1. Seizures
2. Coma
3. Death

1. Osmoreceptors in the hypothalamus (primary mechanism)
2. Low pressure baroreceptors in the right atrium and great veins
3. High pressure baroreceptors in the carotid sinus

1. ADH

Binds to V2 receptors on renal tubular cells which stimulates a series of metabolic reactions resulting in insertion of aquaporins into renal tubular cells

2.  Thirst

Located in hypothalamus

• ADH is released and thirst is stimulated when plasma osmolality increases (becomes hypertonic) by > 1-2%
• Combination of increased oral intake (thirst) and decrease water excretion (ADH) results in a decrease in SOsm (Total Body Water increases)

• The Effective Arterial Blood Volume (EABV) -- the vascular component responsible for organ perfusion -- decreases by 5-10%
• Decreased EABV triggers baroreceptors which activates the Renin-Angiotensin-Aldosterone System
• Angiotensin II stimulates both non-osmotic release of ADH and thirst
• Volume status overrides osmotic inhibition of ADH release
• Conservation of water fosters restoration of blood pressure and EABV at the expense of hypo-osmolality

Clinical Presentation for Hyponatremia:

If it is rapid -

Clinical Presentation for Hyponatremia:

If it is transient -

• Cerebral adaptation occurs
• neurons adapt to increased cell volume by transporting K+ and other osmotically active solutes out of the cell
• water then shifts from the neurons to the ECF until osmotic equilibrium is achieved -- this results in reduced neuronal cell volume and prevents cerebral edema

• SOsm 275-290 mOsm/L
• occurs with hyperlipidemia or hyperproteinemia
• seldom occurs with current lab setting

• Excess of effective osmoles in the ECF other than Na+
• this leads to water diffusion from ICF to ECF and a relative dilutional hyponatremia
• No change in total SNa but excess water is secondary to effective osmoles other than Na

1. Hyperglycemia
2. Mannitol - can increase tonicity but shifts water into intravascular space

1. Hypovolemic
2. Euvolemic
3. Hypervolemic

1. Inappropriate fluid replacement
2. Diuretic-induced
3. Adrenal insufficiency

• most patients with ECF contraction lost fluids that are hypotonic relative to plasma (diarrhea, excessive sweating, diuretics) that leads to a hypovolemic condition
• this hypovolemia is usually in combination with a transient hypernatremic hypertonic state which stimulates ADH and thirst (osmotic stimulation)
• If additional Na and water loss continues, then additional ADH is released in response to hypovolemia (non-osmotic stimulation)
• patients who drink hypotonic fluids or who are given hypotonic fluids IV can develop hyponatremia from ADH induced water retention
• The problem arises because Na in ECF is not replenished well

• ECF volume depletion leads to non-osmotic stimulation of ADH
• In addition, thiazides interfere with urinary dilution and water excretion by blocking tubular Na and K reabsorption in the distal tubule
• Water is retained in excess of Na by virtue of ADH and there is a high Na and K urine loss

• < effect than thiazide diuretics
• shorter t_1/2 and thus less non-osmotic stimulation of ADH as patients can replete the urinary Na and water losses between doses
• In addition, loops interfere with both urinary dilution and concentration leading to less water reabsorption in the presence of ADH

• Lack of mineralocorticoid activity (aldosterone) leads to renal Na wasting
• Water follows Na leading to ECF volume depletion and non-osmotic stimulation of ADH

• Presents when water intake exceeds water loss (net water gain) with normal to slightly decreased ECF Na+ concentrations
• Increased ECF volume usually is not enough to cause pulmonary edema or peripheral edema and thus patient appears euvolemic

1. Increased release of ADH via non-osmotic and/or non-physiologic or pathologic processes

OR

2.  Enhanced renal sensitivity to ADH

1. CNS disorders
2. Pituitary surgery
3. ADH secreting tumors
4. Pulmonary disease
5. SSRIs
6. Methylenedioxymethamphetamine "Ecstasy"

1. Carbamazepine
2. NSAIDs
3. Cyclophosphamide
4. Chlorpropamide

• Both renal sodium and water elimination are impaired
• Patients have an exanded ECF but this is primarily in the ISF leading to signs of volume overload (peripheral and pulmonary edema)
• However, patients have a diminished EABV leading to a non-osmotic stimulation of ADH
• Think "low protein, lack of oncotic pressure"

1. CHF
2. Cirrhosis
3. Nephrotic Syndrome

Never correct > 12 mEq/L

• this is necessary to prevent demyelinating brain injury and death
• an acute correction can lead to a rapid decrease in neuronal cell volume and demyelinating brain injury
• patients who have a significant degree of cerebral adaptation are at greatest risk
• Usually manifests 5-7 days after therapy by paralysis or coma

1. Free water restriction
2. IV hypertonic saline administration
3. Identify and correct underlying cause if possible

1. Treat aggressively until severe symptoms resolve
2. Treat to serum Na+ of 120-130 mEq/L
3. If initial Na < 105 mEq/L, then use lower initial serum Na goal

Initial correction should not be > 135 mEq/L and should definitely not exceed 145 mEq/L

1-2 mEq/L/hr

Max rate of correction = 12 mEq/L/day

• For the majority of severe symptomatic cases (CNS disorders (lethargy, seizures, coma))
• It should NOT be administered if patient is hypovolemic

• In cases of hypovolemia
• Use NaCl 0.9% until patient is euvolemic

• Rapid correction is not required
• Treatment is dependent on underlying etiology
• Correction occurs over at least 2-3 days

No faster than SNa 0.5 mEq/L increase per hour

Max correction: 12 mEq/L per day

Isotonic fluid resuscitation with 0.9% NaCl

• Increasing ECF will decrease non-osmotic ADH stimulation by replacing intravascular volume and decreasing intravascular baroreceptors stimulation
• Decreased ADH release will then decrease free water reabsorption through aquaporins

Free water restriction = 500-1000 ml/day

this is primary therapy

1. Demeclocycline
2. Lithium Carbonate
3. Conivaptan

Asymptomatic Hyponatremic and/or slow/chronic onset: SIADH (euvolemic hypotonic hyponatremia)

Limitations: nephrotoxicity

Asymptomatic Hyponatremic and/or slow/chronic onset: SIADH (euvolemic hypotonic hyponatremia)

Must monitor levels closely (toxic > 1.5)

Asymptomatic Hyponatremic and/or slow/chronic onset: SIADH (euvolemic hypotonic hyponatremia)

• Vasopressin receptor antagonist
• IV ONLY!

Limited clinical data available

• Treat underlying condition (i.e. CHF, liver, nephrotic syndrome)
• Free water restriction (1000-1500 ml/day)
• Diuresis with loop diuretics

• Check SNa q 2-4 hrs until patient asymptomatic and stable
• Once patient asymptomatic -- check SNa levels q 4-8 hrs until SNa is within normal range
• Check for signs and symptoms continuously

• Check SNa q 12-24 hrs initially while patient in hospital
• Outpatient SNa monitoring at follow-up visits
• If Conivaptan therapy -- check more frequently initially q 6-8 hrs while patient on infusion

• Reflects a water deficit relative to total body Na levels
• Always associated with hypertonicity
• Most commonly seen in patients 1) with impaired thirst response and 2) wihtout access to water

1. Lack of water intake
2. Loss of hypotonic fluids w/o proper replenishment
3. Diarrhea
4. Extreme sweating
5. Ventilated patients
6. Febrile patients
7. Osmotic diuresis (hyperglycemia, mannitol)
8. Diabetes Insipidus

1. Hyperglycemia

Renal glucose spill-over due to serum glucose levels exceeding renal threshold for glucose

Glucose is additional effective osmoles in renal tubules --> pulls water into tubules and increases water excretion w/o Na loss

2.  Mannitol

Hypertonic sol'n that is cleared renally

Creates hypertonic urine and pulls water into the renal tubules, preventing free water absorption by the kidney

Fluid loss is often exacerbated by loop diuretics when used in combo to treat cerebral edema

1. Idiopathic
2. brain tumor
3. head trauma
4. cerebral edema
5. CNS infection
6. Hypothalamic injury
7. Psychological stress
8. Medications (ethanol, morphine, chlorpromazine, phenytoin)

1. Idiopathic
2. Pregnancy
3. Renal Disease
4. Medications (lithium carbonate, demeclocycline)

Never correct > 12 mEq/L

• this is necessary to prevent demyelinating brain injury and death
• an acute correction can lead to a rapid decrease in neuronal cell volume and demyelinating brain injury
• patients who have a significant degree of cerebral adaptation are at greatest risk
• Usually manifests 5-7 days after therapy by paralysis or coma

• Isotonic fluid (0.9% NaCl or LR) until hemodynamically stable
• THEN - hypotonic fluids (D5W or 0.45% NaCl) to replace remaining fluid deficits