Dr Abdul Rauf KK. FNB Pediatric intensive care, SGRH, Delhi

1. Hyponatremia in critically ill
children
Dr Abdul Rauf KK
PICU Seminar
19/04/2017

2. Outline
• Total Body Water compartmentalization in children
• Basics of electrolytes, osmolality and Water
homeostasis
• Hyponatremia – Diagnostic approach
• Clinical symptoms
• Treatment
• Brief description on SIADH and CSW

4. Basics of fluids and electrolytes

5. Electrolyte concentration of body fluid

6. Basic Concepts-Osmolarity and
Osmolality
• Volume of water in body fluids >>>>> volume of solutes. (little
difference)
• Thus, the terms osmolality and osmolarity are often used
interchangeably
Osmolarity is the
osmotic activity per
litre of the whole
solution .
This is expressed as
mOsm/L of total
solution.
Solvent
Solute
Osmolality is the
osmotic activity per kg
of solvent (water).
This is expressed as
mOsm/kg of H2O.

7. Definitions
• Plasma Osmolality :
2 x Na + glucose (mg/dl)/18 + BUN (mg/dl)/2.8
– Normal value is 285-295 mOsm/kg)
– Plasma sodium concentration is the major
determinant
• Tonicity ( Effective osmolality) :
Determine osmotic force that mediate shift of
water between ECF and ICF
– BUN and glucose (in normal conditions ) contribute
little to tonicity

8. ICF and ECF are in Osmotic Equilibrium

9. Basic Concepts
• If plasma sodium is 140
• Glucose - 90
• BUN – 14
• Calculate plasma osmolality
?
• Plasma osmolality = (2 x
140) + 5 +5
= 290
• Used to be measured in the
clinical laboratory using
freezing point depression
method.
Lab result
Plasma osmolality
300 mmol/Kg H20

10. Basic Concepts
• Denotes unmeasured solutes
other than sodium, chloride,
glucose
• Normal gap is less than 10
• An increase in the osmolal gap
occurs with certain toxins.
• (E.G., Ethanol, methanol,
ethylene glycol and Unidentified
toxins of renal failure)
LAB RESULT
Measured
Osmolality
300 mmol/Kg H20
CALCULATED
Plasma osmolality
290 mmol/Kg H20
WHAT IS THIS
DIFFERENCE ?
OSMOLAL
GAP
In absence of unmeasured osmoles and pseudohyponatremia,
Calculated osmolality gives accurate estimation of plasma osmolality

11. Regulation of ECF osmolality and volume
** Volume depletion takes precedence over osmolality

12. Sodium balance
• Dominant cation of ECF
• Principal determinant of extracellular osmolality
• Necessary for maintenance of intravascular volume
Intake
Diet determines the amount of sodium ingested
Infants: breast milk (7 mEq/L) and formula (7-13 mEq/L)
Readily absorbed throughout the GIT
Presence of glucose Na absorption

13. Excretion
• Kidney, stool and sweat
• Stool:
– Some sodium loss in stool ( 50mEq/L )
– Minimal unless diarrhea is present
• Sweat:
– 5-40 mEq/L of sodium
Increased sweat sodium concentration
– Cystic fibrosis, aldosterone deficiency, or
pseudohypoaldosteronism
– Higher sweat losses may cause or contribute to sodium
depletion
• Kidney
– Regulates sodium balance
– Principal site of sodium excretion

14. Renal handling of sodium
• Mechanisms of sodium regulation revolve around changes in
fluid volume/blood pressure which includes
Activating factors
• Renin Angiotensin System -- Blood volume/BP
• Aldosterone -- Angiotensin 2, Na, K
• Natriuretic peptides ( ANP, BNP) -- intravascular volume
ANP- produced by both hypothalamus and atria
Patients effective plasma volume determine amount of urinary sodium
In hyponatremia or hypernatremia, underlying pathophysiology determines
amount of urinary sodium, not serum sodium
Hypovolemia--- Urine Na<20, FENa <1 % Hypervolemia- Urine Na>30, FENa >1%

15. Sodium regulation
• Sodium is unique among electrolytes because
– Water balance, not sodium balance, usually determines its
concentration
• Serum sodium 135-145 mEq/1 ,Osmolality 285-295 Osm/kg
• When the sodium concentration increases
Higher plasma osmolality, Increased thirst ,increased
secretion of ADH--which leads to renal conservation of
water
Both of these mechanisms increase water content of body
Sodium concentration returns to normal

16. Hyponatremia- Prevalance in critically ill children
• Hyponatremia (<130 mEq/L) : Very common electrolyte abnormality in
critically ill children (20-45%)
• 25% of hospitalized children
• Increased in PICU admitted children ( 25-40 %)
• In severe bronchiolitis, occurrence as high as 70 %
• In Community aquired pneumonia, 49 (45.4%) of 108 ambulatory
and hospitalized children had hyponatremia
• Outcomes are negatively and independently affected by presence
of hyponatremia
Don M, Valerio G, Korppi M, Canciani M. Hyponatremia in pediatric community-
acquired pneumonia. Pediatr Nephrol 2008;23:2247-53.
Prasad SV, Chugh KS. Hyponatremia in sick children seeking pediatric emergency care. Indian Pediatr
1994; 31 : 287-294.
Eulmesekian PG, Peraz A et al. Hospital aquired hyponatremia in post operative pediatric
patients: A prospective obserational study. Pediatr Crit care med2010;11:479-83

17. Hyponatremia…
• 49 (45.4%) of 108 ambulatory and hospitalized children had hyponatremia
• Mild (> 130 mmol/l): 92% of cases
• Hyponatremic patients:
Higher
– Body temperature (38.96 C vs 38.45 C, p=0.008)
– White blood cell count (21,074/microl vs 16,592/microl, p=0.008)
– Neutrophil percentage (78.93% vs 69.33%, p=0.0001)
– Serum C-reactive protein (168.27 mg/l vs 104.75 mg/l, p=0.014)
– Serum procalcitonin (22.35 ng/ml vs 6.87 ng/ml, p=0.0001)
Don M, Valerio G, Korppi M, Canciani M. Hyponatremia in pediatric community-
acquired pneumonia. Pediatr Nephrol 2008;23:2247-53.

18. Etiology…
• Impaired free water excretion
• Inappropriate release of vasopressin
• Redistribution of sodium and water
--Redistribution and accumulation of sodium within cells in sepsis
-Sick cell syndrome- Critically ill -- ↑membrane permeability -- IC solutes
leak out -- ↑ osmolality of plasma -- shift of water from IC to EC space
• Use of hypotonic fluids
• Several drugs and primary illness
• Body sodium: Low, normal, or high
• Body water: Low, normal, or high
Guglielminotti J, Pernet P, Maury E et al. Osmolar gap hyponatremia in critically ill
patients: Evidence for sick cell syndrome?. Crit Care Med 2002;30 :1051-1055.

19. AVP in critically ill children
Study population – 103 infants – Admitted with acute illness
Control - 31 children posted for elective surgery
Plasma AVP and PRA level estimated in both groups
Both Plasma AVP significantly elevated in 80% patients
Significant hypo - osmolality in study group
AVP elevations – Independent of underlying disease
Resp infections
Gastroenteritis
Bacterial infections
Viral syndrome

20. AVP in hospitalized children
Causes of Vasopressin effect in hospitalized children
High AVP state Risk for “HYPONATREMIA”

21. Impaired free water excretion
• Dilutional hyponatremia: most common
• Caused by water retention/free water excess due to
impaired free water excretion
• Pneumonia and bronchiolitis --impaired free water
clearance
• Maintenance water requirements <well children
• Using normal maintenance or greater of hypotonic
fluid -- hyponatremia
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581-9.
Singhi S, Jayashre M. Free water excess is not the main cause for hyponatremia in critically
ill children receiving conventional maintenance fluids. Indian Pediatr 2009;46:577-83.

23. Pseudohyponatremia
• Laboratory artifact
• When plasma contains very high concentrations of
– Protein (multiple myeloma, intravenous immunoglobulin
infusion)
– Lipid (hypertriglyceridemia, hypercholesterolemia)
• In true hyponatremia, measured osmolality is low
whereas it is normal in pseudohyponatremia
• To avoid: direct ion-selective electrode method to
determines sodium

24. Hyperosmolality
• Mannitol or glucose
• Water moves down its osmotic gradient from the IC space to EC
space, diluting sodium
• Because manifestations of hyponatremia are due to low plasma
osmolality
• Patients with hyponatremia resulting from hyperosmolality do not
have symptoms of hyponatremia
• When the etiology of hyperosmolality resolves, water moves back
into cells and sodium concentration returns to normal

25. Hypovolemic hyponatremia
• Pathologic increase in fluid loss with sodium
• Sodium loss > water loss
• Usually a combination of sodium loss and water retention to
compensate for volume depletion
• Volume depletion:
– Stimulates ADH synthesis, resulting in renal water retention in CDs

26. Hypovolemic hyponatremia…
• Gastroenteritis: most common cause in children
• Emesis: hyponatremia if patient takes in hypotonic fluid, either
intravenously or enterally
• Burns: cause massive losses of isotonic fluid-- volume depletion +
receives hypotonic fluid
• Sweat: sodium loss in hot climate; in children with cystic fibrosis,
aldosterone deficiency, or pseudohypoaldosteronism
• Third space losses: isotonic and can cause significant volume
depletion -- ADH production -- water retention + if patient receives
hypotonic fluid
Urine sodium <10 mEq/L
As part of the renal response to maintain IV volume

27. Hypovolemic hyponatremia…
• Diuretics: Thiazide > Loop diuretics
• Osmotic diuretics:
– Glucose in DKA cause loss of both water and sodium
• Juvenile nephronophthisis , ARPCKD, RTA-II
• CSW: CNS injury (production of natriuretic peptide --
renal salt wasting)
• CAH, pseudohypoaldosteronism
• In diseases associated with urinary sodium loss, the urine
sodium level is >20 mEq/L despite volume depletion
Renal sodium loss

28. Hypervolemic hyponatremia
• Excess of TBW and sodium, increase in water > increase in sodium
• Conditions with hypervolemic hyponatremia
– A decrease in effective blood volume (Eg- third spacing)
– Regulatory systems sense decrease in effective blood volume
– Attempt to retain water and sodium to correct problem
– ADH causes renal water retention
– Aldosterone and other intrarenal mechanisms retains sodium
• In these disorders, there is a low urine sodium (<10 mEq/L) and
excess of both total body water and sodium

29. Euvolemic hyponatremia
• Hyponatremia + no evidence of volume overload or
volume depletion
• Patients typically have an excess of TBW and a slight
decrease in total body sodium
• Some of these patients have an increase in weight,
implying that they are volume-overloaded
• From a clinical standpoint, they usually appear normal
or have subtle signs of fluid overload

30. Euvolemic hyponatremia…
• SIADH:
• Inappropriate secretion of ADH
• Secretion of ADH is not inhibited by either low serum osmolality or
expanded intravascular volume
• Unable to excrete water
• Dilution of the serum sodium
• Expansion of EC volume due to retained water causes a mild
increase in IV volume
• Kidney increases sodium excretion in an effort to decrease IV
volume to normal
• Mild decrease in body sodium
• SIADH is a state of IV volume expansion: low serum uric acid and
BUN levels

31. Euvolemic hyponatremia…
• SIADH…
• Stress
Stress, pain, anxiety, PPV
Hyponatremia: A Review. J Intensive Care Med 2015

32. Euvolemic hyponatremia…
Diagnostic criteria for SIADH
Hyponatremia: A Review. J Intensive Care Med 2015
• Absence of
– Renal , adrenal , thyroid insufficiency
– Heart failure , nephrotic syndrome or cirrhosis
– Diuretic ingestion
– Dehydration
• Urine osmolality > 100mosm/kg
• Serum osmolality < 280mosm/kg and serum
sodium <135
• Urine sodium >30 meq/L
• Correction of hyponatremia with water restriction

33. Hyponatremia-Clinical manifestations
• Hypoosmolality--Cellular swelling is not problematic in
most tissues
• Potentially dangerous in brain -- increase in ICP
• Anorexia, nausea, emesis, malaise, lethargy, confusion,
agitation, headache, seizures, coma
• Hypothermia and Cheyne-Stokes respirations
• Acute, severe hyponatremia: brainstem herniation
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction.
N Engl J Med 2015 Jan 1;372(1):55-65.

34. Brain shrinkage triggers
demyelination of pontine and
extrapontine neurons
Can cause neurologic dysfunction
(quadriplegia, pseudobulbar palsy,
seizures, coma, and even death)
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581-9.
Brain swelling can be significantly obviated if hyponatremia develops gradually
Brain adapts to the decreased EC osmolality by decreasing its internal osmolality
Symptoms in hyponatremia is related to both serum sodium level and rate of decrease
Patient chronic hyponatremia may be asymptomatic with a serum sodium 110 mEq/L
Another may have seizures due to acute decline from 140 to 125 mEq/L

35. Diagnosis
• History: usually points to a likely etiology of hyponatremia
• History of volume depletion: Diarrhea and diuretic use
• History of polyuria (with enuresis) and/or salt craving: primary
kidney diseases or absence of aldosterone effect
• CNS disease: SIADH or CSW
• Liver disease, nephrotic syndrome, renal failure, or congestive heart
failure: acute or chronic
• Review of intake, both IV and enteral, careful attention to the
amount of water, sodium, and protein

36. Diagnosis…
• 1st step: determination of plasma osmolality and urine
osmolality
• Low, normal, or high osmolality
• Normal osmolality: pseudohyponatremia
• High osmolality: Glucose or effective osmole (mannitol)
• Low osmolality:
– Indicates true hyponatremia
– These patients are at risk for neurologic symptoms
– Require further evaluation to determine etiology

37. Diagnosis…
• 2nd step: clinically evaluate the patient's volume status
• Hypovolemic, hypervolemic, or euvolemic
• Hypervolemia: edematous, may have ascites,
pulmonary edema, pleural effusion, or hypertension
• Hypovolemic hyponatremia: renal or nonrenal causes

38. Diagnosis…
• 3rd step: Urine sodium
• Useful in differentiating between renal and nonrenal causes
• Nonrenal losses: (kidney is working properly) renal retention of
sodium, a normal homeostatic response to volume depletion
• Urinary sodium low (typically <10 mEq/L)
• Renal losses: Urine sodium >20 mEq/L, reflecting the defect in renal
sodium retention
• Interpretation of urine sodium is challenging with diuretics
• High when diuretics are being used, low after diuretic effect is gone

39. ?
?
Algorithm for Hyponatremia evaluation
Hypotonic hyponatremia

40. Treatment
• Treatment decision is based on
– Severity and symptoms of hyponatremia
– Onset of hyponatremia
– Underlying disease
– Rate of correction and overcorrection
• Judicious monitoring
• Avoidance of overly quick normalization of serum
sodium
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction.
N Engl J Med 2015 Jan 1;372(1):55-65.

41. Treatment…
• Symptomatic (encephalopathy or seizures)
– Bolus of hypertonic saline to produce a small, rapid increase in serum
sodium
• Each mL/kg of 3% sodium chloride increases sodium by ~1 mEq/L
• A child with active symptoms often improves after receiving 4-6
mL/kg of 3% sodium chloride
• 4-6 ml/kg over ½ to 1 hour
• Less severe symptoms: 3% NaCl at a rate of 1-2 mL/kg/h with goal
to increase serum sodium up to 2 mEq/L/h
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction.
N Engl J Med 2015 Jan 1;372(1):55-65.
Hyponatremia: A Review. J Intensive Care Med 2015

42. Treatment…
Recommendation
Acute symptomatic
-3% NS
-Correct not more than 2mEq/l/hr
- 24 hr maximum correction- 12-15 mEq
Chronic symptomatic hyponatremia (>48 hrs/Unknown
duration)
– 3%NS
– Correct not more than 1.5mEq/l/hour
– Maximum limit of 10-12 mEq/L for first 24 hours and 18 mEq/L
over first 48 hours
– Goal is reduced in those patients with high risk of developing
ODS
Hyponatremia: A Review. J Intensive Care Med 2015
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction.
N Engl J Med 2015 Jan 1;372(1):55-65.

43. Dividing the change in serum sodium targeted for a given treatment period by the
output of this formula determines the volume of infusate required, and hence the rate
of infusion
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581-9.

44. • Asymptomatic hyponatremia
2 year old boy .Wt 10 kg, Na 120.....
Sodium deficit= TBW (140- Plasma Na)
=0.6 10 20 = 120meq
Generally , ½ of total sodium deficit replaced at 0.5 mEq/l/hr
Plan to raise sodium to 130 in 20 hrs
How to Calculate?
Volume of NS -10/ (154-120/7) * 1000 =2061 ml in 20 hrs
Volume of 3%NS - 10/(513-120/7) *1000= 178ml in 20 hrs

45. Treatment…
• Indications for stopping rapid correction of
symptomatic hyponatremia:
– Cessation of life-threatening symptoms
– Achievement of a serum sodium of 125-130 mmol/L
– (or even lower if the base-line sodium is below 100
mmol/L)
• Long-term management of hyponatremia
initiated
Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581-9.

46. Treatment…
• Rapid correction may cause central pontine myelinolysis (CPM)
• Neurologic symptoms: confusion, agitation, flaccid or spastic
quadriparesis, and death
• Characteristic pathologic and radiologic changes in brain, especially
pons
• CPM is more common in chronic hyponatremia
• Adaptation of brain cells to hyponatremia
• Reduced IC osmolality: adaptive mechanism
• Makes brain cells susceptible to dehydration during rapid correction
of hyponatremia
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction.
N Engl J Med 2015 Jan 1;372(1):55-65.

47. Treatment…
• Risk factors for Osmotic Demyelination Syndrome
– Chronic hyponatremia
– Serum [Na] <105 mEq/L
– Hypokalemia
– Alcoholism
– Malnutrition
– Liver cirrhosis
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction.
N Engl J Med 2015 Jan 1;372(1):55-65.

48. Treatment…
• Overcorrection:
• Free water:
– water or 5% glucose iv or 0.45% NaCl
• Desmopressin

49. Hypovolemic hyponatremia
• Deficiency in water > sodium
• 1st step: In treating any dehydrated patient is to
restore the IV volume by isotonic fluid
• Frequently needed in hyponatremic dehydration
• Because low serum osmolality causes water to move to
IC space, further depleting IV volume
• Complete restoration of IV volume suppresses ADH
production
• Permits excretion of excess water

50. Hypovolemic hyponatremia…
• CSW:
– Volume repletion
– Hypertonic saline if
neurologic
symptoms
– Addition of
fludrocortisone
acetate for
refractory cases
CSW SIADH
Serum Na Low Low
Fluid
balance
-ve Even or +ve
CVP Low Normal or high
Urine
volume
High Low
Volume Hypovolemia Euvolemia
Urine Na >20 >20
Hematocrit Increased Normal or
Decreased
Plasma osm Low Low
Urine osm >plasma osm >plasma osm

51. Hypervolemic hyponatremia
• Difficult
• Excess of both water and sodium
• Patients are retaining water and sodium because of their ineffective
IV volume or renal insufficiency
• Administration of sodium leads to worsening volume overload and
edema
• Cornerstone of therapy: water and sodium restriction and
treatment of underlying cause of decreased effective circulatory
volume
• Diuretics may help by causing excretion of both sodium and water

52. Hypervolemic hyponatremia…
• Low albumin (nephrotic syndrome):
– Better response to diuretics after an infusion of albumin
– Sodium often normalizes due to expansion of the IV volume
• CCF:
– Have an increase in renal water and sodium excretion if there is
an improvement in Cardiac output
– Will turn off regulatory hormones that are causing renal water
(ADH) and sodium (aldosterone) retention
• Renal failure:
– Cannot respond to any of these therapies except fluid restriction
– Dialysis to remove water and sodium

53. Hypervolemic hyponatremia…
• Furosemide may be used in patients with
dilutional hyponatremia to remove excess
water while giving hypertonic saline
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction.
N Engl J Med 2015 Jan 1;372(1):55-65.

54. Isovolemic hyponatremia…
• SIADH:
• Fluid restriction (60-75%)
• Fluid restriction obviously requires time
• Treat underlying cause
• Occasionally loop diuretics to lower urine osmolality
• Therapy with saline can create problems
– Temporarily increase sodium concentration
– Causes kidneys to eliminate almost all of the sodium, eliminating any
benefit from therapy
– Water contained in the saline is retained
– Hyponatremia may actually worsen

55. Isovolemic hyponatremia…
• Treatment of chronic SIADH is challenging
– Fluid restriction in children is difficult for nutritional
reasons
– Demeclocycline and lithium: blunt effect of ADH
– Problematic in children because of their potential toxicity
– Chronic furosemide therapy with sodium supplementation
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction.
N Engl J Med 2015 Jan 1;372(1):55-65.

56. V2-receptor antagonist
• Conivaptan:
– V2-receptor antagonist
– Decreases the permeability of CDs to water producing an aquaresis
– Approved for short-term treatment of
• Euvolemic patients with hyponatremia (usually SIADH)
• Hypervolemic hyponatremia (heart failure, cirrhosis)
• Risk of overcorrection
• Avoid in : hypovolemic hyponatremia, liver injury
• Although promising, subsequent clinical trials are necessory before
routine use of Vaptans are recommended in children with hypervolemic
hyponatremia
Sterns RH. Disorders of plasma sodium--causes, consequences, and correction. N Engl J Med 2015 Jan
1;372(1):55-65.
Lehrich RW, Ortiz-Melo DI. Role of vaptans in the management of hyponatremia. Am J Kidney Dis 2013; 62:
364-76.
Initial Experience With Conivaptan Use in Critically Ill Infants With Cardiac Disease. J Pediatr Pharmacol
Ther 2012

57. ?
?
Algorithm for Hyponatremia Evaluation
Hypotonic hyponatremia

58. Cerebral salt wasting
• Concept first recognised in 1950,
• Support over this diagnosis over the years has been controversial
• Brian injury natriuretic factors natriuresis and volume depletion
• Controversy ( ?accuracy of volume assessment)
• In a recent study, when volume status was assessed with CVP
measurement, diagnosis of CSW could be supported only in 6% of
hyponatremic patients, far more had SIADH
• Conclusion: If CSW occurs, it is a very uncommon cause of
hyponatremia
Scott A. Differentiating appropriate ADH secretion, SIADH and cerebral salt wasting:
the common, uncommon and misnamed. Current opinion in pediatr 2008;20:448-52