Hypermagnesemia

Etiology

Decreased renal excretion

Hypermagnesemia occurs primarily in patients with acute or chronic kidney disease. In these individuals, some conditions, including proton pump inhibitors, malnourishment, and alcoholism, can increase the risk of hypermagnesemia. Hypothyroidism and especially cortico-adrenal insufficiency, are other recognized causes.

Hyperparathyroidism and alterations in calcium metabolism involving hypercalcemia and/or hypocalciuria can lead to hypermagnesemia through an increased calcium-induced magnesium absorption in the tubule. Patients with familial hypocalciuric hypercalcemia (FHH), a rare autosomal dominant condition, can manifest hypermagnesemia.[5][6]

Lithium-based psychotropic drugs can also lead to hypermagnesemia by reducing excretion.

Increased intake

The disorder may rarely develop even without renal impairment, mostly in the elderly, where an underlying bowel condition may lead to increased absorption through a decreased gut motility. Patients treated with anticholinergics or opioids, or those with inflammatory bowel diseases are at higher risk.[7]

Some drugs such as laxatives and antacids that contain magnesium (e.g., magnesium oxide) can lead to increased values of magnesium, especially in elderly patients with renal function impairment. For instance, although poor bioavailability makes magnesium oxide relatively safe, its prolonged use may lead to risks of hypermagnesemia.[8] Periodic evaluation is a recommendation in geriatric patients treated with magnesium oxide for extended periods. Nevertheless, magnesium oxide intake under 1000 mg/day seems to be relatively safe.[9]

Severe hypermagnesemia has also been described after the administration of bowel preparation agents (e.g., sodium picosulphate magnesium citrate).[10] Moreover, excessive oral intake can lead to hypermagnesemia in patients on hemodialysis, as ingestion primarily influences plasma levels in these patients.[11]

Patients with milk-alkali syndrome due to the ingestion of large amounts of calcium and absorbable alkali are more susceptible to develop hypermagnesemia.

Since magnesium is useful in the management of eclampsia (e.g., therapeutic serum magnesium level 1.7 to 3.5 mmol/L), the excessive infusion can induce iatrogenic hypermagnesemia. Newborns of mothers who have received magnesium sulfate parenterally during labor may present with toxicity even with normal serum magnesium levels. 

Compartment shift or leak

Magnesium levels can increase in hemolysis patients. Red blood cells contain three times as much magnesium as compared to plasma. The rupture of these cells pours magnesium into the plasma. However, symptomatic hypermagnesemia occurs only in the case of aggressive hemolysis.

Tumor lysis syndrome, rhabdomyolysis, and acidosis (e.g., decompensated diabetes with ketoacidosis) can also induce hypermagnesemia through extracellular shifts. 

Epidemiology

Hypermagnesemia is an uncommon electrolyte disorder. It occurs in approximately 10 to 15% of hospitalized patients with renal failure.[12] Furthermore, epidemiological data suggest that there is a significant prevalence of high levels of serum magnesium in selected healthy populations. For instance, Syedmoradi et al. demonstrated that the overall prevalence of hypermagnesemia was 3.0%, especially in males (p < 0.05) in Iranian subjects.[13] It could be interesting to evaluate hypermagnesemia as a risk factor for other diseases. For instance, Cheungpasitporn et al. found that high magnesium concentrations were typical in people with cardiovascular disease, and 2.3 mg/dL or higher values were associated with worse hospital mortality.[14]

Pathophysiology

Renal function plays a crucial role in the metabolism of magnesium. Of note, only approximately 10% of filtered magnesium is absorbed in the proximal tubule, whereas most of the filtered magnesium gets passively reabsorbed in the ascending limb of the loop of Henle. This factor is essential for the pathophysiology of kidney-related hypermagnesemia as along the loop of Henle, not only the volume of the filtrate gets reduced, but also the osmolarity decreases significantly (-66%), and consequently the solutes become less concentrated. Furthermore, this explains the high resorbent capacity of the kidney, which generally maintains magnesium equilibrium until the creatinine clearance falls below 20 ml/min. Thus, an increase in plasma magnesium levels is practically impossible to achieve with diet alone in conditions of perfect renal health. However, the odds of hypermagnesemia can increase by taking mega-doses of magnesium. The pathophysiology of hypermagnesemia related to excess laxative use is different. In this case, the huge amount of magnesium given through the digestive tract can lead to overwhelming the excretory mechanism, especially in cases with underlying subclinical renal failure. 

Magnesium works as a physiologic calcium blocker. Increased levels determine substantial electrophysiological and hemodynamic effects. Moreover, the potential concomitance of hyperkalemia increases the risk of cardiac arrhythmias and cardiac arrest. The neurologic manifestations are the result of the inhibition of acetylcholine release from the neuromuscular endplate due to increased extracellular magnesium levels.

History and Physical

Patients with symptomatic hypermagnesemia can present different clinical manifestations depending on the level and the time in which the electrolytic disturbance has occurred. Hypermagnesemia is generally well tolerated. Thus patients with altered values (under 4 mg/dL) may be asymptomatic or paucisymptomatic. The most frequent symptoms and signs may include weakness, nausea, dizziness, and confusion (less than 7.0 mg/dL). Increasing values (7 to 12 mg/dL) induce decreased reflexes, worsening confusional state, drowsiness, bladder paralysis, flushing, headache, and constipation. A slight reduction in blood pressure and blurred vision caused by diminished accommodation and convergence can manifest. For higher values (over 12.0 mg/dL) muscle paralysis, paralytic ileus, decreased breathing rate, low blood pressure, electrocardiogram (ECG) changes including an increase in PR and QRS interval with sinus bradycardia, and atrioventricular block, coma and cardiac arrest (exceeding 15.0 mg/dL) may occur. When associated with hypocalcemia, hypermagnesemia may induce choreiform movements and seizures. The clinical picture becomes particularly severe, and there are few case reports of patients who survived to higher hypermagnesaemia levels.[8]

In summary:

• Mild hypermagnesemia (less than 7 mg/dL) - Asymptomatic or paucisymptomatic: weakness, nausea, dizziness, and confusion
• Moderate hypermagnesemia (7 to 12 mg/dL) - Decreased reflexes, worsening of the confusional state and sleepiness, bladder paralysis, flushing, headache, and constipation. A slight reduction in blood pressure, bradycardia, and blurred vision caused by diminished accommodation and convergence are usually present.
• Severe hypermagnesemia (greater than 12 mg/dL) - Muscle flaccid paralysis, decreased breathing rate, more evident hypotension and bradycardia, prolongation of the P-R interval, atrioventricular block, and lethargy are common. Coma and cardiorespiratory arrest can occur for higher values (over 15 mg/dL).

Evaluation

Evaluation of a patient suspected of having hypermagnesemia includes:

• Serum magnesium level
• The basic metabolic panel focusing on renal biochemistry: glomerular filtration rate (GFR), blood urea nitrogen, creatinine, glucose, urine specific gravity
• Arterial blood gas
• Clinical evaluation of renal function with urinary output
• Potassium, phosphate, calcium levels (plasma and urinalysis)
• ECG

During the high dose magnesium therapy for eclampsia, it is necessary to measure serum magnesium levels periodically to prevent hypermagnesemia. 

Treatment / Management

Patients with normal renal function (GFR over 60 ml/min) and mild asymptomatic hypermagnesemia require no treatment except the removal of all sources of exogenous magnesium. One must consider that the half-time of elimination of magnesium is approximately 28 hours.

In more severe cases, close monitoring of the ECG, blood pressure, and neuromuscular function and early treatment are necessary:

• Intravenous calcium gluconate or chloride [Dosage: 1 g in 2 to 5 min (repeatable over 5 minutes)]. The rationale is that the actions of magnesium in neuromuscular and cardiac function become antagonized by calcium.
• Intravenous normal saline (e.g., at 150 ml/hour)

Severe clinical conditions require increasing renal magnesium excretion through:

• Intravenous loop diuretics (e.g., furosemide 1 mg/kg), or
• Hemodialysis, when kidney function is impaired, or the patient is symptomatic from severe hypermagnesemia. This approach usually removes magnesium efficiently (up to 50% reduction after a 3- to 4-hour treatment). Dialysis can, however, increase the excretion of calcium by developing hypocalcemia, thus possibly worsening the symptoms and signs of hypermagnesaemia.

The use of diuretics must be associated with infusions of saline solutions to avoid further electrolyte disturbances (e.g., hypokalemia) and metabolic alkalosis. The clinician must perform serial measurements of calcium and magnesium. In association with electrolytic correction, it is often necessary to support cardiorespiratory activity. As a consequence, the treatment of this electrolyte disorder can frequently require intensive care unit (ICU) admission.[15]

Particular clinical conditions require a specific approach. For instance, during the management of eclampsia, the magnesium infusion is stopped if urine output drops to less than 80 mL (in 4 hours), deep tendon reflexes are absent, or the respiratory rate is below 12 breaths/minute. A 10% calcium gluconate or chloride solution (10 mL intravenously repeatable over 5 minutes) can serve as an antidote.

Differential Diagnosis

Sometimes the diagnosis of hypermagnesaemia can be challenging because:

• Checking serum magnesium is not routine
• Many clinicians are unfamiliar with this uncommon condition.
• Symptoms and signs are non-specific. A more characteristic clinical picture is an expression of overt disease.

Hypermagnesaemia is often a diagnosis of exclusion among a wide range of causes of neurologic or cardiorespiratory depression. These causes include: 

• Acute renal failure
• Hypercalcemia
• Hyperkalemia
• Hypoparathyroidism
• Hypothyroidism
• Lithium toxicity
• Hemolysis
• Rhabdomyolysis

Prognosis

The prognosis of hypermagnesemia depends on magnesium values and on the clinical condition that induced hypermagnesemia. Values that are not excessively high (mild hypermagnesemia) and in the absence of triggering and aggravating conditions (e.g., renal insufficiency) are benign conditions. On the contrary, high values (severe hypermagnesemia) expose the patient to high risks and high mortality.

Complications

Severe hypermagnesemia (levels greater than 12 mg/dL) can lead to cardiovascular complications (hypotension, and arrhythmias) and neurological disorder (confusion and lethargy). Higher values of serum magnesium (exceeding 15 mg/dL) can induce cardiorespiratory arrest and coma.