Sodium (Na+) is the major extracellular cation and is a primary determinant of plasma osmolality and extracellular fluid (ECF) volume. Sodium concentration is inextricably linked with ECF volume, therefore interpretation of sodium levels should always include consideration of the hydration status of the patient (and, therefore, changes in “free” water). The body attempts to maintain a constant ECF volume, as major changes in ECF volume can have profound effects on cells. The kidney plays a critical role in maintenance of ECF volume, via sodium and water retention in response to antidiuretic hormone (ADH) and aldosterone. Thirst is also stimulated by decreases in ECF volume (hypovolemia) or increases in effective osmolality (hypertonicity). Regulation of body water is accomplished through osmoreceptors and baroreceptors, with the kidney being the main organ where sodium is retained (for more on renal resorption of sodium, refer to the renal physiology page). Sodium concentrations can also be affected by epinephrine, which stimulates renin release and sodium absorption. This effect is transient (for example, an increase in sodium concentration of between 5-10 mEq/L was seen in goats 60 minutes after injection of 2 mg epinephrine and sodium normalized by 90 minutes (Abdelatif and Abdalla et al 2012).

  • Osmoreceptors: These receptors are found primarily in the hypothalamus, although peripheral osmoreceptors do exist (e.g. in the liver). These respond to changes in effective osmolality, principally sodium concentration (major effective osmol in health, whereas glucose only acts as an osmol when insulin is deficient or impaired from causing glucose movement into cells). Osmolality should be thought of as a relative change of sodium to water. 
    • Increased osmolality: Increases in water intake and ADH-mediated water absorption in the kidney will result in water uptake without sodium and act to reduce sodium concentration. When there is hypertonicity and hypovolemia, the drive for water retention will continue.
      • ADH release: Hypernatremia will stimulate ADH release from the posterior pituitary gland (remember ADH is produced in the hypothalamus and released from the pituitary).  ADH stimulates thirst and promotes water retention in the kidneys by binding to a receptor (VP-2), which results in opening up of water channels (aquaporin-2) in the luminal membrane of principle cells in the collecting ducts. This leads to passive water uptake by the principle cells along a concentration gradient into the hypertonic medullary interstitium and, thus, water retention by the kidney (water in excess of sodium).
      • Thirst: Thirst is stimulated by as little as a 1-2% increase in osmolality in humans (1-3% in dogs). 
    • Decreased osmolality: This is usually due to low sodium (when not an artifact). A decrease in osmolality has the opposing effect to increased osmolality, and will suppress ADH secretion and thirst, thus raising sodium in circulation. However, if the cause of hypo-osmolality results in sufficient hypovolemia (5-10% reduction), the inhibition of ADH and thirst does not occur and water retention mechanisms dominate (stimulation of ADH, activation of renin-angiotensin-aldosterone system).
    • The macula densa can be thought of as an “osmoreceptor” that is in the renal tubules and responds to decreased NaCl absorption (usually due to hypochloremia) in the thick ascending limb of the loop of Henle (this will stimulate similar responses to hypovolemia, i.e. activation of the renin-angiotensin-aldosterone system)
  • Baroreceptors: Baroreceptors are sensitive to changes in pressure or stretch of blood vessel or cardiac atrial walls and are thus affected by effective circulating volume (ECV), i.e. that is in the arterial system and is effectively perfusing the tissues. Pressure is usually directly proportional with ECF volume, which is dependent on sodium concentration. Baroreceptors sense changes in pressure (high or low) and exist in carotid arteries, aortic arch and sinus, carotid sinus, pulmonary arteries and cardiac atria. The primary determinant of blood volume is sodium. Unlike osmolality, which reflects a relative change in sodium with respect to water, volume changes result in absolute changes in sodium concentration (with proportional changes in chloride).
    • Hypovolemia: With hypovolemia (decreased ECV by 5-10%), the body responds as follows:
      • Juxtaglomerular apparatus: The drop in afferent arteriolar pressure is sensed by low-pressure baroreceptors which stimulate the renin-angiotensin system, the end result being mineralocorticoid (aldosterone) release from the adrenal cortex.
        • Angiotensin II:
          • Stimulates sodium resorption in the proximal convoluted tubules (water will follow).
          • Causes vasoconstriction (increasing blood pressure)
          • Stimulates thirst (increase water intake will take in water without sodium). A decrease in ECV of 8-10% is required for thirst stimulation. An inadequate thirst response will limit the body’s response to hypovolemia and may result in hypernatremia.
        • Aldosterone:
          • Stimulates increased absorption of Na and promotes the excretion of potassium and hydrogen (when K is deficient) in the connecting segment and collecting tubules of the distal nephron. NaCl retention promotes water resorption, thus correcting the hypovolemia (water follows sodium). This is very efficient.
      • Baroreceptors in the carotid sinus and left atria sense low pressure and stimulate:
        • ADH production in the hypothalamus and release from the pituitary. This will increase water retention (water > sodium) as indicated above. Remember that ADH needs functioning renal tubules and a hypertonic medulla (depends on sodium chloride absorption without water in the thick ascending limb of the loop of Henle and urea, which is absorbed in the distal nephron under the influence of ADH, but is produced in the liver). A hypertonic medulla also needs adequate (not increased) renal medullary blood flow in the vasa recta.
        • Catecholamine release. These cause:
          • Absorption of sodium (and water) in the proximal convoluted tubule (α1 effect).
          • Renin release (β1 effect)
          • Vasoconstriction
    • Hypervolemia
      • Low-pressure baroreceptors respond to increased volume in the cardiac atria (right):
        • Inhibit ADH secretion
        • Increase natrial natriuretic peptide. This:
          • Is a vasodilator (decreases blood pressure). This is thought to be the main action of this hormone.
          • Inhibits renin release and angiotensin release, as well as potassium-induced release of aldosterone. It also inhibits the response of the renal tubules to these hormones (particularly AgII).
      • Non-receptor mediated pressure natriuresis: This is thought to be the main mechanism protecting against hypervolemia. 


Serum or plasma concentrations of these major electrolytes can be measured by ion-specific electrodes or flame photometry. Measurement of electrolytes by ion-specific electrodes is called potentiometry. There are two types of potentiometry: direct and indirect. Direct potentiometry is utilized by blood gas machines and does not involve sample dilution. Indirect potentiometry is utilized by automated chemistry analyzers, such as the ones used at Cornell University, and involves sample dilution before analysis. This distinction is important because endogenous interferents such as lipemia may falsely decrease electrolyte concentrations with indirect, but not direct, potentiometry.

Technique used at Cornell

Direct potentiometry (blood gas machine) or indirect potentiometry (chemistry analyzer), which involves sample dilution.


With this technique, an electrode containing an internal electrolyte solution is immersed in the patient sample, which is separated from the internal solution by a membrane that can detect the electromotive force (EMF) generated by the ions in both solutions. This EMF is determined by the difference in concentration of the test ion in the test solution and internal filling solution (test ion at fixed concentration). The EMF is predicted by the Nernst equation (see Techniques for more details on the method). For testing purposes with the chemistry analyzer, the sample is diluted 1:32 before analysis (indirect potentiometry).

Units of measurement

The concentration of sodium is measured in mg/dL (conventional units), mEq/L (conventional units), or mmol/L (SI units). At Cornell University, results are provided as mEq/L. The unit conversion formulas are shown below:

mEq/L x 1 = mmol/L
mg/dL ÷ 2.3 = mmol/L

Sample considerations

Sample type

Serum, plasma, and urine


Heparin is the only anticoagulant that should be used on samples for Na+ measurements. The used of Na2EDTA should be avoided because it will cause spurious increases in Na+ concentration from the sodium in the anticoagulant.


In human serum and plasma samples, sodium is reportedly stable for 2 weeks at 15 – 25°C or 2 – 8°C. Samples of urine should be stored at 4°C.


  • Lipemia: Severe lipemia due to chylomicrons (e.g. postprandial) will falsely decrease sodium concentrations measured with indirect potentiometry (chemistry analyzer) but not direct (blood gas) potentiometry. Since indirect potentiometry is the main method used to determine electrolyte concentrations on chemistry panels, lipemia (when severe) may affect sodium results.
  • Hemolysis: If severe, this may decrease sodium concentrations, due to dilution with intra-erythrocytic water.
  • Icterus: No effect.

Test interpretation

Changes in sodium should be interpreted with respect to the hydration status of the patient. Different causes are operative depending on if the patient is hyper-, norm-, or hypovolemic.


Serum Na+ concentration within the reference interval can still indicate an abnormal state if body water is abnormally high or low. Animals that are normonatremic but dehydrated have proportional deficits in body water and body Na+. Vomiting, diarrhea, and renal disease are common conditions in which normonatremia and dehydration are found.  Normonatremic animals with increased extracellular fluid have increased total body Na+.


This can develop if water is lost in excess of sodium (hypotonic fluid losses or pure water loss) or if sodium is ingested in excess of water. Hypotonic fluid loss is the most common cause of hypernatremia and is usually accompanied by hypovolemia with the body responses serving to drop the sodium, but only if the thirst reflex and ADH responses are intact. Hypernatremia in a hypovolemic animal usually means ADH is dysfunctional (e.g. renal tubular disease) or the thirst response is inhibited or there is reduced or no access to water.

Hypernatremia is always associated with hyperosmolality and results in CNS signs due to cellular dehydration. In a study of 957 dogs and 338 cats, the most common pathophysiologic processes causing hypernatremia were gastrointestinal fluid losses (e.g. vomiting and diarrhea in dogs and cats), central diabetes insipidus (dogs, “free” water loss via kidneys), chronic kidney disease and nonoliguric acute kidney injury (cats, hypotonic fluid losses), and fever or hyperthermia (dogs, obligatory insensible losses via the respiratory tract). Animals frequently had more than one process occurring. Clinical signs were frequently obtundation (preventing water intake), vomiting and lethargy in both dogs and cats and interestingly, clinical signs of dehydration were more evident in cats than dogs with only 27% of dogs versus 55% of cats having signs of hypovolemia. Hypernatremia was associated with a higher mortality rate, particularly when moderate to severe (defined as 11-15 and >15 mmol/L above the reference interval) (Ueda et al 2015). In large animals, hypernatremia is due to water restriction and salt poisoning (large animals), hypotonic fluid losses with diarrhea plus inadequate access to water or water deprivation or renal disease (salt-losing nephropathy). In calves, hypernatremia is associated with mortality (Trefz et al 2017). In both small and large animals, hypertonic saline administration can result in hypernatremia.

The following are general mechanisms of hypernatremia:

  • Artifact: Hypernatremia (pseudohypernatremia) can occur if water is lost from the blood sample tube (not sealed properly).
  • Iatrogenic: Hypertonic fluid administration can result in hypernatremia, particularly if animals have limited access to water. Similarly, calves with diarrhea that are given hypertonic oral electrolyte replacers can develop hypernatremia (Pringle and Berthiaume 1988).
  • Pathophysiologic
    • Water deficit: Animals are usually normovolemic. Moderate to severe hypernatremia is more likely to develop in these situations if the animal does not drink or access to water is concurrently restricted.  The following are causes of water deficit:
      • Inadequate intake: Lack of access to water, neurological disease causing decreased drinking (e.g. primary adipsia/hypodipsia – no thirst reflex). Primary adipsia has been reported in Miniature Schnauzers and in cats. Lack of access to water is an uncommon cause of hypernatremia in dogs and cats (Ueda et al 2015).
      • Hypotonic fluid losses: This most commonly occurs through the gastrointestinal tract and kidney and less commonly through the respiratory tract and skin. Hypernatremia will often be due to decreased water intake (primary mechanism) or deficient ADH responses in these cases (since these compensatory mechanisms should kick in).
        • Respiratory tract: Panting (fever, heat stroke) will result in excessive loss of water.
        • Kidney: “Free” water loss (water > sodium) can occur with diuresis associated with central or nephrogenic diabetes insipidus (lack of ADH or inability of diseased tubules to respond to ADH). Renal losses can also occur with any cause of polyuria (e.g. hyperadrenocorticism in dogs), including osmotic or chemical diuresis or renal disease (e.g. polyuric renal disease in horses and cattle).
        • Gastrointestinal system: Vomiting, diarrhea.
        • Other sources of loss: Third space losses (very uncommon, e.g. peritonitis, uroabdomen), cutaneous losses (severe burns, uncommon).
    • Salt gain: Increased sodium intake (with restricted water access, e.g. salt poisoning in calves, wrongly mixed oral electrolyte replacement) and increased sodium retention by the kidneys, such as in hyperaldosteronism (rare).


Hyponatremia results from gain of water, retention of “free” (or electrolyte-poor) water, or excess losses of sodium from the body (latter is uncommon, e.g. hypertonic fluid loss), which causes hyponatremia due to hypovolemia and water intake and retention [via ADH]). Hyponatremia usually (but not always) indicates a hypo-osmolar state. Severe hyponatremia is associated with central pontine myelinolysis from oligondendrocyte necrosis. This results in CNS signs after rapid correction of severe hyponatremia, usually within 3-4 days of therapy. It is important to correct severe hyponatremia gradually to prevent this fatal complication.

Below is a list of mechanisms with potential causes for hyponatremia. The most common diseases resulting hyponatremia in small animals include hypotonic fluid losses (gastrointestinal, renal, e.g. osmotic or chemical diuresis or Addison’s disease, third space “losses” or sequestration). The fluid losses are usually concurrent with dilution of sodium by water replacement (either shifting of intracellular or interstitial water into the intravascular space, ADH resorbing water in the collecting tubules of the kidney, or drinking water). When hyponatremia occurs in conditions associated with hypervolemia due to perceived volume depletion (e.g. congestive heart failure [with or without diuretics], liver disease and nephrotic syndrome), the drive to rectify the perceived volume depletion results in continued retention of water despite the already existing hypervolemia (i.e. a low sodium concentration in hypervolemic states usually indicates a defect in water excretion, because the body can get rid of water readily via the kidneys). Diuretics will also cause hyponatremia due to sodium loss in kidney and compensatory renin-vasopressin responses. Common causes of hyponatremia in large animals include hypotonic fluid losses with water retention as indicated above, such as diarrhea, sweating (horses), drainage of fluid from thoracic and abdominal effusions, and sequestration within third spaces.

  • Artifact
    • Lipemia and hyperproteinemia: False decreases in sodium (pseudohyponatremia) occur with indirect potentiometry or flame photometry in hyperlipemic and hyperproteinemic (hyperglobulinemic) states. This is due to volume displacement (see lipemia under related links). This will only occur in very lipemic samples, with increases in chylomicrons (e.g. triglyceride concentrations >1500 mg/dL or lipemic index > 120 units) or marked increases in globulins (usually as a consequence of plasma cell neoplasms or intense antigenic stimulation resulting in monoclonal and polyclonal immunoglobulin increases, respectively). We have seen a severe lipemia due to chylomicrons result in a pseudohyponatremia but it is rarely encountered with increases in globulins, since an increase in total protein by 1 g/dL may only decrease the sodium concentration by 0.25 mEq/L (i.e. minimal effect). Accurate electrolyte concentrations can be obtained by direct potentiometry (or use of a blood gas machine to measure electrolytes).
  • Iatrogenic
    • Diuretic therapy: Will result in obligate losses of sodium (chemical diuresis). Animals may be normovolemic (if they have access to water) or hypovolemic. 
    • Hypotonic fluid administration
  • Pathophysiologic

    • Hyperosmolar states: Sodium concentrations can be reduced in hyperosmolar states, such as diabetes mellitus with hyperglycemia or mannitol therapy, which cause hyperosmolality, resulting in a shift of water from cells into blood, diluting out electrolytes (so-called solvent drag). Clinically, correction formula are often applied to take into account the fluid shifts in patients with diabetes mellitus. Increases in 100 mg/dL increments in glucose may decrease sodium by 1.6 mEq/L when glucose is <400 mg/dL, but a larger decrease (2.4 mEq/L) occurs at glucose concentrations higher than this value. The latter formula was based on a transient hyperglycemia induced in human volunteers by giving intravenous infusions of 20% dextrose but were also prevented from releasing insulin in response to a glucose load via administration of somatostatin (Hillier et al 1999), however the latter situation does not truly reflect the diabetic state. It is unclear if these fluid shifts occur with transient hyperglycemias with insulin available, e.g. stress or epinephrine response.
    • Volume overload (hypervolemic hyponatremia): Inappropriate water retention occurs when the body perceives a decrease in ECV and stimulates non-osmotic ADH release (often due to hypoalbuminemia in liver disease or nephrotic syndrome). In congestive heart failure, decreased blood pressure results in decreased effective circulating volume and stimulates water and salt retention, despite increased extracellular fluid and pulmonary edema or ascites. In advanced renal failure, there are reduced numbers of nephrons to appropriately excrete the excess water from polydipsia. In these situations, animals are hypervolemic.
    • Excessive water intake (normovolemic hyponatremia): This will result in increased GFR and decreased sodium absorption with natriuresis. This occurs with psychogenic polydipsia (has been reported in large breed dogs), the syndrome of inappropriate ADH release (ADH release without appropriate osmotic or volemic stimuli – has been reported in dogs secondary to heartworm infection and neoplasia), antidiuretics and hypotonic fluid administration. In these situations, animals are normovolemic as the water is equally distributed between intra- and extra-vascular compartments. The increased water intake overwhelms the kidney’s ability to excrete the excess fluid.
    • Hypertonic fluid losses (hypovolemic hyponatremia): Sodium can be lost in excess of water with secretory diarrhea (mostly in calves), sequestration of sodium-rich fluids with abomasal disorders in cattle (displaced abomasa, atony – the sodium-rich fluids likely originate from refluxed biliary secretions [Gaishauser and Seeh 1996], which are sodium-rich), small intestinal obstruction or ileus, sweating in horses, and rarely severe burns.
    • Hypotonic fluid losses (hypovolemic hyponatremia) with a thirst, ADH or renin-AgII-aldosterone response: This is the most common cause of hyponatremia and can be due to renal or non-renal (gastrointestinal, third space, cutaneous) mechanisms. Dilutional effects due to movement of water from the interstitial or intracellular space into the blood, increased water intake via drinking or increased ADH with water retention by the kidneys (limited by volemic status in non-renal causes of fluid loss) are major contributory factors to the hyponatremia. Movement of water from outside to within the vasculature and water intake via drinking are the main mechanisms of sodium dilution in renal or non-renal fluid losses.
      • Renal losses:
        • Proximal renal tubule dysfunction: Results in reduced sodium (and water) absorption in renal disease (especially in horses and cattle). Cattle with renal failure have a consistent moderate to marked hyponatremia.
        • Lack of aldosterone (hypoaldosteronism): Aldosterone is necessary for sodium (and water) absorption in the aldosterone sensitive portion of the distal nephron (late distal tubules, collecting tubules) of the kidney via a transporter ENaC. This transporter is linked to paracellular chloride absorption or potassium excretion in principal cells.
        • Osmotic or chemical diuresis: Diabetes mellitus (osmotic) or diuretics (especially loop diuretics). It is debatable if sodium is really lost in osmotic diuresis or if the hyponatremia is due to dilutional effects.
      • Gastrointestinal losses: Diarrhea and vomiting. Horses and cattle with severe diarrhea are very likely to be moderately or markedly hyponatremic and dehydrated. Dogs and cats with vomiting and diarrhea are less likely to be hyponatremic, unless there are other sources of sodium loss or marked hypovolemia.
      • Third space losses (ruptured or obstructed urinary tract, peritonitis, repeated drainage of chylothorax). Accumulation of fluid in body cavities will cause perceived volume depletion with stimulation of ADH secretion, resulting in water intake and water retention by the kidneys, which serves to dilute blood sodium. With uroabdomen, sodium and water will move into the abdominal cavity since urine is usually sodium poor (favorable concentration gradient for sodium to move out of plasma and into the cavity.
    • Other causes:
      • Intracellular translocation: Sodium can move intracellularly into skeletal muscle after severe muscle injury.
      • Decreased intake: A low sodium diet or decreased food intake from anorexia or inappetence is unlikely to result in a hyponatremia. Ruminants may be an exception, where a mildly decreased sodium concentration may be seen (most of their sodium comes from diet).


  • DiBartola SP: Disorders of sodium and water: Hypernatremia and hyponatremia. In: Fluid, electrolyte and acid-base disturbances in small animal practice, 4th edition. Ed. Dibartola SP. 2011.
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