What is the diagnosis, evaluation, and treatment for hypomagnesemia (low magnesium levels) and hypermagnesemia (high magnesium levels) in patients?

Magnesium Disorders: Comprehensive Clinical Management

Definitions and Diagnostic Thresholds

Hypomagnesemia is defined as serum magnesium <0.70 mmol/L (equivalent to <1.4 mEq/L or <1.7 mg/dL), while hypermagnesemia occurs at levels >2.5 mmol/L, with life-threatening toxicity developing at 6-10 mmol/L. 1, 2

• Serum magnesium poorly reflects total body stores since less than 1% of total body magnesium is found in blood 3, 4
• Severe hypomagnesemia is classified as <0.50 mmol/L and typically requires parenteral treatment 1
• Normal serum magnesium range is 1.5-2.5 mEq/L (1.8-2.2 mEq/L by some references) 5, 6

Etiology and Pathophysiology

Hypomagnesemia Causes

The most common causes are renal wasting (often drug-induced) and gastrointestinal losses, with secondary hyperaldosteronism from volume depletion creating a vicious cycle of ongoing magnesium loss. 1, 3

• Renal losses: Diuretics, aminoglycosides, amphotericin B, cisplatin, calcineurin inhibitors (cyclosporine, tacrolimus), and proton pump inhibitors 7, 2, 1
• Gastrointestinal losses: Diarrhea, short bowel syndrome, jejunostomy (each liter contains ~100 mmol/L sodium and significant magnesium), malabsorption syndromes 1, 3
• Metabolic conditions: Diabetes mellitus, alcoholism, sepsis, post-transplant state 7, 8
• Critical illness: 60-65% of patients on continuous renal replacement therapy develop hypomagnesemia, especially with citrate anticoagulation 1, 3

Volume depletion triggers secondary hyperaldosteronism, which increases renal retention of sodium at the expense of both magnesium and potassium, overriding the normal protective mechanism of reducing fractional magnesium excretion to <2%. 3

Hypermagnesemia Causes

Hypermagnesemia is almost exclusively seen in patients with substantially decreased kidney function (GFR <30 mL/min) receiving magnesium-containing medications, supplements, or cathartics. 9, 8

• Iatrogenic overdose, particularly in preeclamptic patients receiving high-dose magnesium sulfate 2, 10
• Magnesium-containing antacids or laxatives in renal failure 9, 4
• Rare: tumor lysis syndrome, rhabdomyolysis 4

Clinical Manifestations

Hypomagnesemia Symptoms

Neuromuscular hyperexcitability is the hallmark, with cardiac arrhythmias representing the most life-threatening complication. 1, 4

• Neuromuscular: Tetany, tremors, muscle cramps, fasciculations, seizures, paresthesias 1, 4
• Cardiac: QT prolongation, torsades de pointes, ventricular arrhythmias, increased risk at magnesium <1.7 mg/dL 1, 2
• Metabolic: Refractory hypokalemia (magnesium deficiency causes dysfunction of potassium transport systems), hypocalcemia (PTH resistance) 1, 3, 4
• Other: Fatigue, abdominal cramps, poor wound healing, bone pain 3

Hypermagnesemia Symptoms

Symptoms progress from ECG changes at 2.5-5 mmol/L to complete cardiovascular collapse and respiratory paralysis at 6-10 mmol/L. 2, 5

• Cardiovascular (2.5-5 mmol/L): Prolonged PR, QRS, and QT intervals, hypotension, bradycardia 2, 9
• Neuromuscular (4-5 mmol/L): Loss of deep tendon reflexes (patellar reflex disappearance is earliest sign), sedation, severe muscle weakness, respiratory depression 2, 5, 9
• Severe (6-10 mmol/L): AV nodal block, cardiac arrest, respiratory paralysis, coma 2, 9
• Other: Nausea, vomiting, flushing, hypophosphatemia 2

Diagnostic Evaluation

Initial Assessment for Hypomagnesemia

Measure serum magnesium, potassium, calcium, and renal function simultaneously, as these electrolytes are interdependent and hypomagnesemia causes refractory hypokalemia and hypocalcemia. 1, 3

• Check ECG for QT prolongation (>500 ms requires urgent correction regardless of baseline magnesium level) 1, 3
• Assess volume status: look for signs of dehydration, high-output stoma, diarrhea, or other gastrointestinal losses 1, 3
• Review medication list for magnesium-wasting drugs (diuretics, PPIs, aminoglycosides, calcineurin inhibitors) 1, 7
• Calculate fractional excretion of magnesium if renal wasting suspected (>2% indicates renal wasting when serum magnesium is low) 3

Hypermagnesemia Evaluation

Check serum magnesium level, renal function, and assess for magnesium-containing medication exposure in any patient with unexplained hypotension, bradycardia, or loss of reflexes. 2, 9

• Obtain ECG to assess for conduction abnormalities 2
• Test patellar reflex (disappearance indicates magnesium >4-5 mmol/L) 5, 9
• Review all medications, supplements, and over-the-counter products for magnesium content 9

Treatment of Hypomagnesemia

Step 1: Correct Volume Depletion First

Before any magnesium supplementation, correct sodium and water depletion with IV saline to eliminate secondary hyperaldosteronism, which causes ongoing renal magnesium wasting that will defeat supplementation efforts. 1, 3

• This is the most critical and commonly missed step 3
• Failure to correct volume status first results in continued magnesium losses despite supplementation 3
• Each liter of jejunostomy fluid contains ~100 mmol/L sodium requiring replacement 3

Step 2: Oral Magnesium for Mild-Moderate Cases (>0.50 mmol/L)

Administer magnesium oxide 12-24 mmol daily (approximately 480-960 mg elemental magnesium), with the initial 12 mmol dose given at night when intestinal transit is slowest to maximize absorption. 1, 6

• Magnesium oxide is preferred as first-line because it contains more elemental magnesium and converts to magnesium chloride in the stomach 6
• Divide doses throughout the day for continuous repletion if higher doses needed 6
• Organic magnesium salts (aspartate, citrate, lactate) have higher bioavailability than oxide or hydroxide and can be considered as alternatives 6, 1
• Target serum magnesium >0.6 mmol/L minimum, ideally within normal range (1.8-2.2 mEq/L) 6, 1

Common pitfall: Most magnesium salts are poorly absorbed and may worsen diarrhea or stomal output in patients with gastrointestinal disorders. 1, 6

Step 3: Parenteral Magnesium for Severe or Symptomatic Cases

For severe symptomatic hypomagnesemia (<0.50 mmol/L) or life-threatening presentations, give 1-2 g magnesium sulfate IV bolus over 5-15 minutes, followed by continuous infusion. 1, 5

• For torsades de pointes with prolonged QT: Give 1-2 g magnesium sulfate IV bolus over 5 minutes regardless of baseline magnesium level 1, 2
• For cardiac arrhythmias: Administer IV magnesium even if measured levels are normal 1, 6
• Pediatric dosing: 25-50 mg/kg IV/IO (maximum 2 g) over 10-20 minutes for hypomagnesemia with pulses; give as bolus for pulseless torsades 3
• Monitor for magnesium toxicity during IV replacement: loss of patellar reflexes, respiratory depression, hypotension, bradycardia 1, 5
• Have calcium chloride available to reverse magnesium toxicity if needed 3, 5

Step 4: Address Refractory Hypokalemia and Hypocalcemia

Replace magnesium FIRST before attempting to correct hypocalcemia or hypokalemia, as both will be refractory to treatment until magnesium is normalized, with calcium normalization typically occurring within 24-72 hours after magnesium repletion begins. 1, 3

• Hypomagnesemia causes dysfunction of potassium transport systems and increases renal potassium excretion 3
• Calcium supplementation is ineffective until magnesium is repleted due to PTH resistance 1
• Do not administer calcium and magnesium supplements together; separate by at least 2 hours as they inhibit each other's absorption 1

Step 5: Alternative Approaches for Refractory Cases

If oral magnesium supplements fail to normalize levels despite adequate dosing, add oral 1-alpha hydroxy-cholecalciferol (0.25-9.00 μg daily) in gradually increasing doses to improve magnesium balance. 1, 3

• Monitor serum calcium regularly to avoid hypercalcemia 1, 3
• For short bowel syndrome or severe malabsorption, subcutaneous magnesium sulfate (4-12 mmol added to saline bags) may be necessary 1-3 times weekly 1, 3
• Reduce dietary lipids to improve magnesium absorption 6

Special Populations

For patients on continuous renal replacement therapy, use dialysis solutions containing magnesium to prevent ongoing electrolyte derangements, as 60-65% develop hypomagnesemia. 1, 3

Post-transplant patients on calcineurin inhibitors: Increase dietary magnesium initially, but the amount required typically necessitates supplements rather than dietary modification alone 1

Treatment of Hypermagnesemia

Immediate Management

Stop all magnesium-containing medications, supplements, antacids, and cathartics immediately. 9, 4

Mild Hypermagnesemia (2.5-5 mmol/L)

Administer IV isotonic saline to promote renal magnesium excretion in patients with adequate kidney function. 9, 4

• Monitor vital signs, reflexes, and ECG continuously 9

Severe Hypermagnesemia (>5 mmol/L) or Symptomatic

Give 10-20 mL of 5% calcium gluconate (or calcium chloride) IV over 5-10 minutes to antagonize the cardiovascular and neuromuscular effects of magnesium. 5, 10

• Calcium does not lower magnesium levels but reverses its toxic effects 5
• Provide artificial ventilation if respiratory paralysis develops 5, 10
• Consider subcutaneous physostigmine 0.5-1 mg for severe cases 5

Life-Threatening Hypermagnesemia

Initiate urgent hemodialysis for severe hypermagnesemia with cardiovascular collapse, respiratory failure, or when basic supportive interventions (calcium and fluids) are ineffective. 10, 9

• Hemodialysis is the most effective method for rapidly removing magnesium 10
• Particularly indicated in patients with renal failure who cannot excrete magnesium 10, 9

Monitoring Guidelines

Hypomagnesemia Monitoring

Check magnesium levels 2-3 weeks after starting oral supplementation or after any dose adjustment, then every 3 months once on stable dosing. 3

• High-risk patients (short bowel syndrome, high GI losses, CRRT, medications affecting magnesium): Check every 2 weeks during first 3 months, then monthly 3
• Cardiac emergencies or QTc prolongation: Recheck within 24-48 hours after IV magnesium 3
• Monitor potassium and calcium simultaneously, as these normalize after magnesium correction 1, 3
• Assess for symptom resolution: muscle cramps, tetany, fatigue, paresthesias 3

Hypermagnesemia Monitoring

Monitor serum magnesium, vital signs, patellar reflexes, and ECG continuously in symptomatic patients until levels normalize. 9

• Disappearance of patellar reflex indicates magnesium >4-5 mmol/L and impending toxicity 5, 9

Critical Contraindications and Precautions

Magnesium Supplementation Contraindications

Avoid all magnesium supplementation when creatinine clearance <20 mL/min due to life-threatening hypermagnesemia risk. 1, 3

• Use extreme caution with CrCl 20-30 mL/min; avoid unless life-threatening emergency (e.g., torsades) 3
• Reduce doses with close monitoring when CrCl 30-60 mL/min 3
• Maximum dose in severe renal insufficiency: 20 grams/48 hours with frequent serum monitoring 1

Drug Interactions

Do not mix magnesium sulfate with vasoactive amines or calcium in the same IV solution. 1

• Separate calcium and iron supplements from magnesium by at least 2 hours 1
• Use central venous catheter for IV administration to avoid tissue injury from extravasation 1
• Rapid infusion causes hypotension and bradycardia 3

Special Clinical Scenarios

For pregnant women with preeclampsia/eclampsia receiving magnesium sulfate, monitor closely for oliguria and toxicity; empirical calcium administration may be lifesaving in overdose. 2

Patients with QTc prolongation >500 ms require magnesium repletion to >2 mg/dL regardless of baseline level as anti-torsadogenic countermeasure. 3

In Bartter syndrome type 3, target plasma magnesium >0.6 mmol/L using organic magnesium salts for better bioavailability. 3