Hyponatremia is the most common electrolyte abnormality seen in hospitalized patients. It is caused by an imbalance of water in the body, resulting in a dilution of sodium concentration. The document discusses the various types of hyponatremia (hypovolemic, euvolemic, hypervolemic) based on extracellular fluid volume status and their underlying causes such as SIADH, heart failure, liver cirrhosis. It also covers the diagnostic evaluation, management principles, and treatment approaches for acute symptomatic and chronic hyponatremia which involves slow correction of sodium levels to avoid osmotic demyelination syndrome.

1. -DR MAHENDRA M MASKE

2.  Introduction
Hyponatremia-Most common abnormality
15-30% of hospitalized pnts
Independent predictor of mortality
Acute – 50 %; Chronic- 10-20%
Challenge among physicians > CAUSE
Basically a water imbalance.

3.  Total Body Water
- 60 % of body weight in Male
- 50% of body weight in Female
Fat holds less water, obese will have proportionately less
body water.

5. Electrolyte Composition

6. Plasma Osmolality { mOsm/kg }
Normal Plasma Osmolarity > 275-295 mOsm/kg

7. Effective Osmolality
 Effective Osmolality { mOsm/Kg }
= 2 x Na + Glucose
18
 Determine by those solutes which does not permeate
cell membrane & act to hold water within ECF.
 Lipid soluble substances like Urea can cross cell
membrane, does not contribute to Osmotic pressure
gradient b/w ECF & ICF.

8. SODIUM 11Na23
 Na major ECF cation
{ 140 mEq/l ECF vs 25 mEq/l intracellular}
 Total body Na > 5000mEq
 85-90% Na extra-cellular
 Responsible for > 90% total osmolarity of ECF.
 Maintain ECF volume & hence Blood pressure.
 Daily requirement > 100 mEq i.e. 6 gm salt.
 1 gm of NaCl contains 17.1 mEq of Na.
 from Latin : natrium

9. Hyponatremia
Plasma Na+ concentration <135 mM
 The concentration of sodium in ECF is a reflection of
the tonicity of body fluids, not of total body sodium
content.
 Hyponatremia can be associated with low, normal or
high tonicity.

10. Pseudo-hyponatremia > associated with normal or
increased tonicity.
Isotonic hyponatremia
 expansion of extracellular fluid with isotonic fluids
that do not contain Na
 there is no transcellular shift of water but the [Na+]
decreases
 Ex- hypertriglyceridemia
hyperproteinemia( as in Multiple Myeloma)
 rise in plasma lipids of 4.6 g/L or plasma protein
concentrations greater than 10 g/dL will decrease the
sodium concentration by approximately 1 mEq/L.

11. Hypertonic hyponatremia
 Seen when there is increase in effective osmoles in the
extracellular fluid
 Shift of water from the cells to the ECF and thus
causing translocational hyponatremia
 Ex-
 hyperglycaemia in DM {plasma Na+ falls by 2 mEq/l
for every 100-mg/dL increase in Glucose b/w 200-400
mg/dl; and by 4 mEq/l at Glucose > 400mg/dl}
hypertonic mannitol

12. Hypotonic Hyponatremia
 Hypotonic hyponatremia is the most common form of
hyponatremia
 Hypotonic hyponatremia occurs by two mechanisms
1) impaired renal water excretion
2) excess water intake
 Hypotonic hyponatremia can be classified as
hypovolemic, euvolemic and hypervolemic on the
basis of ECF volume as assessed clinically by changes
in blood pressure and heart rate, edema, jugular
venous distension, skin turgor, mucous membranes.

14. Hypovolemic Hyponatremia
Total body water
Total body Na
Conditions with UNa > 20
 The renal causes of hypovolemic hyponatremia
 inappropriate loss of Na+-Cl– in the urine
 volume depletion and an increase in circulating AVP;
 Mineralocorticoid deficiency
 Hyperkalemia
 hyponatremia
 hypotensive and/or hypovolemic patient with
 high urine Na+ concentration (much >20 mM)

15.  Salt-losing nephropathies
-sodium intake is reduced due to impaired renal tubular
function
 reflux nephropathy
 interstitial nephropathies
 post-obstructive uropathy
 medullary cystic disease
 the recovery phase of acute tubular necrosis.
 Diuretics Excess
 Thiazides
 Loop diuretics > blunting the countercurrent mechanism
{Water diuresis > Natriuresis}

16. Osmotic diuresis
 Excretion of osmotically active nonreabsorbable or
poorly reabsorbable solute
glycosuria,
 ketonuria (e.g., in starvation or in diabetic or alcoholic
ketoacidosis), and
 bicarbonaturia (e.g., in renal tubular acidosis or
metabolic alkalosis, in which the associated
bicarbonaturia leads to loss of Na.

17. Cerebral salt wasting
Rare cause of hypovolemic hyponatremia,
• hyponatremia
• clinical hypovolemia
• inappropriate natriuresis
Intracranial disease SAH, trauma, craniotomy,
encephalitis and meningitis.
Release of BNP {brain natriuretic peptide} in cerebral
dysfunction
 D/D syndrome of inappropriate antidiuresis (SIAD)
 Cerebral salt wasting typically responds to aggressive
Na+-Cl– repletion.

18. Conditions with Una < 20
Nonrenal causes of hypovolemic hyponatremia
gastrointestinal (GI) loss vomiting, diarrhoea, tube
drainage, etc.
Third space loss of fluids. Ex- pancreatitis, burns
 a rapid increase in plasma Na+ concentration in
response to intravenous normal saline.
 saline induces a water diuresis in this setting, as
circulating AVP levels decreases.

19. Euvolemic Hyponatremia
Hyponatremia with normal ECF volume is seen in
Syndrome of inappropriate antidiuresis (SIAD)
Endocrine deficiency
-hypothyroidism
-adrenal insufficiency

20. SIAD
 Syndrome of inappropriate antidiuresis (SIAD)
 SIAD more accurate term
 ADH is inappropriately elevated in SIAD by a variety of
mechanisms
 enhanced and unregulated ADH secretion (by tumor or
hypothalamus)
 elevated secretion of ADH in basal state and in response to
hypertonicity
 Reset osmostat
 Activating mutation of the V2 receptor permitting reabsorption
of water in absence of ADH.
• Natriuresis (increases ANP) in presence of water retention leads
to inappropriately concentrated urine.

22. Diagnostic Criteria for SIADH:
 plasma sodium concentration <135 mmol/l
 plasma osmolality <280 mOsmol/kg
 urine osmolality > 100 mOsmol/kg
 urinary sodium concentration >20mEq/L
 patient clinically euvolaemic
 absence of clinical or biochemical features of adrenal and
thyroid dysfunction

23.  Serum uric acid is often low (<4 mg/dL) in patients
with SIAD, consistent with suppressed proximal
tubular transport in the setting of increased distal
tubular Na+-Cl– and water transport.
 In contrast, patients with hypovolemic hyponatremia
are often hyperuricemic due to a shared activation of
proximal tubular Na+-Cl– and urate transport.

24.  Endocrine deficiency
Hypothyroidism or adrenal insufficiency
- impairs reduced cardiac output > ADH release.
Isolated glucocorticoid deficiency
-through corticotropin releasing factor mediated
release of ADH.
Correction of these hormonal deficits corrects for the
water excretion defect and hyponatremia.

25. Hypervolemic Hyponatremia
 Causative disorders can be separated by the effect on urine Na+
concentration
 UNa > 20
-Acute renal failure (ARF)
-Chronic renal failure (CRF)
 UNa < 20
-congestive heart failure
-nephrotic syndrome
-hepatic cirrhosis
 Low intraarterial filling
 Movement of water from the vascular to the interstitial space –
due to hypoalbuminemia
 Activation of the neurohormonal compensatory mechanisms

26. Exercise induced hyponatremia
 Marathon runners
 Females and with low body weight.
 Excessive drinking of hypotonic solutions (>1.5
l/hour of water or hypotonic sport drinks) and
 Inappropriate secretion of ADH due to muscle derived
interleukin-6.

27. Primary polydipsia (compulsive water drinking 10-15 liter/day)
 psychiatric patients -schizophrenia.
 central defect in thirst regulation
 excessive secretion or renal action of ADH and
 Antipsychotic drugs by anticholinergic action.
Low Solute Intake
 A low dietary solute intake (tea-toast diet, extreme vegetarian
diets.) as in debilitated residents in nursing homes or chronic
alcohol ingestion (beer potomania) causes hyponatremia by
decreasing the ability of the kidney to excrete water.
 Water intake above this renal and insensible water loss will
cause hyponatremia
 Beer is very low in protein and salt content, containing only 1–2
millimole per liter of Na+.
 Associated with low urine osmolality, <100–200 mosmol/kg, with
a urine Na+ concentration that is <10–20 mM.

28. Clinical diagnosis
 The symptoms primarily neurologic
 Development of cerebral edema within a rigid skull.
headache, lethargy,
confusion, gait disorder,
 nausea, vomiting and
in severe hyponatremia as seizures, coma, brain-stem
herniation, permanent brain damage or death.
Hypo-natremia < 135 mild
<130 moderate
< 120 severe

29. Severe hyponatremia (Na+<120meq/l) and rapid
development of hyponatremia (<48 hours)
 A key complication is normocapnic or hypercapnic
respiratory failure.
 Normocapnic respiratory failure is noncardiogenic,
neurogenic pulmonary edema, with a normal
pulmonary capillary wedge pressure.

30.  Persistent, chronic hyponatremia
 efflux of organic osmolytes (creatine, betaine,
glutamate, myo-inositol, and taurine) from brain cells
> intracellular osmolality > water entry.
 complete within 48 h, time period defines chronic
hyponatremia
vomiting, nausea
 confusion and seizures
subtle gait and cognitive defects
increases risk of falls
risk of bony fractures

31. Diagnostic Evaluation of Hyponatremia
 Clinical assessment
underlying cause
detailed drug history
volume status
 multifactorial,
 Consider all the possible causes

32. Laboratory
 Serum osmolality, Na, K
 BUN and creatinine
 Serum glucose, uric acid
 Urine Na, K
 Urine Osmolarity
 Serum proteins & Lipid profile
 Thyroid, adrenal, and pituitary function
Radiology
 CXR-PA
 CT Thorax & Brain

33. Hyponatremia
Na < 125 mEq/l Sr. Osmolarity>280 mOsm/k
Sr Osm < 280
mOsm/kg
Pseudo-
Hyponatremia
{Iso/Hyper tonic }
Primary Polydipsia
Low solute intake
Hypotonic
Hyponatremia
Hypovolemia Euvolemia Hypervolemia
Una<
20
Una
>20
Renal
causes
Extra-Renal
causes
0.9%
NS
Urine Osmolarity < 100 mOsm/kg H20
SIAD
HYPOTHY-ROIDISM
Adrenal insufficiency
CHF
Cirrhosis
Nephrotic syndrome
Fluid restriction
Demeclocycline
Fluid Restriction
Furosemide

34. Management
 Three major considerations to guide therapy for
hyponatremia.
1. Severity of symptoms
2. Risk for ODS
3. Highly unpredictable response
Once the urgency in correcting the plasma Na+
concentration has been established and appropriate
therapy instituted, the focus should be on treatment
or withdrawal of the underlying cause.

35. Acute Symptomatic hyponatremia –
medical emergency.
 Rate of correction
1.5-2 meq/l/h for the first 3-4 hours;
total 8-12 meq/l/day
 Na+ deficit = 0.6 x body weight x (target Na+conc – starting
Na+ conc).
 Hypertonic saline (3% NaCl) @ 1-2 ml/kg/hour
 For mild symptoms @ 0.5 ml/kg/hour + lasix 20-40 mg IV
 For seizures & coma @ 2-4 ml/kg/hour + lasix 20-40 mg IV
 Monitored every 2–4 h
 Vaptans- no role

36.  Chronic or slowly developing hyponatremia
0.5 meq/l/h
total 8-12 meq/l/day or
< 10 mMol in 1st 24 hrs, < 18 mMol in 48 hrs
 Water Restriction
 The urine:plasma electrolyte ratio (urinary [Na+]+[K+]/plasma [Na+]) indicator
of electrolyte-free water excretion
 >1 restricted more aggressively (<500 mL/d),
 1 restricted to 500–700 mL/d,
 <1 restricted to <1 L/d.
 In hypokalemic pnts > inj KCl or Pottasium supplements.
By this, generally Na levels are corrected.
Oral salt tablets
oral furosemide 20 mg bd plus oral salt tablets
Demeclocycline 600 to 1200 mg/day
Vaptans

37.  Equations are available to help calculate the initial rate of
fluids to be administered.
A widely used formula is the Adrogue-Madias formula.
 Change in serum Na+ with infusing solution=
[infusate (Na + K)]-serum Na
(total body water +1)
 Infusate Na+ is the [Na+] in the infused fluid (154meq/l in
0.9%NS, 513meq/l in 3%NS, 77meq/l in 0.45%NS & 0
meq/l in D5W).
 The above equation predicts the amount of [Na+] change
by 1 liter of infusate.
 Dividing the targeted change in Sr Na by the result of above
equation gives volume of infusate required & thus the rate
of infusion.

38. For ex
 60 kg female with Na- 110 m Eq/l.
 Correction using 3% NaCl (513 mEq/l) –
 (513-110 ) / 30 +1 = 400 /31 = 13 mEq/l
 So infusion of 1 L of 3% NaCl in this pnt will raise Na by 13 mEq/l.
 Since correction to be done at 2 mEq/hr, 1 litre of 3% NaCl
should be infused over 6.5 hrs.
 i.e. 154 ml/hour or 2.5 ml/min @ 40 macrodrops/min or 150
udrops/min.
Other formulae
 Barsoum-Levine
 Nguyen-Kurtz

39. Euvolemic and hypervolemic hyponatremia
 Fluid restriction (upto 800-1000ml/day)
 furosemide > excretion of 70-80meq/l urine Na+ and
K+ (tonicity similar to 0.45NS).
 Replacement of these electrolyte losses with 0.9NS
would require a volume equal to half the urine output,
with the resulting net free water clearance being half
the total urine volume.

40. OSMOTIC DEMYELINATION SYNDROME
 Rapid correction
 movement of water out of the edematous neurons, causing shrinkage and disruption
myelin sheaths.
 Predisposed - chronic alcohol abuse, hepatic failure and malnutrition.
 Central pontine myelinolysis (CPM)
- quadriplegia
- pseudobulbar palsy
- seizures
- coma and death.
 Extra-pontine Myelinolysis
 Cerebellum
 Lateral geniculate body
 Thalamus
 Putamen
 Cerebral cortex
 Hyponatremia reinduced by Desmopressin acetate (DDAVP) and/or the administration
of free water, typically intravenous D5W;
 Goal is to prevent or reverse the development of ODS.

41. Vasopressin antagonists (vaptans)
 highly effective in treating SIAD and hypervolemic
hyponatremia due to heart failure or cirrhosis,
 Aquaretic effects (augmentation of free-water
clearance).
 Important role in circulatory & water homeostsis
 3 receptor sub-types:
 V1a vascular smooth musclevasoconstriction/cardiac
hypertrophy
 V2renal collecting duct systemresorption of free water
 V3 (V1b)limbic systemstimulates ACTH & endorphins

42. Tolvaptan
 oral V2 antagonist
 approved by the U.S. Food and Drug Administration.
 most appropriate for the management of significant and
persistent SIAD
 Dosage- 30 mg, 60 mg od
 Conivaptan
 intravenous vaptan
 a mixed V1A/V2 antagonist
 risk of hypotension due to V1A receptor inhibition
 inflammation at infusion sites
 20-40 mg/day IV

43.  Therapy with vaptans must be
initiated in a hospital setting,
with a liberalization of fluid restriction (>2 L/d) and
close monitoring of plasma Na+ concentration.
 Vaptans are not to be used in
hypovolemic hyponatremia
acute hyponatremia
SIAD caused by activating mutation in vaopressin
receptor
Cerebral salt wasting
Psychogenic polydipsia

44.  Other Vaptans
 V2 selective V1A selective V1B selective
-Satavaptan -Relcovaptan -Nelivaptan
-Lixivaptan
-Mozavaptan

45.  Vaptans in Cirrhosis
 Tolvaptan effective in raising Na
 Conivaptan – increase risk of GI bleed
 Vaptans in CHF
 Rapid & sustaine decrease in body weight
 Normalization of Sr Na with Tolcapone
 Trend towards lower mortality in patients with congestion,
hyponatremia & abnormal renal function
 No significant difference in worsening of heart failure
compared to placebo.

46.  Safety of Vaptans?
Trials showed correction of hyponatremia faster than
recommended
No guidelines for back titration once overcorrection
occurs
No case of ODS reported till date with vaptans

47.  Fallacies in ppt:
 -no consideration of Heat related hyponatremia
 -treatment not properly explained
 -more elaboration of ODS
 CMDT
 In severely symptomatic patients, the clinician should
 calculate the sodium deficit and deliver 3% hypertonic
 saline. The sodium deficit can be calculated by the following
 formula:

 Sodium deficit = Total body water (TBW) × (Desired serum Na–Actual serum Na)

 where TBW is typically 50% of total mass in women and 55% of total mass in men.
 For example, a nonedematous, severely symptomatic 70 kg woman with a serum sodium of 122 mEq/L should have her serum sodium
corrected to
 approximately 132 mEq/L in the first 24 hours.
 Her sodium deficit is calculated as:

 Sodium deficit = 70 kg × 0.5 × (132 mEq/L – 122 mEq/L)
 = 350 mEq

 3% hypertonic saline has a sodium concentration of 514
 mEq/1000 mL. The delivery rate for hypertonic saline can
 be calculated as:

 Delivery rate = Sodium deficit/514 mEq/1000 mL/24 hours

 = 350 mEq/514 mEq/1000 mL/24 hours
 = 28 mL/hour

 In general, the 3% hypertonic saline infusion rate should not exceed 0.5 mL/kg body weight/h; higher rates may represent
 a miscalculated sodium deficit or a mathematical error.
 The goal is not to correct the serum sodium by more tha 10–12 mEq/L over the first 24 hours.

48. References
 Harrison 18th edition
 JAPI Hyponatremia and Hypernatremia : Disorders of Water Balance V Agrawal*, M
Agarwal Dec 2008; 956-60
 Medicine Updates 2012
 Medicine updates 2013
 Text book of critical care.
 Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia.Am J Kidney Dis
2008; 52 (1) : 144-53.
 Gennari FJ. Hypo–hypernatraemia: disorders of water balance.
 In:Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG,eds.
 Oxford Textbook of Clinical Nephrology, 2nd Edition.
 Oxford University Press, Oxford, New Y ork, Tokyo: 1998: 175-89.
 Asadollahi K, Beeching N, Gill G. Hyponatraemia as a risk factor for hospital
mortality.QJM 2006;99(12):877-80.
 Rose BD, Black RM (eds): Clinical Problems in Nephrology, ed 1. Boston,Little, Brown,
1996, pp 3-17.
 Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl
J Med 2007;356:2064-72.

49. THANK YOU….