- Hyponatremia in ICU patients is commonly caused by inappropriate secretion of antidiuretic hormone leading to retention of free water. - The brain adapts slowly to changes in serum sodium levels over 48 hours; rapid corrections can cause serious complications like osmotic demyelination syndrome. - Treatment goals for hyponatremia are to correct the sodium level slowly at a rate of no more than 6 mEq/L per day to prevent neurological complications while relieving symptoms.

1. PULMONARY AND CRITICAL
CARE- NOON CONFERENCE
HYPONATREMIA IN ICU PATIENTS
Avaneesh Jakkoju, M.D.

2. What we are going to cover…
 Why serum sodium falls
 How the brain responds to a change in serum
Na concentration.
 What the goals of therapy should be.

3. Why serum Sodium level rises and
falls…
• Serum Sodium is a function of exchangeable
Sodium, Potassium and total body water.
Total body (Nae+Ke)
Serum Sodium = -----------------------------------
Total body water

4. Serum Sodium levels…
• Extra renal losses do not cause fall in serum
sodium levels.
– For example GI losses such as vomiting and
diarrhea leads to loss of Na and K along with free
water loss and serum sodium level will be same.
– Sweating.
What causes hyponatremia in the above situations
is replacing the lost fluid with regular water, that
makes the Sodium levels to drop.

5. Why does hyponatremia develop…
 Renal loss of Sodium leads to hyponatremia.
 To put it simply, if the urine is more
concentrated than plasma then there is net
loss of Sodium leading to hyponatremia.
 ADH (vasopressin) plays a crucial role to this
effect.

6. ADH in normal human beings..
 Secreted by hypothalamus Vasopressin is
released from posterior pituitary in response to
dehydration and/or hyponatremia.

7. Abnormal secretion of ADH…
• Pathologically ADH secretion is released in
spite of normal or even low Na concentration
in response to stimuli such as
– Inadequate circulation
– Stress
– Hypoxia
– Cortisol deficiency
– Neurological diseases
– Ectopic vasopressin release such as SCC of lung.

8. Cerebral Salt Wasting…
 In acute neurological conditions particularly in
SAH, to maintain cerebral perfusion large
volumes of isotonic fluids are commonly
prescribed.
 Volume expansion suppresses aldosterone
secretion and enhances natriuretic hormones
that increase urine Na excretion leading to
hyponatremia.

9. Hyponatremia in Kidney
disease…
 Acute kidney injury or advanced chronic
kidney disease results in a urine osmolality
equal to that of plasma.
 Replacing fluid losses with electrolyte free
water in kidney diseases leads to
hyponatremia due to dilution.

10. Brain response to changing serum
Na concentration…
 Na does not readily cross BBB.
 If the serum sodium falls rapidly then free
water crosses blood brain barrier leading to
increase in Intra cranial pressure some times
with fatal outcomes.
 On the other hand if the serum Sodium
concentration increases rapidly, water is drawn
from brain.

11. Slow vs. fast serum Na
changes…
• Brain cells achieve osmotic equality with plasma
by exchanging organic solutes as well as taking
on water.
• Loss of these organic osmolytes leads to
decreased brain swelling.
• This is an effective mechanism to prevent cerebral
edema in response to hyponatremia, but
unfortunately this is a slow process.
• It takes 48 hours for the brain to adapt to
hyponatremia, any fall in Na faster than this leads
to fatal rise in ICP.

12. Slow vs. fast Na changes…
• Rapid correction of chronic hyponatremia
starts a cascade of adverse events leading to
programmed death of myelin producing
oligodendrocytes.
• This is because of the delay in repletion of
organic osmolytes within the brain cells.
• This injury presents clinically as a progressive
neurological disease- Osmotic demyelination
syndrome (ODS).

13. Osmotic demyelination
syndrome…
• Classically associated with demyelination of
the central pons- central pontine myelinolysis.
• Extra pontine myelinolysis is also equally
common.
• Clinical symptoms start 2 to 6 days after the
correction and include
dysarthria, dysphagia, paraparesis or
quadriparesis, behavioral
disturbances, lethargy, confusion, disorientatio
n, obtundation and coma.
• Seizures although uncommon are seen.
• Severe cases, patients are „locked in‟;

14. Predisposition to ODS…
• ODS is seen not with hyponatremia but with rapid
correction; can be prevented by lowering Na with
Desmopressin after rapid correction.
• Patients who has a very longstanding
hyponatremia, with serum Na<105
mEq/L, hypokalemia, alcoholism, malnutrition and
liver disease are prone to develop ODS.
• On the other hand serum Na<120 mEq/L, with out
above risk factors and whose hyponatremia is of
very short duration are not prone to develop
ODS, they can be treated with rapid Na
correction.

15. Goals of Therapy…
 Serum Na concentration should be increased
enough to prevent complications of untreated
hyponatremia.
 Treatment should be at the optimal rate so as
not to cause any iatrogenic brain injury.

16. Acute hyponatremia…
 Brain death from cerebral edema is the most
feared complication of acute hyponatremia.
 This was observed in patients..
 Who were given hypotonic IV fluids after surgery.
 Water intoxication associated with psychosis,
marathon running or recreational drug use of
„ecstasy‟.
 Intracranial pathology.

17. Acute hyponatremia-clinical
picture…
• Headache, nausea, vomiting, drowsiness and
mild confusion can be seen.
• These non specific symptoms rapidly progress
to seizure, respiratory arrest and permanent or
fatal brain injury.
• Seizures are uncommon in chronic
hyponatremia even with very low Sodium
concentration and they usually reflect and
underlying seizure pathology.

18. Acute hyponatremia- how to
correct…
• Serious neurological symptoms warrant
aggressive treatment irrespective of any other
factors.
• Treatment with hypertonic saline to raise serum
sodium concentration 4 to 6 mEq/L is suggested
by several studies.
• A 4 year, single center study of 63 patients treated
for transtentorial herniation caused by a variety of
neurosurgical conditions found that, an increase in
plasma sodium concentration by 5 mEq/L promptly
reversed clinical signs of herniation and reduced
ICP by 50% with in 1 hour.
• Seizures due to hyponatremia do not respond to
anti epileptic drugs.

19. Severe chronic hyponatremia…
 Patients with chronic hyponatremia rarely are
symptomatic.
 There is little evidence to suggest Sodium
level to be brought to „safe‟ (>120 mEq/L or in
some cases >130 mEq/L) levels for better
outcome.
 In spite of lack of evidence correcting well
compensated hyponatremia continues to be
the standard of care.

20. Severe Chronic hyponatremia-
rationale for treatment…
• Typically patients with serum Na<110 mEq/L
are admitted to the hospital.
• These patients have a very good prognosis
and there is no need for aggressive treatment
or large increase in Sodium.
• As serum sodium levels fall mortality rate
rises, but below 120 mEq/L paradoxically
mortality rate falls, and at 110 mEq/L mortality
rate is same as that of normonatremic
patients.

21. Severe Chronic Hyponatremia-
clinical picture…
• Although hyponatremia that developed over
days rarely ever presents with life threatening
symptoms such as seizures and coma, it still
causes distressing symptoms.
• Even mild chronic hyponatremia which is
seemingly “asymptomatic” can cause gait
disturbances and disturbed cognition.
• It markedly increases the risk of falls and
fractures.

22. Severe Chronic hyponatremia-
treatment goals…
• Goal of treating chronic hyponatremia should
not be aimed at bringing the Sodium level to
„normal‟ levels, but bringing it to a level where
it provides symptom relief.
• Rapid or over correction of Sodium is
associated with adverse neurological
outcomes that we have reviewed in the
beginning.
• A correction of 4 to 6 mEq/L/day is considered
an ideal Sodium correction rate.

23. ODS- treatment goals…
 It takes about 1 week for the repletion of organic
osmolytes in the brain.
 Several observational studies have
shown, treatment of severe (defined as
<120mEq/L) and chronic (>48 h) hyponatremia
by >10 to 12 mEq/L/d or >18 mEq/L/2days has
been shown to be associated with ODS.
 However these values do not represent the
treatment guidelines for the correction of
hyponatremia, therapeutic goals should be
much lower than these values.

24. A Universal Therapeutic Goal: Rule of
Sixes…
Six a day makes sense for safety; so give six
in six hours for severe Sx and stop.

25. Rule of Sixes- What does it mean?
 For all patients with severe symptoms of
hyponatremia therapeutic range of correction
should be <6 mEq/L/D.
 Give 6 mEq/L on the first day for 6 hours and
stop.
 Can be resumed on day 2 with a goal of 4 to 6
mEq/L/D.

26. Rule of Sixes- Why?
 An increase of 4 to 6 mEq/L/D is enough to
treat most symptoms of hyponatremia.
 This level allows enough room for error should
correction inadvertently exceed the rate that
was intended.
 As previously mentioned upper limit of
correction 10 to 12 mEq/L/D or 18 mEq/L/2day
reported by previous observational studies.

27. How to treat: General Measures…
 Unless urine is maximally dilute, patients
should be fluid restricted.
 No unintended sources of electrolyte-free
water such as tube feedings and IV meds
administered in D5W.
 If it is unavoidable, give 300 ml of 3% saline
(150 mEq of Na) for every liter of free water.

28. How to treat: Avoiding hyponatremia in
patients with Intracranial disease…
 High risk for cerebral edema and resultant
tentorial herniation.
 Fluid restriction will be ineffective in presence
of concentrated urine and not suggested as it
can compromise cerebral circulation.
 Most reliable way is to give sodium rich fluids
based on this proposed sliding scale.

29. How to treat: Sliding Scale protocol to avoid Hypo-natremia
in Neurosurgical patients with serum Sodium < 140 mEq/L…
Serum Sodium Infusion Rate
<130 mEq/L Increase by 20 ml/h to maximum
of 80 ml/h
130 – 135 mEq/L Increase by 10 ml/h to maximum
of 80 ml/h
136 – 140 mEq/L No change in infusion rate
>140 mEq/L Hold infusion and resume when in
therapeutic range.
3 gm of NaCl orally or NG tube Q6hr RTC and 3% IV NaCl given at an initial rate of 20 ml/hr
and adjusting infusion rates Q6hrs based on serum sodium.

30. How to treat: Urgent intervention…
 Acute (<24 h) symptomatic
hyponatremia, Severe neurological sx (seizures
and/or coma) regardless of duration of
hyponatremia and patients with coexistent
intracranial pathology…
 Should be treated urgently with hypertonic saline.
 100 ml bolus of 3% saline with two additional doses
administered every 15 min till the patient improves.

31. How to avoid over correction in
Chronic hyponatremia…
• In many patients SIADH and/or concentrated
urine resolves after initial management such as
fluid repletion in hypovolemia, hormone
replacement in adrenal insufficiency or
discontinuation of thiazide diuretics etc.
• In such circumstances, body starts to lose free
water instead of making concentrated urine and
Sodium level may start to rise more than
anticipated.
• Once the urine becomes maximally dilute the
resulting water diuresis can increase serum Na
level by >2mEq/L/h

32. How to avoid over correction in
Chronic hyponatremia:
Desmopressin..
• If urine sodium concentration is increasing too
rapidly, urine water losses can be matched
with D5W.
OR
• We can give desmopressin 2 to 4 mcg
parenterally to halt water diuresis.

33. How to avoid over correction in Chronic hyponatremia:
D5W or Desmopressin?
 If serum sodium level has already increased
by >10 to 12 mEq/L over 24 hours
 Or by >8 mEq/L in high risk patients*
 Bring the sodium level down again.
 Bring to 8 mEq/L more than previous day.
 Do this by giving infusions of 3ml/kg D5W over
1 hour or 2 to 4 mcg of Desmopressin
parenterally.

34. Correction of chronic hyponatremia:
Desmopressin and 3% saline…
• Rather than giving desmopressin to stop water
diuresis after it has begun we can start giving
desmopressin along with 3% saline to achieve
a more controlled rate of correction.
• Hypertonic saline is titrated to achieve the
desired rate of correction, with an initial bolus
if clinically indicated.
• Combination therapy is continued until the
serum Na concentration has been increased to
>128 mEq/L.

35. Correction of chronic hyponatremia:
When to avoid combination
treatment?
• We avoid desmopressin combination
treatment when there is little likelihood of a
reversible cause of water retention such as
SIADH due to small cell lung cancer or brain
tumor.
• In hypotensive patients with hyponatremia who
require large amounts of isotonic fluid for
volume resuscitation we would still give
desmopressin but avoid 3% saline, as each
liter of NS increases serum Na by 1mEq.

36. Correction of chronic hyponatremia:
Patients who are hypokalemic…
• In patients who are hypokalemic, Potassium
replacement will increase serum Na level too as it
is a function of exchangeable K as well as Na.
• In such patients dose of hypertonic saline must be
reduced.
• A recent report described a case of ODS following
overcorrection primarily attributable to
replacement of a large K deficit.
• In such patients KCl infusion along with
desmopressin achieved a controlled rate of
correction of both Na and K levels.

37. Renal replacement therapy…
• Hyponatremia is commonly seen in oliguric
kidney failure.
• Conventional hemodialysis has shown to
increase serum Na concentration very rapidly.
• Luckily ODS after dialysis is rare and uremia
has been shown to be protective.
• However large increases in the serum Na
concentration during dialysis should be
avoided if possible.

38. Hyponatremia in edematous
conditions…
 Hyponatremia is associated with poor
outcomes in heart failure and liver disease.
 Hypertonic saline is usually not advisable in
volume overloaded patients, but it can be
given combined with high doses of loop
diuretics.
 Alternatively “aquaretics” can be used to treat
hyponatremia in volume overloaded patients.

39. Samsca
(tolvaptan)
• Tolvaptan is an oral vasopressin V2 receptor
antagonist.
• Increases free water clearance and increases
serum Sodim concentrations.
• Indicated for the treatment of clinically
significant hypervolemic and euvolemic
hyponatremia that is symptomatic and has
resisted correction with fluid restriction.
• Most commonly used in heart failure and
SIADH.

40. Samsca (tolvaptan)
Dosing…
• Initial dose of 15 mg P.O. qD
• Can be increased to 30 mg P.O qD after
atleast 24 hours of beginning of the treatment.
• Can be increased to a maximum of 60 mg P.O.
qD titrating at 24 hours intervals to desired
Sodium concentration.
• Avoid fluid restriction for first 24 hours.
• Can be used for a maximum duration of 30
days.

41. Samsca (tolvaptan)
Contraindications…
• As of April 2013, the U.S. Food and Drug
Administration (FDA) determined that tolvaptan
can not be used in patients with underlying liver
disease including cirrhosis.
• A double blinded, placebo controlled trial showed
an increase in serum ALT and total bilirubin in 3
patients (n=1445) with ADPKD.
• Other contraindications include acute
hyponatremia with sever symptoms, anuria,
patients who have altered mental status who
cannot respond to thirst and anuria.

42. Samsca (tolvaptan)
Adverse reactions…
• GI: Nausea (21%), Xerostomia (7% to 13%),
GI bleeding (10%, in cirrhosis patients),
Constipation (7%), anorexia (4%),
hepatotoxicity (<4%)
• Renal: Polyuria (4% to 11%)
• Endocrine and metabolic: hyperglycemia (6%),
hypernatremia (<2%)
• Musculoskeltal: Weakness (9%)
• Misc: Thirst (12% to 16%), Fever (4%)

43. Thank you
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