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Dr Ishtiaq

1. Conditions for free H2O excretion


2. Loop diuretics DONOT cause hyponatremia!
3. Causes of hyponatremia
4. Criteria for SIADH
5. Cerebral edema – <48hours hx or too efficient first dialysis
6. Osmotic demyelination syndrome (previously called CPM) –
too fast correction or dialysis of hyponatremic patient
7. Desalination
8. Correcting hypokalemia can sometimes correct hypo Na
9. Daily osmolar load
10. Auto-correction
• Defined usually as serum Na < 135 mEq/L
• In most cases of hyponatremia, there is a relative excess of free
water compared to sodium
• Usually mediated by ADH
• There are also minority of iatrogenic cases of hyponatremia
secondary to thiazide diuretics, anti-depressants,
carbamazepine, and desmopressin
• Other cases include hypo-thyroidism, hypo-adrenalism,
psychogenic polydipsia, pseudohyponatremia etc
1. GFR
2. Separation of water from solute in the thick ascending loop of
Henle, so that free water can be excreted. This section of the
tubule is impermeable to water. Therefore, sodium pumped out
of the lumen leaves free water within the tubule.
3. Excretion of free water. Finally, water must travel through the
tubules without being reabsorbed into the kidney. This requires
absent or low levels of ADH. (ADH increases the permeability
of the tubules [via aquaporin channels] allowing water within
the tubules to leak back into the interstitium.)
• NaCl reabsorption in the TAL of the loop of Henle is the first step in
the generation of HYPEROSMOTIC gradient in the medullary
interstitium
• Therefore, in the presence of ADH, the highly concentrated interstitium
allows water to move from the tubular lumen down the osmotic
gradient into interstitium, resulting in the excretion of a concentrated
urine
• Loop diuretics REDUCE THE TONICITY OF THE MEDULLARY
INTERSTITIUM by inhibiting Na/K/2Cl pump
• Although LOOP diuretics can induce ADH release due to
HYPOVOLEMIA, but as we know that ADH function depends upon
HYPERTONIC INTERSTITIUM, so the effect is blunted and usually
DOES NOT result in HYPONATREMIA
1. Disorders in which ADH levels are elevated
2. Disorders in which ADH levels may be appropriately
suppressed
3. Hyponatremia with normal or elevated plasma osmolality
• Apart from few exceptions all cases of hyponatremia have low
plasma osmolality and high urine osmolality
• Urine osm <100 mosm/kg suggests psychogenic water drinking
is the cause of hyponatraemia
ECF

hypervolemic euvolemic hypovolemic

UNa <10 UNa >20 UNa <10

UNa >20 UNa >20


• Euvolaemia
• Low serum sodium <130 mmol/l
• Low serum osmolality <275 mosm/kg
• Urine osm >100 mosm/kg
• Urine Na typically >30 mmol/l
• No recent diuretic use
• Normal serum potassium, urea and urate
• Normal adrenal and thyroid function
• SUPPLEMENTAL CRITERIA
• Abnormal water-load test (failure to dilute urine to
<100mOsm/kg four hours after 20ml/kg water load)
• Cancers (eg, pancreas, lung)
• CNS disease (eg, cerebrovascular accident, trauma, infection,
hemorrhage, mass)
• Pulmonary diseases (eg, infections, respiratory failure)
• Drugs
• Thiazides
• Antidiuretic hormone (ADH) analogues (vasopressin, desmopressin acetate
[DDAVP], oxytocin)
• Chlorpropamide (6–7% of treated patients)
• Carbamazepine
• Antidepressants (tricyclics and selective serotonin reuptake inhibitors) and
antipsychotics
• Nonsteroidal antiinflammatory drugs (NSAIDs)
• Ecstasy (MDMA)
• Others (cyclophosphamide, vincristine, nicotine, opioids, clofibrate)
• In acute hyponatremia, water moves rapidly into the brain;
specifically the ASTROCYTES (glial cell that also forms the
socalled BBB); there is presence of AQP1 and AQP4 channels
on the glial cell membranes.
• These glial cells therefore selectively swell in acute hypo-
osmolar conditions, sparing the NEURONS
• Brain tries to adapt to this situation via displacement of fluid
from the interstitial space to the CSF and then into the systemic
circulation; and Volume Regulatory Decrease (VRD)
• VRD is the extrusion of intracellular solutes together with
osmotically obligated water to reduce cellular swelling
• In the first 3 hours, cells mainly lose inorganic ions, such as Na+,
K+ and Cl-; by Na+-K+ ATPase pump, starting with extrusion
of Na+
• Followed by Ca+ dependent and independent K+ channels
• Second adaptive response is the loss of small organic osmoles
(glutamate, taurine, glycine) and myo-inositol through volume-
sensitive organic osmolyte and anion channel
• The efflux of organic osmoles is sustained and will remain until
hyponatremia persists
Clinical features of hyponatremic
encephalopathy
Early Nausea/Vomiting/Anorexia
Headache
Muscular cramps
Weakness
Advanced Lethargy
Restlessness
Disorientation
Depressed reflexes
Seizures
Far advanced Coma
Respiratory arrest
• Glutamate is neuroactive and could produce transient seizure
activity in case of fluctuations in its concentration in the brain
• In order to prevent excessive fluid loss from brain cells (when
hyponatremia is corrected), the lost organic osmolytes are
RECAPTURED, but this is a very slow process and sometimes
takes several days
• Therefore, rapid correction of chronic hyponatremia can result in
dehydration and demyelination of the white matter, socalled
ODS or Osmotic Demyelination Syndrome, this occurs especially
in the pons
Impairment in Short-Term
Mutism
Memory
Attention deficit Parkinsonism
Dysarthria Catatonia
Dysphagia Dystonia
Flaccid Quadriparesis Tremor
Oculomotor abnormalities “Locked-in” syndrome
Ataxia Seizures
Coma
• Pediatric brain is especially susceptible to rapid changes in
plasma tonicity
• They have a reduced Na+-K+ ATPase activity compared with
adult brain; thus impairing the adaptive extrusion/recapture of
solutes during brain swelling
• ODS especially seen:
• when initial Na < 105; corrected by > 20 mEq/L over 24 h
• DI patient who becomes hyponatremic after desmopressin administration
but then Na corrects rapidly after desmopressin is discontinued
• HTS
• > 48 hours symptoms/hx
• EtOH, malnutrition, liver disease, hypokalemia
• In cases of unknown history/duration of illness.. It is often better
and safe to assume that it may be chronic and going slow is
safer
• The plasma Na may fall spontaneously if the urine is hypertonic
to plasma
• This phenomenon has been called “desalination”
• Occurs in 2 settings
• (a) patients with SIADH who have been volume expanded with
intravenous fluids
• (b) patients with renal salt wasting disorders
• Consider a 50 kg man with post operative SIADH, having
received 2 liters of “normal saline”
• Normal 0.9% saline as we know contains 154mEq of Na
• Therefore, 2 litres of saline would contain 308 mEq of Na
• Incase of SIADH, the urine is concentrated, let’s say Urine Na
concentration is 308 mEq/L
• Now he passes 1 liter of urine, excreting all of the sodium in 2
LITER drips of “saline”
• NET EFFECT IS 308 mEq of Na given and 308 mEq of Na
excreted!
• Worse still we have ADDED 1 liter of solute free water, further
decreasing the serum Na by 5 mEq/L
• Intracellular Na moves into the ECF
• Extracellular Chloride moves intracellular with K
• increased cellular osmolality promotes free water entry into the
cells
• Correcting K from 2 to 4 mEq/L can correct Na by almost 10
mEq/L
1. Restoration of EU-volemia in HYPO-volemic patients; results in
suppression of ADH (half-life about 15 min)
2. Glucocorticoids in addison’s
3. Stopping offending drug that can cause SIADH (SSRI,
carbamazepine, desmopressin)
4. Stopping HCTZ
5. Resolution of ADH stimuli (surgical stress, nausea, pneumonia)
6. Treatment with ADH-antagonists
• Serum Na (every 2-3 hours)
• In acute setting, usually NOT needed if the cause is APPARENT
in history/exam (marathon runner presenting with symptomatic
hyponatremia)
• Like recent initiation of HCTZ, stigmata of CLD, CCF,
hypothyroid, beer potomania
• SERUM OSMOLALITY
• URINE OSMOLALITY
• URINE SODIUM (40-220mEq/L)
• Optional tests for thyroid and adrenal function
• Serum OSMOLALITY is usually calculated
• Measured OSMOLALITY sometimes needed TO EXCLUDE RARE
CASES OF pseudohyponatremia
(hyperlipidemia/hypergamaglobulinemia)
• Serum Na falls by 1 meq/L for every 62 mg/dL rise in the
serum glucose concentration
1. Treat underlying cause
2. Free water restriction (50% negative water balance)
3. Oral or IV NaCl
4. Vasopressin antagonists
• Simple calculation can tell if fluid restriction alone would raise
the sodium
• Ratio of Urine (Na+K)/serum Na
• < 0.5 predicts rise in serum Na
• >1 suggests that fluid restriction alone won’t raise Na
• Loop diuretics and HTS may help in rapidly correcting Na in
acute settings
• Calculate Na Deficit
• TBW x (desired Na – actual Na)
• Example:
• A 70kg male with serum Na 114, plan to correct Na by 6
mEq/L
• 0.6 x 70 x (120-114) = 252 mEq
• Clinically judge the ECF (eu/hypo/hyper)
• History (acute <48 hours or chronic > 48 hours)
• Decide speed and method of correction
• Always consult senior on-call if acute hyponatremia
(symptomatic) - don’t be too shy to ask for help!
• Decide to give HTS or not
• Predict the rate of correction with ADROGUE-MADIAS formula
• Goal in Chronic hyponatremia should be to correct Na by NOT
MORE THAN 6 mmols/L over 24 hours
• Calculate Na loss in urine:
• Spot Urine Na
• Example:
• In the same patient, we found urine spot Na of 35 mmol/L and
he passes 1.5 liters of urine daily; therefore his Na lost via urine
would be 1.5 x 35 = 52.5mmols/day
• Add this to 252 mmol deficit that needs correction over next 24
hours = 304.5 mmols
• Keep in mind that as soon as ADH shuts off, patient would start
making dilute urine (Uosm <100) and Na correction could
potentially overshoot the intended target!
• calculate the rate of infusion:
• rate of infusion = deficit/infusate(conc./ml)/hours
• for example:
• 304mEq/0.513mmol/24 = 24 ml/h
• 0.513 mmol/ml in HTS (1000ml contains 513mEq
NaCl)
• Produce “selective” water diuresis
• They also increase thirst, which may limit their use and prevent
rise in Na
• Tolvaptan, Conivaptan
• Tolvaptan may raise LFTs
• Conivaptan may increase risk of variceal bleeding, and
development of HRS in cirrhotics
• Reduces cerebral edema, specially in cases of acute
symptomatic hyponatremia (marathon runners)
• 100ml should increase Na by 2 to 3 mEq/L
• Repeat if necessary with 10 minute intervals
• Symptomatic hyponatremia corrected by 4 to 6 mEq/L can
reverse severe neurologic sx like seizures
• Use especially if initial Na 120 or less and corrected by over
10 mEq/L over 12 to 24 hours (even absence of ODS
symptoms)
• Beneficial even AFTER development of ODS!
• Rate of relowering should be 1mEq/L/hour
• 5% dextrose infusions (6 mL/kg, infuse over 2 hours,; this
reduced Na by about 2 mEq; repeat until goal reached)
• Desmopressin (2 mcg IV or SQ q6H; taper slowly or Na can
rapidly shoot again)
• Minocycline (thought to be neuroprotective in ODS in animal
studies)
• There are a few case studies suggesting that aggressive
plasmsapheresis therapy may have a role in reversing clinical
ODS (without improving MRI findings)
• 27 yo male 4 month post LRRTx
• 66 kg
• Serum Na drop from 138 to 119 over less than 48 hours
• clinically euvolemic
• No change in creatinine (1.4)
• Na 119 Urea 41 Glucose100
• Urine Osm 143
• Spot Na 42, spot K 12.7
1. HTS
2. normal saline
3. tolvaptan
4. free water restriction
5. lasix
6. demeclocycline/minocycline
7. dialysis!
8. all of the above
• Calculated serum osmolality = 255
• Na deficit = 66 x 0.6 (6) = 39.6 x 6 = 237.6 mEq
• Urine Na + K/serum Na ratio = 54.7/119 = 0.45
• Na rises to 123 mEq within 24 h with free water restriction!