© Manning, AM (2001) 'Electrolyte disorders'. VCNA 31(6); 1289-1321

Maintenance of electrolytes within a normal range is important to reduce clinical symptoms of disease, to prevent complications and to minimise mortality in the patient. The electrolytes of particular importance are sodium (Na), potassium (K), chloride (Cl), Magnesium (Mg), phosphate (P) and Calcium (Ca).

Sodium (Na⁺)

Sodium is the primary extracellular cation and osmole and it acts to maintain water in osmotic equilibrium. The serum sodium concentration and serum osmolality are closely controlled by water homeostasis, which is mediated by thirst, arginine vasopressin, and the kidneys. Osmoregulation is normally tightly regulated by the release of antidiuretic hormone (ADH), which is secreted by the hypothalamus and stored in the posterior pituitary. ADH release and thirst are stimulated by increases in plasma osmolality. ADH release causes increased renal-collecting tubule permeability, leading to increased reabsorption of water, water retention and excretion of concentrated urine. Volume receptors in the cardiopulmonary circulation, carotid sinuses, and aortic arch stimulate the release of ADH when they sense decreased pressure or volume. Volume receptors in the afferent arterioles of the kidneys also respond to decreased volume by activating the renin-angiotensin-aldosterone system, leading to sodium and water retention. Normal sodium homeostasis maintains a serum sodium concentration in the range of 145-155mE/L.

Renal fluid and sodium losses resulting in sodium depletion are most commonly caused by hypoadrenocorticism ( Addison's disease) or diuretic administration. Non-renal causes of sodium depletion include gastrointestinal losses (e.g. vomiting, diarrhoea) and third space losses such as pleural effusion (e.g. neoplasia, chylothorax, lung lobe torsion) or abdominal effusion (e.g. carcinomatosis, pancreatitis, uroabdomen).

Potassium (K⁺)

Potassium (K) is the most abundant intracellular cation, with 95% to 98% of total body potassium contained within cells. Potassium plays several important roles within the body, the most important of which is maintaining normal resting membrane potential in conjunction with sodium. The normal ratio of sodium to potassium is established by the Na-K-ATPase pump, which maintains high intracellular levels of potassium relative to extracellular levels. If this ratio is disturbed, the membrane potential is altered and neuromuscular conduction is affected. Potassium is also critical to many enzyme systems, including protein, DNA, and glycogen synthesis. Because of the important role that potassium plays in cell membrane potential, serum potassium levels are maintained within a narrow range of approximately 3.5-5.5 mEq/L.

Potassium homeostasis is regulated by renal excretion, hormonal redistribution and changes in acid-base status. Potassium absorption is unregulated, and after a meal, excess potassium is redistributed to an intracellular location under the effects of insulin and ß-adrenergic catecholamines. During the hours after a meal, potassium is gradually released from the cells into the serum for glomerular filtration, tubular resorption and eventually, renal excretion. Renal tubular potassium secretion is influenced by renal intracellular potassium concentrations, aldosterone, tubular flow rate in the distal nephron and sodium-generated tubular transepithelial potential difference. High intracellular potassium concentrations, aldosterone, increased tubular flow rates and sodium reabsorption favour renal potassium excretion. The colon also excretes a limited amount of potassium. In the presence of metabolic acidosis, potassium moves out of cells into the serum in exchange for hydrogen ions. If organic ions are not present, the amount of potassium present in the serum as a result of metabolic acidosis may be predicted by the following calculation. For each 0.1 decrease in blood pH, a 0.6 mEq/L increase occurs in serum potassium. In acidotic patients that have low total body potassium stores, the extracellular movement of potassium ons can create a falsely elevated serum potassium concentration. This is particularly true of diabetic ketoacidotic patients, in whom the potassium level may drop precipitously after initiation of insulin therapy and correction of acidosis.

Gastrointestinal losses of potassium usually result from vomiting stomach fluids rich in sodium, potassium, hydrogen ion, and chloride. Minor losses occur with diarrhoea. Loss of hydrogen ions through vomiting results in metabolic alkalosis with a subsequent shift of potassium into the cells in exchange for hydrogen ions as the body attempts to increase acidity of blood. The renin-angiotensin system is stimulated by hypovolaemia and releases aldosterone, which further enhances potassium excretion by the kidneys.

Urinary loss of potassium can occur after the administration of several drugs and under the influence of several disease conditions. Loop and thiazide diuretics promote renal potassium excretion by increasing the flow rate in the distal tubule and by enhancing aldosterone secretion in response to vascular volume contraction. Administration of amphotericin B may promote kaliuresis by increasing renal tubular cell membrane permeability. Penicillins increase urinary potassium secretion by acting as non-resorbable cations.  Increased mineralocorticoid activity and increased sodium delivery to the distal nephron such as that occurring with hyperadrenocorticism (Cushing's) and primary hyperaldosteronism also promote kaliuresis. 

Intracellular shifts of potassium are frequent causes of hypokalemia. Metabolic alkalosis causes an intracellular shift of potassium in exchange for hydrogen ions. Administration of insulin and glucose also causes potassium to shift into cells by stimulating glucose metabolism and as a result of the direct effect of insulin on the cellular uptake of potassium. Increased levels of circulating catecholamines such as occurs with pain, sepsis, traumatic injuries and hypothermia also cause an intracellular shift of potassium.

Hyperkalemia may be caused by increased uptake, reduced renal excretion or by a shift of potassium from intra- to extracellular fluids. Reduced renal excretion is the most common cause of hyperkalemia and may result from acute, oliguric or anuric renal failure, urinary bladder rupture, urethral tear, urethral obstruction, hypoadrenocorticism or gastrointestinal disease. Hyperkalemia resulting from transcellular shifts includes metabolic acidosis, snake bites, heat stroke, and severe crushing injuries.

Chloride (Cl^-)

Chloride is the principal anion in the body and the predominant anion in the extracellular fluid. The most important role of chloride in the body is its contribution to acid-base balance. Low serum chloride concentrations promote metabolic alkalosis, whereas high serum concentrations promote metabolic acidosis. Normal serum chloride concentrations are 1017-123 mEq/L in cats.

Hypochloremia in cats is defined as a serum chloride concentration of less than 110 mEq/L. Decreases in serum chloride concentration may be artifactual, which is termed pseudohypochloraemia, often associated with CHF, hypoadrenocorticism, and pleural or peritoneal effusion (e.g. carcinomatosis, pancreatitis). In these situations, the corrected chloride level is normal. Chronic respiratory acidosis or hypercapnia of any cause increases renal excretion of chloride, leading to hypochloremia. Gastrointestinal losses are the result of vomiting chloride-rich gastric contents and hypovolaemia. If more chloride is reabsorbed in the proximal convoluted tubule during volume depletion, less is available in the distal convoluted tubule for exchange with bicarbonate. By holding bicarbonate, the kidney conserves sodium to maintain electrochemical neutrality, and because more sodium is reabsorbed in the distal convoluted tubule, more potassium and hydrogen are exchange and subsequently excreted.

Hyperchloremia is associated with pure water loss (such as is seen with diabetes insipidus) or with hypotonic fluid fluid loss (osmotic diuresis). Other potential causes include lipaemia, hemoglobinemia, bilirubinemia and potassium bromide administration. Renal chloride retention occurs with renal failure, renal tubular acidosis, diabetes mellitus and chronic respiratory alkalosis.

Magnesium (Mg²⁺)

Magnesium is one of the most abundant intracellular cations, second only to potassium. Most magnesium is contained within the crystal mineral lattice of bone (60%) and skeletal muscle (20%), with only a small amount present in serum and interstitial body fluid (1%). The remaining magnesium is found in other tissues, primarily the heart and liver. Approximately one-third of the magnesium in the skeletal system is available in a surface-limited exchange pool and serves as a reservoir for maintenance of extracellular magnesium concentration. Three forms of magnesium exist in serum: the physiologically active ionised form (55%), the protein bound form (30%) and the anion-complexed fraction. Serum magnesium levels may appear normal despite whole-body depletion or excess. Normal values range from 1.89-2.51 mg/dL.

Magnesium serves as a requires coenzyme for Na-K-ATPase, Ca-ATPase and proton pumps, thereby regulating the sodium-potassium gradient across cell membranes and intracellular calcium concentrations. By this mechanism, magnesium is responsible for maintenance of electric excitability in nerve, cardiac, and muscle cells. Magnesium is also integral to the production and functioning of ATP, protein and nucleic acid synthesis, regulation of vascular smooth muscle, cellular second messenger systems and cell signal transduction. Magnesium homeostasis is regulated primarily through small intestinal reabsorption and renal excretion.

Hypomagnesaemia has been reported to occur in approximately 54% of critically ill patients, establishing hypomagnesaemia as the most clinically significant electrolyte abnormality in ill patients. Hypomagnesaemia can lead to  inappropriate kaliuresis by increasing cellular membrane permeability, which allows potassium to leak from cells and to be excreted in the urine. This type of hypokalaemia may be refractory to parenteral potassium supplementation until the magnesium deficiency has been corrected.

Magnesium deficiency may occur as a result of decreased intake or increased loss, associated with inadequate intake, chronic or small bowel diarrhoea, IBD, malabsorption syndromes, pancreatic insufficiency, cholestatic liver disease, renal disease (e.g. glomerulonephritis, pyelonephritis, drugs such as Amphotericin B, aminoglycosides, cyclosporine, and diuretics), diabetic ketoacidosis, Cushing's disease, hyperthyroidism, primary hyperparathyroidism and catecholamine excess states (e.g. trauma, sepsis, burns, hypothermia).

Phosphorus (P^-)

Phosphorus is the most abundant intracellular anion. As with magnesium, most phosphorus is contained within the skeleton as hydroxyapatite (80-85%) and in skeletal muscle (9-15%), with relatively little in the extracellular fluid (1%). Two forms of phosphate are present in the body: an inorganic phosphate and an organic phosphate ester. The inorganic form is present in the extracellular fluid, where 12% to 15% is protein bound, primarily to albumin, and the rest exists freely as monohydrogen or dihydrogen phosphate. When measuring serum phosphate, only the inorganic (monohydrogen and dihydrogen) phosphate is measured. Organic phosphate is an important component of phospholipids, phosphoproteins, nucleic acids, enzymes and cofactors. Organic phosphorus is a component of mitochondria in the electron transport system, a component of cyclic AMP used in the second messenger system for hormones, an ATP energy source, and a component of 2,3 diphosphoglycerate (2,3-DPG) in red blood cells. Inorganic phosphate is involved in oxidative phosphorylation, production of 2,3-DPG in red blood cells, and glycogenesis, and it serves as a vital source of ATP. The small intestine, kidneys, and skeleton regulate phosphate homeostasis. Most phosphate is absorbed in the small intestine and excreted in the faeces. Serum phosphate is filtered by the glomerulus and primarily reabsorbed in the proximal convoluted tubules before excretion in the urine. During periods of chronic depletion, the skeleton functions as a reservoir and mobilises phosphorus from the skeleton into the serum. 

Severe phosphate depletion may exist in spite of a normal or increased level of serum phosphate concentration as often occurs in untreated diabetic ketoacidosis, respiratory alkalosis and nutritional recovery syndrome.

Hyperphosphatemia is common with chronic renal failure, because of decreased glomerular filtration and phosphorus retention. Other causes include tumour lysis syndrome, tissue injury, rhabdomyolysis, hemolysis, Vitamin D toxicosis, hypoparathyroidism and acromegaly. Hyperphosphatemia can cause soft tissue calcification, hypernatremia, hypocalcaemia, tetany and diarrhoea. Hyperphosphatemia may also contribute to renal secondary hyperparathyroidism by decreasing calcitriol, with a resulting decrease in calcium reabsorption, which leads to increased parathyroid hormone levels.

The normal range of serum inorganic phosphate is 2.5-6.0 mg/dL

Calcium (Ca²⁺)

Normal serum calcium ranges from 9.4-11.2 mg/dL

As with other divalent cations, magnesium and phosphorus, most calcium is contained within the skeletal system. 99% is stored as hydroxyapatite in the bone, and the remaining 1% is distributed in the soft tissues and extracellular space. Calcium circulates in the blood in three forms: a protein-bound fraction (40%), a non-ionised fraction that is chelated with other circulating ions such as bicarbonate, lactate, citrate and phosphate (10%) and a free or ionised fraction (50%) that is thought to be the physiologically active form. Calcium is required for many important cellular level functions, including muscle contraction, hormonal and neurotransmitter secretion, cell division and motility, axonal flow, enzyme activity, cell membrane structure, blood coagulation, generation and propagation of the cardiac action potential and cardiac pacemaker automaticity. Calcium also plays an important role in second- and third-messenger systems.

Calcium homeostasis is controlled by the activities of parathyroid hormone (PTH) and vitamin D (cholecalciferol). Vitamin D is a fat-soluble steroid that is present in the diet and can be synthesised by the skin in the presence of ultraviolet light. In response to low serum calcium levels, the parathyroid glands release PTH, which acts to increase calcium concentrations by the following mechanisms. In the presence of Vitamin D, PTH stimulates bone marrow resorption and release of calcium. PTH also promotes kidney formation of 1,25-dihydroxycholecalciferol (calcitriol), a major metabolite of vitamin D, which in turn enhances intestinal and renal absorption of calcium. Thyroid hormone also has an effect on serum calcium levels through its effect on the skeleton. Increased thyroid hormone levels increase bone resorption and may increase serum calcium levels, whereas decreased thyroid hormone levels decrease bone resorption and may decrease serum calcium levels.

Hypocalcemia is often of multifactorial origin, resulting from impaired PTH secretion or action, impaired vitamin D synthesis or action, and calcium chelation or precipitation. Causes of hypocalcemia include: primary hypoparathyroidism, secondary hypoparathyroidism (thyroidectomy, parathyroidectomy, cervical trauma, hypomagnesemia), impaired vitamin D synthesis (anorexia or malnutrition, intestinal malabsorption, liver disease, renal disease, sepsis), chelation (urethral obstruction, acidosis, pancreatitis, lactation, soft tissue trauma, sodium phosphate enemas).

Hypercalcemia is usually the result of malignancy, hyperadrenocorticism, hyperparathyroidism, exogenous calcium administration, vitamin D intoxication, or hypercalcemia of renal failure.