1. health and fitness
2. disease

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.
Journal, Indian Academy of Clinical Medicine
Vol. 7, No. 2
April-June, 2006
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
Vol. 7, No. 2
April-June, 2006
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
Journal, Indian Academy of Clinical Medicine
Vol. 7, No. 2
April-June, 2006
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.
Vol. 7, No. 2
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
Journal, Indian Academy of Clinical Medicine
Vol. 7, No. 2
April-June, 2006
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.
Vol. 7, No. 2
April-June, 2006
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
Ringer’s 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 body’s 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-
Journal, Indian Academy of Clinical Medicine
Vol. 7, No. 2
April-June, 2006
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,
Guillain–Barré 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
V2–receptor 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
Vol. 7, No. 2
April-June, 2006
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
Cushing’s 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
April-June, 2006
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.
References
1.
Vol. 7, No. 2
Genanri FJ. Hypo-hypernatraemia: disorders of water
April-June, 2006
101
balance. In: Davison AM, Cameron JS, Grunfeld J-P, Kerr
DNS, Ritz E, Winearls CG, eds. Oxford textbook of clinical
nephrology. 2nd ed. Vol 1. Oxford, England: Oxford
University Press, 1998; 175-200.
2.
Genanri FJ. Serum osmolality: uses and limitations. N Engl
J Med 1984; 310: 102-5.
3.
Lin M, Liu SJ, Lim IT. Disorders of water imbalance. Emerg
Med Clin North Am 2005; 23 (3): 749-70.
4.
McKinley MJ, Mathai ML, McAllen RM et al. Vasopressin
secretion: osmotic and hormonal regulation by the lamina
terminalis. J Neuroendocrinol 2004 ; 16 (4): 340-7.
Nephrol Necker Hosp 1984; 13: 1-28.
21. Ashraf N, Locksley R, Arieff AI. Thiazide-induced
hyponatremia associated with death or neurologic
damage in outpatients. Am J Med 1981; 70 (6): 1163-8.
22. Votey SR, Peters AL, Hoffman JR. Disorders of water
metabolism: hyponatremia and hypernatremia. Emerg Med
Clin North Am 1989; 7 (4): 749-69.
23. Fichman MP, Vorherr H, Kleeman CR, Telfer N. Diureticinduced hyponatremia. Ann Intern Med 1971; 75 (6): 853-63.
24. Lee CT, Guo HR, Chen JB. Hyponatremia in the emergency
department. Am J Emerg Med 2000; 18 (3): 264-8.
5.
Berliner RW, Levinsky NG, Davidson DG, Eden M. Dilution
and concentration of the urine and the action of
antidiuretic hormone. Am J Med 1958; 24 (5): 730-44.
25. Linas SL, Berl T, Robertson GL et al. Role of vasopressin in
the impaired water excretion of glucocorticoid deficiency.
Kidney Int 1980; 18 (1): 58-67.
6.
Al-Salman J, Kemp D, Randall D. Hyponatremia. West J Med
2002; 176 (3): 173-6.
7.
Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia:
a prospective analysis of its epidemiology and the
pathogenetic role of vasopressin. Ann Intern Med 1985; 102
(2): 164-8.
26. Schrier RW, Linas SL. Mechanisms of defect in water
excretion in adrenal insufficiency. Miner Electrolyte Metab
1980; 4: 1-18.
27. Derubertis FR Jr, Michelis MF, Bloom ME et al. Impaired
water excretion in myxedema. Am J Med 1971; 51 (1): 41-53.
28. Abraham A, Jacob CK. Severe hyponatraemia: current
concepts on pathogenesis and treatment. Natl Med J India
2001; 14 (5): 277-83.
8.
Tierney WM, Martin DK, Greenlee MC et al. The prognosis
of hyponatremia at hospital admission. J Gen Intern Med
1986; 1 (6): 380-5.
9.
Lee CT, Guo HR, Chen JB.Hyponatremia in the emergency
department. Am J Emerg Med 2000; 18 (3): 264-8.
29. Riggs AT, Dysken MW, Kim SW, Opsahl JA. A review of
disorders of water homeostasis in psychiatric patients.
Psychosomatics 1991; 32 (2): 133-48.
10. Arieff AI. Hyponatremia, convulsions, respiratory arrest,
and permanent brain damage after elective surgery in
healthy women. N Engl J Med 1986; 314 (24): 1529-35.
30. Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders
of osmoregulation. Am J Med 1982; 72 (2): 339-53.
11. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;
342 (21): 1581-9.
12. Oh MS. Pathogenesis and diagnosis of hyponatremia.
Nephron 2002; 92 (Suppl 1): 2-8.
13. Aviram A, Pfau A, Czaczkes JW, Ullmann TD. Hyperosmolality
with hyponatremia, caused by inappropriate
administration of mannitol. Am J Med 1967; 42 (4): 648-50.
14. Palevsky PM, Rendulic D, Diven WF. Maltose-induced
hyponatremia. Ann Intern Med 1993; 118 (7): 526-8.
15. Maas AH, Siggaard-Andersen O, Weisberg HF, Zijlstra WG.
Ion-selective electrodes for sodium and potassium: a new
problem of what is measured and what should be
reported. Clin Chem 1985; 31 (3): 482-5.
16. Gonzales R, Brensilver JM, Rovinsky JJ. Post-hysteroscopic
hyponatremia. Am J Kidney Dis 1994; 23:735-8.
31. Fenves AZ, Thomas S, Knochel JP. Beer potomania: two
cases and review of the literature. Clin Nephrol 1996; 45 (1):
61-4.
32. Arieff AI. Central nervous system manifestations of
disordered sodium metabolism. Clin Endocrinol Metab 1984;
13 (2): 269-94.
33. Schrier RW, Berl T. Disorders of water metabolism. In: Schrier
RW ed: Renal and Electrolyte Disorders. Ed 2. Boston, Little
Brown and Co, 1986; 1.
34. Melton JE, Nattie EE. Brain and CSF water and ions during
dilutional and isosmotic hyponatremia in the rat. Am J
Physiol 1983; 244 (5): R724-32.
35. Verbalis JG, Gullans SR. Hyponatraemia causes large
sustained reductions in brain content of multiple organic
osmolytes in rats. Brain Res 1991; 20; 567 (2): 274-82.
17. Agarwal R, Emmett M. The post-transurethral resection of
prostate Syndrome: therapeutic proposals. Am J Kidney Dis
1994; 24:108-11.
36. Paredes A, McManus M, Kwon HM, Strange K.
Osmoregulation of Na(+)-inositol co-transporter activity
and mRNA levels in brain glial cells. Am J Physiol 1992; 263
(6 Pt 1): C1282-8.
18. Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical
assessment of extracellular fluid volume in hyponatremia.
Am J Med 1987; 83 (5): 905-8.
37. Karp BI, Laureno R. Pontine and extrapontine myelinolysis:
a neurologic disorder following rapid correction of
hyponatremia. Medicine (Baltimore) 1993; 72: 359-73.
19. Kennedy PG, Mitchell DM, Hoffbrand BI. Severe
hyponatraemia in hospital inpatients. Br Med J 1978; 2 (6147):
1251-3.
38. Sterns RH, Riggs JE, Schochet SS Jr. Osmotic demyelination
syndrome following correction of hyponatremia. N Engl J
Med 1986; 314: 1535-42.
20. Abramow M, Cogan E. Clinical aspects and
pathophysiology of diuretic-induced hyponatremia. Adv
39. Tanneau RS, Henry A, Rouhart F et al. High incidence of
neurologic complications following rapid correction of
102
Journal, Indian Academy of Clinical Medicine
Vol. 7, No. 2
April-June, 2006
severe hyponatremia in polydipsic patients. J Clin Psychiatry
1994; 55: 349-54.
53. Gross P, Palm C. The treatment of hyponatraemia using
vasopressin antagonists. Exp Physiol 2000; 85: S253-257.
40. Gocht A, Colmant HJ. Central pontine and extrapontine
myelinolysis: a report of 58 cases. Clin Neuropathol 1987; 6
(6): 262-70.
54. Long CA, Marin P, Bayer AJ et al. Hypernatraemia in an
adult in-patient population. Postgrad Med J 1991; 67 (789):
643-5.
41. Sterns RH, Cappuccio JD, Silver SM, Cohen EP.
Neurologic sequelae after treatment of severe
hyponatremia: a multicenter perspective. J Am Soc
Nephrol 1994; 4 (8): 1522-30.
55. Janz T. Sodium. Emerg Med Clin North America 1986; 4 (1):
115-30.
42. Laureno R. Central pontine myelinolysis following
rapid correction of hyponatremia. Ann Neurol 1983; 13
(3): 232-42.
43. Srivastava T, Singh P, Sharma B. Pontine and extrapontine
myelinolysis following rapid correction of hyponatremia.
Neurol India 2000; 48 (1): 97.
44. Finsterer J, Engelmayer E, Trnka E, Stiskal M.
Immunoglobulins are effective in pontine myelinolysis.
Clin Neuropharmacol 2000; 23 (2): 110-3.
56. Robertson GL. Antidiuretic hormone. Normal and
disordered function. Endocrinol Metab Clin North Am 2001;
30 (3): 671-94.
57. DeRubertis FR, Michelis MF, Davis BB. Essential
hypernatremia. Report of three cases and review of the
literature. Arch Intern Med 1974; 134 (5): 889-95.
58. Robertson GL. Posterior Pituatry. In: Felig P, Baxter JD,
Broadus AE et al (eds): Endocrinology and Metabolism. Ed
2. New York. McGraw Hill.1987; 338.
59. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;
342 (20): 1493-9.
45. Arieff AI. Hyponatremia, convulsions, respiratory arrest,
and permanent brain damage after elective surgery in
healthy women. N Engl J Med 1986; 314 (24): 1529-35.
60. Mattar JA, Weil MH, Shubin H, Stein L. Cardiac arrest in the
critically ill. II. Hyperosmolal states following cardiac arrest.
Am J Med 1974; 56 (2): 162-8.
46. Ayus JC, Krothapalli RK, Arieff AI. Changing concepts in
treatment of severe symptomatic hyponatremia. Rapid
correction and possible relation to central pontine
myelinolysis. Am J Med 1985; 78 (6 Pt 1): 897-902.
61. Snyder NA, Feigal DW, Arieff AI. Hypernatremia in elderly
patients. A heterogeneous, morbid, and iatrogenic entity.
Ann Intern Med 1987; 107 (3): 309-19.
47. Schrier RW. Pathogenesis of sodium and water retention
in high-output and low-output cardiac failure, nephrotic
syndrome, cirrhosis, and pregnancy. N Engl J Med 1988; 319
(16): 1065-72.
48. Paterna S, Di Pasquale P, Parrinello G et al. Effects of highdose furosemide and small-volume hypertonic saline
solution infusion in comparison with a high dose of
furosemide as a bolus, in refractory congestive heart
failure. Eur J Heart Fail 2000; 2 (3): 305-13.
49. Oh MS, Kim HJ, Carroll HJ. Recommendations for
treatment of symptomatic hyponatremia. Nephron 1995;
70:143-50.
50. Berl T. Treating hyponatremia: damned if we do and
damned if we don’t. Kidney Int 1990; 37: 1006-18.
51. Van Reeth O, Decaux G. Rapid correction of
hyponatraemia with urea may protect against brain
damage in rats. Clin Sci (Lond) 1989; 77: 351-5.
52. Forrest JN Jr, Cox M, Hong C et al. Superiority of
demeclocycline over lithium in the treatment of chronic
syndrome of inappropriate secretion of antidiuretic
hormone. N Engl J Med 1978; 298 (4): 173-7.
Journal, Indian Academy of Clinical Medicine
62. Macaulay D, Watson M. Hypernatraemia in infants as a
cause of brain damage. Arch Dis Child 1967; 42 (225):
485-91.
63. Morris-Jones PH, Houston IB, Evans RC. Prognosis of the
neurological complications of acute hypernatraemia.
Lancet 1967; 2: 1385-9.
64. Hogan GR, Dodge PR, Gill SR et al. Pathogenesis of seizures
occurring during restoration of plasma tonicity to normal
in animals previously chronically hypernatremic. Pediatrics
1969; 43: 54-64.
65. Palevsky PM. Hypernatremia. In: Greenberg A, ed. Primer
on kidney diseases. 2nd ed. San Diego, Calif.: Academic
Press, 1998; 64-71.
66. Kahn A, Brachet E, Blum D. Controlled fall in natremia and
risk of seizures in hypertonic dehydration. Intensive Care
Med 1979; 5: 27-31.
67. Blum D, Brasseur D, Kahn A, Brachet E. Safe oral rehydration
of hypertonic dehydration. J Pediatr Gastroenterol Nutr 1986;
5: 232-5.
68. Arieff AI, Guisado R. Effects on the central nervous system
of hypernatremic and hyponatremic states. Kidney Int 1976;
10 (1): 104-16.
Vol. 7, No. 2
April-June, 2006
103