Although magnesium (Mg) is the fourth most common cation in the body, less than 0.5 percent is present in the serum, y of which about 30 percent is protein bound, 15 percent is chelated to serum anions, and 55 percent exists in the ionized (physiologically active) form. y The amount of protein-bound Mg is directly proportional to the serum albumin concentration and the pH, and is inversely proportional to the serum anion concentration. In addition, transcellular shifting between the intracellular and extracellular compartments can occur. Although the Mg contained in bone is not readily exchangeable with that present in the serum, a shift of Mg from the ECF to the intracellular fluid occurs with insulin administration y and the correction of acidosis. y Intracellular Mg functions as an essential co-factor in hundreds of important enzymatic reactions. Mg balance is regulated by the GI tract and the kidney, which maintains the serum Mg concentration between 1.6 and 2.1 mEq/L. An interrelationship exists between Mg and Ca, as evidenced by the development of hypocalcemia in response to Mg depletion. y In fact, Mg depletion is the most common cause of hypocalcemia in a general hospital population. y An interrelationship also exists between Mg and K, and although the mechanism is unknown, it may be related to the Mg requirement of the Na/K ATPase enzyme system.y
Because the serum Mg concentration contributes less than 0.5 percent of total body Mg, the terms hypomagnesemia and Mg deficiency are defined separately. Hypomagnesemia refers to a serum Mg concentration below the normal range, whereas Mg deficiency refers to a decrease in the total body or intracellular Mg contents. In the clinical setting of severe tissue Mg deficiency, the serum Mg may be normal or even elevated. Conversely, in the setting of normal tissue stores, hypomagnesemia may be present.
Pathogenesis and Pathophysiology. Mg affects both the PNS and CNS. Peripherally, Mg has a curare-like action at the neuromuscular junction, an action counteracted by acetylcholinesterase inhibitors and Ca. y Mg is both a Ca channel antagonist (opposes Ca) and a membrane stabilizer (acts synergistically with Ca).y Centrally, Mg has a depressant effect (interestingly, hibernating animals are hypermagnesemic), which is opposed by pentylenetetrazol (Metrazol). y
Epidemiology and Risk Factors. Among hospitalized patients, the prevalence of hypomagnesemia is about 10 percent; it is approximately 20 percent when only intensive care unit patients are considered. y Because Mg deficiency is more common than hypomagnesemia,y the true incidence of Mg deficiency must exceed 10 percent. Risk factors for the development of hypomagnesemia include chronic diarrheal disorders, ketoacidosis, loop diuretic or digitalis usage, and alcoholism ( ... TabJe.38-5 )  Among patients with steatorrheic states, the prevalence of Mg depletion is about one third; the correlation between fecal Mg and fat content suggests that Mg depletion may be due to formation of a complex between Mg and fat. The recommended daily allowance (RDA) of Mg (1200 mg) for pregnant and lactating women is 50 percent greater than that for nonpregnant women.y
Clinical Features and Associated Disorders. Hypomagnesemia may be asymptomatic, yet when it is symptomatic, the neurological manifestations include agitation, tremor, myoclonus, seizures (rarely), confusion, coma, paresthesias, muscle fasciculations, weakness, presence of Chvostek's and Trousseau's signs, tetany, and hyperreflexia.y , y , y , y In addition, a cardioskeletal mitochondrial myopathy has been described in association with chronic hypomagnesemia. y Athetoid and choreiform movements have also been reported during hypomagnesemia, although these signs may have reflected co-existent liver disease. y Unfortunately, the association of hypomagnesemia with hypokalemia, hypocalcemia, and other metabolic disorders makes it difficult to state with certainty which manifestations truly reflect hypomagnesemia. Importantly, the efficacy of Mg repletion in relieving manifestations of neuromuscular irritability may reflect its curare-like action (i.e., a therapeutic effect rather than reversal of deficiency symptoms). When the clinical manifestations of Mg deficiency are determined by induction of deficiency in human volunteers, GI features (anorexia, nausea, and vomiting), CNS features (lethargy, weakness, and personality change), PNS features (positive Trousseau's and Chvostek's signs, carpopedal
_TABLE 38-5 -- MAJOR CAUSES OF HYPOMAGNESEMIA_
Redistribution (correction of acidotic state) Nutritional deficiencies
Gastrointestinal tract losses (chronic diarrhea) Renal excretion (osmotic diuresis) Drug induced
Acetazolamide, alcohol, aminoglycosides, amphotencin-B, cisplatin, digoxin, ethacrynic acid, furosemide, mannitol, methotrexate, pentamidine theophylline, thiazides Endocrine disorders (hyperthyroidism hyperparathyroidism and hypoparathyroidism, ketoacidosis) Multifactorial (chronic alcoholism, diabetic ketoacidosis)
Data from Olinger ML: Disorders of calcium and magnesium metabolism. Emerg Med Clin North Am 1989;7:795 822; Tosiello L: Hypomagnesemia and diabetes mellitus. Arch Intern Med 1996;156:1143-1148; and Alfrey AC: Disorders of magnesium metabolism. ln Bennett JC, Plum F (eds): Cecil Textbook of Medicine, 20th ed. Philadelphia, WB. Saunders, 1995, pp 1137-1138.
spasm), tremor, and muscle fasciculations may be observed. Unfortunately, these features correlate with the development of hypocalcemia and hypokalemia.
Differential Diagnosis and Evaluation. Although the differential diagnosis of hypomagnesemia is long, it most commonly reflects an inadequate intake superimposed on impaired renal reabsorption or GI absorption. The two major problems in diagnosing Mg deficiency are that the serum Mg content represents only 0.5 percent of the total body content, and that the relationship between the serum level and the intracellular and total body content is poor. Thus, it is not uncommon to suspect hypomagnesemia and be faced with a normal serum Mg level. In this situation, an Mg loading test has been suggested. y The presence of either hypokalemia or hypocalcemia, especially when it is resistant to treatment, makes the likelihood of symptomatic hypomagnesemia even greater, and for that reason, the concentrations of these two electrolytes should be determined. A urine Mg level helps differentiate renal from nonrenal etiologies.
Mg, like Ca, affects both the CNS and the PNS. Because Mg functions as a membrane stabilizer (synergistic with Ca), hypomagnesemia (like hypocalcemia) produces membrane instability. For that reason, it should always be considered in the neurological differential diagnosis of hypocalcemia, especially when hypocalcemia is unresponsive to treatment. Diagnostic considerations to entertain vary with the clinical manifestations; they parallel those of hypocalcemia.
Management. The treatment of Mg deficiency depends on the underlying disorder, the clinical status of the patient, and the degree of deficit. In an emergency setting (e.g., seizure), Mg-sulfate heptahydrate solution may be infused. y In the nonemergent setting, when hypomagnesemia is severely decreased, treatment may be IV or intramuscular. The intramuscular route is safer and preferred, when possible. Because serum Mg equilibrates with intracellular Mg slowly, rapid replacement may cause transient hypermagnesemia. Consequently, total body Mg repletion may require several days of treatment. Finally, in nonemergent settings when the degree of hypomagnesemia is not severe, oral replacement therapy can be undertaken using Mg-oxide. In mild, asymptomatic cases, dietary modification to include high Mg-containing foods (e.g., dried fruits, grains, legumes, green leafy vegetables, and unprocessed cereals) may suffice. During Mg replacement therapy, the serum Mg level should be monitored frequently and treatment continued until a normal serum Mg level is achieved. Because Mg is a neuromuscular depressant, tendon reflexes should be monitored for evidence of overtreatment (diminished reflexes); the infusion should be discontinued if either hypermagnesmia or hyporeflexia is observed. y When Mg is replaced intravenously, Ca gluconate should be on hand to counteract transient hypermagnesemic-induced problems, such as apnea caused by respiratory muscle paralysis.y
Because the kidney is the major regulator of serum Mg levels, hypermagnesemia is frequently observed in patients with renal impairment, especially when the condition is combined with increased Mg intake. By blocking the presynaptic Ca channels, Mg acts to limit depolarization-induced Ca influx. Because exocytosis of acetylcholine-containing vesicles is Ca dependent, neuromuscular depression occurs. Symptomatic hypermagnesemia is infrequently encountered.
In contrast to the neuromuscular irritability observed with hypomagnesemia, the neurological manifestations of hypermagnesemia are characterized by nervous system depression. The predominant neuromuscular manifestation is muscle weakness (or paralysis) due to neuromuscular junction transmission blockade. y The manifestations of hypermagnesemia, both neurological and non-neurological, have been studied in experimental animals and human patients and reflect the degree of elevation of the serum Mg level. In general, patients are asymptomatic until the serum Mg level exceeds 4 mEq/L. y Blood pressure depression begins at levels between 3 and 5 mEq/L,y at which time the reflexes may be slightly depressedy and responsiveness may be slightly impaired. y As the serum Mg level increases further, hypotension becomes more pronounced. At levels between 7 and 10 mEq/L, the reflexes diminish and weakness and ataxia appear. y At this level, lethargy and confusion have been reported, y although this is controversial. In one study, levels as high as 12.4 mEq/L resulted in profound paralysis without significant changes in level of consciousness. y Possible explanations for the mental decline observed in patients with hypermagnesemia include chronicity, which permits the CNS Mg level to rise; hypermagnesemia-induced hypoxic-ischemic encephalopathy; or neuromuscular junction blockade mistaken for mental status decline. y At 10 mEq/L, respiratory impairment appears with resultant hypoxia and hypercapnia. y At levels of 10 to 15 mEq/L, reflexes disappear and a flaccid quadriplegia may develop, and as respiratory embarrassment worsens, CNS narcosis results in coma and death. Other symptoms associated with hypermagnesemia include nausea, lethargy, dilated pupils, bradycardia and, rarely, complete heart block and cardiac arrest. y
The underlying cause of the hypermagnesemia, as well as its neurological and cardiovascular manifestations, should be identified. Respiratory, cardiac, and renal status should be determined. In the setting of hypermagnesemia, sources of Mg should be identified and discontinued. In asymptomatic patients with normal or mildly impaired renal function, this action alone may suffice. Because natriuresis enhances urinary Mg excretion, furosemide may be administered and the urine volume replaced.y Of course, this may induce hypocalcemia. In life-threatening situations, Ca salts can be administered to counteract the neuromuscular blockade and cardiotoxicity. Hemodialysis, using an Mg-free dialysate, is the most effective way of reducing serum Mg levels. y
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