Magnesium plays a fundamental role in many functions of the cell, including energy transfer, storage, and use; insulin release; protein, carbohydrate, and fat metabolism; maintenance of normal cell membrane function; and regulation of parathyroid hormone (PTH) secretion (Guerrero-Romero & Rodriguez-Moran, 2006; Tong & Rude, 2005; Topf & Murray, 2003; Rubeiz et al., 1993). It also has been linked to more than 300 enzymatic reactions. Approximately two thirds of magnesium stores are located in the bones, about one third is found in voluntary and involuntary muscles, and less than 1% is measurable in the extracellular space (Agraharkar & Fahlen, 2002; Dacey, 2001; Topf & Murray, 2003).

Plasma concentrations of magnesium are kept within a very narrow range and are regulated by adjustment in renal excretion, bone uptake, intestinal uptake, and soft tissue stores. Magnesium differs from other ions in two major respects: (1) it is not hormonally regulated, and (2) bone, as the principal storage site for magnesium, does not readily exchange with extracellular magnesium. This inability to mobilize magnesium stores means that in states of negative magnesium balance, initial losses come from the extracellular space, and equilibrium from bone stores does not begin for several weeks (Agraharkar & Fahlen, 2002).

The body contains an average of about 24 total grams of magnesium. Approximately 60% of magnesium is bound to protein, but it is the ionized, unbound magnesium that is ionically active (Topf & Murray, 2003). Despite this fact, ionized calcium levels have not proven to reliably reflect magnesium depletion, and no albumin correction factor has been defined (Topf & Murray, 2005; Dacey, 2001). Magnesium may be reported in mg/dL, mmol, or mEq/L. Plasma concentrations are usually reported in mEq/L, but replacement therapy is administered in units or grams.

The normal plasma magnesium concentration is 1.4 to 1.7 mEq/L (0.7 to 0.9 mmol, or 1.7 to 2.1 mg/dL) (Agraharkar & Fahlen, 2002). Hypomagnesemia is defined as a plasma level less than 1.4 mEq/L (0.7 mmol or 1.6 mg/dL). It is an accepted concept that plasma levels do not always indicate the body’s true status of depletion, yet there are no established methods to define the body’s total magnesium level (Topf & Murray, 2003; Dacey, 2001). Because so little magnesium is located extracellularly, plasma hypomagnesemia often indicates a more severe underlying cellular deficiency. Inability to readily recognize increases in plasma magnesium levels in response to replacement therapy may indicate this intracellular deficiency.

The average American diet contains approximately 360 mg (15 mmol) of magnesium; healthy individuals ingest 0.15 to 0.2 mmol/kg each day to maintain balance (Agraharkar & Fahlen, 2002). Magnesium is absorbed via the small intestine, and the amount absorbed depends on the amount ingested. When dietary ingestion is normal, approximately 30% to 40% is absorbed; when intake is low, approximately 80% is absorbed; if intake is increased (as with oral replacement therapy), only about 25% is absorbed.

The two major pathophysiologic mechanisms of hypomagnesemia are losses via the kidney or gastrointestinal tract. Because the exchange of stored and ionized active magnesium is a slow process, magnesium deficiency is apparent even with minimal losses. Uncommon disorders of metabolism cause a selective defect in magnesium absorption; these have been described as both an X-linked recessive trait and an autosomal recessive disorder linked to chromosome 9 (Chubanov et al., 2005; Schlingmann et al., 2005). There is a physiologic change in the TRPM6 gene that encodes proteins present in intestinal epithelia and kidney tubules that is similar to the receptor channels for magnesium and calcium (Schlingmann et al., 2005; Voets et al., 2004).

Studies of the incidence of hypomagnesemia in the general population are sparse, but its prevalence is estimated to be 1.5% to 15% (Mouw, 2005; Topf & Murray, 2003). Dietary evaluations suggest that magnesium deficiency may be even more prevalent than estimated because of the effects of low dietary intake and the inability of standard testing measures to reflect true intracellular magnesium deficiency (Mouw, 2005; Topf & Murray, 2003). Hypomagnesemia occurs in approximately 12% of hospitalized patients, with the highest incidence in the critically ill (60% to 65%) (Agus, 2006a; Mouw, 2005; Tong & Rude, 2005; Topf & Murray, 2003). A proposed reason for this high incidence in the critically ill is the extent of oxidative stress and inflammation experienced by these patients (Guerrero-Romero & Rodriguez-Moran, 2006).

Patients with acute onset of hypomagnesemia from a clearly identifiable cause have an excellent prognosis for complete recovery from this condition. In conditions of chronic loss, correction of the disorder and its symptoms may be a continuous challenge, although death attributable solely to hypomagnesemia is rare. Despite this lack of evidence regarding the importance of magnesium contributory to death, studies of intensive care patients have shown that the mortality rate is two to three times higher among patients with hypomagnesemia (Topf & Murray, 2003; Rubeiz et al., 1993).