Cellular Physiology and Metabolism of Magnesium

Magnesium is a divalent cation (Mg⁺⁺) that is predominantly localized to the intracellular compartment (99%). It is the second most abundant intracellular cation after potassium and plays an important role in cellular metabolism and homeostasis. At the cellular level, Mg⁺⁺ influences membrane function by regulating ion transport; Mg⁺⁺ is required for sodium/potassium–adenosine triphosphatase (Na⁺/K⁺-ATPase) activity, which maintains transmembrane gradients for Na⁺ and K⁺.^2,3 Magnesium also regulates intracellular calcium (Ca⁺⁺) flux by competing for Ca⁺⁺ binding sites and influencing intracellular Ca⁺⁺ transport.^2,3 It is an essential cofactor for most ATP-requiring processes. Magnesium acts by neutralizing the negative charge on the phosphate anion of ATP to facilitate enzyme binding and hydrolysis of the phosphate moiety. Intracellular Mg⁺⁺ is required for numerous critical biochemical processes, including DNA synthesis, activation of gene transcription, initiation of protein synthesis, and regulation of energy metabolism via glycolytic and tricarboxylic acid cycles.^2–5

Total body magnesium (21-28 g) is distributed in bone (53%), muscle (27%), soft tissue (19%), and blood (0.8%).² The normal concentration of total magnesium in serum is 1.5 to 2.3 mg/dL. Approximately 19% of circulating magnesium is bound to protein (predominantly albumin), whereas 14% is complexed to serum anions (citrate, phosphate, and bicarbonate). The majority in serum exists in ionized form (67%), which represents the physiologically active species.^2,6 Consequently, measurements of total serum magnesium may not accurately reflect the relative abundance of circulating Mg⁺⁺.^1,2

Magnesium homeostasis is maintained by the small intestine, kidney, and bone.^2,7 Average dietary intake is approximately 300 mg per day. Normally, only one-third of dietary Mg⁺⁺ is absorbed.^7,8 However, intestinal Mg⁺⁺ uptake may increase to compensate for dietary or total body Mg⁺⁺ deficiency.^2,7,8 Unlike calcium, there are no hormonal mechanisms for regulating Mg⁺⁺. Consequently, normal renal filtration and reabsorption of Mg⁺⁺ represent important regulatory mechanisms for Mg⁺⁺ homeostasis.^2,7 Non–protein bound Mg⁺⁺ is filtered by the glomerulus. Under normal conditions, up to 95% of filtered Mg⁺⁺ is reabsorbed in either the proximal tubule (35%) or in the thick ascending loop of Henle (60%). Mg⁺⁺ reabsorption in the loop of Henle is linked to sodium chloride (NaCl) transport and inversely related to flow. Consequently, diuretic use and other conditions associated with increased tubular flow result in decreased Mg⁺⁺ reabsorption.^2,7 Under conditions of persistent Mg⁺⁺ deficiency, mobilization of Mg⁺⁺ from bone also represents a potential homeostatic mechanism.²

Prevalence and Etiology of Hypomagnesemia in Patients in the Intensive Care Unit

The reported prevalence of hypomagnesemia in adult intensive care unit (ICU) admissions ranges from 15 to 60, depending on whether total or ionized magnesium is measured.^1,9 A recent study identified severe ionized hypomagnesemia most commonly following liver transplantation and in patients with severe sepsis.¹ Magnesium deficiency in critically ill patients may be caused by inadequate Mg⁺⁺ intake, increased renal or gastrointestinal (GI) losses, acute intracellular shifts of Mg⁺⁺, and other medical conditions (e.g., burn injury, massive blood transfusion, or cardiopulmonary bypass [CPB]). Increased renal losses of Mg⁺⁺ are associated with alcohol abuse, diabetes, acute tubular necrosis (ATN), diuretics, aminoglycosides, amphotericin, cyclosporin, cisplatin, digoxin, and other medications.^1,2,7,10 Vomiting, diarrhea, nasogastric tube losses, and pancreatitis are associated with increased GI losses of Mg⁺⁺.^1,2,7,11 Acute intracellular shifts caused by refeeding with glucose or amino acids, insulin, catecholamines, or metabolic acidosis also may result in hypomagnesemia.^1,2,7,