Sodium Disorders: Hyponatremia

William Harper, MD, FRCPC

Endocrinology & MetabolismAssistant Professor of Medicine

McMaster University

PNa (mEq/L)130 135 140 1450

5

ADH(pM)

Thirst↓ ECFv

Normal Serum [Na] (135-145 mEq/L) Closely Guarded

1) Complete DI2) Defective osmoreceptor, normal AVP release to ECFv contraction3) High-set osmoreceptor: AVP release is sluggish/delayed4) AVP release at normal Posm but subnormal in amount

What is Appropriate Urine Concentration?

Osmolality

• Plasma Osmolality:Posm = 2 (Na) + glucose + ureaNormal = 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

HyponatremiaSerum OSM

Low Normal High

HypotonicHyponatremia

ECFv *

LowNormal High

HyperglycemiaMannitol

Marked hyperlipidemia(lipemia, TG >35mM)Hyperproteinemia(Multiple myeloma)

•CHF•Cirrhosis•Nephrosis

•Hypothyroidism•AI•SIADH•Reset Osmostat•Water Intoxication 1° Polydipsia TURP post-op

Renal loss (UNa > 20)•Diuretics

•Thiazide•K-sparing

•ACE-I, ARB•IV RTA, Hypoaldo• Cerebral salt wasting

Extra-renal loss (UNa <10)•Bleeding•Burns•GI (N/V, diarrhea)•Pancreatitis

*Note: all have ↑ADH•SIADH: inappropriate•Rest: appropriate

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)

SIADHDiagnosis• 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 DisordersHypernatremia

William Harper, MD, FRCPC

Endocrinology & MetabolismAssistant Professor of Medicine

McMaster University

Diabetes Insipidus

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

Polyuria: > 3 L/d + Polydipsia: > 3.5 L/d

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

1) Complete DI2) Defective osmoreceptor, normal AVP release to ECFv contraction3) High-set osmoreceptor: AVP release is sluggish/delayed4) AVP release at normal Posm but subnormal in amount

What is Appropriate Urine Concentration?

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 Chicken or the Egg? (Egg)

The Polyuria or the Polydipsia?

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

1 6 11 POD #

50

100

150

PNa(mEq/L)

50

100

400

U/O(cc/h)

U/O #1

U/O #2

1 6 11 POD #

50

100

150

PNa(mEq/L)

50

100

400

U/O(cc/h)

Na #1

U/O #1

1 6 11 POD #

50

100

150

PNa(mEq/L)

50

100

400

U/O(cc/h)

Na #2

U/O #2

1 6 11 POD #

50

100

150

PNa(mEq/L)

50

100

400

U/O(cc/h)

Na #1

Na #2U/O #1

U/O #2

#1 DI#2 Normal

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)