Hypomagnesemia

Background: Magnesium (Mg) is the second-most abundant intracellular cation and, overall, the fourth-most abundant cation. Almost all enzymatic processes using phosphorus as an energy source require magnesium for activation. Magnesium is involved in nearly every aspect of biochemical metabolism (eg, deoxyribonucleic acid [DNA] and protein synthesis, glycolysis, oxidative phosphorylation). Almost all enzymes involved in phosphorus reactions (eg, adenosine triphosphatase [ATPase]) require magnesium for activation. Magnesium serves as a molecular stabilizer of ribonucleic acid (RNA), DNA, and ribosomes. Because magnesium is bound to ATP inside the cell, shifts in intracellular magnesium concentration may help regulate cellular bioenergetics such as mitochondrial respiration.

Extracellularly, magnesium ions block neurosynaptic transmission by interfering with the release of acetylcholine. Magnesium ions also may interfere with the release of catecholamines from the adrenal medulla. Magnesium has been proposed as an endogenous endocrine modulator of the catecholamine component of the physiologic stress response.

Approximately 60% of total body magnesium is located in bone, and the remainder is in the soft tissues. This soft tissue intracellular compartment comprises about 38% of total body magnesium; relatively higher concentrations are found in skeletal muscle and liver. Because less than 2% is present in the extracellular fluid (ECF) compartment, serum levels do not necessarily reflect the status of total body stores.

Serum concentration typically ranges from 1.8-2.5 mEq/L. Approximately a third of this is protein-bound. Analogous to plasma calcium, the free (ie, unbound) fraction of magnesium is the active component. No accurate method exists to assess ionized serum magnesium.

Less than 40% of dietary magnesium is absorbed throughout the small intestine (predominantly in the ileum) and in the colon. A minimal daily intake of 0.3 mEq/kg of body weight has been suggested to prevent deficiency. Infants and children tend to have higher daily requirements.

Elimination is predominantly renal. The threshold for urinary excretion is near the normal serum concentration. Thus, when serum levels rise above 2.5 mEq/L, magnesium excretion increases dramatically. Conversely, the kidney retains a strong capacity to resorb magnesium, and the main site for reabsorption is the thick ascending loop of Henle. Several factors may impair renal reabsorption, such as volume expansion, ethanol ingestion, hypercalcemia, and diuretic administration (eg, osmotic, thiazide, loop). Of these 3 types of diuretics, loop diuretics have the greatest effect on renal magnesium wasting because of their site of action.

Pathophysiology: Hypomagnesemia is widespread among hospitalized patients. Hypomagnesemia has been reported in as many as 60% of ICU patients. Prolonged administration of magnesium-free parenteral fluids may be a contributing factor. Prolonged nasogastric suction, infectious diarrhea, steatorrhea, inflammatory bowel disease, and GI neoplasms may cause hypomagnesemia. A congenital defect in GI magnesium absorption also has been described.

Incidence of hypomagnesemia among people with alcohol dependence is approximately 25% and mainly is due to magnesium diuresis caused by alcohol.

Several drugs can cause increased urinary loss of magnesium. Magnesium deficiency is especially common in patients receiving furosemide diuretics. A congenital defect in tubular reabsorption of magnesium also has been described.

Severe hypomagnesemia may occur during the recovery phase of diabetic ketoacidosis. Patients with diabetes who have chronically poor glycemic control may have a total body magnesium deficit, possibly caused by ineffective insulin-mediated cellular uptake of magnesium.

Frequency:

• In the US: Although the incidence of hypomagnesemia in the general population has been estimated at less than 2%, hospitalized patients are more prone to develop hypomagnesemia. Exact inpatient incidence is unknown. Recent studies of ICU patients have estimated frequencies in that setting as high as 60%.

Age: While no comprehensive studies have addressed the actual incidence of hypomagnesemia stratified by age group, neonates may be more predisposed to develop hypomagnesemia. The mechanism for this is unknown, although several studies suggest that neonates have an increased requirement for intracellular magnesium in growing tissues.

History: Symptomatic hypomagnesemia may manifest clinically as CNS and neuromuscular hyperexcitability. Early manifestations may include painful muscle cramps, nausea, vomiting, and lethargy.

Physical:

• At serum magnesium levels less than 1.0 mEq/L, patients with hypomagnesemia may have tremor, hyperactive deep-tendon reflexes, hyperreactivity to sensory stimuli, muscular fibrillations, positive Chvostek and Trousseau signs, and carpopedal spasms progressing to tetany.

• Mental status changes may become evident and include irritability, disorientation, depression, and psychosis.

• Reversible respiratory muscle failure may occur in severe hypomagnesemia.

Lab Studies:

• Laboratory analysis by atomic absorption spectrophotometry (AAS) is the most specific technique available to measure total serum magnesium. Ion-selective electrodes for measurement of free magnesium have been developed; however, their use has not been rigorously tested, and they currently are not readily available for clinical use.

Other Tests:

• Hypomagnesemia may be associated with nonspecific ECG changes, including ST-segment depression, altered T waves, or loss of voltage. Severe magnesium deficiency may cause PR prolongation or widened QRS complexes.

Medical Care:

• When an underlying cause (eg, prolonged GI loss) exists, direct treatment toward correcting the problem. If hypomagnesemia is mild (ie, serum magnesium levels >1.2 mEq/L) and the patient is asymptomatic, PO replacement is appropriate. Little is understood about the uptake kinetics at the cell membrane level, so the optimal dosage to produce an effective intracellular uptake is unknown. Dosage also varies from patient to patient.

• In patients with normal renal function, if serum magnesium levels are less than 1 mEq/kg, the estimated total body replacement requirement is approximately 4 mEq/kg of body weight. With renal impairment, reduce these doses by at least half.

• In emergent cases (eg, refractory ventricular tachycardia) 16 mEq (2 mL of a 10% solution) of magnesium sulfate may be administered IV over 5-7 minutes.

• Base magnesium replacement in children on the child's weight. Administer 1 mEq/kg on the first day, then administer approximately half this amount daily during the next 3 days.

• Rapid IV administration can be life threatening. Risks involved with IV magnesium therapy include hypermagnesemia, hypocalcemia, and sudden hypotension. IV infusion rates should not exceed 67 mEq over 8 hours. Continuously monitor electrolytes and hemodynamic parameters during replacement under high infusion rates.

Diet: Magnesium is a component of chlorophyll and occurs in high concentrations in green leafy vegetables. Magnesium also is found in nuts, seeds, peas, beans, and cocoa. Do not discount the possibility of hypomagnesemia in patients with malnutrition.

Treatment for hypomagnesemia depends on the degree of deficiency and the patient's clinical symptoms and signs. Therapy can be PO for patients with mild symptoms or IV for patients with severe symptoms.

Drug Category: Magnesium salts -- Magnesium can be administered either PO in an oxide or gluconate form or parenterally as a sulfate salt.

Drug Name	Magnesium gluconate (Almora, Magonate) -- 500 mg contains 27 mg of elemental Mg.
Adult Dose	500-1000 mg PO tid
Pediatric Dose	10-20 mg/kg elemental Mg PO tid/qid; not to exceed 400 mg/d
Contraindications	Documented hypersensitivity; heart block, myocardial damage; hepatitis
Interactions	Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; also may worsen neuromuscular blockade seen with aminoglycosides, tubocurarine, vecuronium, succinylcholine; Mg may increase CNS effects and toxicity of CNS depressants, betamethasone, ritodrine
Pregnancy	A - Safe in pregnancy
Precautions	Caution in renal failure; may alter cardiac conduction leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when administered parenterally; caution when administering Mg dose since may produce significant hypertension or asystole; diarrhea is most common adverse effect

Drug Name	Magnesium sulfate -- 1 g contains 8.12 mEq of Mg (98 mg elemental Mg)
Adult Dose	2 g IV solution over 20 min, then 1 g q6h until levels corrected
Pediatric Dose	1 mEq/kg IV infused over 2-6 h on day 1, then half that amount over next 3 d
Contraindications	Documented hypersensitivity; heart block, myocardial damage; hepatitis
Interactions	Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; also may increase neuromuscular blockade seen with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants, betamethasone, and cardiotoxicity of ritodrine
Pregnancy	A - Safe in pregnancy
Precautions	Mg may alter cardiac conduction leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when electrolyte is administered parenterally; caution when administering Mg dose since may produce significant hypertension or asystole; dilute to 5-20% before IV administration; maximum concentration of 20%; rate of administration should be <1.5 mL of 10% solution or equivalent per min (150 mg/min with ECG monitoring); rapid IV administration can lead to cardiac dysrhythmias, hypotension, flushing, sweating, and/or sensation of warmth; in overdose, calcium gluconate, 10-20 mL IV of 10% solution, can be given as antidote for clinically significant hypermagnesemia; hypotension; hypocalcemia; respiratory depression; or venous irritation may occur

Medical/Legal Pitfalls:

• Although abnormally low levels of serum magnesium typically occur in adult patients hospitalized for prolonged periods, failure to include hypomagnesemia in the differential diagnosis for a similarly affected pediatric patient may be disastrous because hypomagnesemia is treated readily.

• Because hypomagnesemia can masquerade as other electrolyte imbalances, obtain magnesium levels with other electrolytes (eg, calcium, phosphorus) when ordering laboratory tests.

BIBLIOGRAPHY

• Knochel JP: Disorders of Magnesium Metabolism. Harrison's Principles of Internal 1994; 2: 2187-2189.
• Nadler JL, Rude RK: Disorders of Magnesium Metabolism. Clinical Disorders of Fluid and Electrolyte Metabolism 1995; 24: 623-637.
• Reinhart RA: Magnesium metabolism. Archives of Internal Medicine 1988; 148: 2415-2420[Medline].

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Constructed by Dr N.A. Nematallah Consultant in perioperative medicine and intensive therapy, Al Razi Orthopedic Hospital , State of Kuwait, email : razianesth@freeservers.com