Hypermagnesemia

Background: Magnesium is the second most abundant intracellular cation and the fourth most abundant cation overall. Almost all enzymatic processes using phosphorus as an energy source require magnesium for activation. Magnesium is involved in most biochemical reactions such as glycolysis and oxidative phosphorylation. Because magnesium is bound to adenosine triphosphate (ATP) inside the cell, shifts in intracellular magnesium concentration may help to regulate cellular bioenergetics.

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. In fact, magnesium has been proposed as being an endogenous endocrine modulator of the catecholamine component of the physiologic stress response.

Approximately 60% of total body magnesium is located in the bone, and the remainder is in the soft tissues. In this soft tissue intracellular compartment, which comprises about 38% of total body magnesium, relatively higher concentrations are found in the skeletal muscle and the 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 of magnesium.

The reference range of serum concentration of magnesium is 1.8-2.5 mEq/L. Approximately one third of this magnesium is protein-bound. Analogous to plasma calcium, the free (ie, unbound) fraction of magnesium is the active component. Unfortunately, ionized serum magnesium cannot accurately be assessed at this time.

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

Elimination is predominantly renal; the threshold for urinary excretion nears the reference range of serum concentration. Thus, when serum levels are greater than 2.5 mEq/L, magnesium excretion dramatically increases. Conversely, the kidney retains a strong capacity to resorb magnesium, and the main site for reabsorption is the thick ascending loop of Henle. Renal reabsorption is impaired by several factors such as volume expansion, ethanol ingestion, hypercalcemia, and diuretic administration (eg, osmotic, thiazide, loop). Of these 3 types of diuretics, loop diuretics have a greater effect on renal magnesium wasting because of their site of action.

Pathophysiology: The reference range of serum magnesium levels is 1.8-2.5 mEq/L. Thus, hypermagnesemia is defined as a serum concentration greater than 2.5 mEq/L. Most cases of hypermagnesemia have been noted in patients with severe renal failure in whom magnesium intake has been excessive. This may result from iatrogenic administration of medications that contain magnesium. Fatal hypermagnesemia has resulted from the administration of enemas containing magnesium to patients with renal failure. In fact, hypermagnesemia is rarely observed in individuals with a glomerular filtration rate (GFR) that is within reference range. In patients with acute renal failure and hypermagnesemia, levels usually remain less than 4 mEq/L.

Rapid mobilization of magnesium from soft tissues may result in hypermagnesemia following trauma, shock, cardiac arrest, or burns.

Hypermagnesemia usually occurs in individuals with significant diabetic ketoacidosis and often turns into hypomagnesemia during treatment. Thus, the initial hypermagnesemia is likely a pseudo-elevation secondary to dehydration, and the resulting hypomagnesemia may reflect intracellular shifting following insulin administration.

Neonates with hypermagnesemia whose mothers have received intravenous magnesium sulfate for pregnancy-induced hypertension may present with respiratory impairment, generalized hypotonia, and GI hypomotility mimicking intestinal obstruction.

Frequency:
 

• In the US: Although the occurrence of hypermagnesemia is not defined precisely, the disorder tends to occur in certain patient populations, particularly in patients with preexisting renal insufficiency.

History:

• Symptoms of hypermagnesemia are nonspecific at lower levels (2-4 mEq/L) and may include the following:

• Nausea

• Vomiting

• Flushing

• Lethargy

• Weakness

• Dizziness

• Higher levels may lead to a depressed sensorium, and cardiopulmonary arrest may occur at extreme levels (>10-15 mEq/L).

Physical:

• Hypermagnesemia results in loss of deep-tendon reflexes at levels of 4-6 mEq/L. At magnesium levels greater than 5 mEq/L, CNS depression, which may range from drowsiness to coma, begins. While concentrations of magnesium greater than 10 mEq/L lead to respiratory depression in adults, this may occur at much lower levels in the newborn.

• Hypermagnesemia has a negative effect on heart rate. Beginning with magnesium serum levels of 4.5 mEq/L, depression of sinoatrial node activity and atrial fibrillation may occur. Higher magnesium levels increase the P-R interval, widen the QRS complex, and can cause intraventricular conduction delays. Serum magnesium concentrations greater than 15 mEq/L can lead to complete heart block and asystole.

• At varying levels (5-8 mEq/L), hypermagnesemia may produce vasodepression of vascular smooth muscle leading to systemic hypotension.

Causes:

• Major predisposing factors for the development of hypermagnesemia include the following:

• Renal failure (acute or chronic)

• Iatrogenic overadministration of magnesium

• Neonates born to mothers treated with magnesium sulfate for eclampsia

• Laboratory analysis by atomic absorbance spectrophotometry (AAS) is the most specific technique available for measuring total serum magnesium.

• While ion-selective electrodes for measuring free magnesium have been developed, their use has not been tested rigorously, and they are not readily available in a clinical setting at this time.

• Hypermagnesemia usually is not found as an isolated electrolyte abnormality; hyperkalemia and hypercalcemia often are present concurrently. Hypermagnesemia may secondarily cause hypocalcemia by suppressing parathyroid hormone (PTH) and by directly suppressing non–PTH-mediated renal tubular calcium reabsorption.

• Obtain BUN and creatinine levels to determine the presence of renal insufficiency, as serum magnesium levels rise when the creatinine clearance is less than 30 cc/min.

• Check creatine phosphokinase (CPK) or urine myoglobin in patients with suspected rhabdomyolysis.

• Because hypothyroidism and adrenal insufficiency are rare causes of hypermagnesemia, perform thyroid function tests and at least an early morning serum cortisol test in recurrent or refractory cases of hypermagnesemia.

Other Tests:
 

• An ECG and cardiac monitor may demonstrate prolongation of the P-R interval, intraventricular conduction delay, or other nonspecific findings.

Medical Care:

• Symptoms and signs of magnesium intoxication respond to intravenous calcium. Calcium chloride (5 mL of a 10% sol) may be administered intravenously over 30 seconds to directly antagonize the cardiac and neuromuscular effects of excess extracellular magnesium. Monitor these patients in an ICU setting and give careful attention to ECG parameters.

• In order to promote a more sustained decrease in serum magnesium, patients with normal urine output and renal function may be treated with intravenous saline infusions and furosemide diuresis.

• Dialysis for hypermagnesemia may be used for patients with the following:

• Renal insufficiency

   

• Severe asymptomatic hypermagnesemia (>8 mEq/L)

   

• Serious cardiovascular or neuromuscular symptoms at any serum magnesium level

• Cathartics or enemas that do not contain magnesium may be used to enhance gastrointestinal clearance of excess ingested magnesium.

Consultations: A nephrology consult may be obtained for refractory cases of hypermagnesemia or for patients with hypermagnesemia who require urgent dialysis.

MEDICATION

Treatment depends upon the degree of hypermagnesemia and the presence of symptoms. In patients with mildly increased levels, the source of magnesium may simply be removed. In patients with higher concentrations of magnesium or severe symptoms, other treatments are necessary. Reserve calcium for patients with life-threatening symptoms, such as arrhythmias or severe respiratory depression.
 

Drug Category: Intravenous fluids -- Dilution of the extracellular magnesium concentration is the rationale behind intravenous use. Fluids are used with diuretics to promote diuresis of magnesium by the kidneys.

Drug Category: Diuretics -- Increases renal excretion of magnesium.

Drug Category: Calcium -- Directly antagonizes the effects of magnesium.

Medical/Legal Pitfalls:
 

• Although abnormally high levels of serum magnesium are unusual, failure to include hypermagnesemia in the differential diagnosis of the signs and symptoms listed in this chapter may be harmful to the patient. Because hypermagnesemia can masquerade as other electrolyte imbalances, obtain magnesium levels along with other electrolytes (eg, calcium, phosphorus) when ordering laboratory tests.

• Knochel JP: Disorders of magnesium metabolism. Harrison's Principles of Internal Medicine 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. Arch Int Med 1988; 148: 2415-2420.

• Rude RK, Singer FR: Magnesium deficiency and excess. Ann Rev Med 1981; 32: 245-259