Hyponatraemia

Hyponatraemia, defined as an excess of water in relation to the sodium in the extracellular fluid
is the most common electrolyte disorder in the hospitalized patients. 1,2 Hyponatraemia is defined
as a serum sodium concentration below 135mmol/l, it appears in up to 8% of the general
population and in up to 60% of hospitalized patients.3,4
Studies have showed that hyponatraemia is, very often, neglected by the clinicians despite the
frequency and severity of the aasociated complications.5
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is te most common
cause of hyponatraemia, even thought hyponatraemia asociated with hypovolemia is also very
common.6 The first studies have assumed that vasopressin secretion was inappropriate in SIADH
because it was independent of plasma osmolality or volume status. This is the case of 1/3 of
patients with SIADH.10 Vasopressin secretion can result from a increased pituitary activity or
from a ectopi production.9
SIADH has been described for the first time in patients with bronchogenic carcinoma in whom
was lacking a physiologic stimlus for the release of antidiuretic hormone.7The risk to develop
SIADH rises with increasing age and is hiigh among the residents of nursing homes.8
Experts from different specialties often propose different diagnostic algorithms to facilitate the
management of hyponatraemic patients in the hospital setting. Traditionally, diagnosis and
treatment of hyponatraemia has fallen within the remit of practitioners of nephrology and
endocrinology. Therefore, endocrinologists and nephrologists were brought together at the
European Hyponatraemia Network Academy Meeting to discuss two approaches to the
differential diagnosis of hyponatraemia using different diagnostic algorithms.

Diagnosis of SIADH
Usually, in patients with hyponatraemia the serum is hypotonic, but sometimes the serum
contains osmoles that increase effective osmolality and reduce the serum sodium concentration.
Serum osmolality must be measured to rule out pseudohyponatremia, a laboratory artifact
occurring when 11when abnormally high concentrations of lipids or proteins in the blood interfere
with the accurate measurement of sodium 12,13,14,15Serum osmolalilty in pseudohyponatraemia is
normal and no shifts of water occur.
Hypertonic (or translocational) hyponatremia occurs when osmotically active solutes (glucose or
mannitol) draw water from cells. For each increase of 100 mg per deciliter (5.6 mmol per liter) in
plasma glucose levels, serum sodium declines by 1.6 to 2.4 mmol per liter.16

A normal or elevated measured osmolality value, however, does not rule out hypotonic
hyponatremia, because urea is an ineffective osmole. Thus, the effective osmolality (sometimes
called tonicity) is equal to the measured osmolality minus (blood urea nitrogen2.8), with blood
urea nitrogen measured in milligrams per deciliter.17
For a diagnosis of hypotonic hyponatremia, the effective osmolality must be less than 275
mOsm per kilogram of water .
In the clinical routine it has been adopted a pragmatic aproach to hypotonic hyponatremia in
which classification of causation is based on clinical and biochemical estimation of extracellular
volume status. This divides hyponatraemia into hypovolaemic, euvolaemic and hypervolaemic
aetiologies (see Table 1). 18
Although it is relatively simple to detect hypervolemic patients through clinical signs, as they
will show signs of edema etc., it is less straightforward to make a distinction between
hypovolemic and euvolemic patients, especially in the elderly 19. It is therefore important to
perform a thorough clinical assessment. In addition, further diagnostic tests are key to making
the right diagnosis.
Table 1
Causes of hyponatraemia.
Clinical signs
Dry mucous
Hypovolaemic membranes

Urinary Na+<20 mmol/l Urinary Na+>40 mmol/l

GI losses

Diuretics

Decreased turgor

Mucosal losses

Addison's disease

Tachycardia

Pancreatitis

Cerebral salt wasting

Hypotension
(orthostatic)

Sodium depletion post

diuretics

Salt wasting nephropathy

Hypothyroidism

SIADH

SIADH with ongoing fluid

restriction

ACTH deficiency

Raised urea,
rennin
Euvolaemic

Underlying illness

Primary polydipsia
Inappropriate fluid
replacement
Hypervolaemi Peripheral
c
oedema

Cirrhosis

Ascites

Cardiac failure

Raised JVP

Nephrotic syndrome

Pulmonary

Cardiac failure or cirrhosis on

diuretic therapy

Clinical signs

Urinary Na+<20 mmol/l Urinary Na+>40 mmol/l

oedema
Underlying illness

JVP, jugular venous pressure.

Euvolaemic hyponatraemia is the commonest cause of hyponatraemia in hospitalised patients.

SIADH is the most common cause of hyponatremia,with higher rates found in patients with
SCLC (small cell lung cancer) than with other malignancies 20,21. Four different patterns of
vasopressin secretion have been identified in patients with SIADH (Figure 1):

Figure 1: Patterns of plasma vasopressin levels where compared with plasma sodium levels in
patients with SIADH 22. Type A is characterized by unregulated secretion of vasopressin, type B
by elevated basal secretion of vasopressin despite normal regulation by osmolality, type C by a
reset osmostat and type D by undetectable vasopressin. The shaded area represents normal
values of plasma vasopressin. Adapted from Ellison and Berl 22.
The first step in the diagnosis of SIADH is to differentiate it from other causes of
hyponatraemia. There have been some experimental models of SIADH that show that blood
volume is increased in SIADH 23 but this expanded volume is not clinically important and
doesnt cause oedema. SIADH is the most common cause of euvolaemic hyponatraemia in
modern clinical practice.
SIADH is a diagnosis of exclusion that needs to be distinguished from other causes of
euvolaemic hyponatraemia, such as inappropriate hypotonic fluid replacement (particularly in
patients following surgery).
ACTH deficiency is another important cause of euvolaemic hyponatraemia which must be
excluded.

ACTH deficiency is caracterised by cortisol deficiency and not aldosterone deficiency;

glucocorticoid deficiency is associated with retention of free water 24, because cortisol fail to
suppress vasopressin. It has been shown that glucocorticoid therapy suppress AVP secretion25 and
determines the excretion of free water and plasma sodium concentrations are normalized.
The differential diagnosis between SIADH and ACTH deficiency is very important, especially in
patients with neurosurgical conditions26. Hyponatraemia is been discover in over 50% of patients
with acute subarachnoid haemorrhage, most of it diagnosed as SIADH 27 and only 16% of
neurosurgical patients develope ACTH deficiency.28
Another essential differentiation, in neurosurgical patients, is between SIADH and cerebral saltwasting syndrome because. Cerebral salt wasting syndrome was initially describe on patients
with neurological disorders and hyponatraemia, hypovolemia, diuresis, natriuresis and a normal
hypotalamic-pituitary-adrenal axis29. The main feature to distingush SIADH is the extracellularflui volume depletion. Only 6,5% cases of patients with subarachnoid hemorrahage were
attributed to salt wasting.30
There are a few similarities between SIADH and cerebral salt-wasting syndrome (Tabel 2):

Table 2

Differences between SIADH and cerebral salt wasting. Adapted from Sherlock M, O'Sullivan E,
Agha A, Behan LA, Rawluk D, Brennan P, Tormey W & Thompson CJ. The incidence and
pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clinical
Endocrinology 2006 64 250254.31
SIADH
Cerebral salt wasting
Serum urea concentration
Serum uric acid concentration
Urine volume
Urine sodium concentration
Blood pressure
Central venous pressure

Normallow
Low
Normallow
>30mmol/l

Normal
Normal

Normalhigh
Low
High
30mmol/l

Normalorthostatic hypotension
Low

The use of diuretics should also be excluded prior to diagnosing SIADH. Urine sodium
concentrations >30mmol/l should be interpretated with caution in patients that are using

diuretics. In order to differentiate SIADH as un underlying cause of hyponatraemia, in patients

using diuretics, a fractional excretion of uric acid <12% may be more usefull. 32
There are a lot of diseases that can cause SIAD and the most common are lung cancer,
pulmonary infections, CNS infections, stroke, antiepileptics, antidepressants and idiopathic
origins. (Table 3). 33 Its very important not to skip an underlying cause, especially if it is a
malignancy.

Table 3
Causes of SIADH 33
Malignancy
Pulmonary/mediastinal (bronchogenic carcinoma, mesothelioma,
thymoma)
Non-chest (duodenal carcinoma, pancreatic carcinoma, ureteral/prostate
carcinoma, uterine carcinoma, nasopharyngeal carcinoma, leukemia)
CNS
Mass lesions (tumors, brain abscesses, subdural hematoma)
disorders
Inflammatory diseases (encephalitis, meningitis, systemic lupus, acute
intermittent porphyria, multiple sclerosis)
Degenerative/demyelinative diseases (GuillainBarr syndrome, spinal cord
lesions)
Miscellaneous (subarachnoid hemorrhage, head trauma, acute psychosis,
delirium tremens, pituitary stalk section, transsphenoidal adenomectomy,
hydrocephalus)
Drugs
Stimulated vasopressin release
Direct renal effects and/or potentiation of vasopressin antidiuretic effects
Mixed or uncertain actions
Pulmonary
Infections (tuberculosis, acute bacterial and viral pneumonia, aspergillosis,
diseases
empyema)
Mechanical/ventilatory (acute respiratory failure, COPD, positive pressure
ventilation)
Other
AIDS and ARC
Prolonged strenuous exercise (marathon, triathlon, ultramarathon, hot-weather
hiking)
Prolonged nausea and vomiting (e.g. with chemotherapy)
Senile atrophy
Idiopathic
ARC, AIDS-related complex; COPD, chronic obstructive pulmonary disease.
Adapted from Verbalis et al.

33

There are some formal criterias for the diagnosis of SIAD and have been classified in essential
criteria and supplemental criteria (Tabel 4):
Table 4
Diagnostic criteria for the syndrome of inappropriate antidiuresis. Adapted from Schwartz WB,
Bennett W, Curelop S & Bartter FC. A syndrome of renal sodium loss and hyponatremia
probably resulting from inappropriate secretion of antidiuretic hormone. American Journal of
Medicine 1957 23529542 (29) and Janicic N & Verbalis JG. Evaluation and management of
hypo-osmolality in hospitalized patients. Endocrinology and Metabolism Clinics of North
America 2003 32 459481, vii. 34

Essential criteria
Effective serum osmolality <275mOsm/kg

Urine osmolality >100mOsm/kg

at some level of decreased effective osmolality

Clinical euvolaemia
Urine sodium concentration >30mmol/l

with normal dietary salt and water intake

Absence of adrenal, thyroid, pituitary or renal insufficiency
No recent use of diuretic agents

Supplemental criteria
Serum uric acid <0.24mmol/l

(<4mg/dl)

Serum urea <3.6mmol/l

(<21.6mg/dl)

Failure to correct hyponatraemia after 0.9% saline infusion

Fractional sodium excretion >0.5%
Fractional urea excretion >55%
Fractional uric acid excretion >12%
Correction of hyponatraemia through fluid restriction

The minimum information required for the diagnosis of SIADH is hyponatraemia in a

euvolaemic patient with inappropriately concentrated urine, and the exclusion of hypothyroidism
and glucocorticoid deficiency.
Hypouricemia, low blood urea nitrogen, and a urinary sodium level greater than 40 mmol per
liter in patients with hyponatremia suggest SIAD, but are not diagnostic35; for example, a serum
uric acid level of less than 4 mg per deciliter (238 mol per liter) (in the presence of
hyponatremia) has a positive predictive value for SIAD of 73 to 100%. A urinary sodium level
of less than 30 mmol per liter has a positive predictive value of 71 to 100% for an infusion of
0.9% saline to increase the serum sodium level.36,37

Management of Hyponatraemia

Acute Symptomatic Hyponatremia

The severity of hyponatremia is the factor that dictates the management. For symptomatic
patients with sever hyponatraemia , that has began within 48 hours, is recommended to raise the
serum sodium concentration by 1 to 2 mmol/l by infusing saline 3%.
The infusion of 3% hypertonic saline is an effective way to increase the serum sodium
concentration, 5mmol/l

increase in serum sodium concentration can be sufficient to improve

symptoms.42 We suggest repeating the 150ml
infusions of 3% hypertonic saline until the serum
sodium concentration has increased 5mmol/l,

or until the symptoms improve, whichever comes

first.
Many studies recommend concomitant Furosemide 1, and others recommend to avoid it 10 or
reserving it for patients with extracellular-fluid volume expansion.38,39
Studies have shown that the correction of hyponatraemia during the first 24 hours shouldnt be
more than 8 to 10 mmol/l, and in the first 48 hours no more than 18 to 5 mmol/l, even when the
hyponatraemia is acute. 38,39
One approach is to aim for the cessation of neurologic symptoms, such as seizures, and then
reduce the correction rate.41 An increase in serum sodium levels of less than 10 mmol per liter is
usually sufficient to reduce the symptoms and prevent complications.40 Its important to
minimize the neurologic symptoms, and the n to correct the sodium deficit.41

Chronic Hyponatremia
Most cases of hyponatremia that occur out of the hospital are chronic and minimally
symptomatic, except in marathon runners, users of 3,4-methylenedioxymethamphetamine
(MDMA, also known as ecstasy), and people who drink water to excess; in these groups,
severe symptoms usually indicate acute hyponatremia and require rapid correction.43
Patients with chronic hyponatraemia, u nlike patients with acute hyponatremia, have a bigger
risk of osmotic demyelination if the serum sodium level has raised more than 12 mmol per liter
in 24 hours.44 Many case series have showed that this complication results from a rapid increase
of the sodium concentration in 48 hours.44 To minimize the risk, authorities recommend a
modest rate of correction (an increase in serum sodium of 0.5 to 1.0 mmol /lper hour), using
lower rates of saline infusion for patients with symptomatic hyponatremia of unknown duration.
45
There has been established a limit of correction 8 mmol /l over 24 hours and 18 mmol/l over a
period of 48 hours, with the close monitoring of the rate of correction (every 2 to 3 hours)46,
which is recommended to avoid overcorrection.

Syndrome of inappropriate antidiuresis

The only definitive treatment of SIAD is elimination of its underlying cause. Most cases caused
by malignant disease resolve with effective antineoplastic therapy, and most of those due to
medication resolve promptly when the offending agent is discontinued.
There is no formal evidence thata fluid restriction can increase serum sodium concentration
more than placebo, and similary theres is no good evidence fluid restriction is associated with
important adverse effects.
However, Hence, the guideline development group unanimously preferred fluid restriction as
first-line treatment in SIADH (Tabel 5).
Table 5. Recommendations for fluid restriction
(NaUrine+K Urine)/ NaSerum

Fluid restriction

>1.0

0 mL

0.51.0
<500 mL
<0.5
<1 L
These recommendations assume that urinary sodium and potassium losses are replaced that a
patient has an average body surface area of 1.73 m2 and eats a normal diet, and is calculated for
the period during which the next 1 L of urine is excreted. Adapted from Furst et al.
The principal drawback is that patients find it extremely difficult to maintain fluid restriction, as
thirst in SIADH is inappropriately normal due to a downward resetting of the osmotic thirst
threshold50.
As a second-line treatment, the guidelie suggests an increased intake of osmotic solutes to
enhance clearance of water.Another paractical method to achieve increase solute intake is oral
urea, but it is unavailable in many countries, and the unpleasant taste has limited its use.
For demeclocycline and lithium, because there are some evidence of possible harm, the guideline
is against their use for management of any degree of chronic hyponatraemia in patients with
SIAD. Demeclocycline and lithium cause nephrogenic diabetes insipidus in 60%, respectively
305 of patients whom it is prescribed.51,52
Although vasopressin receptor antagonists do increase serum sodium, the guideline development
group dont recommend these drugs, because the most important safety-related factor is the
increased risk for overly rapid correction of hyponatraemia, putting patients at risk for osmotic
demyelination As this risk is greatest in patients with profound hyponatraemia, the guideline
development group is against the use of vasopressin receptor antagonistsin patients with
profound hyponatraemia.
In addition,high use of tolvaptan in autosomal dominant polycystic kidney disease has been
associated with hepatotoxicity in the reports of the U.S. Food and Drug Administration

Case1:
A 59 years male was brought in to the emergency department of Cluj-Napoca presenting
dizziness, psychomotor agitation, dellirrium with visual and auditory hallucinations, temporospatial disorientation. The patient is known as a heavy smoker (40 cigarettes per day) and a
chronic alcoholic.
Heteroanamnesis reveals that his simptoms have started 1 month ago when he went to the
Pneumology Unit accusing right chest pain, dyspnoea, fatigue, cought with phlegm, fever 38C
and shaking chills. After clinical examination, CT scan, bronchoscopy and blood cultures has
been established the diagnose of right basal pneumonia with Pseudomonas Aeruginosa and has
been treated with Ceftriaxone 2X1g per day (during 7 days), Azythromycin 5 days and, after that,
a combination of Amikacin and Colistin 10 days. Over the last 4 days he has began the treatment
with Levofloxacin 500mg per day.
His medical history includes a squamos cell carcinoma cT3N3Mx treated with combined
chemoterapy (Docetaxel, Cisplatin and Capecitabine) and radiation therapy.
The clinical examination, at the addmision time, revealed an overweight patient (BMI=27kg.m),
, worm and moist skin and psychomotor agitation.
CT scan has been performed in the emergency room and it has shown periventricular
leukoaraiosis, old ischemic insults and diffuse cerebral atrophy. The lab exams showed a low
serum sodium concentration of 114mmol/l indicating a severe hyponatraemia, with
correspondingly low serum osmolality of 233,9 mOsm/kg, normal creatinine, urea and uric acid.
Her urinary [Na+] was high 40mEq/l and his central venous pressure was normal. Given the
severity of the hyponatremia , treatment with hypertonic saline 3% was started and his existing
levofloxacine treatment was stopped. Following 24h the patient serum [Na+] rose to 120,28
mmol/l. Hypertonic saline treatment was stopped and replaced with fluid restriction. In within
48h serum [Na+] increased to 131mml/l and his symptoms have stopped.
The final diagnose was of hyponaetremia secondary to SIADH caused by multiple underlying
causes: squamos cell carcinoma, the right basal pneumonia and his treatment with levofloxacine.
Tabel 1 Laboratory results at admission

Laboratory
results
Hb
Ht
VEM
HEM
CHEM
Leukocytes
Tr

8,3 g/dl
24,1%
88,9fl
30,5pg
34g/dl
4780 /mmc
344.000/mm
c

Glycemia
Urea
Creatinine
Na
K
Cl
Urine sample

89mg/dl
20mg/dl
0,58 mg/dl
114mEq/l
3,5mmol/l
90mmol/l
Normal

Laboratory results
Serum osmolality= 233,9 mOsm/kg
Volume status: PVC= 5 cmH2O
Urinary [Na+]: 40 mEq/l
Urinary density: 1025
Sodium deficit (mmol)= [120-Naseric (mmol/l)]X G (kg)x0,6 = 284,4 mmol
Table 2 Diagnostic work-up
Analisys
Hb

Results
8,3g/dl

Ht
Glycemia
Cholesterol
Triglycerides

24,1%
89mg/dl
127mg/dl
61mg/dl

Total protein
Uric acid
Urea

6,5mg/dl
4mg/dl
24mg/dl

Analysis
Creatinin
e
Na
K
Ca
Mg
TSH
Cortisol

Results
1,03mg/dl
131mEq/l
3,7mEq/l
9,9mg/dl
0,92mg/d
l
3,15UI/l
327nmol/l

Case 2
A 78 year old woman was brought to the hospital accusing dizziness, parieto-occipital headache,
balance disorders with the impossibility of maintaining orthistatism, vomiting and temporospatial disorientation.
6 months ago she went to the Neurology department, with the same symptoms. After clinical and
paraclinical investigation it was set the diagnose of vertebrobasilar stroke with central vestibular
disorders and right cerebellar syndrome.
Her past medical history revealed the she had hypertension treated with Metoprolol 2x50mg per
day, Felodipine 5mg per day and Indapamide 1,5mg per day. Several years ago she had surgery
for a right frontal meningioma and has been receveing Carbamazepine 200mg per day for
secondary epilepsy.
The clinical assesment revealed a GCS=13, sleepiness, dry and flaky skin, BP=110/60mmHg,
HR=85.CT scan showed a 6mm calcified meningioma in the right superior frontal lobe, multiple
ischemic injuries in the PICA teritory and internal capsule, leukoaraiosis and difusse cerebral
atrophy.

The lab exams highlights a serum [Na+]= 117mEq/l which indicates a severe hyponatraemia, low
serum osmolality= 260mOsm/kg, low central venous pressure. The urinary [Na+] was 64mEq/l.
The patient was treated with hypertonic saline 3%. In within 24h the serum sodium concentration
rose to 126mmol/l. Her existing treatment with Carbamazepine and Indapamide was stopped.
The severe hyponatraemia was caused by multiple causes: central salt wasting syndrome, the use
of diuretics and Carbamazepine.
Tabel 1
Probe de laborator
Hb -12,6 g/dl
Ht -39,6%
L -4500/mmc
Tr- 200.000/mmc
Glycemia-103 mg/dl

Urea -20 mg/dl

Creatinine -0,58 mg/dl
Na -117 mEq/l
K- 5 mEq/l
Cl- 81 mmol/l

Tabel 2
Probe de laborator
Hb= 12,6 g/dl
Ht=40%

Uree 24 mg/dl
Creatinina 1,03 mg/dl

Glicemie 81 mg/dl

Na 134 mEq/l

Colest T 188 mg/dl

TGL 51 mg/dl
Pt 6,4 mg/dl
Acid uric 2,2 mg/dl

K 3,7 mEq/l
Ca 9,9 mg/dl
TSH 3,15 U/ml
Cortizolemia 327 nmol/l

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