HYPONATREMI

Dr Rajashekhar Mulimani
Consultant physician
intensivist
Introduction
• Hyponatremia is present when Plasma Na+ is <135 mmol/L.

• It is the number of mmol of Na+ per litre of ECF.

• The Plasma Na+ however, reflects the ICF volume, but in inverse
fashion.

• Hyponatremia occurs in two occasions

Decrease in the content of Na+
Retention of more water.
Review of pertinent
physiology
 The PNa reflects ICF volume
1. Cell membranes are permeable to water because AQP1.

2. Effective osmoles in the ECF are Na+ and its attendant anions.

3. Effective osmoles in ICF are K+ and small organic anions.

4. Intracellular osmoles rarely change in amount.

CHANGES IN ICF VOLUME ARE INVERSELY PROPORTIONAL TO THE CHANGES IN PLASMA Na+
 • Hyponatremia is associated with an
expanded ICF volume unless its basis is a
gain of effective osmoles in the ECF
compartment (glucose, mannitol etc)

• The term pseudohyponatremia is used

when plasma contains other
osmotically active compounds like
excessive glucose, protein, lipids

ECF volume: either increased (if basis of hyponatremia is a positive water balance)
or decreased (if the basis of hyponatremia is negative Na+ balance)

ICF volume : increased always in hyponatremia

but may be decreased in pseudohyponatremia
 PATHOGENESIS OF HYPONATREMIA

Depends
INABILITY OF KIDNEY
TO EXCRETE A on ADH
WATER LOAD

EXCESS WATER INTAKE 1. Normal but persistent

secretion
2. Abnormally high
secretion
ACUTE HYPONATREMIA CHRONIC HYPONATREMIA
• Acute gain of water in brain cells. • Brain cells have time for adaptation

• When brain cells swell acutely by • Majorly by exporting effective osmoles.

close to 15%, the local defense
mechanisms are overcome. • These adaptive changes will proceed to shrink the
volume of brain cells to their normal size.
• Physical restriction to further
swelling imposed by the rigid • Therefore, if the P Na is rised rapidly in this
skull. setting, brain cells will shrink because water
leaves the ICF compartment.(ODS)
• Herniation, veins are compressed
blocking the venous return. • To restore these essential intracellular osmoles
that were exported from ICF during volume
• May lead to seizure, coma & regulation requires
death. 1. Adequate time.
2. Good dietary intake.
 PATHOGENESIS OF HYPONATREMIA

Depends
INABILITY OF KIDNEY
TO EXCRETE A on ADH
WATER LOAD

EXCESS WATER INTAKE 1. Normal but persistent

secretion
2. Abnormally high
secretion
CAUSES OF A LARGE INPUT OF WATER IN A PATIENT WITH
HYPONATREMIA ACUTE HYPONATREMIA
A very large intake of water
• Aversion to water intake is suppressed by mood-altering drugs (ex: ecstacy)
• Drinking too much of water during marathon (ex: owing to poor advice to avoid
dehydration)
• Beer potomania
• Psychotic state (ex: paranoid schizophrenia)

A large infusion of D5W

• Postoperatively (esp in a young patient with low muscle mass)

Large infusion of hypotonic fluid

• Input of water and organic solutes, with little or no Na+ (ex: hyponatremia
following TURP)
CAUSES OF A LOWER THAN EXPECTED RATE OF EXCRETION
OF WATER
Lower rate of water excretion due to low distal delivery of filtrate
• states with low glomerular filtration rate
• States with increased reabsorption of filtrate in PCT
 Low salt intake (tea & toast syndrome)
 Loss of Na+ & CL- in sweat (cystic fibrosis, marathon runner, heat stroke)
 Loss via GIT (diarrhea)
 Loss via kidneys (diuretics, aldosterone deficiency, renal or cerebral wasting)

Vasopressin release and a normal distal delivery of filtrate

• Non-osmotic stimuli including pain, nausea, anxiety.
• Central stimulation of vasopressin release by drugs (ecstasy, nicotine, morphine,
clofibrate, TCAs, anti-cancer drugs)
• CNS or Lung lesions causing SIADH
• Exogenous administration of dDAVP
• Glucocrticoid deficiency
• Hypothyoroidism
 Issues to consider here……

• Is hyponatremia acute or chronic……..?????????................48 hours

• Symptoms pertaining………..?????????

• Dangers that may develop during therapy……??????

• Proceed with diagnostic issues…..?????..........last

 DIAGNOSIS &
MANAGEMENT OF
HYPONATREMIA
• Hyponatremia is both a diagnostic as well as therapeutic challenge.

• Management of hyponatremia is still suboptimal.

• Hyponatremia is not a disease per se, but rather a pathophysiological

process indicating disturbed water homeostasis.
 Classification of hyponatremia
CLASSIFICATION CRITERIA LIMITATION OF CLINICAL UTILITY
Moderate (125 – 129 mmol/L) Absolute serum Na concentration Symptoms do not always correlate
Severe/Profound ( <125 ) with degree of hyonatremia

Acute vs Chronic Time of development Time of development not always

(cut off is 48 hours) known

Symptomatic vs Asymptomatic Presence of symptoms Nonspecific symptoms

Hypotonic, isotonic or Measured serum osmolality Ineffective osmoles ( ex: urea,

hypertonic ethanol) are also measured

Hypovolemic, euvolemic or Clinical status of volume status Clinical assessment of volume status
hypervolemic has low sensitivity and specificity
DIFFERENTIA
L DIAGNOSIS
FIRST DETERMINING THE TONICITY

HYPOTONIC NON-HYPOTONIC
HYPONATREMIA HYPONATREMIA

HYPERTONIC ISOTONIC
HYPERNATREMIA HYPONATREMIA
• Mannitol
• Glucose • Hyperprotienemia
• Hypertonic
radiocontrast • hyperlipidemia
HYPERTONIC/HYPEROSMOLAR
HYPONATREMIA
ISOTONIC/EU-OSMOLAR
• >290 mOsm HYPONATREMIA
• There is an osmotically active
(PSEUDO-HYPONATREMIA)
solute other than Na+ in the ECF.
• Draws the water, diluting the Na+
• Laboratory phenomenon
content
• High content of plasma lipids and
• M/c seen with hyperglycemia
proteins expands the non-aqueous
• Fall in plasma [Na+] of 1.6 to 2.4
portion of plasma sample.
mEq/L for every 100 mg/dL rise in
• Errant report of low ECF [Na+]
plasma glucose.
• Can be averted with Na+ sensitive
electrodes.
FIRST DETERMINING THE TONICITY

HYPOTONIC NON-HYPOTONIC
HYPONATREMIA HYPONATREMIA

HYPERTONIC ISOTONIC
HYPERNATREMIA HYPONATREMIA
• Mannitol
• Glucose • Hyperprotienemia
• Hypertonic
Check volume radiocontrast • hyperlipidemia
status
HYPOVOLEMIC EUVOLEMIC HYPERVOLEMIA
HYPONATREMIA HYPONATREMIA HYPONATREMIA
1. Dehydration 1. SIADH 1. Heart failure
2. Diarrhoea 2. Postoperative 2. Liver disease
3. Vomiting hyponatremia 3. Nephrotic
3. Hypothyroidism syndrome (rare)
4. Diuretics 4. Psychogenic polydipsia 4. Advanced
5. ACE inhibitors 5. Beer potomania kidney disease
6. Nephropathies 6. Secondary adrenal
7. Mineralocorticoid deficiency
deficiency 7. Endurance exercise
8. Cerebral salt 8. Idiosyncratic drug
wasting syndrome reactions
 A good history is half treatment
• A history of electrolyte-rich fluid loss (due, for example, to vomiting, diarrhea, or diuretic
therapy) that may indicate hypovolemia.
• A history of low protein intake and/or high fluid intake.
• A history consistent with malignancy, central nervous system disease, pulmonary disease,
HIV infection, heart failure, hepatic failure, or a plasma cell dyscrasia.
• Use of medications associated with hyponatremia, such as thiazide and thiazide-type
diuretics, mannitol, intravenous immune globulin, desmopressin (dDAVP), ecstasy
(methylenedioxymethamphetamine), and medications acting on the central nervous system
including some antidepressants, antiepileptics, and antipsychotics.
• Very recent surgery.
• Signs of peripheral edema and/or ascites, which can be due to heart failure, cirrhosis, or
kidney failure.
• Symptoms and signs suggestive of adrenal insufficiency or hypothyroidism.
The serum creatinine concentration, which can be used to estimate glomerular
filtration rate (GFR), and the patient's medication history are typically available at the
time that hyponatremia is discovered.

Both severely reduced GFR and thiazide (or thiazide-type) diuretics impair the ability
to dilute the urine normally, and they are important causes of hypotonic
hyponatremia.

Additional evaluation is needed in patients with hypotonic hyponatremia who do not

have severely reduced GFR and are not taking thiazides, or whose initial history,
examination, and laboratory studies suggest another possible cause of
hyponatremia (eg, peripheral edema and/or ascites, history of lung cancer, history of
vomiting and/or diarrhea, history of a psychotic disorder, etc)
Patients with severely reduced
GFR
• The ability to excrete free water is not significantly impaired in
patients with mild to moderate renal impairment. Thus,
normonatremia is usually maintained.

• The impairment of free water excretion in advanced kidney failure can

lead to the retention of ingested water and the development of
hyponatremia.
Patients taking thiazides

• Thiazides >> loop diuretics.

• Thiazide induced hyponatremia can be severe.
• Typically begins soon after the initiation of thiazide therapy, but can
also develop in patients receiving long-term thiazide therapy who had
previously normal serum Na+ if they develop an intercurrent illness.
• Combination of thiazides + ACEIs increases the risk
• Sometimes, (thiazides induced hyponatremia SIADH).
1. FEUA (>12% in SIADH, <8% in TIH )
2. Response to drug discontinuation.
Patients with edema and/or
ascites
• Even though the plasma and ECF
volumes are increased in HF &
cirrhosis.
• The pressure sensed at
1 HEART FAILURE baroreceptors is generally reduced
2 LIVER CIRRHOSIS due to low cardiac output (in HF)
and to arterial vasodilatation (in
cirrhosis)
• Both ADH release and associated
reduction in Na+ is parallel to the
severity of HF and cirrhosis
Non-edematous patients
• Non edematous patients with hyponatremia are either euvolemic or
hypovolemic.
• Most patients with hyponatremia due to true hypovolemia will have
obvious signs of volume depletion.
• However, some hypovolemic patients have more subtle signs and are
mistakenly judged to euvolemic.
• Additional testing is required for diagnosis
Urinary Na measurement
Urinary osmolarity measurement
Novel diagnostic markers in
hyponatremia
1. Copeptin levels and ratio of copeptin to urinary sodium.

2. Serum apelin levels

3. Midregional – pro ANP (MR-Pro ANP)

SYMPTOMS OF
HYPONATREMIA
Clinical manifestations in acute
hyponatremia
• Nausea & malaise – are the earliest findings, (125-130 mEq/L)

• Headache, lethargy, obtundation --------- seizures, coma and

respiratory arrest (if Na+ falls below 115 – 120)

• Noncardiogenic pulmonary edema has also bee seen

• Acute hyponatremic encephalopathy. Be very much careful in

1. Premenopausal women
2. Young children
Clinical manifestations in
chronic hyponatremia
• Fatigue • Majority are asymptomatic
• Nausea • If at all symptoms occur, they are non-specific
• Dizziness
• Vomiting gait disturbances • Not associated with adverse outcomes

• Forgetfullness • If at all symptoms are severe, often reflect an

• Confusion acute exacerbation of hyponatremia
• Lethargy
• Muscle cramps • Frequent falls in elderly
• Risk of fractures
• Osteoporosis
• Overall mortality
Guideline based classification
• MODERATELY SEVERE • SEVERE SYMPTOMS
SYMPTOMS
• Vomiting
• Nausea without vomiting • Seizures
• Confusion • GCS <8
• Headache • Cardio-respiratory distress
• Abnormal and deep somnolence
 OVERVIEW OF
TREATMENT OF
HYPONATREMIA
 PRETREATMENT EVALUATION
1. DETERMINE THE DURATION/ACUITY

2. DETERMINE THE SEVERITY

3. DETERMINE THE SEVERITY OF SYMPTOMS

4. DETERMINE THE NEED FOR HOSPITALISTION

(ACUTE/SEVERE/SYMPTOMATIC)
 GOALS OF THERAPY
2. PREVENT BRAIN HERNIATION
1.PREVENT FURTHER DECLINE IN SERUM Most dreaded.
Na+ Herniation is almost exclusively reported in
Risk is especially high in • Polydipsia patients
• Polydispisa patients • Women and children with acute
• Postoperative settings postoperative hyponatremia
• Hyponatremia a/w intracranial pathology

3. RELIEVE SYMPTOMS OF HYPONATREMIA

4. AVOID OVERCORRECTION
• Even the most extreme symptoms can be relieved
by a 4-6 mEq/L increase in serum Na+ during first • Be very careful in chronic, severe
24 hours. hyponatremia.
• If symptoms persist after an increase of this • Can lead to ODS (CPM)
magnitude, there is no benefit, and in some cases, • HIGH RISK CASES vs LOW RISK CASES
potential harm of faster correction
 GOALS OF THERAPY
2. PREVENT BRAIN HERNIATION
1.PREVENT FURTHER DECLINE IN SERUM Most dreaded.
Na+ Herniation is almost exclusively reported in
Risk is especially high in • Polydipsia patients
• Polydispisa patients • Women and children with acute
• Postoperative settings postoperative hyponatremia
• Hyponatremia a/w intracranial pathology

3. RELIEVE SYMPTOMS OF HYPONATREMIA 4. AVOID OVERCORRECTION

• Even tha most extreme symptoms can be relieved • Be very careful in chronic, severe
by a 4-6 mEq/L increase in serum Na+ during first
hyponatremia.
24 hours. • Can lead to ODS (CPM)
• If symptoms persist after an increase of this
magnitude, there is no benefit, and in some cases,
potential harm of faster correction
 GOAL RATE OF CORRECTION

GOAL OF INITIAL THERAPY: To rise serum Na+ by 4 to 6 mEq/L in 24 hour

• In symptomatic patients with acute hyponatremia or in patients with severe symptoms,

this goal should be achieved quickly, over six hours or less.
• Thereafter, the serum sodium can be maintained at a constant level for the remainder of
24 hours.
• Because, it is the daily change, rather than the hourly change, in serum sodium that is
associated with ODS

MAXIMUM RATE OF CORRECTION: should be 8 mEq/L in any 24 hour

18 mEq/L in any 48 hour.
ACUTE HYPONATREMIA: INITIAL THERAPY (FIRST SIX HOURS)

ASYMPTOMATIC: SYMPTOMATIC: (EVEN MILD

SYMPTOMS):
• Treat with 50 mL bolus of 3% NS.
• Treat with 100 mL bolus of 3% NS.
• Only to prevent further fall in
• f/b if symptoms persists, with up to
Na+
• Do not give anything if u suspect two additional 100 mL boluses (to a
total dose of 300 mL).
autocorrection.
• Each bolus is infused over 10
• Keep on monitoring for
minutes.
symptoms and worsening serum
Na+ conc.
• Don’t use mannitol in acute hyponatremia even if there is cerebral edema.
• Don’t use vaptans in acute hyponatremia.
• 3% NS is the only rapid way to rise the serum Na+ and improve symptoms
CHRONIC HYPONATREMIA: INITIAL THERAPY (FIRST SIX HOURS)
• Do no treat with hypertonic saline
MILD HYPONATREMIA
• Address the cause
(130 – 134 mEq/L)
• Limit further intake of water

No symptoms OR • Do no treat with hypertonic saline

Moderate symptoms • Address the cause
• Limit further intake of water

MODERATE HYPONATREMIA
(120 – 129 MEQ/L)
• Treat with 100 mL bolus of 3% NS.
• f/b if symptoms persists, with up to two
additional 100 mL boluses (to a total
dose of 300 mL).
Severe symptoms OR • Each bolus is infused over 10 minutes.
Any intracranial pathology
CHRONIC, SEVERE HYPONATREMIA
(<120 mEq/L)
• Initiate 3% NS beginning at a rate of 15-30
mL/hour.

• Alternative approach is to give 1 mL/kg (max 100

mL) boluses of 3% NS IV every six hourly.

• 3% NS better than 0.9% NS.

• Can be safely given via peripheral vein, no CVC

required.

• If 3% NS cannot be given, options include infusion

of 1.5 to 2% NS at rates more rapid than above.
1. Rapidly reversible causes
2. ODS risk category patients • Some patients may require desmopressin to
prevent overly rapid correction
CHRONIC, SEVERE HYPONATREMIA
(<120 mEq/L) • Initiate 3% NS beginning at a rate of 15-30
mL/hour. (0.25 mL/kg/hour)

• Alternative approach is to give 1 mL/kg (max 100

mL) boluses of 3% NS IV every six hourly.

• 3% NS better than 0.9% NS.

• Can be safely given via peripheral vein, no CVC

required.

• If 3% NS cannot be given, options include infusion

of 1.5 to 2% NS at rates more rapid than above.
1. Rapidly reversible causes • Some patients may require desmopressin to
2. ODS risk category patients
prevent overly rapid correction
DESMOPRESSIN
 Used only in circumstances where the hyponatremia appears to be rapidly reversible or
in risk patients for ODS.

 Used only when hyponatremia is corrected using 3% NS.

 If isotonic saline is being used, desmopressin is only given after the serum sodium has
been increased by 4-6 mEq/L.

 Dose used – 1 – 2 mcg iv/sc every 6 to 8 hourly, for a period of 24 – 48 hours (Na+ at
least 125)

 If desmopressin is being used, restrict free water intake.

 Not to be used in
1. Patients with hypervolemic hyponatremia.
2. Patients with recurrent hyponatremia of ADH
 Additional measures in all
patients
• REDUCE THE INTAKE OF ELECTROLYTE FREE WATER:
1. Restrict fluid intake
2. Eliminate hypotonic fluids
3. Increase the dietary salt intake.

• IDENTIFY & TREAT THE CAUSE OF HYPONATREMIA.

1. Stop the culprit drug if possible.
2. Adrenal insufficiency
3. Hypothyroidism.
 Additional measures in all
patients
• REDUCE THE INTAKE OF ELECTROLYTE FREE WATER: How to
1. Restrict fluid intake
2. Eliminate hypotonic fluids
3. Increase the dietary salt intake.
do
• IDENTIFY & TREAT THE CAUSE OF HYPONATREMIA. it…???
1. Stop the culprit drug if possible.
2. Adrenal insufficiency
3. Hypothyroidism.
• Water deprivation has long been
a cornerstone of the therapy of
chronic hyponatremia.

• However, patients who are

excreting minimal electrolyte-
free water will require
aggressive fluid restriction.

• This can be very difficult for Ratio >1, a ratio of ~1 ratio <1
patients with SIAD to tolerate, aggressive fluid should be should be
restriction. restricted to restricted
given that their thirst is also (<500mL/day) 500–700 mL/d, to <1 L/d
inappropriately stimulated.
LOOP DIURETICS

• Used in hypervolaemiac hyponatremia,

in volume overloaded patients.

• Can be used in chronic hyponatremia

secondary to SIADH.

• Avoid over diuresis.

 ORAL SALT TABLETS

• Patients with SIADH with very

mild or moderate symptoms.

• Used when Na+ > 120.

• Used in addition to fluid

restriction.

• 1g of oral salt tablets is

equivalent to 35mL of 3% NS.

• Never to be given in edematous

patients
 UREA
• FUNCTIONS AS AN OSMOTIC DIURETIC.
(AQUARETIC)

• INGESTED UREA IS COMPLETELY

EXCRETED BY KIDNEYS, SO EXCRETED
ALONG WITH WATER.

• SO ULTIMATE REMOVAL OF WATER.

• Asministered orally or enterally.

• Favourable short and long term

outcome in SIADH.
UREA = AQUAMAN
• Cheaper compared to vaptans.
VASOPRESSIN RECEPTOS ANTAGONISTS
(VAPTANS)
• Produces selective water diuresis (aquaretics)
• Without affecting Na+ & K+ excretion.
• Ensuing loss of water will tend to correct the
hyponatremia.
• Limit – increases the thirst & high cost.

• Oral – tolvaptan, mozavaptan, satavaptan,

lixivaptan.
• Iv – conivaptan. (V1a effect)

• Tolvaptan – FDA approval with labelled

indications
1. Adults with ADPKD (mayo 1C, 1D OR 1E)
2. Chronic euvolemic hyponatremia
 PREVENTION &
TREATMENT OF ODS
• In view of the often severe and permanent adverse consequences of
ODS, prevention is essential.

• The risk of ODS is greatest when serum Na+ level is <120 mEq/L.

• Assume hyponatremia as chronic when the duration is unknown.

• Monitoring is essential
1. Serum Na+ frequently.
2. Urine volume monitoring.
PROACTIVE STRATEGY in patients REACTIVE STRATEGY in patients RESCUE STRATEGY in patients
who are likely to develop overly rapid with a worrisome trajectory who have already exceeded the
correction correction limits
• Initial trajectory of correction
• Discussed earlier. appears likely to exceed max • Rate of correction have already
recommended limit. exceeded.
• Desmopressin given proactively at
the beginning therapy with 3% NS. • Often occurs with emergent • Regimens to relower the sodium
water diuresis, when a stimulus levels
for ADH secretion is abated.
1. D5W 6mL/kg infused over 2
• Replacement of urinary water hours, and repeat the infusion
losses using 5% dextrose. till therapeutic goal.
2. Desmopressin 2mcg iv/sc every
• Desmopressin can also be used 6 hours
SOS to concentrate urine.
• Serum Na+ should be lowered
at an avg rate of 1 mEq/L.

• Minocycline
• Dexamethasone
• myoinositol
ESTABLISHED ODS:
• C/F – dysarthria, dysphagia, para/quadriparesis,
behavioural disturbances, movement disorders,
seizures.

• Severely affected patients become locked-in.

• Clinical features may be delayed upto 2-4 days.

• Demyelinating lesions on MRI may be delayed upto 4

weeks.

• Treatment:

1. RELOWERING OF SERUM Na+

2. SUPPORTIVE TERAPY

3. EXPERIMENTAL TEHRAPY
AYUS – ARIEFF SYNDROME

Severe hyponatremia
+
Cerebral edema
+
Noncardiogenic pulmonary
edema