A. Introduction to Sodium and Volume Regulation

1. Normal serum [Na+] is 138-142 mmol/L (mM)
2. Key parameters in evaluating changes in serum [Na+]
   1. Value of serum [Na+]
   2. Overall body volume status (hypovolemic, euvolemic, hypervolemic)
   3. Value of serum osmolality (Osm)
   4. Total body [Na+] levels
3. An abnormal plasma sodium value is indicative of a disorder of water homeostasis
   1. The [Na+] cannot be used to determine the direction of the abnormality in fluid status
   2. This is because the total body Na+ determines the patient's volume status
   3. So hyponatremia / hypernatremia do not correlate with a particular volume status
   4. In addition, total body volume often does not correlate with intravascular volume
   5. Any abnormal serum [Na+] value may associated with high or low or normal volume
4. Determine Serum Osmolality
   1. Osm=2x[Na+](mM) + (urea nitrogen [mg/dL]÷ 2.8) + (glucose [mg/dL]÷ 18)
   2. Normal Osm is ~280-290 mOsm
   3. Thus, serum [Na+] falls 1.6 mmol/L for every 100mg/dL (5.6 mmol/L) increase in glucose
   4. An increase in serum [Na+] always predicts a hyperosmolar state
   5. A reduction in serum [Na+] may occur with eusomolar
5. Thus, total body sodium depletion OR retention can exist in hyponatremic patients
6. Classifying Hyponatremia
   [Figure] "Evaluation of Hyponatremia"
   1. By volume status of patient: body fluid excess, normal, or deficit
   2. By expansion of intracellular or extracellular or both compartments [2]
   3. By serum osmolality in the patient
   4. By total body Na+ level of patient
   5. Elevated glucose and/or urea nitrogen should be ruled out when evaluating hyponatremia
   6. Obtain urine sample for sodium, Urine Osm, creatinine
   7. Calculate fractional excretion of Na+
7. Normal Serum Osmolality and Hyponatremia [3]
   1. Consider pseudohyponatremia, low [Na+] is artifact of measurement
   2. Most commonly due to severe hypertriglyceridemia or hyperchylomicronemia
   3. May be due to severe paraproteinemia
   4. Can also occur when more than one disorder of Na regulation is present

B. Development of Hyponatremia [4]

1. The body PRIMARILY maintains osmolality
   1. Sensors in the hypothalamus
   2. Sensors in the kidney
   3. Therefore, in normal conditions, total serum osmolality should be maintained
2. Urine osmolality is >250mOsm in most patients hyponatremic due to medical causes
   1. This is true if an excess of antidiuretic hormone (ADH) is present (most cases)
   2. Not true for primary polydipsia, where urine osmolality ~80mOsm
   3. Not true in persons with normal renal function responding to free water bolus
3. Abnormal [Na+] may occur when water intake exceeds water output (dilution effects)
   1. Manifestation of impaired renal diluting capacity
   2. Usually results from persistent anti-diuretic hormone (ADH) secretion despite depressed serum osmolality
4. Abnormal [Na+] may occur when urinary loss of monovalent cation exceeds intake
   1. Diuretics are a major cause of sodium loss
   2. Most common cause of hyponatremia in developed nations is congestive heart failure (CHF)
   3. CHF associated hyponatremia is usually associated with diuretic use
   4. Gastrointestinal losses of cations occur, but kidney can usually compensate
5. Hyponatremia may also occur from reduction in glomerular filtration rate (GFR)
6. Compartment Effects in Hyponatremia [2]
   1. Normally, 2/3 of body water is intracellular and 1/3 extracellular
   2. Shifts between compartments occur in response to maintaining osmolality in serum
   3. Bicompartment Expansion - SIADH, renal failure, nephrotic syndrome, CHF
   4. Extracellular Fluid Expansion - hyperglycemia (impermeable solute), CHF and diuretic therapy
   5. Intracellular Compartment Expansion (water retention and Na loss) - diarrhea
7. Hyponatremia on admission or shortly thereafter is a ~2X risk for death in ST-elevation myocardial infarction [6]
8. Hyponatremia occurred in 13% of marathon runners and was associated with long racing time, body-mass index extremes, and weight gain during the race [7]

C. Total Body Sodium Decreased

1. Vomiting (alkalosis often seen)
2. Diarrhea (acidosis often seen)
3. Excessive Insensible Fluid Losses: sweating, burns, other dehydration
4. Diuretics
   1. Very common cause of hyponatremia with hypokalemia (thiazides, loop diuretics)
   2. Manitol can also cause hyponatremia
5. Peri-Operative (may also be associated with near normal volumes; see below)
   1. Usually due to use of hypotonic solutions during surgery
   2. Compounded by water retention due to high level ADH production
   3. Hypotonic glycine solution for irrigation in prostate resection and pelvic surgery [5]
6. Mineralocorticoid Insufficiency
7. Reduction of glomerular filtration rate (GFR) with increased Na+ losses
8. Rare: pancreatitis, rhabdomyolysis, hypothyroidism [11]
9. Symptoms and Signs of (total body) Sodium Depletion (Volume Contraction)
   1. Reduced extracellular fluid (ECF) volume
   2. Orthostatic hypotension (early)
   3. Hypotension (late)
   4. Reduced skin turgor
   5. Dry mucous membranes
   6. Hematocrit (HCT) and BUN increase
   7. Capillary refill time increase
10. Note that clinical evaluation of volume status is often incorrect
11. Laboratory indicators of volume depletion
    1. Urine sodium <25mM (except in diuretic induced hypovolemia and in hypothyroidism)
    2. Fractional sodium excretion (FeNa) <0.5-0.8% is a better marker of volume depletion
    3. Combination of FeNa and fractional excretion of urea (<55%) is a very good marker for hypovolemia (that is, saline response hyponatremia)
12. Treatment of Hyponatremia with Volume Depletion
    1. Gradual replacement with saline solutions
    2. Hypertonic saline may be used if sodium is <115mM with symptoms
    3. Recommend no more than 0.5-1mM sodium increase per hour; maximum 10-12mM per day
    4. Increasing sodium more rapidly can lead to osmotic demyelination (pontine myelinolysis)

D. Mild Total Body Sodium Increase

1. Syndrome of Inappropriate Antidiuresis (SAID) [8]
   1. Most SIAD cases due to in increased secretion of ADH with water retention, called SIADH
   2. In some cases, levels of ADH are normal or low, but concentrated urine still occurs
   3. These low- or normal ADH cases are due to "reset osmostat" or mutations in receptors
   4. Gain of function mutation in vasopressin/ADH receptor V2R can also cause syndrome [13]
   5. Water retention leads to slight increase in vascular volume (mild hypervolemia)
   6. In general, more fluid is retained than Na+, so patients are nearly always hyponatremic
   7. Elevated serum levels of ADH are usually found, and must rule out "CHART" diseases
   8. If Urine Osm <300mOsm, can correct hyponatremia with isotonic (normal) saline
   9. If Urine Osm >300mOsm, correct with hypertonic (for example, 450mM / 3%) saline
   10. For moderate or severe volume overload, add loop diuretic, such as furosemide (Lasix®)
   11. ADH antagonists are being developed and may be useful
2. Other causes of moderate total sodium increases with hyponatremia
   1. For a diagnosis of SIAD, these causes must be ruled out ("CHART" Diseases):
   2. Cardiac Failure
   3. Hepatic Dysfunction - often with ascites
   4. Adrenal Insufficiency
   5. Renal Dysfunction
   6. Thyroid Insufficiency - thyroid hormone needed for normal sodium homeostasis
3. Postoperative Hyponatremia [13]
   1. Common when near-isotonic saline is used in gynecologic surgeries
   2. Due to generation of electrolyte free water during hypertonic urine excretion
   3. ADH retained the electrolyte free water in the body, and sodium was not retained as well
   4. Result is drop in sodium concentration 24 hours after surgery
   5. Recommend that sodium be monitored closely, and slightly hypertonic solutions be used
   6. Use of glycine containing solutions during surgery can exacerbate problems [5]
4. Free water restriction will often lead to partial or full correction of sodium/water status

E. Marked Total Body Sodium Increase

1. These are severe water overload states
   1. Intravascular Overload - acute / chronic renal failure (oliguria / anuria)
   2. Extravascular Overload - most common causes of hyponatremia with hypervolemia
2. Extravascular Fluid Overload
   1. Congestive Heart Failure
   2. Cirrhosis with Ascites
   3. Nephrotic Syndrome
3. Symptoms of (total body) Sodium Excess (Volume Expansion)
   1. Expanded ECF Volume
   2. Pulmonary Edema - particularly in congestive heart failure
   3. Elevated Right Atrial Filling Pressure (with jugular venous distension), S3 Gallop
   4. Hypertension - intravascular volume overload
   5. Hypotension - extravascular volume overload (intravascular depletion)
   6. Frequently will observe a change in weight
   7. Decreased HCT (hematocrit), BUN, glucose (hemodilution effects)
4. Treatment depends on cause
   1. Fluid restriction is often a major part of effective therapy
   2. Diuretic therapy - loop diuretic ± aldosterone antagonist (depending on cause)
   3. Salt restriction is required (since total body sodium is increased)

F. Treatment of Symptomatic Hyponatremia [1,2]

1. Regardless of cause, treatment should focus on removal of free water
2. Acute Symptomatic Hyponatremia
   1. Develops in less than 48 hours
   2. Serum [Na+] <120mmol/L is a medical emergency
   3. Treat promptly since risk of cerebral edema is higher than risk of osmotic demyelination
   4. Raise serum [Na+] by 2 mmol/L per hour at most, to about 5% increase in serum [Na+]
   5. Calculations of "sodium requirement" are not accurate and should not be used
   6. Hypertonic saline (3%) is infused at 1-2mL/kg per hour in symptomatic cases
   7. A loop diuretic such as furosemide will enhance free-water excretion
   8. Severe symptoms may be treated with 4-6mL/kg per hour of hypertonic saline (3%)
   9. Frequent determinations of serum Na+ must be made to insure safe and effective therapy
   10. In general, hypokalemia should be correctly rapidly but safely (see below)
   11. In addition, all serum electrolytes, including magnesium and calcium should be monitored
3. Chronic Symptomatic Hyponatremia
   1. For hyponatremia present for >48 hours or unknown druation, correct carefully
   2. In this more chronic situation, there is increased risk of osmotic demyelination
   3. Cerebral water increases about 10% in severe chronic hyponatremia
   4. However, one requires only ~5% increase in [Na+] to reduce cerebral swelling significantly
   5. Thus, the goal is to increase [Na+] by 8mmol/L or less initially
   6. After this, do not exceed 8-10mmol/L correction in 24 hours
   7. Calculation of amount of fluid needed to be lost (fluid excess or euvolemia) possible (below)
   8. Care must taken with diuretics to insure good rate of [Na+] correction and to normalize levels of other electrolytes, particularly potassium
   9. With chronic hyponatremic encephalopathy, therapy with IV NaCl was associated with better outcomes than fluid restriction [10]
4. Tolvaptan [12]
   1. Oral, vasopressin V2 receptor antagonist
   2. Treatment of euvolemic or hypervolemic hyponatremia (mainly CHF and cirrhosis)
   3. Initial dose is 15mg po qd; increased to 30-60mg daily if necessary based on serum Na+
   4. Showed increased serum Na+ on days 4 and 30 versus placebo
   5. Hyponatremia typically recurred within 7 days of discontinuing drug
   6. Side effects mainly mechanism based: increased thirst, dry mouth, increased urination
   7. Useful particularly in SIADH
5. Predicting Changes in Serum Na+ [2]
   1. Volume calculation for estimating changes in serum Na+ levels with one liter of infusate
   2. Change in serum Na+ = [(infusate Na+ + infusate K+) - (Serum Na+)]/(TBW + 1)
   3. TBW (total body water) = 0.6 x Weight (in kilograms)
6. Concentrations of Ions in Common Infusates

   Per Liter:	Sodium	Dextrose
   D5W	0g	0mEq	50g
   D5 0.25 NS	2.25	37	50
   D5 0.50 NS	4.5	75	50
   D5 NS	9	150	50
   Normal Saline	9	150	0
   Ringer Lactate	8	132	(Lactate 28mEq, Minerals)
   3% Hypertonic Saline	27	450	0

G. Neurologic Complications of Hyponatremia [2,4]

1. Effects on Neurologic System
   1. Slower changes in serum Na+ are accomodated far better than rapid changes
   2. Greater changes in serum Na+ lead to more manifestations of disease
   3. Serum osmolality is the major determinant of brain volume
2. Neurologic symptoms are various:
   1. Initially, CNS Depression, Change in Mental Status occur
   2. Seizures
   3. Cerebral Edema - occurs due to fluid shifts in the brain
   4. Paralytic Ileus
   5. Chronic hyponatremia can also precipitate encephalopathy [10]
3. Central Pontine Myelinolysis (CPM)
   1. Osmotic demyelination which can occur on rapid correction of hyponatremia
   2. Usually occurs when correction of serum Na+ is >10-12 mmol/L per day
   3. Accompanying hypokalemia may increase risk of CPM
   4. Increased risk with alcoholism, malnourishment, women on thiazide diuretics, burns
   5. Therefore, do not exceed increase in [Na+] >8 mmol/L in any 24 hour period [2]

References

1. Lien YH and Shapiro JL. 2007. Am J Med. 120:653
2. Adrogue HJ and Madias NE. 2000. NEJM. 342(21):1581
3. Turchin A, Seifter JL, Seely EW. 2003. NEJM. 349(15):1465
4. Fraser CL and Arieff AI. 1997. Am J Med. 102(1):67
5. Ayus JC and Arieff AI. 1997. Arch Intern Med. 157(2):223
6. Goldberg A, Hammerman H, Petcherski S, et al. 2004. Am J Med. 117(4):242
7. Almond CSD, Shin AY, Fortescue EB, et al. 2005. NEJM. 352(15):1550
8. Ellison DH and Berl T. 2007. NEJM. 356(20):2064
9. Feldman BJ, Rosenthal SM, Vargas GA, et al. 2005. NEJM. 352(18):1884
10. Ayus JC and Arieff AI. 1999. JAMA. 281(24):2299
11. Roberts CGP and Ladenson PW. 2004. Lancet. 363(9411):793
12. Schrier RW, Gross P, Gheorghiade M, et al. 2006. NEJM. 355(20):2099
13. Steele A, Gowrishankar M, Abrahamson S, et al. 1997. Ann Intern Med. 126(1):20