Sodium Disorders:
Hyponatremia
William Harper, MD, FRCPC
Endocrinology & Metabolism
Assistant Professor of Medicine
McMaster University
Normal Serum [Na] (135-145 mEq/L) Closely Guarded
ADH
(pM)
↓ ECFv
Thirst
5
0
130
135
140
145
PNa (mEq/L)
What is Appropriate Urine Concentration?
1)
2)
3)
4)
Complete DI
Defective osmoreceptor, normal AVP release to ECFv contraction
High-set osmoreceptor: AVP release is sluggish/delayed
AVP release at normal Posm but subnormal in amount
Osmolality
• Plasma Osmolality:
Posm = 2 (Na) + glucose + urea
Normal = 2 (140) + 5 + 5 = 290 (275-290 mM)
• Urine Osmolality:
• Normal: 400-500 mM
» Maximal dilution 50-100 mM (USG 1.002-1.003)
» Maximal concentration 900-1200 mM (USG 1.030-1.040)
• Concentrated Urine: > 500 mM (at least!), USG > 1.017
i.e. UOSM > POSM is not enough to R/O Diabetes Insipidus
Urine Specific Gravity USG
• Estimates solute concentration of urine on basis of weight as compared
with an equal volume of distilled water
• Normal Posm is 0.8-1.0% heavier than water so PSG = 1.008-1.010
• Each ↑ in UOSM 30-35 mM ↑ USG by 0.1% (0.001)
• Therefore, USG of 1.010 ~ UOSM 300-350 mM
• Larger MW urinary OSM (glucose, radiocontrast, carbenicillin) if
present will falsely elevate USG
• Nothing falsely lowers USG
Hyponatremia
Serum OSM
Low
Hypotonic
Hyponatremia
Normal
High
Marked hyperlipidemia
(lipemia, TG >35mM)
Hyperproteinemia
(Multiple myeloma)
Hyperglycemia
Mannitol
*Note: all have ↑ADH
•SIADH: inappropriate
•Rest: appropriate
ECFv *
Low
Renal loss (UNa > 20)
Extra-renal loss (UNa <10)
•Diuretics
•Bleeding
•Thiazide
•Burns
•K-sparing
•GI (N/V, diarrhea)
•ACE-I, ARB
•Pancreatitis
•IV RTA, Hypoaldo
• Cerebral salt wasting
Normal
•Hypothyroidism
•AI
•SIADH
•Reset Osmostat
•Water Intoxication
1° Polydipsia
TURP post-op
High
•CHF
•Cirrhosis
•Nephrosis
Rx Hyponatremia
• Na deficit = 0.6 x wt(kg) x (desired [Na] - actual [Na])
(mmol)
• When do you need to Rx quickly?
– Acute (<24h) severe (< 120 mEq/L) Hyponatremia
• Prevent brain swelling or Rx brain swelling
– Symptomatic Hyponatremia (Seizures, coma, etc.)
• Alleviate symptoms
• “Quickly”: 3% NS, 1-2 mEq/L/h until:
• Symptoms stop
• 3-4h elapsed and/or Serum Na has reached 120 mEq/L
• Then SLOW down correction to 0.5 mEq/L/h with 0.9%
NS or simply fluid restriction. Aim for overall 24h
correction to be < 10-12 mEq/L/d to prevent myelinolysis
Rx Hyponatremia (Example)
• Na deficit (mmol) = 0.6 x wt(kg) x (desired [Na] - actual [Na])
•
•
•
•
•
•
•
60 kg women, serum Na 107, seizure recalcitrant to benzodiazepines.
Na defecit = 0.6 x (60) x (120 – 107) = 468 mEq
Want to correct at rate 1.5 mEq/L/h: 13/1.5 = 8.7h
468 mEq / 8.7h = 54 mEq/h
3% NaCl has 513 mEq/L of Na
54 mEq/h = x
513 mEq
1L
x = rate of 3% NaCl = 105 cc/h over 8.7h to correct serum Na to 120 mEq/h
• Note: Calculations are always at best estimates, and anyone getting
hyponatremia corrected by IV saline (0.9% or 3%) needs frequent
serum electrolyte monitoring (q1h if on 3% NS).
Rx Hyponatremia
• Rx slowly (correct < 0.5 mEq/L/h, 10-12 mEq/L/d)
– Symptomatic/Acute: rapid Rx has resolved symptoms and brought
serum Na up to 120 mEq/L
– Asymptomatic, mild, chronic hyponatremia
– Want to prevent myelinolysis
• Increased risk: Women, alcoholics, malnourished
• ECFv contracted
• Bolus NS until BP, HR, JVP stable
• Then correct slowly with 0.9% NS or po salt
• ECFv Normal or ECFv Overloaded
• Fluid Restriction alone (exception: SAH, HI, post-neurosurgery)
• i.e. they do NOT need any IV or po salt!
SIADH Ddx
•
•
•
•
•
•
•
Intracranial disease
Pulmonary disease
Chest wall disorder (surgery, VZV)
Severe pain or emotional distress
Severe N/V
Ectopic ADH: Small cell lung cancer
Drugs: opiods, carbamazepine, chlorpropamide,
cyclophosphamide, cisplatin, vincristine, vinblastine,
amitriptylline, SSRI, neuroleptics, bromocriptine, ecstasy
(MDMA)
SIADH
Diagnosis
•
•
•
•
•
Normal ECFv (or slightly increased)
Hypothyroidism & AI ruled out
↓ serum Na/OSM
UOSM > 100 mM, UNa > 40 mEq/L
Low plasma uric acid (< 238 umol/L)
Treatment
•
•
•
•
•
•
Fluid Restriction
Oral Salt, Hi-protein diet or Urea(30 g/d): promote solute diuresis
Lasix 20 mg po od-bid: Loop direct diminishes medullary gradient
Demeclocycline 300-600 mg bid (can be nephrotoxic)
Lithium (induces NDI)
IV salt solution:
• Rarely if ever needed (i.e. only if symptomatic with SZ/coma)
• Solution given must be of greater OSM than UOSM or in long run will just
make hyponatremia worse (often IV NS not sufficient)
SIADH: Example
• UOSM fixed 600 mM due to ADH action
• 1L NS given: 300 mM (154 mM each of Na and Cl)
• All sodium will be excreted as renal sodium handling is intact in
SIADH.
• 300 mmoles of osmols given excreted in 500cc urine
(300mmoles/500mL = 600 mM)
• Therefore net gain of 500 cc free water!
• 1L 3% saline given: 1026 mmoles
• Excreted in 1.7L to keep UOSM 600 mM
• Therefore net loss of 700 cc free water!
• NOT advocating use of any IV NS (0.9% or 3%) in SIADH unless
absolutely neccesary (i.e. SZ, coma). Most SIADH hyponatremia is
chronic and should be corrected slowly with fluid restriction ONLY.
Reset Osmostat
• 25-30% of circumstances which cause SIADH
• Downward resetting of the threshold for both ADH release
and thirst.
• Mild asymptomatic hyponatremia (Na 125-135 mEq/L)
• Distinguish from SIADH by observing response to water
load (10-15 mL/kg po or IV)
• Normal subjects and those with reset osmostat will secrete
the entire water load over 4h without any worsening of the
hyponatremia
• Attempts to correct hyponatremia in reset osmostat are not
needed and will cause severe thirst
Cerebral Salt Wasting
• Cerebral disease (particularly SAH)
• Mimics SIADH with hyponatremia except primary defect
is salt wasting not water retention.
• Circulating factor which impairs renal tubular fn.
• Atrial natriuretic peptide?
• Brain natriuretic peptide?
• Endogenous ouabain?
• Plasma urate variable (normal or even lower than SIADH)
• Treatment is NS to correct ECFv contraction
SIADH v.s. Cerebral Salt Wasting
SIADH
CSW
Serum Na
↓
↓
ECFv
Normal
↓
UNa
↑
↑↑
UOSM
↑
↑
Urine volume
N or ↓
↑
Serum urate
↓
N or ↓
Urine urate
↑
N or ↑
Rx Hyponatremia: acute SAH/Head injury
• May have SIADH, CSW or Both!
• Often difficult to tell which
• Fluid restriction inappropriate for CSW as may exacerbate
ECFv contraction and precipitate cerebral vasospasm and
subsequent cerebral infarction
• IV NS inappropriate for SIADH if UOSM > 300 mM (will make
hyponatremia worse)
• Rx with IV NS:
• Start with 0.9% NS (as per hypervolemic therapy to prevent cerebral
vasospasm)
• If hyponatremia worsens on 0.9% NS (due to an SIADH component
to hyponatremia) consider switch to 3% NS
• Goal: 0.5 mEq/L/h (only if symptomatic 1-2 mEq/L/h)
• Fludrocortisone
• 0.1-0.4 mg/d
• May also be beneficial in recalcitrant cases to alleviate CSW.
Indications for 3% NaCl
• Symptomatic hyponatremia (SZ, coma)
• Acute severe hyponatremia (<24h, < 120 mEq/L)
• SAH with hyponatremia worsening on 0.9% NaCl
Sodium Disorders
Hypernatremia
William Harper, MD, FRCPC
Endocrinology & Metabolism
Assistant Professor of Medicine
McMaster University
Diabetes Insipidus
Polyuria: > 3 L/d
+
Polydipsia: > 3.5 L/d
Ddx
• Diabetes Mellitus
• Hypercalcemia
• Solute diuresis:
» Volume expansion 2° saline loading
» High-protein feeds (urea as osmotic agent)
» Post-obstructive diuresis
• Diabetes Insipidus:
» Central (CDI)
» Nephrogenic (NDI)
• Primary (Psychogenic) Polydipsia
Diabetes Insipidus Ddx
Central (CDI)
• Idiopathic
– autoimmune
• Neurosurgery, head trauma
• Cerebral hypoperfusion
• Tumor
– Craniopharyngioma, pituitary
adenoma, suprasellar
meningioma, pineal gland,
metastasis
• Infiltration
– Fe, Sarcoid, Histiocytosis X
•
•
•
•
•
•
Nephrogenic (NDI)
X-linked recessive
Hypokalemia
Hypercalcemia (2° to HPT in
particular)
Renal disease: after ATN,
postobstructive uropathy, RAS,
renal transplant, amyloid,
Sickle cell anemia
Sjogren’s
Drugs:
– Lithium, 20% of chronic users
– Demeclocycline, amphotericin,
colchicine
What is Appropriate Urine Concentration?
1)
2)
3)
4)
Complete DI
Defective osmoreceptor, normal AVP release to ECFv contraction
High-set osmoreceptor: AVP release is sluggish/delayed
AVP release at normal Posm but subnormal in amount
Diabetes Insipidus
• Intact thirst & access to water
•
•
•
•
Hi-normal serum sodium (142-145 mEq/L)
Polydipsia (crave cold fluids)
Polyuria, Nocturia  sleep disturbance
1° treatment is pharmacological
• Impaired thirst or access to water:
• Hypernatremia
• Insufficiently concentrated urine
• 1° treatment is free water (enteral or IV D5W)
Diabetes Insipidus
• Healthy out-patients
• DI with Intact thirst or access to water
• Hi-normal serum sodium (142-145 mEq/L)
• Polydipsia (crave cold fluids)
• Polyuria, Nocturia  sleep disturbance
• 1˚ Psychogenic Polydipsia
• Low-normal serum sodium (135-137 mEq/L)
• Anxious middle-aged women
• Psychiatric illness, phenothiazine (dry mouth)
1˚ Polydipsia
1˚ Polydipsia: “What came first?”
The Polyuria or the Polydipsia?
The Chicken or the Egg? (Egg)
Water Deprivation Test
• Hold water intake for 2-3h prior to coming in.
• Continue to hold water & Monitor:
• Urine volume, UOSM q1h
• Serum Na, OSM q2h
• If serum OSM/sodium do not rise above normal ranges &
UOSM reaches 600  1˚ Polydipsia
• If serum OSM reaches 295-300 mM & UOSM doesn’t ↑
• Diabetes Insipidus established
• Endogenous ADH should be maximal, check serum ADH
– 2 green rubber stopper tubes, pre-chilled, on ice, need biochemist
• Give DDAVP 10 ug IN
– CDI: UOSM ↑ by 100-800% (complete CDI), ↑ by 15-50% (partial CDI)
with absolute UOSM > 345mM
– NDI: UOSM ↑ by up to < 9%, sometimes ↑ as high as 45% but absolute
UOSM always < isotonic (290 mM)
Diabetes Insipidus
• Back to in-patients!
• Impaired thirst or access to water
• Elevated serum sodium/OSM
• UOSM < 500 mM, USG < 1.017
• If serum sodium/OSM not elevated
• Not DI!
• UOSM and USG are irrelevant
Pituitary Surgery
• Triphasic response to surgery
• Phase 1: DI
• Axonal injury 2° surgery/swelling
• Begins after POD #1 (pre-existing DI can occur earlier)
• Lasts 1-5d
• Phase 2: SIADH
• Axonal necrosis of AVP secreting neurons with uncontrolled
AVP release
• Lasts 1-5 days
• Phase 3: DI
• Axonal death with cessation of AVP production
• Usually permanent
PNa
U/O
(mEq/L)
(cc/h)
400
150
U/O #1
100
100
50
U/O #2
1
6
11
POD #
50
PNa
U/O
(mEq/L)
(cc/h)
Na #1
400
150
U/O #1
100
100
50
50
1
6
11
POD #
PNa
U/O
(mEq/L)
(cc/h)
400
150
Na #2
100
100
50
U/O #2
1
6
11
POD #
50
#1 DI
#2 Normal
PNa
(mEq/L)
Na #1
U/O
(cc/h)
400
150
Na #2
U/O #1
100
100
50
U/O #2
1
6
11
POD #
50
Treatment of DI
• Rx Dehydration
• NS initially if ECFv contraction
• Then IV D5W or enteral free water to lower serum [Na]
» 1-2 mEq/h if Na > 160, symptomatic (coma, SZ), acute
» Otherwise 0.5-1.0 mEq/h
• Insensible losses? (0.5 L/d)
• Do NOT replace U/O if giving DDAVP
• DDAVP (Desmopressin)
• Reduces U/O and therefore simplifies fluid therapy
• Long t½: duration 8-12h, up to 24h
• Therefore use judiciously
» DDAVP 1ug IV/SC x 1
» Only repeat if breaks-thru again (i.e. becomes
hypernatremic with dilute polyuria)
» Once nasal mucosa stable can switch to intranasal
» Also oral form DDAVP now available
DDAVP: 1ug IV/SC = 10 ug IN = 0.1 mg PO
Treatment of DI
• AVP, Aqueous vasopressin (Pitressin)
• Only parenteral form, 5-10 U SC q2-4h
• Lasts 2-6h
• Can cause HTN, coronary vasospasm
• Chlorpropamide (OHA which stimulates AVP secretion)
• 100-500 mg po OD-bid
• Only useful for partial DI, can cause hypoglycemia
• HTCZ (induces volume contraction which diminishes free water excretion)
• 50-100 mg OD-bid
• Mainstay of Rx for chronic NDI
• Amiloride (blunts Lithium uptake in distal tubules & collecting ducts)
• 5-20 mg po OD-bid
• Drug of choice for Lithium induced DI
• Indomethacin 100-150 mg po bid-tid (PGs antagonize AVP action)
• Clofibrate 500 mg po qid (augments AVP release in partial CDI)
• Tegretol 200-600 mg po od (augments AVP release in partial CDI)