Osmolality and Tonicity

    • Two forms of sodium/osmolality control:
      • ADH - Secreted by posterior pituitary
        • Causes H2O reabsorption in the collecting duct --> increases Urine Osmolality
        • Uosm > 100 mosm/kg --> ADH is considered ON
          • > 100 --> Weak ADH activity
          • > 200 --> good ADH activity
          • > 300 ---> Very high ADH activity
      • Aldosterone - Complex mechanism
        • Causes sodium reabsorption in distal tubule --> Decreases urine sodium.
        • Una < 10 --> Aldosterone is ON
        • Una > 40 --> Aldosterone is OFF
    • Osmolality
      • Can be calculated or measured
      • Osmolar Gap = measured - calculated = big discrepancy between the two --> unmeasured osmole.
        • >10 = abnormal (many poisons can do this) = unmeasured solutes
        • Normal 275-295
        • Regulated by ADH (Post. Pituitary) in response to Osmolality and Volume depletion.
        • Inappropriate ADH release + drink free water = fall in serum osmoles

    Approach to Hyponatremia

    Overall Approach to Hyponatremia

    1. Measure Serum Osmolality
      • Serum osmolality is NORMAL = Pseudohyponatremia
        • Hyperlipidemia (interferes with assay in the way serum is reconstituted) - must by VERY high
      • Serum osmolality is HIGH = "Hyperosmolar Hyponatremia"
        • Hyperglycemia (pull water out of cells)
      • Serum osmoality is LOW = Most common "True"
    2. If osmolality is LOW, must determine volume status
      • Helps understand if it is appropriate for ADH to be present or NOT
      • Volume Depleted = ADH is appropriately on (Aldosterone is on too)
        • Should have HIGH urine Osmolality (ADH is ON) + Urinary sodium should be LOW (Aldosterone is ON)
      • Volume HIGH = ADH is ON because intravascularly dry (all fluid is outside vessels), "effective volume depletion"
        • CHF, Cirrhosis
        • ADH is appropriate, ON, although it's maladaptive
        • Aldosterone is usually also ON
      • Volume is NORMAL
        • Type 1: Very dilute urine (ADH is OFF)
          • Psychogenic polydipsia (>10-20L of urine /day)
        • Type 2:
          • No volume or osmolal stimulant = inappropriate ADH (should not be)
          • Kidneys should be able to dilute urine Uosm < 100, but ADH is on, and Uosm is > 100 (usually ~300)




    • Diuretics
      • Thiazides - interfere with diluting segment of kidney - cannot maximally dilute urine... huge issue if low solute diet and lots of water.
        • "Tea and Toast" patients
      • NOTE: Loop diuretics do not cause hyponatremia --> interfere with concentrating segment of kidney (actually TREATS SIADH), but CAN cause hyponatremia if drink water.
    • SIADH
      • Pain/Nausea in post-op setting  -- do not use hypotonic IV fluids peri-op
      • CNS disorders (hemorrhage, infection)
      • Pulmonary disorders (Pneumonia, Small Cell Lung Ca)
      • Medications (


    • Hyper/hypotonicity - whether water shifts from cells to the extracellular space
    • Hyper/iso/hypoosmolar - whether the concentration of solutes is high or low in extracellular space (measured by lowering freezing point).
    • For example: Infusing mannitol causes a large amount of mannitol-containing and sodium-lacking fluid in the extracellular space.  This causes a iso-osmolar isotonic hyponatremia (no transcellular water shifts).
    • Pseudohyponatremia
      • Spurious form of iso-osmolar and isotonic hyponatremia when severe hypertriglyceridemia or paraproteinemia increases substantially the solid phase of plasma.  If the sodium concentration is measured by flame photometry, this will artificially increase the amount of measured sodium.
      • In present day (2014) sodium concentration is measured by ion-specific electrode, so this laboratory artifcat is mostly not an issue.

    Causes of Hyponatremia:

    • Dilutional Hyponatremia (MOST COMMON) --> aka Hypotonic Hyponatremia
      • Excess of water in relation to sodium.
    • Non-hypotonic hyponatremia:
      • Hyperosmolar (aka translational)
        • Hyperglycemia (Most common), Glycine, Mannitol (no fluids)
          • An increase of 5.6 mmol/L of glucose decreases serum sodium by 1.7 mmol/L.
        • Increase in solute that is unable to cross the cell membrane causes an osmotic shift of intracellular fluid to extracellular space, diluting the sodium.  
        • Hypernatremia can result if osmotic diuresis occurs (if normal kidneys) - since the total Na+ and K+ concentrations in urine falls short of that in serum.
      • Iso-osmolar
        • Pseudohyponatremia 
        • Mannitol: Infusing mannitol causes a large amount of mannitol-containing and sodium-lacking fluid in the extracellular space.  This causes a iso-osmolar isotonic hyponatremia (no transcellular water shifts).
    • Excessive water intake
      • Overwhelms normal water excretory capacity (i.e. psych patients).  ADH (arginine vasopressin) cannot be fully suppressed, and urine is not maximally dilute, leading to water retention.



    • Sodium > 125 mmol/L generally asymptomatic
      • Very subtle neurocognitive deficits (risk of falls, hip fracture, osteoporosis)
    • Sodium < 125:
      • Mild Symptoms:
        • Headache, nausea, vomiting, muscle cramps, lethargy, restlessness, disorientation, depressed reflexes.
      • Severe Symptoms:
        • seizures, coma, permanent brain damage, respiratory arrest, brain-stem herniation, death.
    • Effects on the brain:
      • Initially causes cerebral edema & intracranial hypertension--> Brain tissue responds by losing Na+/K+/Cl-  (within hours) --> adapts to hyponatremia.
      • Central Pontine Myelinolysys
        • RARE (most reported cases if correction > 12 mmol/L, some cases with 10 mmol/L.)
        • Rapid correction of adapted hyponatremia causes shrinkage of cells, and osmotic demyelination of pontine and extrapontine neurons causing neurologic dysfunction:
          • quadriplegia, pseudobulbar palsy, seizures, coma, death
          • Complications: Hepatic failure, potassium depletion, malnutrition.
    • Correcting Sodium:
      • Rapid drop in sodium > 10mEq in 1-3 days = risk of cerebral edema
        • Symptoms are neurologic (all tissues swell, but brain is in skull)
          • Altered mental status --> obtunded --> seizures/coma/hypoxea/resp arrest.
      • Rapid rise in sodium > 10-12 mEq in 24hrs --> risk of cerebral edema
        • Now more conservative strategies --> 8-10 mEq/day
        • Central Pontine Demyelination (Only partially reversible)
          • Progressive quadroparesis
          • Speech + Swallowing Disorders
          • Coma
          • "Locked-In Syndrome"



    • Correction Limit: To avoid Central Pontine Demyelination

      • Do not Exceed 10 mEq/L in first 24hrs
      • Do not Exceed 18 mEq/L in first 48hrs
      • If Symptomatic ACUTE correction: target 4-6 mEq increase is usually enough to correct symptoms


      NOTE: Most reported cases of CPM involve correction > 12 mEq/L in 24hrs with few case reports of

      10-12 mEq/L/24hrs correction.


    • Check the urine osmolality
      • If urine is concentrated (≥200 mOsm/kg of water) and clinically euvolemic or hypervolemic:
        • Infuse hypertonic saline in controlled fashion (use formula to predict correction).
        • +/- Give furosemide (diuresis  is equivalent to one half isotonic saline solution)
        • + limit electrolyte-free water
      • R/O Hypothyroidism or adrenal insufficiency and replace hormones.
        • Hypothyroidism - measure TSH
        • Adrenal Insufficiency - measure AM cortisol, ACTH, aldosterone, renin, K+, Na+.
          • (If in crisis, do ACTH stimulation test)
      • If dilute urine (< 200)
        • Water restriction + close observation (if symptoms not severe).
        • If severe symptoms - hypertonic saline infusion.
    • Monitor for over-correction:
      • Osmotic demyelination reported after increase of Na+ of > 12mmol/L/24hrs (some cases 10-12mmol/L).
      • Therefore, most recommended correction no more than 8mmol/L/day
        • or max 1-2 mmol/L/h
      • If overcorrection occurs:
        • D5W @ 6 mL/kg Lean body weight infused over 2 hours (will lower serum sodium by ~ 2 meq/L)

        • DDAVP @ 2 mcg iv or subcut q 6 hours and increase to 4 mcg in rare pts who don’t respond to lower doses.  Should continue DDAVP after target sodium is reached to prevent bounce back. 

      • In orders write "U/O recording q2hrs with accurate ins/outs and daily weights".
        • "If >=300cc/2hr, call MD for consideration of IV DDAVP push".
        • Rationale:  Pt is hyponatremic, ADH is ON due to hypovolemia.  Once you begin rehydrating, volume receptors turn off (volume receptors trump osmoreceptors), allowing osmoreceptors to pick up hyponatremia and water overload thereby causing ADH to shut off completely, resulting in rapid diuresis (> 300cc/2hr) running the risk of overcorrecting (>1-2mmol/h).  If this happens need to give DDAVP to stop overcorrection.
    • If symptomatic --> Acute sodium correction with IV saline:
      • If patient still has severe symptoms, can correct at higher rate (risk of demyelination does not exceed risk of hyponatremia).
      • Increase Na 4-6 mEq/h in 24hrs --> usually enough to fix symptoms.
      • What to rapidly correct with, depends on cause:
        • If SIADH --> must use 3% Normal Saline
        • If Hypovolemic --> use Normal Saline
      • Acute Hypotonic Hyponatremia Seizure or Coma

        • 100 mL or 2 mL/kg bolus infusions of 3% Saline (Can repeat TWO times if needed)
      • Formula:
        • HyponatremiaCorrectionFormula.png
    • Chronic correction based on reason:
      • SIADH - related Hyponatremia
        • Address underlying cause
        • Remove offending drugs
        • Water restriction (<800mL/day is ideal and < 1.5L/day at MINIMUM).
        • Loop diuretics (can relax fluid restriction, limits kidney concentrating urine).
        • ++ salt intake can help - augments water loss.
        • Ensure adequate solute/protein intake
      • Heart failure
        • ACEi, loop diuretics (NOT THIAZIDE) cause electrolyte-free water excretion.
      • If resistant to all therapies:
        • Can use Demeclocycline 600-1200mg/day  (antibiotics and ADH antagonist off label).
          • Very old drug, tetracycline antibiotic.
          • Induces nephrogenic diabetes insipidus, so need to keep up with fluids.
            • If not taking fluids, can cause hypernatremia
          • Hard to titrate dose, needs weeks to be therapeutic, causes nausea, very long-lasting, long time to wear off.
          • Need to monitor renal function (nephrotoxic) - esp in cirrhosis patients.
        • "Vaptans" class - vasopressor receptor antagonists (NEW!)
          • Block effect of ADH
          • Must remove fluid restriction to avoid hypernatremia.
          • Tolvaptan is classic
            • Causes liver injury (FDA warns against use in liver pts, do not use >30 days).
          • I.e. Canivaptan is authorized (at least in US) for in-hospital hyponatremia (IV only)
            • Cross-reacts V1 and V2 (causes low BP), can worsen variceal bleeding.
            • Others are more V2 selective
          • Oral and IV available (Tolvaptan = oral)

    Lab Approach to Hyponatremia




    Fractional Extretion of Sodium (FeNa)

    • Test used to distinguish re-renal causes of AKI vs. renal.
    • Order Creatinine, Lytes, Urinary Sodium, Urinary Creatinine  (taken at same time)
    • Formula Derivation:
    • Numerator (Sodium excretion rate), and Denominator (Sodium passing through kidneys)
      • FenaEqn4.gif
    • Pflow = GFR ... calculate using this formula:
      • FenaEqn3.gif      (GFR AKA Pflow)
    • Complete Formula:
      • FenaEqn1.gif
    • Simplifies to:
      • FenaEqn2.gif
    • FeNa Cause
      <1% Pre-renal causes (Kidneys reabsorbing and retaining sodium)
      >1% Likely Renal cause (Kidney fails to retain sodium - i.e. ATN)




    • In beer potomania urine contains alcohol, so urine osmolality is falsely high.


    Serum and Urinary Indices in the SIADH vs. Hypovolemia


    Favors SIADH

    Urine sodium >40 meq/L (40 mmol/L)

    FENa >1%

    Serum uric acid <4 mg/dL (0.24 mmol/L)

    FEUA >10%

    BUN <10 mg/dL (3.6 mmol/L)

    FEUN >50%

    Favors Hypovolemia

    Urine sodium <20 meq/L (20 mmol/L)

    FENa <1%

    Serum uric acid >6 mg/dL (0.35 mmol/L)

    FEUA <10%

    BUN >15 mg/dL (5.4 mmol/L)

    FEUN <35%

    BUN = blood urea nitrogen; FENa = fractional excretion of sodium; FEUA = fractional excretion of uric acid; FEUN = fractional excretion of urea; SIADH = syndrome of inappropriate antidiuretic hormone secretion.



    Causes of the SIADH


    Central nervous system disorders



    Inflammatory disorders

    Guillain-Barré syndrome

    Multiple sclerosis

    Mass lesionsa


    3,4-Methylenedioxymethamphetamine (also known as ecstasy)a

    Antipsychotic medications




    Cyclooxygenase-2 inhibitorsa








    Selective serotonin reuptake inhibitorsa

    Serotonin norepinephrine reuptake inhibitorsa

    Tricyclic antidepressants



    Endurance exercise

    Familial disorders


    HIV infection

    Rocky Mountain spotted fever

    Postoperative setting




    Pulmonary disorders


    Inflammatory disorders

    Positive pressure mechanical ventilationa

    Respiratory failure


    Gastrointestinal tract tumors

    Genitourinary tract tumors


    Respiratory tract tumorsa


    Small cell carcinomaa



    Source: MKSAP 16

    Management of Asymptomatic Hypotonic Hyponatremia




    True hypovolemia

    Correct etiology of hypovolemia

    Isotonic saline

    Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

    Treat underlying cause

    Discontinue offending drugs

    Fluid restriction



    Vasopressin receptor antagonists (vaptans)

    Ensure adequate solute and protein intake

    Hypervolemic hyponatremia (chronic heart failure, cirrhosis, nephrosis)

    Treat underlying cause

    Fluid and sodium restriction


    Vasopressin receptor antagonists (vaptans)

    Source: MKSAP 16





    • Serum Na > 145 mEq/L
    • Common in critically ill patients with no water access.
    • VERY overwhelming drive to drink water with hypernatremia (if this is absent- think CNS lesion)
      • If chronic, then very poor prognostic factor


    • Almost always reflects low free H2O
    • Hypotonic fluid loss
    • Pure water loss
    • Hypertonic fluid gain


      Volume Status

      Urine Volume

      Urine Osmolality (mosm/kg H2O)

      Hypotonic Fluid Loss

      Gastrointestinal losses (vomiting, nasogastric suction, diarrhea)




      Diuretics (except osmotic diuretics)




      Osmotic diuresis (hyperglycemia; urea [high protein diet or 

      enteral feeding, relief of urinary tract obstruction, 

      recovery phase of acute tubular necrosis])




      Pure Water Loss

      Insensible water losses (skin, respiratory tract) that are not 

      replaced (impaired mentation, stroke, hypothalamic lesion, 

      functional impairment limiting access to fluids)




      Diabetes insipidus




      Hypertonic Fluid Gain

      Iatrogenic  sodium chloride, hypertonic saline, or sodium bicarbonate




    • Source: MKSAP 16
    • I.e. if person at sea starts drinking sea water, they will excrete extra salt load, but also the extra salt load will take free H2O with it. - Drinking own urine will cause them to excrete extra urea in new urine, and take more H2O with them.


    • Causes of Diabetes Insipidus
      • Central
        • Deficient in ADH (cannot excrete when needed)
        • Malignancy, neurosurgery, trauma, infiltrative disorders (sarcoid etc..), anorexia nervosa, hypoxic encephalopathy, sheehan syndrome, familial, GPA (Wegeners)
      • Peripheral
        • #1 cause: Lithium (Distal nephron through ENaC, cells cannot respond to ADH, cannot deliver aquaporins in distal tubule).
        • Other Meds (Demeclocycline, cidofovir, foscarnet, didanosine, ampho B, ifosfamide, ofloxacin)
          • Demeclocycline - used to reat SIADH
        • Gestational DI (placenta produces vasopressinase - breaks down ADH) - common in twin pregnancies.  Severe thirst and polyurea...
    • Treatment of DI
      • If circulatory collapse --> isotonic saline
      • If hypernatremia and free access to H2O --> will fix themselves by drinking
      • If no access to free water --> correct by no more than 10 mEq/day
      • Do not correct hypernatremia > 10mEq/day to avoid cerebral edema
      • Water deficit calculated, and water provided.
      • If nephrogenic diabetes insipitus, then can give thiazide diuretic:
        • Cause mild volume depletion causing more poximal sodium/water reabsorption
        • Cannot maximally concentrate their urine, they reabsorb proximally.
        • Must replace K+
      • If Lithium is a cause:
        • Can try amiloride (blocks uptake of Lithium in distal nephron), often not sufficient.
        • Does not always reverse with discontinuation of lithium. 
        • Hypovolemia from diuretic can increase proximal lithium reabsorption, worsens toxicity.


    • Either cannot concentrate urine, or drinking too much.
    • If Uosm > 300, suggests solute diuresis..
      • Diabetes Mellitus (glycosuria)
    • If Uosm < 300
      • Patient drinking a lot of fluid
    • Another way:
      • Water deprivation test -- ask not to drink anything.
        • watch serum Osm and urine Osm
        • if serum Osm stable and urine Osm climbs (then patient drinking too much fluid)
        • if serum Osm climbs and urine Osm not increase (then ADH not present or effective)
          • To tell difference: give DDAVP and see if they concentrate urine (increase Uosm)
      • NOTE: Desmopressin does not respond to gestational placental ADH-ase.  Good treatment.
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