gastrointestinal causes
Vomiting
Nasogastric drainage

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99

Enterocutaneous fistula
Diarrhoea
Use of osmotic cathartic agents (e.g., lactulose)
Cutaneous causes
Burns
Excessive sweating
Pemphigus vulgaris
Hypernatraemia due to hypertonic sodium gain
(hypervolaemic)
Hypertonic sodium bicarbonate infusion
Hypertonic feeding preparation
Ingestion of sodium chloride
Ingestion of sea water
Sodium chloride-rich emetics
Hypertonic saline enemas
Intrauterine injection of hypertonic saline
Hypertonic sodium chloride infusion
Hypertonic dialysis
Primary hyperaldosteronism
Cushings syndrome

Clinical features: The principal manifestations of

hypernatraemia largely reflect CNS dysfunction and are

prominent when the increase in serum Na+ is large or

occurs rapidly32. Neurological symptoms occur as a
consequence of cellular dehydration in the brain32, 59. Loss
of brain volume results in traction on the cerebral vessels,
which may then tear. It is also associated with cerebral
bleeding, subarachnoid haemorrhage, and venous sinus
thrombosis33, 62. So the threshold for getting a CT scan in a
patient with hypernatraemia and altered mental status
should be low. Convulsions are usually absent and are more
commonly seen in cases of inadvertent sodium loading or
aggressive rehydration63, 64. Signs and symptoms of
hypernatraemia are listed in Table VII32.
Table VII: Clinical features of hypernatraemia.
Anorexia, nausea, and vomiting
Altered mental status, agitation, irritability
Stupor, lethargy, and coma
Signs of neuromuscular hyperactivity: hyperreflexia,
spasticity, tremor, asterixis, chorea, and ataxia.
Focal neurological deficits: hemiparesis and extensor
plantars.

Management of hypernatraemia
Hypernatraemia (Na+ > 145 meq/l)
Plasma osmolality > 290 mosm/kg
Hypovolaemic

Euvolaemic

Hypervolaemic

Urine osm.

Urine osmolatity

Na overload usually iatrogenic

> 700
mosm/kg

< 700
mosm/kg

Urinary Na

< 10

> 10

Extra-renal
loss

Renal
loss

Hypotonic IVF
isotonic IVG if BP

> 700

< 700

Extra-renal loss
Skin loss
Resp tract loss
1 Hypodipsia
GIT loss

DI
Renal loss

Hypotonic
IVF

Hypotonic IVF
vasopressin

Urinary Na+
> 1,000 mmol/lit

Diuretic and water

replacement

Fig. 2: Algorithm for management of Hypernatraemia.

100

Journal, Indian Academy of Clinical Medicine

Vol. 7, No. 2

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Management
Proper management of hypernatraemia requires a twopronged approach: addressing the underlying cause and
correcting the prevailing hypertonicity. Figure 2 shows an
algorithm for diagnosis and treatment of hypernatraemia.
The treatment of hypernatraemia depends on the volume
status of the patient. Patients with hypovolaemic
hypernatraemia should be treated with isotonic saline
particularly if there is evidence of circulatory collapse3.
Otherwise, if the volume depletion is mild without evidence
of circulatory failure, hypotonic fluids such as one-quarter
saline (0.2% saline), half isotonic saline (0.45%), pure water,
or 5% dextrose should be used59. Even in cases of circulatory
failure, once haemodynamic stability is achieved, hypotonic
fluids should be used3. Euvolaemic patients also require pure
water replacement with hypotonic saline or free water. When
administering dextrose containing solutions, blood glucose
should be closely monitored, because hyperglycaemia will
worsen the hypertonic state and may lead to osmotic
diuresis66. Patients with central DI can be given 5 - 10 units of
aqueous vasopressin subcutaneously every 3 - 4 hours67.
Serum sodium concentration and urinary specific gravity
should be monitored every 2 - 4 hours to prevent overcorrection. Vasopressin is preferred over desmopressin
because vasopressin has a shorter duration of action3. This
will however be ineffective in nephrogenic DI. Hypervolaemic
patients have sodium overload, and they require natriuresis
with a loop diuretic and free water replacement. Dialysis
may be required in patients with severe renal failure to
achieve natriuresis3.

Rate of correction of hypernatraemia

The rate of correction of hypernatraemia depends on the
rate of development of hypernatraemia. In cases of acute
hypernatraemia (< 48 hrs), rapid correction improves the
prognosis without increasing the risk of cerebral oedema,
because accumulated electrolytes are rapidly extruded
from the brain cells. In such patients, the serum sodium
can be reduced by 1 meq/l/hour 65 . In chronic
hypernatraemia, a slower pace is required, as full dissipation
of accumulated brain solutes during adaptation occurs
over a few days. In these patients the appropriate rate of
correction is 0.5 meq/l per hour66, 67. The target should be
to decrease the serum sodium by 10 meq/l in one day,

Journal, Indian Academy of Clinical Medicine

except in those in whom the disorder has developed over

a matter of hours. The goal of treatment is to achieve a
sodium concentration of 145 meq/l59. Lowering the plasma
osmolality with hypotonic fluids too rapidly can lead to
iatrogenic cerebral oedema because of osmotic shift of
water into the brain cells68. Allowances must be made for
ongoing hypotonic fluid loss (obligatory or incidental)
while calculating the fluid requirement. The amount of
fluid required can be calculated using the following
formula:
Serum Na+ change with 1 l of IVF =
Na+ content in IVF measured serum Na+
[Correction factor * weight (kg)] +1
This formula gives the amount of change in serum sodium
with one litre of the given fluid.
The amount of hypotonic fluid required can be calculated
by the formula:
Amount of fluid (l/hr) =
(total body water +1)* rate of correction (meq/l/hr)
Infusate Na+ measured Na+
For example, in an elderly 80 kg male with a serum sodium
concentration of 160 meq/l, the rate of decrease should be
0.5 meq/l/hr. The amount of 0.45% saline required will be
[(0.5*80)+1]*0.5/77-160 = .246 l or 246 ml/hr.
Table V lists the characteristics of various solutions used in
management of hypernatraemia.
Both hypernatraemia and hyponatraemia initially present
with non-specific signs and symptoms and can only be
diagnosed if a high index of suspicion is maintained for
these conditions. The treatment of both these conditions is
tricky, as over-treatment can lead to potentially dangerous
complications and under-treatment is associated with
significant mortality and morbidity. It is therefore essential
to monitor the serum sodium concentration every 2 - 4
hours to prevent treatment related complications. Frequent
neurological examination should also be performed during
treatment as it can help in early detection of ODS and
cerebral oedema.

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