Hypermagnesemia


Article Author:
Marco Cascella


Article Editor:
Sarosh Vaqar


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
10/21/2019 10:01:12 AM

Introduction

Magnesium is a glossy gray solid included in the second column (group 2, or alkaline earth metals) of the periodic table. Joseph Black discovered this element in 1755. The origin of the name derives from Magnesia, a district of Eastern Thessaly in Greece. Magnesium improves the mechanical features of aluminum and is thus has uses as an alloying agent for in airplane and car construction. It also serves as a mordant for dyes (magnesium sulfate), added to plastics to make them fire retardant (magnesium hydroxide), in electronics (e.g., phones, laptop, tablet computers, cameras, and other electronic components), in heat-resistant cookware (magnesium oxide), and in agriculture as a fertilizer. Furthermore, magnesium is widely used in medicine, for instance, in the treatment of ventricular arrhythmia associated with torsade de pointes, or as an antacid and laxative.[1][2] Regimens using intravenous or intramuscular magnesium sulfate are recommendations for the prevention and treatment of eclampsia.[3]

Magnesium is an essential element for the life of plants as it is part of chlorophyll. Moreover, it is abundant in animal tissues, where it is fundamental for enzymatic action, transporters, and the synthesis of nucleic acids. It influences other electrolytes such as sodium, calcium, and potassium. Together with calcium, extracellular magnesium is of paramount importance for neuromuscular functions as well as for electrical activity of the myocardium and vascular tone. Magnesium introduced with the diet, in particular through vegetables, is absorbed in the intestinal tract, especially in the small intestine. Factors that improve its absorption include vitamin D, parathormone, growth hormone, thyroid hormones, and the presence of sodium in the diet. Calcium, fats, phosphates, and phytic acid can decrease intestinal absorption. Normally, an adult individual possesses about 25 g of magnesium. It is present mainly in the bones as salts (about 65%) and muscles, and only 1% in extracellular fluids. Serum levels vary from 0.7 to 1.0 mmol/L (or 1.5 to 2.0 mEq/L, or 1.7 to 2.4 mg/dL). 

Small changes in values may not be clinically relevant, and critical reference values are below 0.5 mmol/L (or 1.0 mg/L) and above 2.0 mmol/L (or 4.9 mg/dL). Hypomagnesemia is quite frequent, although the symptomatology (cramps, muscle spasms, paresthesia, and arrhythmias) appears only when exceeding the critical value.[4] On the other hand, hypermagnesemia is a rare but serious electrolytic disorder, which can be fatal if not recognized and treated promptly.

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), 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 mmol/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 mmol/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. 

Deterrence and Patient Education

As the patient with kidney failure is more exposed to the risk of hypermagnesaemia, thorough patient education must focus on early recognition of the symptoms of hypermagnesaemia, such as weakness, and confusion as well as on the cautious use of laxatives or antacids containing magnesium.

Enhancing Healthcare Team Outcomes

Although hypermagnesaemia is a rare disorder, some medical history (e.g., use of lithium) and clinical data (e.g., chronic kidney failure) may suggest the occurrence of the disorder. An interprofessional team approach involving the nurse, the general practitioner, and the pharmacist is essential to prevent this disease. Hypermagnesemia, in a vast number of cases, is preventable. An integrated approach between the practitioner prescribing the medications associated with the disease and the pharmacist dispensing the drugs is essential for avoiding iatrogenic causes. Intensive patient education by specialized pharmacists and regular follow up with specialized nurses to discuss potential signs of toxicity can prevent this condition in a fair number of patients.  

An integrated interprofessional team approach to medication reconciliation at each pharmacy refill, and each clinic visit is equally important. Multiple other drugs can indirectly increase the patient's risk for the disease. For example, opiate-induced constipation can lead to increased intestinal absorption of magnesium. The use of opiates with magnesium-based laxatives may further worsen the picture. These are examples of where both nursing and pharmacists can assist in monitoring the patient, and alerting the clinician at the earliest sign that something is amiss. WIth an interprofessional team managing the situation, patient outcomes are more likely to have a positive outcome. [Level V]

Clinical research is necessary to show that in specific clinical settings, the serum magnesium evaluation must take place periodically. Further controlled investigations, including randomized controlled trials, are needed for testing the suggestive hypothesis that hypermagnesemia could be a stronger predictor for poor outcomes in hospitalized patients or a risk factor for various diseases in healthy people.


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Hypermagnesemia - Questions

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A term infant is born by caesarian section to a mother with high blood pressure, and urinary protein excretion 3.8 g/day during the second half of pregnancy. In the last days of pregnancy, she presented several episodes of tonic-clonic seizures. Due to this severe clinical condition, the woman was admitted to the hospital to be monitored closely and continuously. She received treatment to stabilize blood pressure values and to stop the seizures. Although the mother's clinical conditions had rapidly improved after the caesarian section, the infant's tone was decreased, and he was lethargic. Moreover, the Apgar scores were 5 after 1 minute and 6 after 5 minutes. What is the most likely cause of these findings in the newborn?



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A 67-year-old man with is being treated with proton pump inhibitors due to gastroesophageal reflux disease has weakness and nausea. Laboratory tests show a chronic kidney disease. The clinical evaluation demonstrates only a loss of deep tendon reflexes and apart from weakness and nausea the patient is asymptomatic. Which of the following is most likely to be seen on serum electrolyte profile of this patient?



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A 76-year-old male with a past medical history of chronic kidney disease comes to the emergency room because of intense fatigue and confusion. The clinical evaluation shows a heart rate of 50 beats per minute, a respiratory rate of 10 breaths per minute, and decreased deep tendon reflexes. He also has a history of alcoholism. Which of the following electrolyte disturbances could be the most appropriate diagnosis?



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A 79-year-old male presents in a confused state in the emergency department on a hot summer day. He was scheduled for right colectomy to treat colon cancer within two days. His vital signs include a blood pressure of 90/40 mmHg and heart rate of 58/min. The history highlights hypothyroidism, not well managed through an irregular intake of hormonal substitutes, and compensated diabetes. A few years ago, he had an episode of nephrotic syndrome, treated with medications and no longer investigated. Blood sugar is within the normal range. This episode could affect the timing of the intervention, although he has already started bowel preparation with osmotic laxatives. Which of the following is the most likely cause of the patient's current symptoms?



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A 22-year-old male carries out a series of blood chemistry tests because he must obtain a competitive sport certification. All the tests carried out, including kidney function, appear to be normal. The electrolytes show serum magnesium of 4.0 mg/dL, sodium of 139 mEq/L and potassium of 3.5 mEq/L. The athlete has no symptoms, there are no signs of hemolysis, and he does not take osmotic laxatives or antacids. He refers to taking dietary supplements. What is the most appropriate therapeutic approach in this patient?



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Hypermagnesemia - References

References

Dalia AA,Essandoh M,Cronin B,Hussain N,Gerstein NS,Schulman P, A Narrative Review for Anesthesiologists of the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. Journal of cardiothoracic and vascular anesthesia. 2019 Jun;     [PubMed]
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Bao G,Fan Q,Ge D,Sun M,Guo H,Xia D,Liu Y,Liu J,Wu S,He B,Zheng Y, In vitro and in vivo studies on magnesium alloys to evaluate the feasibility of their use in obstetrics and gynecology. Acta biomaterialia. 2019 Aug 3;     [PubMed]
Gragossian A,Friede R, Hypomagnesemia 2019 Jan;     [PubMed]
Kraft MD,Btaiche IF,Sacks GS,Kudsk KA, Treatment of electrolyte disorders in adult patients in the intensive care unit. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2005 Aug 15;     [PubMed]
Bamgbade OA, Preoperative bowel preparation complicated by lethal hypermagnesaemia and acute nephropathy. The Nigerian postgraduate medical journal. 2017 Oct-Dec;     [PubMed]
Yamaguchi H,Shimada H,Yoshita K,Tsubata Y,Ikarashi K,Morioka T,Saito N,Sakai S,Narita I, Severe hypermagnesemia induced by magnesium oxide ingestion: a case series. CEN case reports. 2019 Feb;     [PubMed]
Shoaib Khan M,Zahid S,Ishaq M, Fatal Hypermagnesemia: an acute ingestion of Epsom Salt in a patient with normal renal function. Caspian journal of internal medicine. 2018 Fall;     [PubMed]
Afzal M,Kathuria P, Familial Hypocalciuric Hypercalcemia (FHH) 2019 Jan;     [PubMed]
Horino T,Ichii O,Terada Y, A Rare Presentation of Hypermagnesemia Associated with Acute Kidney Injury due to Hypercalcemia. Internal medicine (Tokyo, Japan). 2019 Apr 15;     [PubMed]
Felsenfeld AJ,Levine BS,Rodriguez M, Pathophysiology of Calcium, Phosphorus, and Magnesium Dysregulation in Chronic Kidney Disease. Seminars in dialysis. 2015 Nov-Dec;     [PubMed]
Wyskida K,Witkowicz J,Chudek J,Więcek A, Daily magnesium intake and hypermagnesemia in hemodialysis patients with chronic kidney disease. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2012 Jan;     [PubMed]
Syedmoradi L,Ghasemi A,Zahediasl S,Azizi F, Prevalence of hypo- and hypermagnesemia in an Iranian urban population. Annals of human biology. 2011 Mar;     [PubMed]
Cheungpasitporn W,Thongprayoon C,Qian Q, Dysmagnesemia in Hospitalized Patients: Prevalence and Prognostic Importance. Mayo Clinic proceedings. 2015 Aug;     [PubMed]
Mori H,Suzuki H,Hirai Y,Okuzawa A,Kayashima A,Kubosawa Y,Kinoshita S,Fujimoto A,Nakazato Y,Nishizawa T,Kikuchi M, Clinical features of hypermagnesemia in patients with functional constipation taking daily magnesium oxide. Journal of clinical biochemistry and nutrition. 2019 Jul     [PubMed]

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