Hypermagnesemia

Hypermagnesemia

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Hypermagnesemia is an uncommon laboratory finding and symptomatic hypermagnesemia is even less common. This disorder has a low incidence of occurrence, because the kidney is able to eliminate excess magnesium by rapidly reducing its tubular reabsorption to almost negligible amounts.

In healthy adults, plasma magnesium ranges from 1.7-2.3 mg/dL. Approximately 30% of total plasma magnesium is protein-bound and approximately 70% is filterable through artificial membranes (15% complexed, 55% free Mg²⁺ ions). With a glomerular filtration rate (GFR) of approximately 150 L per day and an ultrafiltrable magnesium concentration of 14 mg/L, the filtered magnesium load is approximately 2,100 mg per day.

Normally, only 3% of filtered magnesium appears in urine; thus, 97% is reabsorbed by the renal tubules. In contrast to sodium and calcium, only approximately 25-30% of filtered magnesium is reabsorbed in the proximal tubule. Approximately 60-65% of filtered magnesium is reabsorbed in the thick ascending loop of Henle and 5% is reabsorbed in the distal nephron.^[1]Relatively little is known about cellular magnesium transport mechanisms.^[2]

The most common cause of hypermagnesemia is renal failure. Other causes include the following^{[3, 4]}:

Patients with end-stage renal disease often have mild hypermagnesemia, and the ingestion of magnesium-containing medications (eg, antacids, cathartics) can exacerbate the condition.^{[5, 6]}In patients undergoing regular dialysis, the serum magnesium level directly relates to the dialysate magnesium concentration.^[7]

In patients with acute renal failure, hypermagnesemia usually presents during the oliguric phase; the serum magnesium level returns to normal during the polyuric phase. If a patient receives exogenous magnesium during the oliguric phase, severe hypermagnesemia can result, especially if the patient is acidotic.

People often take magnesium-containing medications (eg, antacids,^[8]laxatives,^{[9, 10]}enemas). Hypermagnesemia can develop after treatment of drug overdoses with magnesium-containing cathartics,^[11]and it also occurs in patients taking magnesium-containing medications for therapeutic purposes^{[12, 13]}; however, most of these patients have normal renal function.^[14]

With certain gastrointestinal disorders (eg, gastritis, colitis, gastric dilation), increased absorption of magnesium may lead to hypermagnesemia even if the patient does not ingest a large amount of magnesium.^{[15, 16, 17]}In any case, monitoring serum magnesium levels in patients taking magnesium-containing medications is prudent. Suicide attempts using magnesium-containing salt can lead to life-threatening hypermagnesemia, as well.^[18]

Excessive tissue breakdown (sepsis, shock, large burns), especially with concurrent renal failure, can deliver a large amount of magnesium from the intracellular space, along with a massive elevation of phosphorus and potassium.^[4]

In the treatment of eclampsia, hypermagnesemia is induced deliberately and sometimes can be symptomatic.^{[12, 19, 20, 21]}Occasionally, hypermagnesemia also can occur in the newborn infant.^{[22, 23]}Maternal magnesium therapy can increase the need for feeding and respiratory support^[24]and may cause neurobehavioral disorders in the newborn.^[25]

Magnesium-containing phosphorus binders are rarely used in end-stage renal disease patients^{[26, 27]}and can lead to elevated magnesium levels.

Lithium therapy causes hypermagnesemia by decreasing urinary excretion, although the mechanism for this is not completely clear.

Familial hypocalciuric hypercalcemia may cause modest elevations in serum magnesium.^[28]This autosomal dominant disorder is characterized by very low excretion of calcium and magnesium and by a normal parathyroid hormone level. Abnormalities of calcium and magnesium handling are due to mutations in the calcium-sensing receptor,^[29]resulting in increased magnesium reabsorption in the loop of Henle. More recently, mutations of the codon Arg15 (p.R15) in the adaptor-related protein complex 2, σ-2 subunit that interacts with the calcium-sensing receptor have been described.^[30]

Hypothyroidism, adrenal insufficiency, milk-alkali syndrome^{[3, 4]}and theophylline intoxication occasionally produce mild elevations of serum magnesium.

There has been some interest in the use of magnesium in the treatment and prevention of cardiac arrhythmias and in the treatment of subarachnoid hemorrhage.^{[31, 32]}However, significant hypermagnesemia has not been reported in these settings.

The role of mild elevation of serum magnesium levels in select patient populations is still being defined. In a study examining the prevalence of serum magnesium (Mg) alterations and outcomes in 65,974 hospitalized adult patients, Mg levels of 2.1 mg/dL or higher were found in 20,777 patients (31.5%). An elevated Mg level of 2.3 mg/dL or higher was a predictor of adverse outcomes and associated with worse hospital mortality.^[33]

In a different study by the same authors, both hypomagnesemia (<1.5 mg/dL) and hypermagnesemia (>2.3 mg/dl) on hospital admission were associated with an increased risk of developing in-hospital acute respiratory failure. the odds ratio (OR) was 1.69 (95% confidence index [CI], 1.19-2.36) with hypomagnesemia and 1.40 (95% CI, 1.02-1.91) with hypermagnesemia.^[34]

In patients admitted to intensive care units, initial magnesium levels ≥2.4 mg/dL (reference: 2.0 to <2.2 mg/dL) was independently associated with increased in mortality (adjusted OR of 1.80; 95% CI: 1.25-2.59.^[35]In a large study of 5339 critically ill patients from Switzerland, hypermagnesemia was a strong independent risk factor for 28-day mortality (hazard ratio, 11.6, P<0.001).<ref>36</ref>

Similarly, in patients with chronic heart failure, a meta-analysis of 7 prospective studies with a total of 5172 subjects demonstrated that those with baseline hypermagnesemia had a significantly higher risk of cardiovascular mortality (risk ratio [RR],, 1.38; 95% CI, 1.07-1.78) or all-cause mortality (RR 1.35; 95% CI, 1.18-1.54).^[37]On the other hand, in end-stage renal disease patients on dialysis—a population characterized by a particularly high mortality rate—a mild elevation of serum magnesium appeared protective against cardiovascular mortality, albeit without impacting all-cause mortality.^[38]

Symptoms of hypermagnesemia usually are not apparent unless the serum magnesium level is greater than 2 mmol/L. Concomitant hypocalcemia, hyperkalemia, or uremia exaggerate the symptoms of hypermagnesemia at any given level.

These are the most common presenting problems. Hypermagnesemia causes blockage of neuromuscular transmission by preventing presynaptic acetylcholine release and by competitively inhibiting calcium influx into the presynaptic nerve channels via the voltage-dependent calcium channel.^[39]

One of the earliest symptoms of hypermagnesemia is deep-tendon reflex attenuation. Facial paresthesias also may occur at moderate serum levels.

Muscle weakness is a more severe manifestation, occurring at levels greater than 5 mmol/L. This manifestation can result in flaccid muscle paralysis and depressed respiration and can eventually progress to apnea.

Hypermagnesemia depresses the conduction system of the heart and sympathetic ganglia.^[39]A moderate increase in serum magnesium can lead to a mild decrease in blood pressure, and a greater concentration may cause severe symptomatic hypotension. Magnesium is also cardiotoxic and, in high concentrations, can cause bradycardia. Occasionally, complete heart block and cardiac arrest may occur at levels greater than 7 mmol/L.

Apparently, hypocalcemia can result from a decrease in the secretion of parathyroid hormone (PTH) or from end-organ resistance to PTH.^[40]In patients with end-stage renal disease, high magnesium levels are associated with relative suppression of PTH,^[41]which may, in turn, contribute to hypocalcemia in this population.

Paralytic ileus develops from smooth-muscle paralysis,^[15]and mothers being treated with magnesium for preterm labor suppression are at risk.^[42]

Hypermagnesemia may interfere with blood clotting through interference with platelet adhesiveness, thrombin generation time, and clotting time.

These symptoms include the following:

Hypermagnesemia usually results from a combination of excess magnesium intake and a coexisting impairment of renal function. Diagnosis is usually straightforward and involves measuring serum magnesium levels, as many cases are unsuspected.^[43]If a magnesium level is not immediately available, a clue to the existence of hypermagnesemia would be the disease context (preeclampsia, renal failure), the presence of magnesium-containing preparations, or a decreased anion gap.

Prevention of hypermagnesemia is usually possible. Anticipate hypermagnesemia in patients who are receiving magnesium treatment, especially those with reduced renal function. Initially, withdraw magnesium therapy, which often is enough to correct mild to moderate hypermagnesemia.

In patients with symptomatic hypermagnesemia that is causing cardiac effects or respiratory distress, antagonize the effects by infusing calcium gluconate. Calcium antagonizes the toxic effect of magnesium, and these ions electrically oppose each other at their sites of action. This treatment usually leads to immediate symptomatic improvement. In subjects with frankly impaired ability to excrete magnesium (eg, end-stage renal disease), renal replacement therapy may also be necessary.

Agents that promote magnesium excretion are effective in treating hypermagnesemia.

Furosemide (Lasix) may promote excretion of magnesium. It increases excretion of water by interfering with the chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule.

Calcium may moderate nerve and muscle performance in hypermagnesemia.

Calcium gluconate (Kalcinate) directly antagonizes neuromuscular and cardiovascular effects of magnesium. Use in patients with symptomatic hypermagnesemia that is causing cardiac effects or respiratory distress.

Agents that shift magnesium ions into cells are helpful in treating hypermagnesemia.

Glucose and insulin may help promote magnesium entry into cells. Glucose should be administered with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.

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Tibor Fulop, MD, PhD, FACP, FASN Professor of Medicine, Department of Medicine, Division of Nephrology, Medical University of South Carolina College of Medicine; Attending Physician; Medical Services, Ralph H Johnson VA Medical Center

Tibor Fulop, MD, PhD, FACP, FASN is a member of the following medical societies: American Academy of Urgent Care Medicine, American College of Physicians, American Society of Diagnostic and Interventional Nephrology, American Society of Hypertension, American Society of Nephrology, International Society for Apheresis, International Society for Hemodialysis, Magyar Orvosi Kamara (Hungarian Chamber of Medicine), Southern Society for Clinical Investigation

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Fresenius Medical Care, Hungary; Dialysis Clinic Inc., USA.

Sohail Abdul Salim, MD, FASN, FACP Consultant Physician, Central Nephrology; Affiliate Faculty, Department of Internal Medicine, Division of Nephrology, University of Mississippi Medical Center

Sohail Abdul Salim, MD, FASN, FACP is a member of the following medical societies: American College of Physicians, American Society of Nephrology, Mississippi State Medical Association, Renal Physicians Association