Hypomagnesemia: Evaluation and treatment

INTRODUCTION — Most of the body's magnesium stores are intracellular, principally within bone. In the extracellular fluid, magnesium can be ionized (free), bound to anions, or bound to protein. (See "Regulation of magnesium balance".)

The plasma magnesium concentration is not usually measured as part of routine blood tests. Thus, the identification of patients with hypomagnesemia often requires clinical suspicion in patients with risk factors for hypomagnesemia (eg, chronic diarrhea, proton pump inhibitor therapy, alcohol use disorder, diuretic use) or with clinical manifestations of hypomagnesemia (eg, unexplained hypocalcemia, refractory hypokalemia, neuromuscular disturbances, ventricular arrhythmias) [1,2]. (See "Hypomagnesemia: Causes of hypomagnesemia" and "Hypomagnesemia: Clinical manifestations of magnesium depletion".)

This topic will review the evaluation and treatment of hypomagnesemia. The regulation of magnesium balance and the causes and clinical manifestations of hypomagnesemia are presented in detail elsewhere:

●(See "Regulation of magnesium balance".)

●(See "Hypomagnesemia: Causes of hypomagnesemia".)

●(See "Hypomagnesemia: Clinical manifestations of magnesium depletion".)

EVALUATION — In patients diagnosed with hypomagnesemia, the cause can usually be obtained from the history. (See "Hypomagnesemia: Causes of hypomagnesemia".)

If no etiology is apparent, the distinction between gastrointestinal and renal losses can be made by measuring the 24-hour urinary magnesium excretion or the fractional excretion of magnesium (FEMg) on a random urine specimen.

The latter can be calculated from the following formula (calculator 1 and calculator 2):

The terms "U" and "P" refer to the urine and plasma concentrations of magnesium (Mg) and creatinine (Cr). The plasma magnesium concentration is multiplied by 0.7 since only approximately 70 percent of the circulating magnesium is free (not bound to albumin) and therefore able to be filtered across the glomerulus.

Renal magnesium excretion should be reduced in patients with plasma magnesium depletion. Thus, measurement of 24-hour urinary magnesium excretion or the fractional excretion of magnesium can help distinguish between gastrointestinal and renal losses of magnesium [3,4]:

●A daily excretion of more than 10 to 30 mg (in a 24-hour urine specimen) or a fractional excretion of magnesium above 3 to 4 percent in a person with hypomagnesemia and normal kidney function indicates renal magnesium wasting.

●By contrast, a 24-hour urinary magnesium excretion less than 10 mg or a fractional excretion of magnesium less than 2 percent usually indicates an extrarenal source of magnesium losses (typically gastrointestinal).

In one study of 74 hypomagnesemic patients, for example, the mean fractional excretion of magnesium in patients with hypomagnesemia of extrarenal origin was 1.4 percent (range 0.5 to 2.7 percent) [4]. By comparison, the fractional excretion of magnesium in those with renal magnesium loss was 15 percent (range of 4 to 48 percent). (See "Hypomagnesemia: Causes of hypomagnesemia".)

Normomagnesemic magnesium depletion — The possibility of normomagnesemic magnesium depletion (in which there is isolated cellular magnesium depletion) should be considered as a possible cause of refractory hypokalemia or unexplained hypocalcemia in patients at high risk for magnesium loss [3]. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Normomagnesemic magnesium depletion'.)

One suggested method to detect underlying magnesium depletion is to demonstrate reduced excretion (less than 80 percent over 24 hours) of an infused magnesium load (2.4 mg/kg of lean body weight given over the initial four hours) [3,5,6]. However, the utility of this test is uncertain. Patients with malnutrition, cirrhosis, diarrhea, or long-term diuretic use typically have a positive test, whether or not they have signs or symptoms referable to magnesium depletion [7]. It seems prudent, therefore, to simply administer magnesium to these patients if they have unexplained hypocalcemia and/or hypokalemia.

TREATMENT — The route and dose of magnesium repletion should be selected on the basis of the severity of the clinical manifestations and the degree of hypomagnesemia (algorithm 1).

Patients with severe symptoms — Symptomatic patients, such as those with tetany, arrhythmias, or seizures should receive intravenous (IV) magnesium (algorithm 1). Such patients should have continuous cardiac monitoring:

●In the acute setting, hemodynamically unstable patients (including those with arrhythmias consistent with torsade de pointes or hypomagnesemic hypokalemia), 1 to 2 grams of magnesium sulfate (8 to 16 mEq [4 to 8 mmol]) can be given initially over 2 to 15 minutes [8]. If the patient remains hemodynamically unstable after this initial bolus, a repeat bolus can be administered. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Hypomagnesemia and redistributive hypokalemia' and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)

●In hemodynamically stable patients with severe symptomatic hypomagnesemia (less than or equal to 1 mg/dL [0.4 mmol/L or 0.8 mEq/L]), 1 to 2 grams of magnesium sulfate (8 to 16 mEq [4 to 8 mmol]) in 50 to 100 mL of 5 percent dextrose in water can be given initially over 5 to 60 minutes followed by an infusion (infusion described in the following bullet) [8].

●A simple infusion regimen for nonemergency repletion is 4 to 8 grams of magnesium sulfate (32 to 64 mEq [16 to 32 mmol]) given slowly over 12 to 24 hours [9]. This dose can be repeated as necessary to maintain the plasma magnesium concentration above 1 mg/dL (0.4 mmol/L or 0.8 mEq/L). In the normomagnesemic patient with hypocalcemia, it has been suggested to repeat this dose daily for three to five days [5,6].

●Patients with kidney function impairment (creatinine clearance less than 30 mL/min/1.73 m²) are at risk for severe hypermagnesemia if large doses of magnesium are given because plasma magnesium concentrations are regulated solely by renal excretion. Thus, we reduce the IV magnesium dose in such patients by 50 percent or more and closely monitoring magnesium concentrations. (See 'Treating patients with impaired kidney function' below and "Hypermagnesemia: Causes, symptoms, and treatment", section on 'Kidney impairment'.)

●In children, we use a slow infusion of magnesium sulfate; the dose is 25 to 50 mg/kg (0.2 to 0.4 mEq/kg [0.1 to 0.2 mmol/kg]) with a maximum single dose of 2 grams (16 mEq [8 mmol]) [10,11]. (See "Significance of hypomagnesemia in cardiovascular disease".)

(Conversion relationships: 1 mmol = 2 mEq = 24 mg of elemental magnesium = 240 mg magnesium sulfate.)

The magnesium concentration should be measured 6 to 12 hours after each dose of IV magnesium. Repeat doses are given based upon the follow-up measurement. Of note, plasma magnesium levels do not correlate well with total body stores, as the majority of magnesium is intracellular; plasma concentrations may be transiently elevated for a few hours after administration of an IV dose.

Inefficiency of intravenous magnesium supplementation — It must be appreciated that plasma magnesium concentration inhibits magnesium reabsorption in the loop of Henle, the major site of active magnesium transport (see "Regulation of magnesium balance"). Thus, when an IV magnesium infusion is given, an abrupt but temporary elevation in the plasma magnesium concentration will partially inhibit the stimulus to magnesium reabsorption in the loop of Henle. Thus, up to 50 percent of the infused magnesium will be excreted in the urine. In addition, magnesium uptake by the cells is slow, and therefore adequate repletion requires sustained correction of the hypomagnesemia.

Patients with no or minimal symptoms — If available and tolerable, oral replacement should be given to the hypomagnesemic patient with no or minimal symptoms (algorithm 1). However, many patients are unable to take oral magnesium or have side effects such as gastrointestinal discomfort and diarrhea. Thus, many hospitalized patients with hypomagnesemia are given IV rather than oral magnesium supplementation, even if symptoms are minimal or absent.

Oral repletion if available and tolerable — A number of oral magnesium salts are available (table 1). Each differs in the content of elemental magnesium, but all suffer from limited bioavailability. A typical daily dose in a patient with normal kidney function is 240 to 1000 mg (20 to 80 mEq [10 to 40 mmol]) of elemental magnesium in divided doses.

Sustained-release preparations have the advantage that they are slowly absorbed and thereby minimize renal excretion of the administered magnesium. Available sustained-release preparations include magnesium chloride containing 64 to 71.5 mg elemental magnesium (eg, MagDelay, SlowMag) and magnesium L-lactate containing 84 mg elemental magnesium (eg, Mag-Tab SR). Six to eight tablets (30 to 56 mEq [15 to 28 mmol]) should be taken daily in divided doses for severe magnesium depletion. Two to four tablets (10 to 28 mEq [5 to 14 mmol]) may be sufficient for mild hypomagnesemia. The use of sustained-release preparations may permit the use of lower doses, which minimizes the associated diarrhea (the major dose-limiting side effect).

If a sustained-release preparation is not available, magnesium oxide 800 to 1600 mg (20 to 40 mmol [40 to 80 mEq]) daily in divided doses may be used for moderate to severe hypomagnesemia. Diarrhea frequently occurs with magnesium oxide therapy.

Intravenous repletion in stable hospitalized patients — In some hospitalized patients, oral magnesium supplementation may be unavailable or not tolerable (eg, in postoperative patients who cannot take medications orally). Even if such patients with hypomagnesemia are asymptomatic or minimally symptomatic, IV magnesium therapy can be used (algorithm 1). Clinicians should be aware of the inefficiencies of IV magnesium as described above. (See 'Inefficiency of intravenous magnesium supplementation' above.)

For routine IV repletion or maintenance in the inpatient setting, we use the following regimen in which the dose and rate of repletion depends upon the plasma magnesium concentration [9,12]: severe (eg, <1 mg/dL), moderate (1 to 1.5 mg/dL), and mild (1.6 to 1.9 mg/dL combined with suspicion of magnesium depletion) depletion with an estimated repletion dose:

●If the plasma magnesium is less than 1 mg/dL (0.4 mmol/L or 0.8 mEq/L), give 4 to 8 grams (32 to 64 mEq [16 to 32 mmol]) of magnesium sulfate over 12 to 24 hours and repeat as needed.

●If the plasma magnesium is 1 to 1.5 mg/dL (0.4 to 0.6 mmol/L or 0.8 to 1.2 mEq/L), give 2 to 4 grams (16 to 32 mEq [8 to 16 mmol]) of magnesium sulfate over 4 to 12 hours.

●If the plasma magnesium is 1.6 to 1.9 mg/dL (0.7 to 0.8 mmol/L or 1.4 to 1.6 mEq/L), give 1 to 2 grams (8 to 16 mEq [4 to 8 mmol]) of magnesium sulfate over one to two hours.

In stable hospitalized patients receiving magnesium therapy, the plasma magnesium concentration should be measured daily or more frequently if indicated. Repeat doses are given based upon the follow-up measurement.

Correction of the underlying disease — The underlying disease should also be corrected, if possible. Patients with hypomagnesemia due to renal magnesium wasting may benefit from the addition of a potassium-sparing diuretic such as amiloride or triamterene. These drugs have been shown to effectively reduce urinary magnesium excretion in animal studies [13]. The mechanism is unknown, but these drugs may decrease magnesium excretion by increasing its reabsorption in the distal nephron [14]. (See "Effect of diuretics on magnesium handling by the kidney".)

However, data on the efficacy of potassium-sparing diuretics for the treatment of hypomagnesemia in humans is limited. In one series of 12 healthy human subjects treated with a thiazide diuretic, amiloride at a dose of 20 mg daily increased plasma magnesium by only 5 percent on average [15]. Similarly, in a randomized crossover trial of patients with Gitelman syndrome, six weeks of treatment with amiloride reduced urinary magnesium excretion but had no effect on plasma magnesium concentration [16].

Treating patients with impaired kidney function — In general, great caution should be exercised in treating patients who have acute or chronic kidney injury with magnesium-containing medications. However, patients with reduced kidney function may require magnesium repletion if they have severe hypomagnesemia (ie, <1 mg/dL [0.4 mmol/L or 0.8 mEq/L]).

There are no published data to guide therapy in such patients, and it is critical that the plasma magnesium concentration be followed closely (ie, after each magnesium dose). In addition, the patient should be monitored for signs of hypermagnesemia such as facial flushing, decreased tendon reflexes, hypotension, and atrioventricular block. (See "Hypermagnesemia: Causes, symptoms, and treatment", section on 'Symptoms of hypermagnesemia'.)

In the absence of published data, we take the following approach:

●A symptomatic patient who has moderately reduced kidney function (ie, estimated glomerular filtration rate of 15 to 30 mL/min/1.73 m²) and severe hypomagnesemia should be treated with 2 to 4 grams of IV magnesium sulfate given slowly over 4 to 12 hours. The plasma magnesium should be checked prior to subsequent doses and daily if doses are given less frequently.

●Asymptomatic patients who have severe hypomagnesemia and moderately decreased kidney function may be treated with approximately one-half the dose of the selected oral preparation that is recommended for the patient with normal kidney function. The plasma magnesium concentration should be measured before giving a subsequent dose.

It would be extremely unusual for a patient with no kidney function (ie, on dialysis) to have severe magnesium depletion in the absence of an extrarenal loss such as diarrhea. In such cases, treating the diarrhea may be sufficient to correct the hypomagnesemia.

Duration of therapy — Serum magnesium levels usually rise quickly with therapy, but intracellular stores take longer to replete. It is therefore advisable in patients with normal kidney function to continue magnesium repletion for at least one to two days after the serum magnesium concentration normalizes.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS

●When to suspect hypomagnesemia – Hypomagnesemia should be suspected in patients who have risk factors for hypomagnesemia (eg, chronic diarrhea, proton pump inhibitor therapy, alcohol use disorder, diuretic use) or clinical manifestations of hypomagnesemia (eg, unexplained hypocalcemia, refractory hypokalemia, neuromuscular disturbances, ventricular arrhythmias). (See 'Introduction' above.)

●Evaluation – If an etiology is not apparent from the history, gastrointestinal and renal losses may be distinguished by measuring the 24-hour urinary magnesium excretion or the fractional excretion of magnesium on a random urine specimen (calculator 1 and calculator 2). The daily excretion of more than 10 to 30 mg or a fractional excretion of magnesium above 3 to 4 percent in a patient with normal kidney function indicates renal magnesium wasting. (See 'Evaluation' above.)

●Normomagnesemic magnesium depletion – Normomagnesemic magnesium depletion, or isolated cellular magnesium depletion, may be a cause of refractory hypokalemia or unexplained hypocalcemia. Normomagnesemic magnesium depletion may be detected by demonstrating reduced excretion of an infused magnesium load. Alternatively, magnesium may be empirically administered to patients at high risk for magnesium depletion who have unexplained hypocalcemia and/or hypokalemia. (See 'Normomagnesemic magnesium depletion' above.)

●Treatment of hypomagnesemia

•Magnesium repletion – The route of magnesium repletion varies with the severity of the clinical manifestations (algorithm 1). Patients with severe signs and symptoms of hypomagnesemia should receive intravenous (IV) magnesium with cardiac monitoring. Oral replacement should be given to the asymptomatic outpatient, preferably with a sustained-release preparation, in order to prevent abrupt elevations in the plasma magnesium concentration. (See 'Patients with severe symptoms' above and 'Patients with no or minimal symptoms' above.)

•Correction of the underlying disease – The underlying disease should also be corrected, if possible. Patients with hypomagnesemia due to renal losses may benefit from the addition of a potassium-sparing diuretic such as amiloride. (See 'Correction of the underlying disease' above.)

•Patients with reduced kidney function – In general, patients with reduced kidney function should not receive magnesium-containing medications. However, patients with moderately reduced kidney function who have severe hypomagnesemia may require magnesium repletion. The appropriate regimen for magnesium repletion in such patients depends upon the presence or absence of signs and symptoms of hypomagnesemia. It is critical that the plasma magnesium be followed closely (ie, after each dose) and the patient be monitored for signs of hypermagnesemia. (See 'Treating patients with impaired kidney function' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gunjeet K Kala Ahluwalia, MD, who contributed to earlier versions of this topic review.