Hyponatremia Hypernatremia SIADH

1. Dr. T.R.Chandrashekar
Intensivist, Liver transplantation.
Dept of Surgical Gastroenterology and organ transplant
PMSSY super-specialty Hospital.
BMC, Bangalore.
Sodium Disturbances

2. Outline of my Talk
 Sodium –Physiology
 Sodium - Regulation in the body
 Hyponatremia
 Hypernatremia
 Take home thoughts

3. Physiology to understand Na+
and water disturbances

4. Sodium
 Sodium is a Ca ion – positively charged ions
 Sodium is univalent, so 1 mmol/ L =1 mEq/L
 Sodium was discovered by Sir Humphry Davy in 1807.
The origin of the name sodium is soda. The meaning in
latin is natrium hence Symbol- (Na)
 Atomic Number- 11and atomic weight 23
 Only 2.5% is inside cells 33% is in the bones &
Rest 65% in ECF
 1500 to 2300 mg is the required daily intake

5. COMPOSITION OF BODY FLUIDS
CATIONS (mmol/l) Plasma Interstitial Intracellular
Na 142 139 14
K 4.2 4.0 140
Ca 1.3 1.2 0
Mg 0.8 0.7 20
ANIONS (mmol/l)
Cl 108 108 4.0
HCO3 24.0 28.3 10
Protein 16 1 40
HPO4 2.0 2.0 11
CATIONS =ANIONS always electrical neutrality is maintained

6. Hyponatremia in low K states
 Sodium shifts out of cells in exchange for
potassium as deficits of the latter are corrected
after supplementation
 Administering potassium will raise the [Na+] to
an equivalent degree as administering sodium;
therefore, potassium dosing should be taken
into account in the hyponatremia treatment
plan.
Diabetic ketoacidosis

7. Where’s the water?
Na 2%

8. Na & Water
v
v
Water with salt
Add water
Less salty
Remove water
More salty
Sodium is unique among electrolytes…
because water balance, not sodium
balance, usually determines its
concentration.

9. Normal Serum osmolality is 280-
295mOsm/Kg
v
Water with Na+
 Body fluids protect circulatory blood volume
by altering Na+ and water balance.
 Which in turn maintains a Steady intracellular
water and osmolality which is necessary for
cell membrane integrity and cellular processes.
 This is the most vital homeostatic function of
the body.
Steady intracellular water =Effective Circulatory blood volume=Volume status=
Blood pressure= MAP
Osmolality=Na+

10. Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Urea
Urea
Urea
Urea moves
freely across
membranes
hence does not
contribute to
osmolality or
tonicity
Capillary
endothelium
Cellular
membrane
Osmolarity is determined by the number of particles in a solution(
weight), regardless of whether they are capable of exerting an osmotic
force (make water move) across a biological cell membrane
Tonicity or osmolality is determined by that subset of particles,
called effective osmoles, which exert an osmotic force across a biological
cell membrane
Osmolarity and Tonicity

11. Osmolarity vs. Tonicity
 Posm = 2 [Na] + [glucose]/18 + BUN/2.8
 95% Posm is contributed by Na
 But urea is not an effective osmole in plasma as it crosses cellular
membrane easily it contributes to osmolarity but not for tonicity
 Tonicity = 2 [Na] + [glucose]/18
 To check the tonicity of a solution, just ask:
 What happens to RBCs placed in the solution?
 If isotonic "no net water movement
 If hypotonic"water influx "cell swells
 If hypertonic "water efflux "cell shrinks

12. Na Functions
Maintain balance of extracellular fluid, thereby it
controls the movements of the water between fluid
compartments
Transmission of nerve impulses
Neuro muscular and myocardial impulse transmission
Principal determinant of extracellular osmolality

13. Na+/K+-ATPase PUMP
present in all the cells
 Inside Cell:
 High K+ / Low Na+ relative to extracellular medium
 The sodium potassium pump uses energy to
generate and maintain these concentration
gradients
 Moves Na+ out, K+ in whilst hydrolysing ATP
 Uses up approx. 30% cell‘s energy

14. Intra cellular water is maintained by ECF
Effective blood volume
is the system
which gets water intake
and regulates output
according to cellular
requirement

15. Sodium and water regulation
Input
(oral or IV)
Sodium and Water
ECF volume
Serum Na+
Serum osmolality
Total body water
Output
(urine/faeces ,skin)
Sodium and Water
EffectorsSensors
CVS
Arterial / Atrial
Hypothalamus
Osmoreceptors
Renal
JG cells/Macula
densa
Neural
Physical
Hormonal
Sympathetic
RAAS, ADH
Thirst

16. Osmo.reg. Vs Vol.reg
• What is sensed?
• Plasma OSMOLALITY
• Sensor?
• Osmo Receptor
• Effector?
• ADH and Thirst
• Final say
• Water excretion /
retention
• What is sensed?
• Eff.Circ.Blood Volume
• Sensor?
• Baroreceptors
• Catotid sinus / Aortic
/Renal Afferent
Arterioles
• Effector?
• RAAS, ANP,
Sympathetic System
• Final say
• Urine Na
excretion/Retention
The body protects volume
At the expense of osmolality.

17. The Thirst Mechanism
An increase of 2 – 3% in plasma osmolality triggers the thirst
center of the hypothalamus.
Secondarily, a 10 – 15% drop in blood volume also triggers thirst.
This is a significantly weaker stimulus.

18. Na and Water homeostasis
Osmol receptor
(hypothalamus)
AVP secretion
(Post.pituitary)
Thirst center
(hypothalamus
Baro receptor
•Aortic arch
•Carotid body
•Afferent arteriole
(kidney) Lt atrium
Water reabsorption Na and water
reabsorption
Water intake
Renin
(JG cells/Macula densa)
Angiotensin II
Aldosterone
Angiotensinogen
Blood volume Na+
Reduces stretch in renal
afferent arterioles
filtrate volume or
osmolality in DT
Na+
Angiotensin I

19. Na, water
reabsorption
=isotonic
Na
reabsorption
Na
reabsorption
Water
Reabsorption
If AVP +
isotonic
50-100
mosmol/kg
(free water)
~1200
Mosmol/kg
Na+ and Kidney
ADH zone

20. Kidney and Na+
 Every minute 125 mL (180 L/day) of filtrate containing 17
mmoL of Na (daily 25,000 mmoLs) enters the proximal
tubule (PT)
 99% is reabsorbed and 1% excreted.
 The kidney can handle large variation in salt and water intake
with enormous efficiency.
 Daily, it can excrete 0.5 to 25 L of urine with osmolality
varying from 40-1400 mosm/L.
 Thus, depending on the demands from the body for
conservation or excretion, urine volume can vary 50-fold and
urine osmolality 35-fold.

21. ANP
BNP
Raising Blood
volume and Blood
Pressure
Responses to ANP
Increased Na+ loss in urine
Increased water loss in urine
Reduced thirst
Peripheral vasodilation
Inhibition of ADH, aldosterone,
epinephrine, and
norepinephrine release
Combined Effects
Reduced blood
volume
HOMEOSTASIS
RESTORED
Declining blood
pressure and
volume
Atrial natriuretic peptide (ANP)

23. Hyponatremia – Basics
Na + K
Total Body Water
Loss of Na,K
Excess water
Intake
Retention
Add to Numerator
Subtract from denominator

24. Insufficient
Correction
CEREBRAL EDEMA
Herniation
Too Rapid
Correction
OSMOTIC
DEMYELINATION
Hyponatremia

25. It was decided to update the guideline at least every 5 years. New evidence requiring additional
recommendations or changes to existing statements could instigate an earlier update.

26. Assessment of the relative
importance of the outcomes
Correction of serum sodium concentration’ were considered less important
than the critically and highly important clinical outcomes

27. Hyponatremia
Incidence and Prevalence
• 1% of healthy population
• 5 to 20% of hospitalised
patients/geriatric patients
• 30% of ICU patients
Association of Hyponatremia with
Adverse Outcomes
In virtually every disease state examined
to date, the presence of hyponatremia has
been found to be an independent risk
factor for increased mortality.
Asymptomatic” patients had gait
instability and increased incidence of falls
and fractrures.
Hyponatremia is associated with
increased bone loss in experimental
animals and with a significantly increase
of osteoporosis in the femoral neck

28. Plasma Osm
280-295mosm/Kg of
H2O
High
Glucose,
Mannitol
Normal
Protein,
Lipids
Low
True HypoNa
Hypertonic and Isotonic osmolar hyponatremia
conditions are not due to Na+

29. Normal osmolality
Pseudohyponatraemia
 Pseudohyponatraemia is a laboratory artefact that occurs
when abnormally high concentrations of lipids or
proteins in the blood interfere with the accurate
measurement of sodium.
 This laboratory abnormality has been essentially
eliminated by the use of ion-specific electrodes rather
than flame photometry to determine the serum sodium
concentration.

30. Isotonic or Hypertonic
Hyponatremia
 Hyponatremia with normal or even increased
osmolality occurs when effective solutes other
than sodium are present in the plasma. The
initial hyperosmolality produced by the addi-
tional solute causes an osmotic shift of water
from the ICF to the ECF compartment that, in
turn, produces a dilutional decrease in the serum
[Na+].
 Cause hyponatremia but not hypoosmolality, a
condition known as translocational

31. Isotonic or Hypertonic
Hyponatremia
 Hyperglycemia is the most common example of this phenomenon.
 This translates into adding 2.4mmol/l to the measured serum
sodium concentration for every 100 mg/dl incremental rise in
serum glucose concentration above a standard serum glucose
concentration 100 mg/dl.
Other effective osmoles which may cause are
 Mannitol,
 Radiographic contrast agents, or
 Glycine / sorbitol from surgical irrigant solutions,
 plasma osmolality cannot be calculated accurately and must be ascertained by
direct measurement.

32. DIAGNOSIS AND MANAGEMENT
 Hyponatremia is not a disease but a manifestation of a
variety of disorders and requires accurate history physical
examination and lab investigations for diagnosis.
 Important investigation for the diagnosis of hyponatremia
are –
1. Plasma osmolality
2. Urinary osmolality
3. Urine sodium concentration
4. Volume status

33.  Therapeutic strategy in hyponatremia is dictated
by the underlined disorder as well as
 1. presence or absence of symptoms.
 2. Duration of the disorder
 3. The risk of neurological complications.

34. Definition of hyponatraemia based on
biochemical severity
 ‘Mild’ hyponatraemia 130 -135mmol/l
 ‘Moderate’ hyponatraemia 125 -129 mmol/l
 ‘Profound’ hyponatraemia <125 mmol/l
 As measured by ion-specific electrode

35. Definition of hyponatraemia
based on time of development
 ‘Acute’ hyponatraemia <48 h.
“Chronic’ hyponatraemia exist for at least 48 h.
 If hyponatraemia cannot be classified, we
consider it being chronic, unless there is clinical
or anamnestic evidence of the contrary

36. Definition of hyponatraemia
based on symptoms
 We define ‘moderately symptomatic’
hyponatraemia as any biochemical degree of
hyponatraemia in the presence of moderately
severe symptoms of hyponatraemia .
 We define ‘severely symptomatic’ hyponatraemia as
any biochemical degree of hyponatraemia in the
presence of severe symptoms of hyponatraemia

37. True hyponatremia
 Hypotonic Hyponatremia
Plasma Osmolality less than 280-mOsm/kg
Serum Sodium less than 135 mmol/L

38. 4 essentials
1. History / Physical examination
2. Plasma osmolality.
3. Urine spot Osmolality /Sodium
4. Volume status- last consideration
because difficult to estimate

39. Urine osmolality
 Urine osmolality is used to assess vasopressin
(ADH) activity
 In hyponatraemia primarily caused by excess water
intake, vasopressin release is suppressed resulting in
urine osmolality usually < 100 mOsm/kg
 By contrast, in case of non- suppressed vasopressin
activity, urine osmolality usually exceeds serum
osmolality > 300mOsm/kg

40. Urine osmolality
 This leaves a ‘grey area’ for urine osmolalities
between 100 mOsm/kg and the value of the
serum osmolality.
 In this range, one cannot be clear about the
presence or absence of vasopressin activity and
excessive fluid intake may outweigh only
moderately suppressed vasopressin activity.
Dilute urine or solute free -less osmolality
Concentrated or solute rich -high osmolality
Normal 500-800mOsm/kg (50 -1500 mOsm/kg range kidney can make urine)

41. Urine osmolality and specific gravity
Specific gravity Urine osmolality
1.000 0
1.010 350
1.020 700
1.030 1050
oNormal urine osmolality: 400-500 mM
Maximal dilution 50-100 mM (USG 1.002-1.003)
Therefore, USG of 1.010 ~ UOSM 300-350 mM
Maximal concentration 900-1200 mM (USG 1.030-
1.040)
oConcentrated Urine: > 500 mM (at least!), USG > 1.017

42. Urine sodium
 If urine sodium concentration ≤30 mmol/L, we
suggest accepting low effective arterial volume
as a cause of the hypotonic hyponatraemia. (2D)
 If urine sodium concentration>30 mmol/L, we
suggest assessing extracellular fluid status and
use of diuretics to further differentiate likely
causes of the hyponatraemia
Kidneys reabsorb solutes to retain water and volume

43. Caveats
 As urine osmolality and sodium may no longer
reflect the effects of the regular hormonal axes
regulating water and sodium homeostasis, any
diagnostic algorithm for hyponatraemia must be
used with caution in patients with kidney disease
and also diuretic use.

44. WORKUP FOR
HYPONATREMIA
• 3 mandatory lab tests
– Serum Osmolality
– Urine Osmolality
– Urine Sodium Concentration
• Additional labs depending on clinical suspicion
– TSH, cortisol (Hypothryoidism or Adrenal insufficiency)
– Albumin, triglycerides (psuedohyponatremia, cirrhosis), MM
– Plasma urea and uric acid
– Acid base balance
Plasma Uric acid
FeNA
Urea
Fractional excretion of
uric acid

45. Scenario
 57 years old male from old age home
 persistent vomiting and diarrhea since on day

Restlessness, not responding to deep stimuli, had
one episode of Seizure
 Reduced urine output, BP 100/60mm Hg HR
 120/mt, RR 38/mt
 Sodium 113
What do we do?
Investigate or Treat?

46. Severely symptomatic hyponatraemia always immediate Rx
Which should be prioritised over further diagnostic differentiation

47. Hyponatraemia with severe
symptoms
1) Prompt i.v. infusion of 150 ml 3% hypertonic over 20 min
(1D).
2) Check the serum Na+ after 20 min while repeating an
infusion of 150 ml 3% hypertonic saline for the next 20 min
(2D).
We suggest repeating therapeutic recommendations A and B
twice or until a target of 5 mmol/l increase in serum sodium
concentration is achieved (2D) or until the symptoms
improve, whichever comes first.
2ml/kg in obviously -deviant body composition.
Around 500ml is required to achieve 5 mmol/l increase in serum Na+
HDU or ICU

48. Severe hyponatrema
Acute or chronic
 Limiting the increase in serum sodium for first
DAY1( 24 hrs )= 10 mmol/l
 Every subsequent DAY =Additional 8 mmol/l
until the serum sodium concentration reaches
130 mmol/l (1D).
 Example 48 hrs limit to 18 mmol/l
 Check Na+ every 6 and 12 h -until stabilised
under stable treatment
Aim for 5 mmo/L correction in the first hour when death due
to cerebral edema is at the highest

49. Calculation
• Na+ required = TBW x Desired Na+ – Measured Na
• 60% of body weight is water
• 65 x 0.6 = 39 L
• 120-113 = 8
• 39x 8 = 312 Meq needed
• 1ml of 3% saline = 0.5 mEq of Na
• Sodium deficit = 624 ml
• 624 /24 hours = 26 ml/hr
• Serum Na measure q2-4 hrs
49

50. Janinic and Verbalis formula
 Rate ml/Kg/Hr = Goal rate of rise
mmol/Kg/Hr
 1ml/kg/hr = 1ml/kg/hr rise in Serum Na
 Ideal for those allergic to Math !!

51. Adrogue’s Formula*
 Change in serum Sodium with 1L of fluid=
Bottle Na+ - serum Na+
total body water + 1
 Easier to calculate
*Horacio J Adrogue, Nicholas E Madias: Hyponatremia; NEJM Vol 342, No 21
May 25 (2000)
One lite 3 % NS=513
Patients sodium is 113
513-113=400
70kg x 0.6=42
42+1=43
400/43 =9.2mmol change with one
liter of 3 % NS
1000ml/24 hrs =41ml/hr

53. Clinical advice
If urine output suddenly increases, we would advise measuring the serum
sodium concentration every 2 h until it has stabilised under stable
treatment. The implicit advice to monitor urine output does not imply we
advise a bladder catheter solely for this purpose. Most patients will be able
to void spontaneously and collect urine for output monitoring.
A sudden increase in urine output to >100 mL/h signals increased risk of
overly rapid rise in serum sodium concentration.
If vasopressin activity is suddenly suppressed, as happens when
intravascular volume is restored in hypovolaemia, free water clearance can
dramatically increase, resulting in serum sodium concentrations rising more
rapidly than expected.
Reduced urine osmolality and Na+ should gives a clue about free water

54. Why safe limits?
The capacity of the kidneys to excrete electrolyte-free water can vary
substantially during treatment and the actual change in serum sodium
concentration may be unpredictable
This reflects interplay between a number of factors:
Suppression of appropriate endogenous vasopressin secretion by
fluid and salt loading,
Natural history of the underlying condition
Potential impact of cause-specific treatments.
Given the uncertainty in biochemical response to treatment, the
guideline development group believes that the increase in serum
sodium concentration aimed for initially should be sufficient to
allow an appropriate margin of safety

55. Scenario
 57 years old male from old age home
 persistent vomiting and diarrhea since one day

Restlessness reduced , responding to deep
stimuli,
 Had one episode of Seizure
 BP 100/60mm Hg HR 120/mt, RR 38/mt
 Sodium 113,
 After 1 hours Na 119 What do we do?
Correction adequate ?

56.  Stop the infusion of hypertonic saline (1D).
 Smallest feasible volume of 0.9% saline until cause-specific
treatment is started (1D).
 Diagnosis-specific treatment if available, aiming at least to
stabilise sodium concentration (1D).
Follow-up management in case of improvement of symptoms after a 5
mmol/l increase in serum sodium concentration in the first hour, regardless
of whether hyponatraemia is acute or chronic
First 24 hrs limit the Na+ rise to 10mmol/l
Additional 8 mmol/l during every 24 h
Until the Na+ reaches 130 mmol/l
Monitor very Na+ 6th hrly

57. Scenario
 57 years old male from old age home
 DM HT – persistent vomiting and diarrhea since
on day

Restlessness, not responding to deep stimuli, had
one more episode of Seizure
 BP 100/60mm Hg HR 120/mt, RR 38/mt
 Sodium 113,
 After 1 hours Na 118
What do we do?
Correction inadequate ?

58.  Contine an i.v. infusion of 3% hypertonic saline or
equivalent aiming for an additional 1 mmol/l per h
increase in serum sodium concentration (1D).
 Stop the infusion of 3% hypertonic saline or
equivalent if
 Symptoms improve,
 Serum sodium increase from 5 to 10 mmol/l
 Total Na+130 mmol/l, whichever occurs first (1D).
Follow-up management in case of no improvement of
symptoms after a 5 mmol/l increase in serum sodium
concentration in the first hour, regardless of whether
hyponatraemia is acute or chronic.

59. Scenario
 57 years old male from old age home
 persistent vomiting and diarrhea since on day

Restlessness, had one episode of Seizure
 BP 100/60mm Hg HR 120/mt, RR 38/mt
 Sodium 113,
 After 6hrs Na+ 118
 After 18 hrs Na+ 127
What do we do?
Over Correction ?

60. What to do if hyponatraemia is
corrected too rapidly?
 We recommend prompt intervention for re-lowering the
serum sodium concentration if it increases >10 mmol/l
during the first 24 h or >8 mmol/l in any 24 h thereafter
 We recommend discontinuing the ongoing active treatment
 To start an infusion of 10 ml/kg body weight of electrolyte-
free water (e.g. glucose solutions) over 1 h under strict
monitoring of urine output and fluid balance (1D).
 Can consider to add i.v. desmopressin 2 µg, with the
understanding that this should not be repeated more
frequently than every 8 h (1D).

61. 3 % NS
 3% Sodium Chloride injection
 pH: 5.8 (4.5–7.0)
 Calculated Osmolarity: 1030
 Contains 513 mmol/L Na+
 1ml of 3% saline = 0.5 mEq of Na
 Central line preferred

62. Hyponatremia
Na and Water deficit Water Excess Na and water excess
HypervolemicHypovolemic Euvolemic
TOTAL Body water
TOTAL Body Na+
TOTAL Body water
Normal total Body Na+
TOTAL Body water
TOTAL Body Na+
Hypotonic Hyponatremia
Plasma Osmolality less than 280-m0sm/Kg of H2O
Serum sodium less than 135 mmol/L

63. 3
1
2
4
If body has to loose
Na in ECF - then
aldosterone should
be absent or kidney is
not responsive to it
Hypotonic Hyponatremia
Plasma Osmolality <280
Serum sodium less than
<135

64. Assessing Intravascular Volume
Clinical (sensitivity ~50%)
• Orthostatic hypotension
• Weak pulse
• Cool extremeties
• Increased HR
• Skin turgor
• Muco
• us membranes
• JVP
Investigation
Urine
Volume & Colour
Osmolality
Sodium
Haemoconcentration
Creatinine, Urea
BNP/ ECHO
CVP
Clinicians often misclassify hyponatraemia when using algorithms that start with a
clinical assessment of volume status.
Clinical assessment of volume status has both low sensitivity (0.5–0.8) and
specificity (0.3–0.5)
Hypervolumia
Edema, Ascitis
Increase JVP,CVP
Pleural effusion and pulmonary congestion

65. Case scenario
 60 year old HT chronic smoker with smalll cell
carcinoma on thiazide diuretics presents with
pneumonia admitted to ward, patient conscious,
comfortable
 Investigations show
 Na+ of 128
 Patient on 3% Nacl 30ml/ hr
Diagnosis or Treatment?

66. Acute
Moderate hyponatremia
 Diagnostic assessment and exploration.
 Stop, if possible, medications and other factors
causing hyponatraemia. (not graded)
 Cause-specific treatment. (1D)
 Single shot 150 ml 3% Nacl
 Aiming for a 5 mmol/L/24 h increase in serum
sodium concentration. (2D)
 Check the serum sodium concentration after 4-6 h

67. Chronic Hyponatraemia without severe
or moderately severe symptoms
 Diagnostic assessment and exploration.
 Stop, if possible, medications and other factors causing
hyponatraemia. (not graded)
 Cause-specific treatment. (1D)
 Against a treatment with the sole aim of increasing the serum sodium
concentration in mild or moderate hyponatraemia.
 Check the serum sodium concentration after 4 h
 In case of unresolved hyponatraemia, reconsider the diagnostic
algorithm and ask for expert advice. (not graded)

68. Case scenario
 60 year old cachexia HT, chronic alcoholic and
smoker with small cell carcinoma on thiazide
diuretics presents restlessness, headache and one
episode of seizures
 Investigations show
 Na+ of 118 K+ 2.0
Serum sodium concentration≤ 105 mmol/L
Hypokalemia
Alcoholism
Malnutrition
Advanced liver disease
What do we do?
Correction how much?

70. Brains response to hyponatremia
 Acute –Neuronal edema Tentorial
herniation & Neurog.Pul.edema
 Adaptation – addition of osmolytes-
inositol/ taurine etc edema decreases
 Rapid correction of hyponatremia brain
shrinkage and demylination

71.  Minimum correction of serum [Na+] by 4-8
mmol/L per day, with a lower goal of 4-6
mmol/L per day if the risk of ODS is high.
 For patients with severe symptoms, the first day’s
increase can be accomplished during the first 6
hours of therapy, with subsequent increases
postponed until the next day.
“rule of sixes,”- “six a day makes sense for safety; so
six in six hours for severe sx’s and stop.”

72. ODS
 Demyelination can be diffuse and not involve the pons
 Symptom onset can be delayed for weeks
• Rate of correction over 24 hours more important than rate of
correction in any one particular hour
• More common if sodium increases by more than 20 mEq/L in
24 hours
• Symptoms generally occur 2-6 days after elevation of sodium
and usually either irreversible or only partially reversible
• MRI

73. ODS TREATMENT
 No effective therapy
 Anticipation and slow correction
 Reinduction of hyponatremia?
 Corticosteroids
 Case reports of improvement with aggressive plasmapheresis
immediately after diagnosis , thyrotropin-releasing hormone
 infusion of myoinositol (a major osmolyte lost in the
adaptation to hyponatremia)protects against mortality and
myelinolysis from rapid correctionof hyponatremia
 Use of Vaptans
Am J Med. 2006;119(suppl 1):S12–S16

75. V1a vasopressin receptor, largely in the vasculature of the renal medulla; this receptor
mediates the effects of vasopressin on renal blood flow.
V2 receptor acts chiefly in the principal cells of the renal collecting duct, the
connecting tubule cells, the distal convoluted tubule cells, and the cells of the thick
ascending limb of Henle
Aquaporin-2, is expressed throughout the collecting-
duct system (i.e., in the region of the renal tubule
where vasopressin regulates osmotic transport of
water).
Vaptans-Vasopressin Receptors
blockers
Aquaporin-Molecular water channel

76. LOOP D block both
Conc. & Dilution
THIAZIDES BLOCK
DILUTION ALONE
Urine Na and K very highUrine Na and K moderate

77. Vaptans blocks activation of the receptor by endogenous AVP
Vaptans produce solute-sparing water excretion in contrast to classic diuretic agents
that block distal tubule sodium transporters, leading to simultaneous electrolyte and
water losses.
Renal effects of vaptans (V2R blockers)= Aquaretic
Classical diuretic agents, =Natriuretic and Kaliuretic as well.
This is not simply a semantic issue, because appreciating these important differences
in renal effects is crucial for the intelligent clinical use of AVP receptor antagonists.
For example, the negative water balance induced by aquaretic agents has less adverse
effect on neurohormonal activation and renal function than comparable degrees of
urine output induced by loop diuretic agents,
Vaptans vs diuretcis
Only 1/3 of the total water loss is from ECF rest from ICF

78. VAPTANS –PURE WATER
EXCRETION
Thirst
Rapid correction
No fluid over load
Relatively safe
Exclude hypovolemic hyponatremia.
Do not use in conjunction with other treatments for hyponatremia.
Do not use immediately after cessation 3% NS
Do not use in severe hyponatremia with Na+ < 120mmol/L
Good fluid intake in first 24 to 48 hrs
Very frequent monitoring of sodium if there is a change or deterioration
in the patient’s condition

80. Who should be treated with
vaptans?
Hypervolemic
Special
Euvolemic
.
SALT-1 and SALT-2 EVEREST SALTWATER TEMPO ACTIV IN CHFADVANCE

81. Hyponatremia with Cirrhosis
 Hyponatremia is an independent risk factor for
decreased quality of life, hepatic encephalopathy,
hepatorenal syndrome, and survival in cirrhotic
patients.
 Severe daily fluid restriction—less than daily urine
output plus insensible losses is necessary to increase the
serum [Na+] in patients with cirrhosis, but often
cannot be maintained because of poor compliance with
this therapy.

82. Hyponatremia with Cirrhosis
 Vaptans have been an alternative choice for treating
cirrhotic patients with hyponatremia in whom fluid
restriction has failed to maintain a serum [Na+] 130
mmol/L;
 Because of recent FDA recommendations that
tolvaptan not be used in patients with underlying
liver disease, its use in cirrhotic patients should be
restricted to cases where the potential clinical
benefit outweighs the risk of worsened liver
function- End-stage liver disease and severe
hyponatremia who are awaiting liver transplantation

83. Hyponatremia with Heart
Failure
 For severely symptomatic patients with very low or rapidly
falling serum [Na+], treatment should consist of hypertonic (3%)
NaCl combined with loop diuretics to prevent fluid overload; for
patients with mild to moderate symptoms, begin with fluid
restriction (1 L/d total) and, if signs of volume overload are
present, administer loop diuretics.
 If the serum [Na+] does not correct to the desired level, lift the
fluid restriction and start either conivaptan (if intravenous route
is preferred or required) or tolvaptan (if oral therapy is
preferred)
 Hyponatremia in HF is almost always chronic, so current limits
for rate of correction of chronic hyponatremias should be
observed

84. Hyponatremia with Heart
Failure
If tolvaptan is used, it may be up-titrated from 15 to 30 to 60 mg/d
as necessary to achieve the desired level of correction of serum Na+.
Continue treatment until the serum [Na+] has either normalized,
symptoms have improved, or the level of serum Na+ is no longer
compromising administration of needed diuretic therapy.
The stimuli for AVP secretion may be more dynamic than in other
disease states; if prescribed after discharge, assessing the need for
chronic therapy of hyponatremia by providing a window of
observation off therapy 2-4 weeks after treatment initiation is a
reasonable approach.

86. Syndrome of inappropriate
antidiuresis (SIADH)
Diagnosis out of exclusion
The vasopressin secretion –inappropriate -occurs independently
from effective serum osmolality or circulating volume.
It may result from increased release by the pituitary gland or from
ectopic production.
Regardless of the stimulus, once it is secreted, AVP binds to the AVP
V2 receptor subtype (V2R) in the kidney collecting ducts and
activates the signal transduction cascade resulting in antidiuresis

87. Criteria for Diagnosing SIADH
 Decreased effective osmolality of the extracellular fluid (Posm <275
mOsmol/kg H2O).
Inappropriate urinary concentration (Uosm >100 mOsmol/kg H2O
with normal renal function) at some level of plasma hypo-osmolality.
 Clinical euvolemia, as defined by the absence of signs of hypovolemia
(orthostasis, tachycardia, decreased skin turgor, dry mucous
membranes) or hypervolemia (subcutaneous edema, ascites).
Elevated urinary sodium excretion (>20-30 mmol/L) while on normal
salt and water intake.
Absence of other potential causes of euvolemic hypo-osmolality:
severe hypothyroidism, hypocortisolism (glucocorticoid insufficiency).
 Normal renal function and absence of diuretic use, particularly thiazide
diuretics.

89. Severe hyponatremia, serum sodium level <125 mmol/liter
Documented as acute
(duration <48 hr)
or coma, seizures
Moderate symptoms
and unknown duration Asymptomatic
Begin diagnostic evaluation (Consider CT or MRI)
Rule out ECF depletion
If present, use 0.9% saline infusion alone
If not Begin correction
0.9% Saline infusion with furosemide, 20 mg
Aim for increase of Na+ by 0.5–2 mmol/liter/hr
Rule out or address correctable factors
Begin diagnostic evaluation
Restrict fluid intake
Encourage dietary intake of salt and protein
If hyponatremia continues
Demeclocycline, 300–600 mg twice daily
or Urea, 15–60 g Daily
vaptans
Algorithm for the Treatment of Hyponatremia Associated with SIAD.
Treatment
Stop when serum sodium level rises by
8–10 mmol/liter within the first 24 hr
Consider conivaptan
Na+level every 4 hr and adjust infusion rate
Urine Na + K > Serum Na
Indicates the renal electrolyte-free water
clearance is negative

90. Diuretic-induced hyponatremia
 Diuretic-induced hyponatremia is always a chronic hyponatremia,
Common with Thiazides and rare with loop diuretics
 Thiazides interfere with urinary dilution. Discontinuation of
thiazides and correction of volume deficits may be followed by a
rapid, spontaneous water diuresis that can raise serum [Na] very
quickly;
 Numerous cases of ODS have been reported after correction of
severe thiazide-induced hyponatremia.
 Serially follow changes in urine osmolality together with urine
volume to detect the development of an aquaresis with heightened
risk of overly rapid correction and ODS

91. Diuretic-induced hyponatremia
 The focus of therapy for patients with serum Na
<120 mmol/L is typically not on achieving adequate
correction but on restraining the rate at which the
Na increases.
 -Frequent (every 6-8 hours) measurement advisable
until the serum Na has reached a stable value
>125mmol/L;
 Aquaresis is pronounced- Enteral water or 5%
dextrose in water can be used to slow the correction
if necessary; desmopressin iv can be used

92. Reintroduction of diuretics
 Patients with thiazide-induced hyponatremia are at high
risk for a recurrence of the disorder and should not be
re-challenged with a thiazide.
 There are no data on the risk of hyponatremia due to
loop-acting agents inpatients who previously developed
thiazide-induced hyponatremia.
 If diuretic therapy is essential in such a patient, the
serum [Na+] should be measured within a few days
after initiation of treatment and frequently within the
first several weeks

93. Expert Panel Recommendations:
Hyponatremia from CSW
In the neurosurgical setting with hyponatremia after subarachnoid hemorrhage, trauma,
or surgery majority have SIADH, not CSW.
 Reduced BUN and uric acid values not useful.
 Fluid challenge test with increased Na and water loss not useful
 Diagnosing CSW requires demonstration of a period of inappropriate
renal sodium and fluid loss preceding the development of volume
depletion and hyponatremia; (check last few days input/ output and
urinary sodium)
 To distinguish between SIADH and CSW, the response to a cautious
reduction in fluid supplementation should be observed;
 CSW patients will develop signs of volume depletion,
 While SIADH patients will demonstrate reduced urine output while remaining
euvolemic.
HypovolumicNS infusion

95. Hypernatremia – four
mechanisms
 First and foremost, the patient must has lost the
sense of thirst or access to water.
 Second usually thier is an impaired ability to
concentrate the urine. Lack of ADH –DI or kidney
not responding to ADH nephrogenic DI -more
common in the setting of renal failure whether it is
acute or chronic
 Third the high serum sodium and urea
concentrations lead them to compete to get out into
the urine which has limited ability to excrete
osmoles

96.  Lastly, the large output, whether it is urine (most
commonly) or stool, leads to a large water
excretion which is not balanced by large sodium
and potassium excretion.
 Large outputs are not mandatory
 Often, patients with hypernatremia in the intensive care
unit are not volume depleted despite having large outputs
as they have received large volumes of fluid earlier in the
course of their illness and have had much less output for
many days .
 Thus, hypernatremia often develops in the setting of large
outputs and not in the setting of volume depletion
Hypernatremia – four mechanisms..

97. Pure Water deficit
Inadequate intake (e.g., Poor water access old /
very young / ICU intubated patients
Insensible losses
Skin
Respiratory tract (mechanical ventilation)
Renal Loss
Diabetes insipidus (Primary Central or
Nephrogenic DI,
Water and Sodium deficit
Skin (burns, excessive sweating)
Gastrointestinal Tract (viral gastroenteritis,
osmotic diarrhoea e.g. lactulose, vomiting Loop
Diuretics, Osmotic diuresis Hyperglycemia,
Mannitol, High Protein Diet)
Extrarenal Loss
Renal disease, Resolving ATN.
Post cardiac arrest, hyperaldosteronism,
Cushing’s syndrome,, Hypertonic feeding)
Renal Loss
5% dextrose
0.45 % NS then 5% dextrose
Hypernatremia causes and treatment
Sodium Gain
1
3
2

98. Clinical features
 Clinical features of hypernatremia are primarily neurological.
 Major neurological –symptoms include :
Nausea, Muscular weakness, altered mental status, neuromuscular
irritability, focal neurological deficit and occasionally coma or seizures
and they depend upon the rapidly of outset, its duration and its
magnitude.
 In severe acute hypernatremia brain shrinkage may be substantial,
exerting traction on the venous causing intra cerebral and SAH.
In ACUTE hypernatremia -rapid correction improves the prognosis without increasing the
risk of cerebral edema, because accumulated electrolytes are rapidly extruded from brain
cells. In such patients, reducing the serum sodium concentration by 1 mmol per liter per
hour is appropriate.

99. Treatment for hypernatremia
 In Chronic or unknown duration, because the full dissipation of
accumulated brain solutes occurs over a period of several days
 In such patients, reducing the serum sodium concentration at a
maximal rate of 0.5 mmol per liter per hour prevents cerebral
edema and convulsions.
 Target fall in the serum sodium concentration of 10 mmol per liter
per day for all patients
 The goal of treatment is to reduce the serum sodium concentration
to 145 mmol per liter.
 Since ongoing losses of hypotonic fluids, whether obligatory or
incidental, will aggravate the hypernatremia, allowance for these
losses must also be made.

100. Formula for Managing
Hypernatremia
CLINICAL USE
Estimate the effect of 1 liter of any
infusate on serum Na+
Estimate the effect of 1 liter of any
infusate containing Na+ and K+ on
serum Na+
FORMULA*
1. Change in serum Na+ =
2. Change in serum Na+ =
infusate Na+ - serum Na+
total body water + 1
(infusate Na+ + infusate K+) -serum Na+
total body water + 1

101. Free water deficit calculation
 A 76-year-old man presents with a severe obtun-
dation, dry mucous membranes, decreased skin
tur- gor, fever, tachypnea, and a blood pressure
of 142/82 mm Hg without orthostatic changes.
The serum so- dium concentration is 168 mmol
per liter, and the body weight is 68 kg.
 Hypernatremia caused by pure water depletion
due to insensible losses is diagnosed

102.  Infusion of 5 percent dextrose is planned. Has zero Na+
 The estimated volume of total body water is 34 liters (0.5 X 68). According to
formula 1, the retention of 1 liter of 5 percent dextrose will reduce the serum
sodium concentration by 4.8 mmol per liter
 Change in serum Na+ =
 The goal of treatment is to reduce the serum sodium concentration by ap-
proximately 10 mmol per liter over a period of 24 hours. Therefore, 2.1 liters
of the solution (10 ÷ 4.8) is required. With 1.5 liters added to compensate for
average obligatory water losses over the 24-hour period, a total of 3.6 liters
will be administered for the next 24 hours, or 150 ml per hour.
 The serum glucose concentration will be monitored, with insulin therapy
started at the first indication of hyperglycemia, a complication that would
aggravate the hypertonicity.
infusate Na+ - serum Na+
total body water + 1
[0-168]
[34+1]
= -4.8
Free water deficit calculation……

103. Case scenario
 25 year old RTA brain dead shifted to our unit
for organ retrival and liver transplantation
 On dopamine small dose BP 120/80
 Urine 350ml/ hr for last four hours Na+ 165
 DI

104. AVP ↓-DI
 Polyuria (more than 200ml/hr for 3 hrs).
 Normal or increased serum osmolality.
 Inappropriately dilute urine (specific gravity < 1.005,
 Urine osmolality < 200 mOsm/kg H2O).
 Hypernatremia (Na+ > 145 mmol/L).
Hypotension present-Vasopressin : 1 unit bolus; Infusion at 1-4
units/hr
IF sodium, > 145–150 mmol/L without hypotension, treatment
with Desmopressin should be initiated. ( Nasal Spray)
Bolus IV dose of 1–4 μg, additional 1 or 2 μg every 6 hours
AVP +Desmopressin can be used concurrently in unstable patients

105. Take home thoughts
 Apply physiology and deduct
 In all severe disturbances treat first
 Hyponatremia correct 5mmol/L at the earliest
 In chronic cases diagnose first, sole aim of
raising Na+ is not warrented
 Total correction per day – first day 10 mmol/L
all subsequent days 8 mmol/L
 Much less in patients with high risk of ODS ( 4
to 6 mmol/L
 Monitor frequently

107. Patients with contracted
circulating volume
 We recommend restoring extracellular volume with
intravenous infusion of 0.9 % saline or a balanced
crystalloid solution at 0.5–1.0 mL/kg/h. (1B)
 Manage patients with haemodynamic instability in an
environment where close biochemical and clinical
monitoring can be provided. (not graded)
 In case of haemodynamic instability, the need for rapid
fluid resuscitation overrides the risk of an overly rapid
increase in serum sodium concentration. (not graded)

108. Patients with expanded
extracellular fluid
 We recommend against a treatment with the sole aim of
increasing the serum sodium concentration in mild or
moderate hyponatraemia. (1C)
 We suggest fluid restriction to prevent further fluid
overload. (2D)
 We recommend against vasopressin receptor
antagonists. (1C)
 We recommend against demeclocycline. (1D)

109.  Volume-depleted patients, as happens in the
nursing home patients, may also be unable to
excrete large sodium loads because of the
kidneys’ role in trying to correct the low volume
state by reabsorbing sodium

110. Importance of Sodium
 Hence Na+ is important in maintaining both
ECF and intra cellular water and osmolality
 The cellular survival depends upon delivery of
oxygen and nutrients to mitochondria.
 Oxygen and Nutrients goes where Blood flows

111. Sensors Three discreet areas are located
in hypothalamus
• Osmoreceptors (OR)
• Thrist center
• SO and PV nuclei
responsible for ADH
synthesis.
Baroreceptors carotid sinus
Aortic Arch
Thirst center
Afferent input from OR to
SO and PV nuclei is
essential for a normal ADH
response.
•Afferent arteriole
(kidney)
Na+

112. Thus there are four primary Effector
mechanisms regulate fluid homeostasis:
 - ADH,
 - Thirst,
 - Aldosterone,
 - Sympathetic nervous system
 Out of the above 4, three mechanisms are in
the kidney

113. Why ODS is not a major threat
• Short acting
• Possible to reverse the effect
• Frequent Na monitoring in major clinical
trials
• No threat of hypok as with diuretic +
Hypertonic saline regimen
• FDA Warning- Liver toxicity on prolonged
use in Cirrhosis

114. Key proteins involved in Water
balance