Hypermagnesemia: Causes, symptoms, and treatment

INTRODUCTION — The kidney is crucial in maintaining the normal plasma magnesium concentration in the narrow range of 0.7 to 1.1 mmol/L. In contrast to most other filtered solutes, only 10 percent of filtered magnesium is absorbed in the proximal tubule; most (50 to 70 percent) of the filtered magnesium is passively reabsorbed in the cortical aspect of the thick ascending limb of Henle [1,2]. Magnesium reabsorption at this site is paracellular and voltage dependent, mediated by the tight junction proteins, claudin-16 and claudin-19. Loop reabsorption is appropriately diminished with magnesium loading, thereby allowing the excess magnesium to be excreted in the urine [1].

Hypermagnesemia is an uncommon problem in the absence of magnesium administration or kidney failure. When it occurs, the elevation in the plasma magnesium concentration is usually mild (<3 mEq/L, 3.6 mg/dL, or 1.5 mmol/L) and the patient is asymptomatic. However, clinical symptoms may be seen when the plasma magnesium concentration exceeds 4 mEq/L (4.8 mg/dL or 2 mmol/L).

The causes, symptoms, and treatment of hypermagnesemia are reviewed in this topic. The normal regulation of magnesium balance and the different units used to measure the plasma magnesium concentration are discussed separately. (See "Regulation of magnesium balance".)

CAUSES OF HYPERMAGNESEMIA — The efficiency of the renal response to a magnesium load is such that hypermagnesemia is primarily seen in three settings: when kidney function is impaired; when a large magnesium load is given, whether intravenously, orally, or as an enema; or when there is increased absorption from the intestinal tract due to constipation, colitis, gastritis, or gastric ulcer disease [3,4]. Hypermagnesemia itself increases the neuromuscular blocking actions of magnesium, further increasing gastrointestinal magnesium absorption and resultant hypermagnesemia [3].

Kidney impairment — Hypermagnesemia can be seen in 10 to 15 percent of hospitalized patients, usually in the setting of kidney failure. Plasma magnesium levels rise as kidney function declines since there is no magnesium regulatory system other than urinary excretion [5]. The typical patient with end-stage kidney disease (ESKD), for example, has a plasma magnesium concentration of 2 to 3 mEq/L (2.4 to 3.6 mg/dL or 1 to 1.5 mmol/L). In patients on dialysis, the plasma magnesium concentration is primarily determined by magnesium intake. This was shown in a cross-sectional study of patients on hemodialysis who completed a dietary questionnaire; the correlation between estimated dietary magnesium intake and the serum magnesium was 0.87 [6]. In addition, hypermagnesemia (defined as a serum magnesium greater than 1.5 mmol/L) occurred with magnesium intakes as low as 281 mg/day, which is considerably lower than the average intake in the general population. Severe and symptomatic hypermagnesemia can also be induced when exogenous magnesium is given as antacids or laxatives in usual therapeutic doses [7]. As a result, these drugs are contraindicated in patients with renal impairment.

Magnesium infusion — Parenteral magnesium is commonly used to decrease neuromuscular excitability in pregnant women with severe preeclampsia or eclampsia. The usual plasma concentration achieved is 5 to 7 mEq/L (6 to 8.4 mg/dL or 2.5 to 3.5 mmol/L), but much higher levels can occur. There are few prospective studies of complications associated with this regimen, but maternal hypocalcemia (since hypermagnesemia can suppress the release of parathyroid hormone [PTH]) and hyperkalemia have been described, as have neonatal hypermagnesemia, hyperkalemia, hypocalcemia, hypotonia, osteopenia, and an increased rate of admissions to the neonatal intensive care unit [8-14]. (See 'Symptoms of hypermagnesemia' below.)

Oral ingestion — Massive oral ingestion can occasionally exceed renal excretory capacity, particularly if there is underlying renal insufficiency, either due to chronic kidney disease (CKD) (see 'Kidney impairment' above) or acute kidney injury (AKI) [3,15]. Several cases of severe hypermagnesemia with life-threatening symptoms have been described with accidental overdose with seemingly harmless over-the-counter products, such as Epsom salts (almost 100 percent magnesium sulfate) and laxatives, and during treatment of a variety of drug overdoses using magnesium as a cathartic [16-27].

Prospective studies of repetitive magnesium catharsis demonstrated that the usual total average dose of 960 mL of magnesium citrate (9.22 g) induced a mean elevation in the plasma magnesium concentration to 2.5 mEq/L (3 mg/dL or 1.25 mmol/L), with 10 percent of patients exceeding 3 mEq/L (3.6 mg/dL or 1.5 mmol/L) [17]. An elevation in the plasma magnesium concentration is much more likely in the presence of gastrointestinal disorders (active ulcer disease, gastritis, colitis) that can enhance magnesium absorption. In one retrospective study of hospital admissions, for example, eight cases of severe hypermagnesemia (plasma magnesium concentration above 6 mg/dL or 2.5 mmol/L) were seen over a five-year period [28]. These patients were of older age, taking normal amounts of magnesium as a cathartic or antacid, did not have significant renal insufficiency, but did have active gastrointestinal disease. The hypermagnesemia was unsuspected despite presentation with severe symptoms, including hypocalcemia, hypotension, and respiratory depression. Prolonged hypermagnesemia in constipated patients with colonic retention has also been described [29].

Extreme hypermagnesemia in conjunction with hypercalcemia is seen as a unique feature of Dead Sea water poisoning since the ingested water contains very high concentrations of both magnesium and calcium [30].

Magnesium enemas — Substantial quantities of magnesium can be absorbed from the large bowel following a magnesium enema. In normal subjects, for example, 400 to 800 mmol of magnesium sulfate per rectum can raise the plasma magnesium concentration to as high as 6 to 16 mEq/L (7.2 to 19.2 mg/dL or 3 to 8 mmol/L). Among patients with kidney failure, the administration of a magnesium enema can be fatal [31].

Miscellaneous — Mild hypermagnesemia can occur in a variety of other clinical settings in selected cases. Examples include:

●Some cases of primary hyperparathyroidism.

●Familial hypocalciuric hypercalcemia. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

●Diabetic ketoacidosis.

●Hypercatabolic states, such as the tumor lysis syndrome, in which magnesium is released from the cells. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

●Lithium ingestion.

●Milk-alkali syndrome. (See "The milk-alkali syndrome".)

●Adrenal insufficiency, perhaps due to volume depletion and hemoconcentration.

●Dialysis with increased dialysate magnesium due to dialysis water contamination [32].

●HELIX syndrome – Mild hypermagnesemia has been described as part of a familial syndrome associated with hypohidrosis, electrolyte imbalance (hypocalciuria and hypokalemic metabolic alkalosis), lacrimal gland dysfunction, and xerostomia (HELIX syndrome) [33-35]. It is caused by mutations in CLDN10, which encodes the tight junction protein, claudin-10. This likely functions as a paracellular sodium channel in the thick ascending limb of Henle. Loss of claudin-10 function reduces paracellular sodium reabsorption, enhancing the transepithelial voltage driving divalent cation (magnesium and calcium) reabsorption.

SYMPTOMS OF HYPERMAGNESEMIA — The approximate relation between clinical manifestations and the degree of hypermagnesemia can be summarized as follows:

●Plasma magnesium concentration 4 to 6 mEq/L (4.8 to 7.2 mg/dL or 2 to 3 mmol/L) – Nausea, flushing, headache, lethargy, drowsiness, and diminished deep tendon reflexes.

●Plasma magnesium concentration 6 to 10 mEq/L (7.2 to 12 mg/dL or 3 to 5 mmol/L) – Somnolence, hypocalcemia, absent deep tendon reflexes, hypotension, bradycardia, and electrocardiogram (ECG) changes.

●Plasma magnesium concentration above 10 mEq/L (12 mg/dL or 5 mmol/L) – Muscle paralysis leading to flaccid quadriplegia, apnea and respiratory failure, complete heart block, and cardiac arrest. In most cases, respiratory failure precedes cardiac collapse.

Most of the symptoms can be divided into three categories: neuromuscular effects, cardiovascular effects, and hypocalcemia. (See 'Neuromuscular effects' below and 'Cardiovascular effects' below and 'Hypocalcemia' below.)

Neuromuscular effects — Neuromuscular toxicity is the most consistently observed complication of hypermagnesemia. Increased magnesium decreases impulse transmission across the neuromuscular junction, producing a curare-like effect [36,37]. The initial clinical manifestation of this problem is diminished deep tendon reflexes, which are usually first noted when the plasma magnesium concentration reaches 4 to 6 mEq/L (4.8 to 7.2 mg/dL or 2 to 3 mmol/L). More severe hypermagnesemia can result in somnolence; loss of deep tendon reflexes; and muscle paralysis, potentially leading to flaccid quadriplegia and, since smooth muscle function is also impaired, decreased respiration and eventual apnea. Parasympathetic blockade inducing fixed and dilated pupils, thereby mimicking a central brainstem herniation syndrome, can also be seen in this setting [38].

Cardiovascular effects — Magnesium is an effective calcium channel blocker both extracellularly and intracellularly; in addition, intracellular magnesium profoundly blocks several cardiac potassium channels [36]. These changes can combine to impair cardiovascular function. Hypotension, conduction defects, and bradycardia begin to appear at a plasma magnesium concentration above 4 to 5 mEq/L (4.8 to 6 mg/dL or 2 to 2.5 mmol/L) [36]. ECG changes are usually seen at concentrations of 5 to 10 mEq/L (6 to 12 mg/dL or 2.5 to 5 mmol/L). These changes include prolongation of the PR interval, an increase in QRS duration, and an increase in QT interval. Complete heart block and cardiac arrest may occur at a plasma magnesium concentration above 15 mEq/L (18 mg/dL or 7.5 mmol/L).

In a cross-sectional study of over 10,000 critically ill patients, hypermagnesemia was independently and significantly associated with both lower systolic blood pressures and intravenous vasopressor requirements during the first 24 hours of care in the intensive care unit [39]. The effect of magnesium on blood pressure may be mediated by vasorelaxation [40,41] and via its effects on transient receptor potential melastatin (TRPM) [42] and aldosterone [43].

Hypocalcemia — Moderate hypermagnesemia can inhibit the secretion of parathyroid hormone (PTH), leading to a reduction in the plasma calcium concentration [44]. This effect has been described after magnesium infusion in normal subjects and in pregnant women with eclampsia [8,45-47]. The fall in the plasma calcium concentration is usually transient and produces no symptoms; in some cases, however, ECG abnormalities associated with hypocalcemia can be seen. In the long term, hypermagnesemia can contribute to osteomalacic renal osteodystrophy and adynamic bone disease, especially in patients with kidney disease. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Other symptoms — Hypermagnesemia may be associated with nonspecific early symptoms such as nausea, vomiting, and flushing. In addition, hyperkalemia has been described in three pregnant women following parenteral magnesium administration [48,49]. The frequency of this complication is uncertain since the plasma potassium concentration is not routinely monitored in this setting. The mechanism responsible for the hyperkalemia is unclear, but decreased urinary potassium excretion due to magnesium-induced blockade of renal potassium channels may be involved [36]. Hypermagnesemia can also cause and/or exacerbate pruritus in dialysis patients, which is possibly due to altered nerve conduction velocity [50].

Side effects associated with the use of magnesium in pregnant women are discussed elsewhere. (See "Inhibition of acute preterm labor", section on 'Maternal and fetal side effects' and "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Signs of magnesium toxicity'.)

TREATMENT — Most cases of symptomatic hypermagnesemia can be prevented by anticipation. Patients in kidney failure should not receive magnesium-containing medications, and patients receiving parenteral magnesium for any reason should be monitored at least daily, and perhaps more frequently, depending upon the amount of magnesium infused and the dosing schedule.

The approach to therapy depends upon the kidney function, magnesium concentration, and clinical symptoms:

Normal or near-normal kidney function — If kidney function is normal, cessation of magnesium therapy will allow prompt restoration of normal magnesium levels. In addition, loop (or even thiazide) diuretics can be used to increase renal excretion of magnesium.

Moderate kidney impairment — Renal elimination of magnesium may be limited in patients with moderate kidney function impairment, such as patients with chronic kidney disease (CKD) who have an estimated glomerular filtration rate (eGFR) between 15 and 45 mL/min/1.73 m², and patients with mild acute kidney injury (AKI), especially if their serum creatinine concentration is increasing progressively. In most such cases, initial treatment consists of cessation of magnesium-containing medications and therapy with intravenous isotonic fluids (eg, normal saline) plus a loop diuretic (eg, furosemide). Higher diuretic doses may be required in these patients since they have reduced glomerular filtration rate (GFR). (See "Loop diuretics: Dosing and major side effects".)

If these measures fail to improve the serum magnesium concentration, dialysis may be required, especially if there are severe neurologic manifestations (eg, paralysis, somnolence, coma) or cardiovascular manifestations (eg, bradycardia, electrocardiographic abnormalities, hypotension).

Severe kidney impairment — Dialysis is often required in patients with severe or symptomatic hypermagnesemia who have advanced CKD (patients with an eGFR less than 15 mL/min/1.73 m² or who are on chronic dialysis) and in patients who have moderate to severe AKI. Hemodialysis, with its higher flow rates, works more rapidly than peritoneal dialysis, lowering magnesium levels to a nontoxic range within two to four hours. Exchange transfusion has been effective in neonatal hypermagnesemia.

Since preparation for hemodialysis often takes one hour or longer, patients with symptomatic hypermagnesemia should be given intravenous calcium as a magnesium antagonist to reverse the neuromuscular and cardiac effects of hypermagnesemia [51]. The usual dose is 100 to 200 mg of elemental calcium over 5 to 10 minutes. Unless the patient is anuric, medical management with intravenous fluids and loop diuretics should also be initiated, especially in severe or symptomatic cases, while preparing for dialysis.

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

●General principles – The kidney is crucial in maintaining the normal plasma magnesium concentration. In contrast to most other filtered solutes, only 10 percent of filtered magnesium is absorbed in the proximal tubule; most (50 to 70 percent) of the filtered magnesium is passively reabsorbed in the cortical aspect of the thick ascending limb of Henle. Loop reabsorption is appropriately diminished with magnesium loading, thereby allowing the excess magnesium to be excreted in the urine. (See 'Introduction' above.)

●Causes of hypermagnesemia – Hypermagnesemia is primarily seen in the following settings (see 'Causes of hypermagnesemia' above):

•Kidney impairment – Plasma magnesium levels rise as kidney function declines since there is no magnesium regulatory system other than urinary excretion. (See 'Kidney impairment' above.)

•Magnesium infusion – Hypermagnesemia commonly occurs when parenteral magnesium is used to decrease neuromuscular excitability in pregnant women with severe preeclampsia or eclampsia. (See 'Magnesium infusion' above.)

•Oral magnesium ingestion – Severe hypermagnesemia with life-threatening symptoms can come from accidental poisoning with Epsom salts and with magnesium-containing drugs used as cathartics or laxatives. (See 'Oral ingestion' above.)

•Magnesium enemas – Substantial quantities of magnesium can be absorbed from the large bowel following a magnesium enema. (See 'Magnesium enemas' above.)

•Miscellaneous causes – Mild hypermagnesemia can occasionally occur in a variety of other clinical settings (eg, primary hyperparathyroidism, diabetic ketoacidosis, tumor lysis syndrome). (See 'Miscellaneous' above.)

●Symptoms – Symptoms of hypermagnesemia include the following:

•Neuromuscular toxicity is the most common complication of hypermagnesemia. Symptoms range from diminished deep tendon reflexes when the plasma magnesium concentration reaches 4 to 6 mEq/L (4.8 to 7.2 mg/dL or 2 to 3 mmol/L) to somnolence, loss of deep tendon reflexes, and muscle paralysis. (See 'Neuromuscular effects' above.)

•Bradycardia and hypotension may occur at a plasma magnesium concentration above 4 to 5 mEq/L (4.8 to 6 mg/dL or 2 to 2.5 mmol/L). Observed electrocardiogram (ECG) changes include prolongation of the PR interval, an increase in QRS duration, and an increase in QT interval. Complete heart block and cardiac arrest may occur at a plasma magnesium concentration above 15 mEq/L (18 mg/dL or 7.5 mmol/L). (See 'Cardiovascular effects' above.)

•Hypermagnesemia may inhibit the secretion of parathyroid hormone (PTH), causing transient hypocalcemia. (See 'Hypocalcemia' above.)

•Hypermagnesemia may also cause nonspecific symptoms such as nausea, vomiting, and flushing. (See 'Other symptoms' above.)

●Treatment – Most cases of symptomatic hypermagnesemia can be prevented by anticipation. Patients in kidney failure should not receive magnesium-containing medications, and patients receiving parenteral magnesium for any reason should be monitored at least daily, and perhaps more frequently, depending upon the amount of magnesium infused and the dosing schedule. (See 'Treatment' above.)

•Normal or near-normal kidney function – If kidney function is normal, cessation of magnesium therapy will allow prompt restoration of normal magnesium levels. In addition, loop (or even thiazide) diuretics can be used to increase renal excretion of magnesium. (See 'Normal or near-normal kidney function' above.)

•Moderate kidney impairment – In patients with chronic kidney disease (CKD) who have an estimated glomerular filtration rate (eGFR) between 15 and 45 mL/min/1.73 m², and also in patients with mild acute kidney injury (AKI), initial treatment consists of therapy with intravenous isotonic fluids (eg, normal saline) plus a loop diuretic (eg, furosemide), in addition to cessation of magnesium-containing medications. Higher diuretic doses may be required in these patients. If these measures fail to improve the serum magnesium, dialysis may be required, especially if there are severe neurologic or cardiovascular manifestations. (See 'Moderate kidney impairment' above.)

•Severe kidney impairment – Dialysis is often required in patients with severe or symptomatic hypermagnesemia who have advanced CKD (eGFR less than 15 mL/min/1.73 m²) or who have moderate to severe AKI. Since preparation for hemodialysis often takes one hour or longer, patients with symptomatic hypermagnesemia should be given intravenous calcium as a magnesium antagonist to reverse the neuromuscular and cardiac effects of hypermagnesemia. The usual dose is 100 to 200 mg of elemental calcium over 5 to 10 minutes. Unless the patient is anuric, medical management with intravenous fluids and loop diuretics should also be initiated, especially in severe or symptomatic cases, while preparing for dialysis. (See 'Severe kidney impairment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman Agus, MD, who contributed to an earlier version of this topic review.