Sodium

 
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Physiology

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 concentration, 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 the cell. The kidney plays a critical role in maintenance of ECF volume, via sodium and water retention in response to antidiuretic hormone (ADH) and aldosterone. Regulation of body water is accomplished through osmoreceptors and baroreceptors.

  • Osmoreceptors: These respond to changes in osmolality, principally sodium concentration. Hypernatremia will stimulate ADH release from the pituitary gland.  ADH stimulates thirst and promotes water retention in the kidneys by opening up water channels (aquaporins) in the distal convoluted tubules and collecting ducts. This results in increased water intake and water retention by the kidney. Thirst is stimulated by as little as a 1-2% increase in osmolality. Increases in free water will thus reduce sodium concentration. Decreased plasma osmolality (low sodium) would suppress ADH secretion.
  • Baroreceptors: Baroreceptors are sensitive to changes in stretch of blood vessel walls, thus are affected by circulating volume (ECV). The ECV is the part of the extracellular fluid that is in the arterial system and is effectively perfusing the tissues. It usually varies directly with ECF volume. With hypovolemia (decreased ECV), baroreceptors stimulate the renin-angiotensin system, the end result being mineralocorticoid (aldosterone) release from the adrenal cortex. Aldosterone stimulates increased absorption of NaCl and promotes the excretion of potassium and hydrogen in the distal tubules of the nephron. NaCl retention promotes water resorption, thus correcting the hypovolemia. Hypovolemia also stimulates thirst (a decrease in ECV of 7-10% is required for thirst stimulation). Opposite changes occur with hypervolemia.

Methods

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.

Procedure

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

Anticoagulant

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.

Stability

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.

Interferences

  • Lipemia: Lipemia 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 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.

Normonatremia

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+.

Hypernatremia

This can develop if water is lost in excess of sodium or if sodium is ingested in excess of water. The first mechanism is the most common one. 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), chronic kidney disease and nonoliguric acute kidney injury (cats), and fever or hyperthermia (dogs). Animals frequently had more than one process occurring. Clinical signs were frequently obrandation, 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, diarrhea with inadequate access to water, water deprivation, renal disease and hypertonic saline administration.

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.
  • 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 respiratory tract, gastrointestinal tract and kidney.
        • Respiratory tract: Panting (fever, heat stroke) will result in excessive loss of water. P
        • Kidney: Pure water loss 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), cutaneous losses (burns, uncommon).
    • Salt gain: Increased sodium intake (with restricted water access, e.g. salt poisoning in calves) and increased sodium retention by the kidneys, such as in hyperaldosteronism.

Hyponatremia

Hyponatremia results from retention of free water or excess losses of sodium from the body. Hyponatremia usually (but not always) indicates a hyposmolar 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 gastrointestinal losses of sodium, diabetes mellitus (although concurrent dehydration may normalize sodium values), congestive heart failure (with or without diuretics), third space losses, Addison’s disease, hypotonic fluid administration, liver disease and diuretic administration. Common causes in large animals include diarrhea, sweating (horses), drainage of fluid, 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 (e.g. triglyceride concentrations >1500 mg/dL) 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). Accurate electrolyte concentrations can be obtained by direct potentiometry (or use of a blood gas machine to measure electrolytes).
    • Hyperosmolar states: Sodium concentrations can also be reduced in hyperosmolar states, such as hyperglycemia or mannitol therapy, which cause hyperosmolality, resulting in shifts of water from cells into blood, diluting out plasma water (so-called solvent drag).
  • Iatrogenic
    • Diuretic therapy: Will result in obligate losses of sodium. Animals may be normovolemic (if they have access to water) or hypovolemic.
  • Pathophysiologic

    • 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). This occurs in congestive heart failure, liver disease, nephrotic syndrome and advanced renal failure (in this condition, 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.
    • Hypertonic fluid losses (hypovolemic hyponatremia): Sodium can be lost in excess of water via renal or non-renal (gastrointestinal, third space, cutaneous) mechanisms. This usually results in hypovolemia. In  cases of non-renal sodium losses, dilutional effects due to stimulation of ADH with increased water intake and water retention by the kidneys will contribute to the hyponatremia.
      • Renal losses:
        • Proximal renal tubule dysfunction: results in reduced sodium 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 absorption in distal convoluted tubules of the kidney).
        • Osmotic diuresis: Diabetes mellitus.
      • 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 causes of sodium loss.
      • Third space losses (ruptured or obstructed urinary tract, peritonitis, 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.
      • Cutaneous losses: Sweating in horses.
    • Other causes:
      • Intracellular translocation: Sodium can move intracellularly into muscle after severe muscle injury.
      • Decreased intake: A low sodium diet or decreased food intake from anorexia or inappetance is highly unlikely to result in a hyponatremia.
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