Hyponatremia and Hypernatremia

Question 1

Hyponatremia and hypernatremia are common clinical problems

Answer 1

• Although the serum Na+ level is abnormal, these clinical syndromes reflect an abnormality in water balance
• May or may not be accompanied by changes in Na+ balance

Question 2

Total Body Water

Answer 2

1. Total Body Water (TBW): Percentage of lean body weight (varies with age)
   a. ~60% of weight in men, 50% of weight in women
   b. TBW is higher in infants and toddlers, lower in elderly (decreased muscle mass) and obesity
2. TBW is subdivided into 2 compartments
   a. Intracellular fluid (ICF): Contains 2/3 of TBW
   b. Extracellular fluid (ECF): Contains 1/3 of TBW
3. The ECF is further subdivided into 2 compartments
   a. Intravascular fluid: Contains ¼ of the ECF
   b. Interstitial fluid: Contains ¾ of the ECF
4. Example: a lean man weighing 80Kg has a TBW of 48Kg or 48L, 32L of which are in the ICF, 16L in the ECF. His intravascular fluid contains 4L of water while the interstitial fluid contains 12L

Question 3

Osmolarity

Answer 3

1. Plasma osmolality (Posm): determined by the ratio of plasma solutes and plasma water
2. Majority of plasma solutes are sodium salts followed by a lesser contribution from other ions (potassium and calcium), glucose and urea.
3. Normal Posm = 275-290 mosmol/Kg
4. Glucose and urea contribute only a small amount to the Posm when they are within normal range a. Posm can be influenced greatly when glucose is markedly elevated (uncontrolled diabetes mellitus) or in reduced renal function (elevated urea)

Question 4

Tonicity

Answer 4

1. Plasma tonicity = Effective plasma osmolality
2. Parameter sensed by osmoreceptors and determines the transcellular distribution of water
3. Water can cross almost all cell membranes freely and moves from areas of lower tonicity (high water content) to high tonicity (lower water content)
4. Difference between plasma tonicity and osmolality

• Plasma tonicity reflects concentration of solutes that do NOT easily cross cell membranes (i.e. most sodium salts) and thus affects distribution of water between cells and ECF
• Plasma osmolality includes the osmotic contribution of urea (an ineffective osmole since it moves across the cell membrane and has little effect on water movement across the cell membrane). Ethanol is another osmole that enters cells rapidly and thus has no tonicity

Question 5

Water Balance: Obligate Osmolar Excretion

Answer 5

1. Obligate osmolar excretion: Amount of osmoles which need to be removed by the kidney in order to maintain osmolar homeostasis.
2. Obligate osmolar excretion is dependent on the dietary intake
   a. Basal metabolism (fasting) - approximately 7 mosmol/kg/day
3. Normal individuals can dilute urine to 50 mosmol/L and concentrate to 1000 mosmol/L
4. This allows a range of urine output of 7 ml/kg/day to 140 ml/kg/day
   a. This capacity allows us to accomplish both osmolar and water balance simultaneously

Question 6

Proximal Tubule

Answer 6

•reclaims most of water and electrolytes which are filtered through the glomerular basement membrane and maintains urine as iso-osmotic fluid (same osmolarity as plasma, about 300 mOsm/L)

Question 7

Thick Ascending Limb

Answer 7

•reabsorbs Na+, K+ and Cl- and generates osmotic gradient in the medulla in association with vasa recta (countercurrent multiplication mechanisms)

Question 8

Distal Tubule

Answer 8

•The distal convoluted tubule and early collecting duct reabsorb more Na+ and Cl- and generate diluted urine

Question 9

Collecting Duct

Answer 9

•The collecting duct determines the production of concentrated or diluted urine depending on the presence or absence of vasopressin (AVP/ADH)

Question 10

. Requirements for Excretion of Maximally Dilute Urine

Answer 10

To excrete significant free water (i.e., urine with an osmolality as low as 50-75 mOsmol/kg H2O), the following are needed:

1. Delivery of solute and water to diluting sites
2. Proper function of the diluting segment
3. AVP/ADH must be absent for the collecting duct to be impermeable to water

Question 11

Decrease in delivery of solute and water to diluting sites…

Answer 11

1. Renal failure (decreased glomerular filtration) decreases delivery of solute to the diluting sites.
2. Volume depletion or effective intravascular volume depletion (e.g., congestive heart failure, cirrhosis, and nephrotic syndrome), proximal tubular sodium and water reabsorption are increased, decreasing distal delivery of solute and water

Question 12

Decreased proper function of the diluting segment…

Answer 12

1. Osmotic diuretics (i.e. Mannitol) prevent dilution because they cannot be reabsorbed by the thick ascending limb
2. Loop diuretics block dilution of the urine by inhibiting Na/K/2Cl cotransporter

Question 13

Presence of ADH/Vasopressin…

Answer 13

The presence of ADH will cause reabsorption of water by insertion of aquaporin (water) channels creating concentrated urine

Question 14

. Requirements for Excretion of Maximally Concentrated Urine

Answer 14

To retain significant free water (i.e. maximally concentrate the urine to 1000- 1200 mOsmol/Kg), the following are needed:

1. Development of a concentrated medullary interstitium by solute reabsorption n the thick ascending limb of the Loop of Henle
2. Presence of AVP/ADH to stimulate insertion of aquaporin channels into the apical membranes of collecting duct cells
3. Ability of collecting duct cells to respond to ADH/AVP by insertion of aquaporin channels

Question 15

Hyponatremia

Answer 15

• too much water
• can exist at any level of total body sodium

Question 16

Hypernatremia

Answer 16

• too little water
• can exist at any level of total body sodium

Question 17

Definition and Epidemiology of Hyponatremia

Answer 17

1. Serum Na+ <135 mEq/L
2. Results from the intake and subsequent retention of water
3. Patients who develop hyponatremia typically have an impairment in renal water excretion
4. Prevalence ~ 2.5% of hospitalized patients with 2/3 acquired during hospitalization
5. Mortality 60-fold increased in this population (hyponatremia is a marker rather than a cause)
6. About 97% of hospitalized hyponatremia is due to nonosmotic release of AVP

Question 18

Effects of Hyponatremia on the Brain

Answer 18

1. The brain is most susceptible to the sudden decrease in serum Na+ because it is confined within the rigid skull
2. Acute hyponatremia causes nausea, vomiting, and confusion due to brain edema
3. Severe brain edema leads to seizures, even herniation and death
4. When hyponatremia develops slowly (over several days), the brain cells can adapt by releasing intracellular K+ and Cl- initially; and subsequently, organic osmolytes (myoinositol, amino acids) such that the cell volume is reduced to near normal levels
5. This is the reason why chronic hyponatremia is frequently asymptomatic unless the serum Na+ is very low (i.e. <120 mEq/L)

Question 19

Clinical Approach to Hyponatremia

Answer 19

There are many ways to approach the diagnosis and workup of a patient with hyponatremia. The 2 most important determinants are the plasma tonicity and the patient’s volume status.

Question 20

Hyponatremia - plasma tonicity

Answer 20

• Hypertonic hyponatremia - Posm > 290 mOsmol/Kg
• Isotonic hyponatremia or “Pseudohyponatremia” -Posm = 275-290 mOsmol/Kg
• Hypotonic hyponatremia - Posm <275 mOsmol/Kg
• AVP/ADH levels
  1. Circulating ADH levels are appropriately elevated
  2. Circulating ADH levels are inappropriately elevated
  3. Circulating ADH levels are appropriately suppressed
• Volume status
  1. Hypovolemic hypotonic hyponatremia
  2. Euvolemic hypotonic hyponatremia
  3. Hypervolemic hypotonic hyponatremia

Question 21

Hypertonic Hyponatremia

Answer 21

•Posm > 290 mOsmol/Kg

Results due to presence of another effective osmole that causes free water to move from the intracellular compartment to the ECF resulting in cell dehydration

• Mannitol (osmotic diuretic)
• glycine (nonconductive irrigant solutions)
• marked hyperglycemia (i.e. diabetic ketoacidosis [DKA] or nonketotic hyperglycemia)

•Treatment includes correcting the underlying condition (i.e. treatment of DKA) or removal of the osmotic agent

Question 22

Isotonic Hyponatremia or Pseudohyponatremia

Answer 22

•Results from a laboratory artifact due to marked hyperlipidemia or hyperproteinemia

-Marked elevation in serum lipids or proteins causes a reduction in the fraction of serum that is water and results in an artificially low serum Na+ concentration

•Laboratories that use ion-specific electrodes and direct potentiometry avoid the misdiagnosis of hyponatremia

Question 23

Hypovolemic hypotonic hyponatremia

Answer 23

• Posm <275 mOsmol/Kg
• True volume depletion (low ECF volume).
• Loss of fluid volume (primarily Na+ which is the main cation of the ECF) from the ECF volume which stimulates ADH secretion thereby retaining free water in attempts to restore ECF volume
• Patients appear volume depleted on physical exam (hypotension, flat neck veins, orthostatic)

1. GI losses (stool losses, gastric losses/emesis)
2. Blood losses
3. Increased insensible losses (excessive sweating, burns) • Urine Na+ will be low 20 mEq/L

Question 24

Euvolemic hypotonic hyponatremia

Answer 24

• Posm <275 mOsmol/Kg
• Primary water gain (normal ECF volume).
• This occurs primarily due to excess ADH (inappropriate), excessive water intake (psychogenic polydipsia), or reduced solute intake.
• Patients appear euvolemic on exam

1. SIADH – syndrome of inappropriate secretion of ADH
   - Can be acquired (drugs, pain, CNS disorders, malignancies, pulmonary disorders, post-operative state) or hereditary (rare)
   - Urine Osm will be high due to ADH activity
   - Urine Na+ typically >40 mEq/L due to small volume expansion induced by water (suppresses renin)
2. Primary polydipsia/psychogenic polydipsia.
   - Excessive water intake that overwhelms the excretory capacity of the kidney.
   - Urine Osm is low due to appropriate suppression of ADH
3. Reduced solute intake (beer-drinkers potomania or tea and toast diet.)
   - Results when water intake exceeds daily osmolar load (i.e. if daily osmolar generation and excretion is 240 mosmol of solute per day and the urine can maximally dilute to 60 mosmol/L, then it would take 4L of urine to excrete the daily osmolar load. If one drinks in excess of this, then hyponatremia will ensue.
   - Urine Osm is low
4. Hypothyroidism (mechanism incompletely understood)

Question 25

Hypervolemic hypotonic hyponatremia

Answer 25

• Posm <275 mOsmol/Kg
• ECF volume excess with intravascular volume depletion (low effective circulating volume). These are typically edematous states.

1. Heart failure, liver cirrhosis, nephrotic syndrome
2. ADH is appropriately activated due to low effective circulating volume
3. Urine Osm will be high due to ADH activity, Urine Na+ <20 mEq/L due to intravascular volume depletion and maximal reabsorption of Na+ at the proximal tubule/renin activation

***Advanced renal failure – impaired free water excretion leading to dilutional hyponatremia. The effective plasma osmolality is low but the measured plasma osmolality may be high due to the contribution of urea which accumulates in renal failure

Question 26

Management of Hyponatremia

Answer 26

• In chronic hyponatremia, the Na+ correction should never exceed >8-10 mEq/L in 24 hours to avoid osmotic demyelination syndrome
• If symptomatic with life-threatening seizures, then raising the serum Na+ by ~ 4-6 mEq/L acutely with 3% hypertonic saline is appropriate
• Correction of the intravascular volume with 0.9% normal saline is appropriate for hypovolemic hyponatremia (caution to avoid correcting too quickly; once volume is repleted, the stimulus for ADH will be suppressed and patients can have a brisk water diuresis increasing the serum Na+ quickly)

-Correction of the underlying cause (treatment of hypothyroidism, increasing solute intake for tea and toasters)

•SIADH – correct the underlying cause if identifiable otherwise free water restriction (generally to 1200 ml per day), increase solute intake (if unable to eat enough protein then salt or urea tablets may be added to increase obligate osmolar excretion – and thus water excretion), and can add loop diuretics in efforts to limit the addition of NaCl to the medullary interstitium which is needed in order to maximally concentrate the urine in the presence of ADH

-V2 receptor antagonists (Conivaptan and Tolvaptan are now available but are costly and are not indicated for long-term use)

• Hypervolemic hyponatremia (edematous states) are typically treated with diuretics and fluid restriction

Question 27

Osmotic Demyelination Syndrome

Answer 27

• Chronic hyponatremia is associated with the loss of osmotically active substances (electrolytes and organic osmolytes) which provides protection against cerebral edema.
• The solutes cannot be as quickly replaced when the brain volume begins to shrink in response to correction of hyponatremia (water moving from the ICF to the ECF); as a result, demyelination can occur in areas of the brain that are slowest in reaccumulating osmolytes after rapid correction.
• Risk factors for ODS include…
• duration of hyponatremia ( >2 days)
• correction of Na+ >20 mEq/L within 24h (although has been seen >10 mEq/L)
• low serum Na+ (<120 with increasing risk <105 mEq/L).

Question 28

Definition and Background of Hypernatremia

Answer 28

• Defined as serum Na+ >145 mEq/L
• . Almost always due to loss of free water and less so to administration of hypertonic sodium solutions 3
• Prevalence in intensive care ~ 9% with 7% developing hypernatremia during their hospital course 4
• Normally, the rise in plasma osmolality stimulates the release of ADH (minimize water loss) and thirst leading to increased water intake a

-Even in diabetes insipidus with marked polyuria due to reduced ADH effect, patients maintain a near normal serum Na+ by increasing their water intake from thirst

•Thus, hypernatremia primarily occurs in patients who cannot express thirst normally (i.e. elderly, infants) OR who do not have access to free water (hospitalized patients in the intensive care unit)

Question 29

Dehydration vs. Hypovolemia

Answer 29

•Loss of free water only is referred to as dehydration whereas loss of both sodium and water is referred to as hypovolemia

Question 30

Etiology of Hypernatremia

Answer 30

1. Pure water losses
2. Hypotonic fluid loss
3. Hypertonic sodium gain

Question 31

Hypernatremia - pure water loss

Answer 31

• Pure water losses
• Hypodipsia (decreased thirst)
• Decreased free access to free water
• Insensible losses (dermal and respiratory)
• Diabetes insipidus (DI) – decreased ADH action at the collecting tubule due to either neurogenic (decreased ADH production or release) or nephrogenic (decreased effect on collecting duct).
• Central DI – due to insufficient release of ADH in response to an increased serum Na+ or osmolarity (can be partial or complete impairment of ADH). Due to lesions of the hypothalamic osmoreceptors, supraoptic/paraventricular nuclei, or superior portion of the supraoptichypophyseal tract due to trauma, surgery, or tumors
• Nephrogenic DI (can be partial or complete)– reduced action of ADH at the collecting tubule due to either mutations in the V2 receptor or the aquaporin channel itself or medications (i.e. lithium)

Question 32

Hypernatremia - hypotonic fluid loss

Answer 32

• both Na+ and water losses but the solute concentration (Na+ plus K+) is hypotonic to plasma osmolality.
• If the free water is not replaced (i.e. no access), then hypernatremia will result
• Skin losses (sensible losses/sweat)
• GI losses (emesis, nasogastric tube output, stool losses)
• Renal losses
• Osmotic diuresis (glucose, urea, Mannitol)
• Intrinsic renal disease that impairs concentrating ability in distal collecting tubule

Question 33

Hypernatremia - hypertonic sodium gain

Answer 33

• Administration of hypertonic sodium bicarbonate
• Systemic absorption intrauterine hypertonic saline to induce abortion
• Salt poisoning

Question 34

Manifestations of Hypernatremia

Answer 34

1. Initial response to hypernatremia is osmotic water movement out of brain and other cells.
2. The resulting shrinkage of brain cells is presumed to be responsible for early neurologic symptoms (i.e. lethargy, seizure, coma)
3. Severe manifestations of acute hypernatremia are seen at serum Na+ >158 mEq/L
4. By 48h, brain volume is restored due to both salt and water movement from the cerebrospinal fluid into the brain (increasing the interstitial volume) and to the uptake of osmotically effective solutes by the brain cells (pulls water back into the cells and restores cell volume).

Question 35

Management of Hypernatremia

Answer 35

1. Underlying cause must be addressed and prevailing hypertonicity corrected by administration of dilute fluids or free water to both correct the water deficit and replace ongoing water losses
2. Interventions to limit further water loss (i.e. Desmopressin – an AVP/ADH analogue can be given in central DI)
3. If thirst is significantly impaired or patients have no free access to oral intake of water (i.e. critically ill/intubated etc.), then administration of parenteral fluid is needed (i.e. intravenous fluid)
   a. If hypovolemic and hypernatremic (i.e. volume depleted and dehydrated due to both Na+ and water losses), 0.45% normal saline can be administered to restore volume and replace water deficit
   b. If euvolemic and hypernatremic then free water can be given parenterally as 5% Dextrose in water (cannot give pure water given hypotonicity - will cause lysis of cells)
   c. Caution: In chronic hypernatremia (>48h duration), the serum Na+ correction should not exceed >10 mEq/L over 24h in efforts to avoid cerebral edema (rapid lowering once cerebral adaptation has occurred causes additional osmotic water movement into brain cells resulting in cerebral edema, encephalopathy, seizure, and permanent neurologic damage)
   d. In both hyponatremia and hypernatremia, the serum Na+ must be followed closely (i.e. checked every 2-4 hours) and therapy should be modified accordingly to AVOID too rapid of correction

Question 36

Osmoregulation

Answer 36

•What is sensed?

-serum osmolality

•Sensors?

-hypothalmic osmoreceptors

•Effectors?

• ADH
• thirst

•What is affected?

• urine osmolaloty
• water intake

Question 37

Volume Regulation

Answer 37

•What is sensed?

-effective tissue perfusion

•Sensors?

• macula densa
• afferent arteriole
• atria
• carotid sinus
• Effectors
• RAAS
• ANP
• ANP related peptides
• norepinephrine
• ADH
• What is affected?
• urine sodium
• thirst

Question 38

Na+ determines ECF volume

Answer 38

– Hypovolemia = volume depleted = Total body Na+ deficit

– Hypervolemia = volume overloaded = Excess total body Na+

– Euvolemic = Normovolemia = Normal total body Na+

Question 39

Hydration impacts cell volume

Answer 39

– Overhydration = water intoxication = cell swelling

– Dehydration = water depletion = cell shrinkage