9 Disorders of Water Homeostasis: Hyponatremia

Question 1

Hyponatremia

• Definition
• Classification
  
  • Hypertonic hyponatremia
  • Isotonic hyponatremia
  • Hypotonic hyponatremia

Answer 1

• Definition
  
  • P_Na < 135 mEq/L
  • Most common electrolyte disorder
• Classification
  
  • Hypertonic hyponatremia
    
    • Aka hyperglycemia
    • Plasma tonicity > 285 mOsm/kg
  • Isotonic hyponatremia
    
    • Aka pseudohyponatremia
    • Plasma tonicity 270 - 285 mOsm/kg
  • Hypotonic hyponatremia
    
    • Aka true hyponatremia
    • Plasma tonicity < 270 mOsm/kg

Question 2

Hypertonic hyponatremia

Answer 2

• Elevated serum conc of glucose or mannitol –> increase plasma tonicity
• Hypertonicity drives water from intracellular –> extracellular compartment
  
  • Dilutes P_Na
• Situations of hyperglycemia
  
  • Katz conversion corrects P_Na for the level of hyperglycemia
  • Add 1.6 mEq/L to P_Na for every 100 mg/dl of P_glucose > 100 mg/dl

Question 3

Isotonic hyponatremia

• Pseudohyponatremia
• Serum
• Ion-selective electrode (ISE)
  
  • Direct ISE
  • Indirect ISE
• When serum contains high proteins (multiple myeloma) or lipids (hypertriglyceridemia)
• ISE in pathological circumstances

Answer 3

• Pseudohyponatremia
  
  • Lab artifact
• Serum
  
  • Composed of aqueous fractions (93%) & nonaqueous fractions (7%)
  • Aqueous fraction: where Na is located
  • Nonaqueous fraction: proteins + lipids
• Ion-selective electrode (ISE)
  
  • Direct ISE: measures Na in plasma water
    
    • Normal Na in plasma water: 150 mEq/L
    • Normal P_Na in total serum = 139.5 mEq/L
    • Ex. arterial blood gas machine
  • Indirect ISE: measures Na in total serum
    
    • Requires a fixed volume of diluent to be added to the serum sample before measuring
    • More commonly used
• When serum contains high proteins (multiple myeloma) or lipids (hypertriglyceridemia)
  
  • Nonaqueous fraction volume increases & displaces water fraction
  • Total serum contains less water & Na per unit volume
• ISE in pathological circumstances
  
  • Indirect ISE: any dilution by a fixed volume of diluent –> dilution error –> falsely low P_Na
  • Direct ISE: this doesn’t occur

Question 4

Hypotonic hyponatremia

• True hyponatremia
• Term hyponatremia
• Increased water intake
• Decreased water excretion

Answer 4

• True hyponatremia
  
  • Water input > water output –> dilute Na conc
• Term hyponatremia
  
  • Misleading b/c altered P_Na are primarily disorders of water homeostasis, not Na
  • Na conc ≠ Na content
• Increased water intake
  
  • Kidney’s capacity to excrete water is exceeded –> hyponatremia
  • Need to ingest > 18 L/day to maximally dilute urine & –> hyponatremia
    
    • Urine volume (L/day)
    • = (normal mOsm solute / day) / (lowest U_Osm kidneys can generate)
    • = (900 mOsm/day) / (50 mOsm/L)
    • = 18 L/day
• Decreased water excretion
  
  • Increased ADH activity
  • Decreased GFR
  • Decreased solute intake

Question 5

Hypotonic hyponatremia: decreased water excretion due to increased ADH activity

• General
• Funciton
• Main physiological stimuli for ADH release
• TBW compartments
• EABV
• EABV vs. ECF volume
  
  • Normally
  • Certain diseases

Answer 5

• General
  
  • Most common mech of hypotonic hyponatremia
• Function
  
  • ADH increases AQP2 expression in the CD –> increases water reabsorption
  • ADH stimulation by baroreceptors can overcome inhibitory effects of hyponatremia (hypotonicity) on ADH secretion
• Main physiological stimuli for ADH release
  
  • Plasma hypertonicity
    
    • Not applicable in hypotonic hyponatremia
    • Hypertonicity –> sensed by osmoreceptors –> trigger thirst & ADH release
    • Hypertonicity –> inhibits thirst & ADH release
  • Decreased effective arterial blood volume (EABV)
    
    • Common cause of hyponatremia
  • SIADH: ADH secreted autonomously when not needed
• TBW compartments
  
  • ICF
  • ECF: water outside cells
    
    • ITF
    • IVF (plasma in veins & arteries)
• EABV
  
  • Arterial blood volume that effectively perfuses organs
    
    • Inffered from other measruements (plasma renin, plasma aldo, urine Na, etc.)
  • Stretch-sensitive receptors in carotid sinus & aortic arch (baroreceptors) sense changes in EABV (not ECF volume)
    
    • Increase EABV –> Aff neural impulses inhibit ADH secretion from posterior pituitary
    • Decrease EABV –> decrease discharge rate of stretch receptors –> ADH secretion
• EABV vs. ECF volume
  
  • Normally
    
    • Changes in EABV vary w/ changes in ECF volume
    • Ex. hypovolemia: both decreased
  • Certain diseases
    
    • ECF increases while EABV decreases
      
      • –> decreased organ perfusion —> increased ADH release
    • Diseases
      
      • Pump failure (ex. CHF)
      • Decreased peripheral resistance (ex. liver cirrhosis)

Question 6

Hypotonic hyponatremia: decreased water excretion due to decreased GFR

Answer 6

• Decrease GFR –> decrease water excretion
• Pts w/ low GFR & limited renal water excretory capacity –> hyponatremic by ingesting the same amt of water that ppl w/ nromal GFR ingest

Question 7

Hypotonic hyponatremia: decreased water excretion due to decreased solute intake

• Normal solute intake
• Main solutes in diet
• Steady state
• Urine volume vs. urine solute load
• Effects of a low solute diet

Answer 7

• Normal solute intake
  
  • 600-900 mOsm/day
• Main solutes in diet
  
  • Urea from metabolism of proteins
  • Electrolytes (ex. salt)
• Steady state
  
  • Solute intake = urine solute load = 600-900 mOsm/day
• Urine volume vs. urine solute load
  
  • Urine volume & water excretion are dependent on urine solute load
    
    • Higher urine solute load –> higher urine volume
    • Lower urine solute load –> lower urine volume
  • Urine volume (L/day) = [urine solute load (mOsm/day)} / [U_Osm (mOsm/L)]
• Effects of a low solute diet
  
  • Reduce max capacity to excrete water
  • Drink a normal amt of water –> only able to excrete a little –> extra wtaer is retained –> diluted P_Na –> hyponatremia

Question 8

Etiology of hypotonic hyponatremia

• Increased water intake
• Decreased water excretion
  
  • Increased ADH activity
  • Decreased GFR
  • Decreased solute intake

Answer 8

• Increased water intake
  
  • Psychogenic polydipsia
  • Marathon runners
  • Ecstasy
  • Water drinking contests
• Decreased water excretion
  
  • Increased ADH activity
    
    • Decreased EABV w/ decreased ECF volume
    • Decreased EABV w/ increased ECF volume
    • Syndrome of Inappropriate ADH Secretion (SIADH)
  • Decreased GFR
    
    • AKI
    • CKD including pts w/ end-stage renal disease on chronic dialysis
  • Decreased solute intake
    
    • Beer potomania

Question 9

Etiology of hypotonic hyponatremia:
Increased ADH activity

• Decreased EABV w/ decreased ECF volume
• Decreased EABV with increased ECF volume

Answer 9

• Decreased EABV w/ decreased ECF volume
  
  • Hemorrhage
  • Vomiting
  • Secretory Diarrhea
  • Thiazide diuretics
  • Mineralocorticoid deficiency (e.g. primary adrenal insufficiency)
    
    • Causes of selective cortisol deficiency
      
      • Secondary adrenal insufficiency (pituitary)
      • Tertiary adrenal insufficiency (hypothalamus)
    • Primary adrenal insufficiency (adrenal gland) causes both aldo & cortisol deficiency
• Decreased EABV with increased ECF volume
  
  • CHF
  • Liver cirrhosis
  • Nephrotic syndrome
    
    • Some pts with nephrotic syndrome actually have an increased EABV

Question 10

Etiology of hypotonic hyponatremia: increased ADH activity:
Syndrome of Inappropriate ADH Secretion (SIADH)

• General
• Etiologies
• Diagnostic criteria

Answer 10

• General
  
  • ADH is secreted autonomously w/o physiological stimuli
• Etiologies
  
  • Pulmonary causes
    
    • Infectious (pneumonia), tumors (lung cancer), etc.
  • CNS causes
    
    • Infectious (meningitis, encephalitis), tumors (craniopharyngioma), etc.
  • Drugs
    
    • Antidepressants (SSRIs), carbamazepine, cyclophophamide, etc.
  • Other causes
    
    • Nausea, pain
• Diagnostic criteria
  
  • Hypotonic hyponatremia
  • Clinical euvolemia
  • U_Osm > 100 mOsm/L
  • U_Na > 30 mEq/L in the presence of normal salt and water intake
  • Serum uric acid < 4 mg/dL
  • Normal renal, thyroid, and adrenal function
  • Absence of diuretic use (particularly thiazides)

Question 11

Etiology of hypotonic hyponatremia: decreased solute intake:
Beer potomania

• Normal solute intake
• Steady state
• Beer potomania
• Other diet that causes decreased solute intake

Answer 11

• Normal solute intake
  
  • 600-900 mOsm/day
• Steady state
  
  • Solute intake = urine solute load
  • Urine water excretion depends on solute intake
• Beer potomania
  
  • Pts w/ alcohol dependence drink large amts of beer & don’t eat enough solutes
  • Poor solute intake –> limited amt of excretable water
  • Drink large amts of beer (90% water) –> ovewhelm limited kidney capacity for water excretion –> retain extra ingested water –> hyponatremia
• Other diet that causes decreased solute intake
  
  • Tea & toast diet

Question 12

Brain adaptation to hypotonic hyponatremia

• Normal brain tonicity
• Effect of decreased plasma tonicity on water in brain
• Main way brain adapts to swelling
• Regulatory volume decrease (RVD)
• Acute hyponatremia (acute hypotonicity)
• Chronic hyponatremia (chronic hypotonicity)
• The more rapid the fall in P_Na…

Answer 12

• Normal brain tonicity
  
  • Brain cell tonicity & ECF tonicity are in equilibirum
  • No net water shift in or out of brain cells
• Effect of decreased plasma tonicity on water in brain
  
  • Water moves into the brain along osmotic gradients –> brain edema
  • Astrocytes swell after hypotonic stress, neurons don’t
• Main way brain adapts to swelling
  
  • Lose solutes to decrease ICF osmolality & stop water movement into astrocytes
• Regulatory volume decrease (RVD)
  
  • Astrocyte adaptation
  • Lose solutes –> decrease IC tonicity –> reestablish normal cellular volume
  • (1) astrocytes lose electrolytes (K, Cl)
    
    • 70% of solute loss
    • Peaks 3 hr after swelling, compete after 6-7 hr
  • (2) astrocytes lose organic osmolytes for osmoregulation
    
    • Mian osmolytes lost: glycerophosphorylcholine, phoscreatine, creatine, glutamate, glutamine, taurine, and myo-inositol
    • Occurs by 48 hr
• Acute hyponatremia (acute hypotonicity)
  
  • Hyponatremia develops in
  • Little time for full adaptation to occur since it occurs rapidly
• Chronic hyponatremia (chronic hypotonicity)
  
  • Hyponatremia develops gradually over >48 hr
  • Brain has more time to fully adapt
• The more rapid the fall in P_Na…
  
  • The more water will be accumulated before the brain is able to fully adapt & lose solute

Question 13

Clinical manifestations (symptoms) of hyponatremia

• Severe symptoms
• Moderate symptoms
• Mild symtpoms
• “Asymptomatic”

Answer 13

• Severe symptoms: hyponatremic encephalopathy
  
  • Seizures
  • Stupor
  • Coma
  • Significant cerebral edema
  • Death from brain herniation
• Moderate symptoms: less cerebral edema
  
  • Lethargy
  • Disorientation
  • Confusion
  • Less cerebral edema
• Mild symtpoms
  
  • Fatigue
  • Nausea
  • Headaches
  • Minimal cerebral edema
• “Asymptomatic”: no apparent symptoms (symptoms are very subtle)
  
  • Attention deficits
  • Gait disturbances
  • Falls
  • Fractures
  • Osteoporosis

Question 14

Acute vs. chronic symptoms of hyponatremia

• Acute hyponatremia (<48 hr)
• Chronic hyponatremia (>48 hr)
  
  • Usual symptoms
  • Once the brain has enough time to volume-adapt via solute losses…
  • Glutamate
  • Osteoporosis

Answer 14

• Acute hyponatremia (<48 hr)
  
  • Moderate or severe symptoms
• Chronic hyponatremia (_>_48 hr)
  
  • Usual symptoms
    
    • Minimal or asymptomatic
    • Could cause moderate or severe when P_Na is very low (<120 mEq/L)
    • Increased mortality
  • Once the brain has enough time to volume-adapt via solute losses…
    
    • Expanded brain volume decreases back toward normal
    • Reduces brain edema & symptoms
  • Glutamate
    
    • Neurotransmitter involved in cerebellar function
    • One of the most important osmolytes that brain cells lose to compensate for hypotonicity
    • Pts w/ chronic hyponatremia have brain glutamate deficiency
    • Deficiency –> ataxia & gait disturbances
  • Osteoporosis
    
    • 1/3 of our total body Na is in our bones
    • Increased bone resportio to mobilize stored Na into circulation –> osteoporosis, bone fractures, falls, & gait disturbances

Question 15

Clinical features of different categories of hyponatremia according to their pathophysiological mechanism

• Increased water intake
• Decreased water excretion
  
  • Increased ADH activity
    
    • Decreased EABV w/ decreased ECF volume (low total body Na)
    • Decreased EABV w/ increased ECF volume (high total body Na)
    • SIADH
  • Decreased GFR
  • Decreased solute intake

Answer 15

• Increased water intake
  
  • Euvolemic: total body Na remains normal
  • Excessive water intake –> decrease plasma tonicity –> inhibit ADH release –> diluted urine (U_Osm < 100 mOsm/L)
• Decreased water excretion
  
  • Increased ADH activity
    
    • ADH release despite low plasma tonicity –> concentrated urine (U_Osm > 100 mosm/L) –> varied ECF volume status
    • Decreased EABV w/ decreased ECF volume (low total body Na)
      
      • Hypovolemia: HoTN, tachycardia, orthostatic HoTN, orthostatic tachycardia, flat jugular veins, clear lungs, no peripheral edema
    • Decreased EABV w/ increased ECF volume (high total body Na)
      
      • Hypervolemia: HTN, distended jugular veins, crackles, peripheral edema
    • SIADH
      
      • Euvolemia despite dilutional hyponatremia from excess water retention
      • Mild volume expansion –> increase weight
      • ADH –> initial water retention –> subsequent natriuresis –> regulate ECF volume toward normal
  • Decreased GFR
    
    • Expanded ECF volume w/ low U_Osm
    • Low GFR –> inability to excrete Na –> hypervolemic
  • Decreased solute intake
    
    • Euvolemic since total body Na remains normal
    • Excessive water intake + limited ability to excrete water –> decrease plasma tonicity –> inhibit ADH release –> increase TBW
    • Decreased solute load –> low U_Osm

Question 16

Diagnostic approach to hyponatremia

• Hypertonic
• Isotonic
• Hypotonic
  
  • Appropriately low U_Osm
  • Inappropriately high U_Osm
    
    • Low ECV
      
      • Low ECF
      • High ECF
    • Normal ECV & ECF

Answer 16

• Hypertonic: plasma tonicity > 285 mOsm/kg
  
  • Hyperglycemia
• Isotonic: plasma tonicity = 270-285 mOsm/kg
  
  • Pseudohyponatremia
• Hypotonic: plasma tonicity < 270 mOsm/kg
  
  • Appropriately low U_Osm (<100 mOsm/kg)
    
    • Psychogenic polydipsia
    • Beer potomania
  • Inappropriately high U_Osm (_>_100 mOsm/kg)
    
    • Low ECV
      
      • Low ECF
        
        • True hypovolemia
      • High ECF
        
        • Heart failure
        • Liver cirrhosis
    • Normal ECV & ECF
      
      • SIADH

Question 17

Treatment for hyponatremia

• Severely symptomatic hyponatremia
  
  • Symptoms
  • Causes
  • Cerebral edema
  • Monitor setting
  • Treatment
  • Frequency of P_Na checks
• Moderately symptomatic hyponatremia
  
  • Symptoms
  • Cerebral edema
  • Monitor setting
  • Treatment
  • Frequency of P_Na checks
• Mildy symptomatic or “asymptomatic” hyponatremia
  
  • Symptoms
  • Cerebral edema
  • Monitor setting
  • Treatment
  • Frequency of P_Na checks

Answer 17

• Severely symptomatic hyponatremia
  
  • Symptoms: seizures, stupor, coma
  • Causes: acute or chronic hyponatremia w/ Na < 120 mEq/L
  • Cerebral edema: +++
  • Monitor setting: ICU (medical emergency)
  • Treatment: NaCl 3% 100 mL IV bolus immediately
  • Frequency of P_Na checks: every 1-2 hr
• Moderately symptomatic hyponatremia
  
  • Symptoms: confusion, disorientation, lethargy
  • Cerebral edema: ++
  • Monitor setting: ICU (medical emergency)
  • Treatment: Na3% IV slow infusion
  • Frequency of P_Na checks: every 1-2 hr
• Mildy symptomatic or “asymptomatic” hyponatremia
  
  • Symptoms: fatigue, nausea, headache / none detectable
  • Cerebral edema: +/-
  • Monitor setting: regular floor (not a medical emergency)
  • Treatment: target underlying pathophysiology
  • Frequency of P_Na checks: every 8-12 hr

Question 18

Pathophysiological targets of therapy in hyponatremia

• Target underlying cause of increased ADH activity
  
  • Decreased EABV due to true hypovolemia
  • Decreased EABV due to heart failure or liver cirrhosis
  • SIADH
    
    • Reversible causes
    • Irreversible causes
• Block ADH action
• Decrease water intake
• Decreased medullary gradient
• Obligate renal water excretion by increasing solute intake

Answer 18

• Target underlying cause of increased ADH activity
  
  • Decreased EABV due to true hypovolemia
    
    • Volume expansion (ex. NaCl 0.9%)
  • Decreased EABV due to heart failure or liver cirrhosis
    
    • Block ADH action in kidneys
    • Usually irreversible & impossible to stop ADH release
  • SIADH
    
    • Reversible causes: stop SSRI, treat penumonia or meningitis, treat pain
    • Irreversible causes (ex. advanced lung cancer): block ADH action in kidneys
• Block ADH action
  
  • V2 receptor antagonists (“Vaptans”): treat hypervolemic (CHF, cirrhosis) or euvolemic (SIADH) hyponatremia
    
    • Must be initiated in an inpatient setting w/ frequent P_Na monitoring
  • Avoid fluid restriction in first 24 hr
  • Expensive
• Decrease water intake
  
  • ​Fluid restriction so water input < water output (negative water balance)
  • Amt of fluid restriction require dto create a state of negative water balance (from ingested water & food)
    
    • Should be less than the sum of urine & insensible losses
  • Worst case scenario (ex. SIADH): restrict fluid to <800 mL/day
• Decreased medullary gradient
  
  • Water is reabsorbed in the IMCD
    
    • Mian driver: hypertonic medulla (1200 mOsm/kg at the renal papilla)
    • Hypertonicity: 50% Na, 50% urea
  • NaCl transport
    
    • Na/K/2Cl in the apical TkAL transports Na to the medulla
  • Loop diuretics
    
    • Reduce medullar gradient –> increase free wtaer excretion
    • Produce hypotonic urine
  • In euvolemic pts: administer w/ 0.9% NaCl to avoid hypovolemia & create an extra stimulus for ADH release
• Obligate renal water excretion by increasing solute intake
  
  • Na tablets
  • Increaes dietary solute (i.e. salt & protein)

Question 19

Treatment of hyponatremia: summary

• Primary polydipsia
• Hypovolemia
• Heart failure or liver cirrhosis
• SIADH
• Renal insufficiency
• Beer potomania

Answer 19

• Primary polydipsia
  
  • Fluid restriction
• Hypovolemia
  
  • Volume expansion
• Heart failure or liver cirrhosis
  
  • Fluid restriction
  • Loop diuretics
  • V2 receptor antagonists (not in liver cirrhosis)
• SIADH
  
  • Treat underlying cause if possible
  • Fluid restriction
  • Loop diuretics
  • Salt tablets
  • Increase dietary solute intake
  • V2 receptor antagonists
• Renal insufficiency
  
  • Fluid restriction
• Beer potomania
  
  • Increase dietary solute intake

Question 20

Correction of hyponatremia

• Goals
  
  • Severely symptomatic hyponatremia
  • Moderately symptomatic, midly symptomatic, and “asymptomatic” hyponatremia
• Max limits of correction

Answer 20

• Goals
  
  • Severely symptomatic hyponatremia
    
    • Raise serum sodium concentration by 6 mEq/L in first 6 hours and postpone any further correction for next day
    • Increasing serum sodium by 6 mEq/L is usually enough to stop symptoms
  • Moderately symptomatic, midly symptomatic, and “asymptomatic” hyponatremia
    
    • Raise serum sodium concentration by 6 mEq/L in any 24h period
• Max limits of correction
  
  • 10 – 12 mEq/L in first 24h
  • 18 mEq/L in first 48h
  • These are limits one should not cross to avoid risk of osmotic demyelination syndrome

Question 21

Osmotic demyelination syndrome (ODS)

• Aka
• Pathogenesis
• Other risk factors
• Clinical Manifestations
• Diagnosis
• Treatment
• Prevention
• Prognosis

Answer 21

• Aka
  
  • Central pontine myelinolysis (CPM)
• Pathogenesis
  
  • Rapid correction of chronic hyponatremia
  • –> acute brain shrinking –> astrocyte death –> loss of cell/cell interactions b/n astrocytes & oligodendrocytes
  • Dying astrocytes –> demyelination via cytokines, inflammatory mediators, T cells, microglia, & macrophages
• Other risk factors
  
  • [Na+] < 105 mEq/L
  • Alcoholism
  • Malnutrition
  • Advanced liver disease
  • Liver transplantation
  • Hypokalemia
• Clinical Manifestations
  
  • Onset of symptoms typically is delayed several days (up to 1 week) after overcorrection of hyponatremia
  • Altered mental status, quadriparesis, dysphagia and dysarthria
• Diagnosis
  
  • Based on the clinical presentation of new-onset neurological symptoms in a patient with a recent overcorrection of hyponatremia
  • MRI may be useful to detect demylinating lesions but may not be (+) for up to 4 weeks after symptom onset
• Treatment
  
  • No effective treatment
  • Could be a benefit from relowering serum sodium concentration, corticosteroids, or plasmapheresis
• Prevention
  
  • Avoid overcorrection of hyponatremia
  • Recognize early overcorrection and act promptly by relowering serum sodium concentration so serum sodium concentration does not cross maximal limits of correction
• Prognosis
  
  • 40% of patients experience full recovery
  • 25% of patients develop persistent neurological deficits
  • 6% succumb to the disease

Question 22

Hypernatremia

• Definition
• Pathophysiology
  
  • Most cases
  • Minority of cases

Answer 22

• Definition
  
  • Serum sodium concentration of greater than 145 mEq/L
  • Always implies plasma hypertonicity
  • Much less common than hyponatremia
• Pathophysiology
  
  • Most cases
    
    • Water input < water output
      
      • –> negative water balance –> increase Na conc
    • Due to…
      
      • Decreased water intake
      • Increased water excretion + decreased water intake
  • Minority of cases
    
    • Na excess
    • Ex. salt tablets or hypertonic sol’ns (ex. Na bicarbonate)
    • Pts are usually also hypervolemic due to increased total body Na

Question 23

Pathophysiology of hypernatremia

• Decreased water intake
• Increased water excretion + decreased water intake
  
  • Increased water excretion by itself
  • Increased water excretion due to extrarenal water loss
  • Increased water excretion due to renal water loss (i.e. polyuria)
• Dehydration vs. hypovolemia
  
  • Definition
  • P_Osm & Na
  • Treatment

Answer 23

• Decreased water intake
  
  • ​Water is unavailable
  • Unconsciousness
    
    • Water is available but patient is not awake to drink water
  • Altered thirst mechanism
    
    • Water is available, pt is awake, but he or she just doesn’t feel thirsty because of problems with his/her neural thirst pathways
• Increased water excretion + decreased water intake
  
  • ​Increased water excretion by itself usually doesn’t result in significant hypernatremia
    
    • For increased water excretion to cause hypernatremia, it must be accompanied by decreased water intake
    • Hypernatremia caused solely by increased water excretion will also increase plasma tonicity
      
      • –> stimulate thirst and water intake –> minimize any increase in serum sodium concentration
    • Thirst: defense mechanism against hypernatremia
      
      • Unless water intake is compromised (e.g. decrease thirst response), hypernatremia won’t develop
  • Increased water excretion due to extrarenal water loss
    
    • ​GI tract (ex. diarrhea, fistula, ostomy)
    • Skin (ex. sweating)
  • Increased water excretion due to renal water loss (i.e. polyuria)
    
    • Decreased ADH activity –> decreased water reabsorption –> water diuresis
    • Increased urine solute load (opp of beer potomania)
      
      • Need to excrete large amts of solutes in urine w/ large amts of water excretion
      • Increased urine solute –> solute diuresis (osmotic diuresis)
• Dehydration vs. hypovolemia
  
  • ​Dehydration
    
    • Loss of pure water or hypotonic fluid
    • P_Osm & Na: increased
    • Treatment: D5W
  • Hypovolemia
    
    • Loss of isotonic fluid
    • P_Osm & Na: unchanged
    • Treatment: 0.9% NS

Question 24

Hypernatremia etiology

• Decreased water intake
• Increased water excretion + decreased water intake
  
  • Extra-renal water loss
  • Renal water loss
    
    • Solute diuresis
    • Water diuresis
      
      • Central
        
        • Idiopathic
        • Genetic
        • Acquired
      • Nephrogenic
        
        • Genetic
        • Acquired

Answer 24

• Decreased water intake
  
  • ​Water is unavailable
    
    • E.g. lost in desert w/ no water
  • Unconsciousness or altered mental status
    
    • E.g. pt intubated & sedated in ICU
  • Altered thirst mechanism
    
    • Adipsia (complete lack of thirst) or hypodipsia (decreased thirst sensation)
    • Caused by CNS disorders that comprise thirst neurla pathways (e.g. brain tumor)
• Increased water excretion + decreased water intake
  
  • ​Extra-renal water loss
    
    • ​Increased GI losses
      
      • Vomiting
      • Nasogastric drainage
      • Non-secretory Diarrhea (e.g. inflammatory diarrhea, osmotic diarrhea, malabsorption)
      • Ileostomy
      • Pancreatobiliary fistula
    • Increased skin losses
      
      • Excessive sweating
  • Renal water loss
    
    • ​Solute diuresis
      
      • ​Glucose (ex. hyperglycemia)
      • Urea (ex. post-ATN diuresis, post-obstructive diuresis, high protein intake)
      • Electrolytes: electrolyte-containing IV fluids (ex. 0.9% NaCl)
    • Water diuresis: diabetes insipidus (DI) –> decreased ADH –> low U_Osm
      
      • Central
        
        • ​Idiopathic
          
          • ​Most common
        • Genetic
          
          • ​Familial Central DI: mutation in ADH gene causing misfolding of ADH protein –> ADH protein is not functional
          • Wolfran syndrome
          • Congenital hypopituitarism
        • Acquired
          
          • Neurosurgery
          • Head trauma
          • Brain tumors
          • Infiltrative disorders: e.g. Langerhans cell histiocytosis, sarcoidosis
      • Nephrogenic
        
        • ​Genetic
          
          • ​Inactivating mutation of V2 receptor gene (most common)
          • Inactivating mutation of Aquaporin 2 gene
        • Acquired
          
          • ​​Renal disease: post-ATN, bilateral urinary tract obstruction, sickle cell disease, autosomal dominant polycystic kidney disease
          • Electrolyte abnormalities: hypercalcemia, hypokalemia
          • Drugs: lithium, amphotericin, demeclocycline, V2 receptor antagonists, ifosfamid

Question 25

Brain adaptation to hypernatremia (hypertonicity)

• Increase plasma tonicity –>
• Main way the brain fully adapts
• Regulatory volume increase (RVI)
• Acute hypernatremia (acute hypertonicity)
• Chronic hypernatremia (chronic hypertonicity)

Answer 25

• Increase plasma tonicity –>
  
  • Water moves out of the brain along osmotic gradients –> brain shrinks
• Main way the brain fully adapts to shrinking
  
  • Gains solutes to increase ICF osmolality and stop water movement out of astrocytes
• Regulatory volume increase (RVI)
  
  • Astrocyte adaptation
  • Gain solutes to increase intracellular osmolality and reestablish normal cellular volume
  • (1) astrocytes gain sodium and chloride
  • (2) accumulation of organic osmolytes similar to hyponatremia
• Acute hypernatremia (acute hypertonicity)
  
  • Hypernatremia that develops in
  • Little time for full adaptation to occur since hypernatremia occurs rapidly
  • Rare
• Chronic hypernatremia (chronic hypertonicity)
  
  • Hypernatremia that develops gradually (>48h)
  • Most common type of hypernatremia
  • When hypertonicity occurs gradually the brain has more time to fully adapt to it

Question 26

Symptoms of hypernatremia

• Mild symptoms
• Moderate symptoms
• Severe symptoms
• Acute hypernatremia can cause…
• Chronic hypernatremia usually cause…

Answer 26

• Mild symptoms
  
  • Irritability
  • Restlessness
• Moderate symptoms
  
  • Stupor
  • Muscular twitching
  • Hyperreflexia
  • Spasticity
• Severe symptoms
  
  • Seizures
  • Coma
  • Death
• Acute hypernatremia can cause…
  
  • Moderate to severe symptoms as a result of rapid brain shrinking
• Chronic hypernatremia usually cause…
  
  • Mild or no symptoms

Question 27

Clinical features of different categories of hypernatremia according to their pathophysiological mechanism

• Decrease in water intake
• Increase in water excretion and decrease in water intake
  
  • Extra-renal water loss
  • Renal water loss
    
    • Decreased ADH activity (water diuresis)
    • Increased urine solute load (solute or osmotic diuresis)

Answer 27

• Decrease in water intake
  
  • Clinically euvolemic since total body sodium remains normal
  • Since plasma osmolality is elevated, ADH release is increased and UOsm is appropriately high (> 600 mOsm/L)
• Increase in water excretion and decrease in water intake
  
  • Extra-renal water loss
    
    • Euvolemic if losing pure water
    • Hypovolemic if losing water associated with significant amounts of sodium
    • Most patients will lose water and sodium
    • Since plasma osmolality is elevated, ADH release is increased and UOsm is appropriately high (> 600 mOsm/L)
  • Renal water loss
    
    • Decreased ADH activity (water diuresis)
      
      • Euvolemic since they lose pure water without sodium
      • Even though plasma osmolality is elevated, ADH activity is decreased –> UOsm is low (< 300 mOsm/L)
      • Urine solute load
        
        • Product of multiplying UOsm x daily urine volume
        • Within normal limits (600 – 900 mOsm/day)
    • Increased urine solute load (solute or osmotic diuresis)
      
      • Euvolemic if losing pure water
      • Hypovolemic if losing water associated with significant amounts of sodium
      • Plasma osmolality is elevated –> ADH activity is increased –> UOsm is moderately elevated (300 - 600 mOsm/L)
      • Urine solute load is high (> 1000 mOsm/day) due to the presence of the osmotic solute in urine

Question 28

Diagnostic approach to hypernatremia

• Hypervolemic
• Not hypervolemic
  
  • No polyuria
    
    • Thirsty
    • Not thirsty
  • Polyuria
    
    • U_Osm = 300-600 mOsm/L & urine solute load > 1000 mOsm/day
    • U_Osm < 300 mOsm/L & urine solute load = 600-900 mOsm/day
      
      • Response to DDAVP
      • No response to DDAVP

Answer 28

• Hypoervolemic
  
  • Salt tablets
  • Hypertonic IV fluids
• Not hypervolemic
  
  • ​No polyuria
    
    • ​Thirsty
      
      • ​Increased skin loss
      • Increased GI loss
    • Not thirsty
      
      • Adipsia
      • Hypodipsia
  • Polyuria
    
    • ​​U_Osm = 300-600 mOsm/L & urine solute load > 1000 mOsm/day
      
      • ​Osmotic diuresis
    • U_Osm < 300 mOsm/L & urine solute load = 600-900 mOsm/day
      
      • Response to DDAVP
        
        • Central diabetes insipidus (DI)
      • No response to DDAVP
        
        • ​Nephrogenic diabetes insipidus (DI)

Question 29

Treatment for hypernatremia

• Acute hypernatremia
• Chronic hypernatremia

Answer 29

• Acute hypernatremia
  
  • Usually associated with moderate to severe neurological symptoms
    
    • Ex. seizures
    • When serum sodium concentration is greater than 158 mEq/L
  • Medical emergency
  • Treatment: D5W IV
    
    • Goal: normalizing serum sodium concentration by 24h
• Chronic hypernatremia
  
  • Usually asymptomatic or associated with minimal symptoms
  • Correction of chronic hypernatremia involves targeting the underlying disorder
    
    • Ex. surgery for a brain tumor causing Central DI
  • Administration of water or hypotonic fluids corrects both the water deficit and replaces ongoing water losses
  • Goal: correct the serum sodium concentration by 10 mEq/L in 24h

Question 30

Example

• 58 year-old woman is brought to the ER after a head injury during an unrestrained motor vehicle crash
• CT head showed epidural hematoma with associated skull fracture
• Over the following 24h, patient develops polyuria with a urine output of 3.1 L/24h
• On exam: BP=120/76 mmHg, HR=67 bpm, RR=18 resp/min. Weight=75 kg. No JVD. Lungs are clear to auscultation. No peripheral edema. Patient is alert and oriented. No focal neurological deficits.
• Laboratory data: Na=167 mEq/L, K=3.6 mEq/L, Cl=112 mEq/L, BUN=10 mg/dL, Cr=0.8 mg/dL, Glucose=151 mg/dL. UOsm=116 mOsm/kg, UNa=30 mEq/L, UK=15 mEq/L.
• Calculate free water deficit
• Calculate the amount of time required to correct the free water deficit
• Calculate the rate of correction of the free water deficit
• Calculate obligatory water losses
• Calculate the final rate of correction

Answer 30

• Calculate free water deficit
  
  • TBW * [(Na / 140) - 1] * 0.5 (for a woman)
  • 70 * [(167 / 140) - 1] * 0.5
• Calculate the amount of time required to correct the free water deficit
  
  • Amt to correct = 167 - 140 = 27 mEq/L
  • Goal: correct serum sodium concentration by no more than 10 mEq/L in 24h
  • Rule of three: 10 mEq/L / 24h = 27 mEq/L / X
• Calculate the rate of correction of the free water deficit
  
  • Volume / time
  • 6750 mL / 64.8 h
• Calculate obligatory water losses
  
  • Skin & stool: 40 mL/h
  • Respiratory insensible losses match metabolic water production and therefore are not taken into account
  • Urine: electrolyte-free water clearance (C_eH20)
    
    • V * { 1 - [(Una + Uk) / Pna] }
    • 3.1 * {1 - [(30 + 15) / 167] }
  • Since patient losses 2.26 L of water in the urine in 24h, we need to replace this in the same amount of time
    
    • Rate of correction = 2260 mL / 24 h
• Calculate the final rate of correction
  
  • Free water deficit + skin & stool + urine
  • Since patients with hypernatremia usually cannot drink on their own, these can be administered either intravenously as D5W or enterally as pure water using a feeding tube

Question 31

Other therapies & complications of rapid correction of hypernatremia

Answer 31

• Other therapies
  
  • Main goal
    
    • Improve associated symptoms (i.e. polyuria)
  • Central DI
    
    • Desmopressin (dDAVP): intranasal or subcutaneous
  • Nephrogenic DI
    
    • Low solute diet
      
      • Low solute intake will limit the amount of water excretion in the urine
    • Thiazide diuretics
      
      • Thiazides induce hypovolemia
      • –> increase proximal tubular reabsorption of sodium and water
      • –> decrease in distal delivery of water to the ADH-sensitive sites in the collecting tubules
      • –> reduce the urine output improving polyuria
• Complications of rapid correction
  
  • Water moving into astrocytes –> cerebral edema
  • Goal: correct no more than 10 mEq/L / 24 hr