CONTENTS
- Diagnosis
- Symptoms
- Causes
- Evaluation of cause
- Treatment
- Physiology: magnesium handling
- Podcast
- Questions & discussion
- Pitfalls
magnesium level
physical examination
- Hyperreflexia.
ECG manifestations
- Hypomagnesemia may prolong all intervals (PR, QRS, QT).
- Most common is prolonged QT interval, which may progress to Torsade de Pointes.
- May increase risk of various other arrhythmias (especially atrial fibrillation).
cardiac
- Cardiac arrest from Torsade de pointes.
- Atrial fibrillation, atrial flutter, or multifocal atrial tachycardia (MAT).
- Frequent premature atrial complexes or premature ventricular complexes.
neuromuscular hyperexcitability
- Seizure.
- Delirium, depression, psychosis.
- Cerebellar dysfunction (ataxia, downbeat nystagmus, slurred speech, tremor).
- Paresthesias.
- Tremors, fasciculation, muscle cramps, hyperreflexia, even tetany.
- Muscle cramps, weakness.
other potential consequences
- Insulin resistance.
Downbeat nystagmus may be caused by hypomagnesemia, Wernicke's encephalopathy, or structural brain lesions. Get a CT scan, but also check electrolytes & consider thiamine.
medications
- Medications that cause intracellular shift of magnesium:
- Insulin.
- Beta-2 agonists (epinephrine, terbutaline, albuterol).
- Theophylline.
- Metformin.
- Alkali therapy. (36872194)
- Medications that cause GI loss of magnesium:
- Proton pump inhibitors.
- Colchicine.
- Patiromer (an oral potassium-binder) may bind magnesium in the gut. (38372687)
- Chemotherapeutics (intestinal mucosal injury).
- Metformin.
- Medications that cause renal excretion of magnesium:
- Diuretics:
- Antibiotics:
- Aminoglycosides.
- Amphotericin B.
- Pentamidine.
- Foscarnet.
- Calcineurin inhibitors (tacrolimus > cyclosporine; hypomagnesemia may worsen adverse renal effects of the calcineurin inhibitor). (36872194)
- mTOR inhibitors (everolimus, sirolimus, temsirolimus).
- Platinum-based chemotherapy (cisplatin > carboplatin/oxaliplatin; may be long-lasting). (38372687)
- EGFR receptor blockers (e.g., cetuximab, erlotinib, matuzumab, panitumumab).
- Digoxin.
- Theophylline.
electrolyte abnormalities that cause hypomagnesemia
- Hypercalcemia.
- Hypophosphatemia.
renal disease
- Chronic tubulointerstitial disease.
- Diuresis:
- Diuretics (discussed above).
- Post-ATN or post-obstructive (auto) diuresis.
- Osmotic diuresis (e.g., hyperglycemia).
- Renal tubular acidosis.
gastrointestinal disease
- Inadequate oral magnesium intake (common).
- Protein calorie malnutrition.
- Anorexia.
- Malabsorption:
- Inflammatory bowel disease.
- Short bowel syndrome.
- Diarrhea, vomiting, NG suction, high-output fistulae.
- Pancreatitis (due to binding by free fatty acids; same mechanism that causes hypocalcemia).
- Medications (listed above).
specific clinical situations
- Chronic alcoholism (due to decreased Mg intake, increased gastrointestinal loss, and magnesuria from alcohol-induced renal tubular damage). (38838313)
- Type-2 diabetes (Elevated endogenous insulin regulates TRPM6 and urinary hyperinflation may cause hypomagnesemia. Subsequently, hypomagnesemia itself may worsen insulin resistance.) (38372687)
- Refeeding syndrome.
- Sepsis.
- Large volume transfusion of citrated blood products.
- CRRT (continuous renal replacement therapy).
- Ethylene glycol intoxication.
- Endocrinopathies:
- Hyperaldosteronism.
- Hyperparathyroidism.
- Hyperthyroidism.
practically useful investigation
- Check complete panel of electrolytes (including Ca/Mg/Phos).
- Review medications and clinical scenario, with consideration of the causes of hypomagnesemia (as listed above).
more extensive evaluation
⚠️ In everyday clinical practice this is usually necessary, since the cause of hypomagnesemia is generally clear based on clinical history.
fractional excretion of magnesium (FeMg)
- Calculation:
- FeMg = 100(uMg*pCr)/(0.7*pMg*uCr)
- 0.7 is utilized to approximate the average free fraction of plasma magnesium.
- Interpretation in the context of hypomagnesemia:
- FeMg >3-4% generally indicates renal Mg wasting.
- FeMg <2% generally indicates a non-renal etiology.
24-hour urine magnesium
- In the context of frank hypomagnesemia:
- <10 mg magnesium represents a normal renal response (indicates a non-renal cause of hypomagnesemia).
- >30 mg magnesium indicates renal magnesium wasting.
treat co-existing electrolyte abnormalities
- Treat hypokalemia:
- Hypomagnesemia causes hypokalemia.
- It is often the combination of these two abnormalities that causes arrhythmia. Thus, prompt treatment of both abnormalities may rapidly reduce the risk of arrhythmia rapidly.
- Treat hypocalcemia:
- Administration of magnesium sulfate to treat the hypomagnesemia may complex with calcium, thereby decreasing the calcium level further. Thus, treatment of the hypomagnesemia may inadvertently exacerbate any coexisting hypocalcemia.
- Treat hypercalcemia or hyperphosphatemia if present (as these may cause hypomagnesemia).
general principles of magnesium treatment
- Magnesium is generally extremely safe, with the following exceptions:
- ⚠️ Patients with myasthenia gravis may be at increased risk of muscle weakness.
- ⚠️ Renal failure (e.g. GFR < 30 ml/min) may cause magnesium accumulation. These patients may be treated with a normal “loading” dose of magnesium up-front, but care is needed with repeated dosing.
- Magnesium repletion can be difficult:
- Oral magnesium is poorly absorbed and causes diarrhea.
- IV magnesium boluses will cause transient elevation in the serum magnesium level, causing magnesium secretion by the kidneys. Most of the administered magnesium may be excreted in the urine.
- Most of the body's magnesium is intracellular. The goal is really to get magnesium into the cells, but cellular uptake occurs slowly.
(1) mild hypomagnesemia (e.g. ~1.5-2 mg/dL or ~0.6-0.8 mM)
- Oral magnesium may be used if:
- i) Patient is taking oral medications
- ii) There is no interaction with other medications (e.g. tetracyclines and calcium channel blockers).
- Dosing of oral magnesium:
- Magnesium oxide, 400 mg PO, 1-4 doses per day. 400 mg of magnesium oxide contains 240 mg of elemental magnesium, which is equivalent to 20 mEq magnesium. Thus, a daily dose of 400-1600 mg magnesium oxide per day provides 20-80 mEq of magnesium. (36872194)
- Oral magnesium sulfate liquid may be a convenient therapy for patients receiving enteral nutrition. One gram magnesium sulfate contains 8 mEq of magnesium. Consequently, an equivalent dose of oral magnesium sulfate may be 2.5-10 grams/day in divided doses. Note that 10-30 grams/day oral magnesium sulfate may be used as an over-the-counter cathartic agent (2-6 teaspoons of epsom salts).
- Organic magnesium salts are absorbed best (magnesium citrate, aspartate, glycinate, gluconate, or lactate). (38838313)
- If unable to give oral magnesium, may give 2 grams IV magnesium sulfate.
(2) moderate hypomagnesemia (e.g. ~1.2-1.5 mg/dL or ~0.5-0.6 mM)
- Intermittent administration of 2-4 grams magnesium sulfate IV.
- Higher doses may be preferred, if renal function is normal and hypomagnesemia is more severe.
- Gradually infusing the dose over a longer time period may improve intracellular absorption and could also be safer.
- Subsequent transition to oral magnesium may help prevent recurrence.
(3) severe asymptomatic hypomagnesemia (e.g. <1.2 mg/dL or <0.5 mM)
- Severe hypomagnesemia generally reflects a low total body magnesium content.
- There are roughly two ways to do this (depending largely on logistics):
- (i) Multiple scheduled doses of IV magnesium (e.g., 2 grams IV magnesium sulfate q6hr-q8hr).
- (ii) Continuous infusion of IV magnesium (e.g., 4-8 grams of IV magnesium sulfate over 24 hours).
- Follow extended electrolyte panel daily (electrolytes plus Ca/Mg/Phos). Draw labs several hours after completion of the infusion, to allow for distribution of the magnesium.
- For patients with normal renal function, electrolytes may be followed ~daily.
- For patients with renal insufficiency, electrolytes should be followed more carefully (since these patients are at greater risk of hypermagnesemia).
(4) management of life-threatening hypomagnesemia (e.g., Torsade de Pointes, seizures)
- Initial loading dose of four grams:
- 2 grams IV magnesium sulfate over 5-15 minutes.
- 2 additional grams IV over 30-60 min.
- Maintenance dose
- GFR > 30 ml/min: magnesium infusion using the protocol shown below. This protocol was initially designed for use in atrial fibrillation, but it is safe and can be used in a variety of situations where aggressive magnesium loading is desired. When the magnesium infusion protocol is being used, this should be pasted into the chart so that everyone is on the same page.
- GFR < 30 ml/min: follow magnesium levels and re-dose based on level.
- Potential complications from intravenous magnesium:
- Hypermagnesemia may occur, resulting in AV block or muscular weakness.
- Magnesium sulfate can reduce calcium levels. This is generally minor, but may exacerbate pre-existing hypocalcemia.
other potential therapeutic strategies:
- SGLT2 inhibitors appear to elevate magnesium levels by decreasing the renal excretion of magnesium. (38838313)
- Potassium-sparing diuretics (amiloride, mineralocorticoid inhibitors) increase tubular magnesium reabsorption. (36872194)
small intestine Mg absorption
- Mg may be absorbed via two routes:
- Paracellular pathways.
- Transcellular transportation (utilizing apical TRPM6/7 channels and basolateral sodium-magnesium exchanger cyclin M4 channels).
proximal tubule
- ~15-20% of Mg is reabsorbed.
- Not an important site of Mg regulation (since distal sites may compensate for Mg wasting).
thick ascending limb of henle
- Major site of Mg reabsorption (~60%).
- Mg transport occurs between cells (paracellular) due to a lumen-positive electrical potential difference.
- The lumen-positive electrical potential difference is generated by the basolateral Na-K ATPase, NKCC2, ROMK, and the basolateral chloride channel. Abnormalities of any of these channels may cause Bartter syndrome and hypomagnesemia.
- CASR (calcium-sensing receptor) regulates paracellular cation permeability via claudin-14.
- Hypercalcemia –> activation of CASR –> reduces paracellular Ca and Mg reabsorption.
- PTH (parathyroid hormone) increases magnesium reabsorption. (38372687)
distal convoluted tubule
- The distal convoluted tubule only reabsorbs ~10% of magnesium, but this is the final site where magnesium can be reabsorbed. Consequently, this site is essential to maintaining fine magnesium homeostasis.
- Magnesium reabsorption is transcellular, allowing for greater control.
- Entry of magnesium through the apical membrane is driven by a hyperpolarized lumen membrane potential, which is created by outward movement of potassium through the KV1.1 potassium channel.
- Magnesium transport across the basolateral membrane into the blood is driven by a sodium gradient generated by basolateral Na/K ATPase. The basolateral Kir4.1 channel recycles potassium to prevent excessive intracellular potassium accumulation.
- Regulation: EGF (epidermal growth factor) stimulates TRPM6 activity, increasing Mg reabsorption.
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- Patients with severe hypomagnesemia often have a total-body magnesium deficiency. Don't just give 2-4 grams magnesium and expect this to fix the problem. Most of the magnesium administered isn't absorbed by the cells, so severe hypomagnesemia often requires a magnesium infusion or repeated doses.
- Make sure to check magnesium levels on patients with atrial fibrillation (especially difficult-to-treat atrial fibrillation). If myocardial irritability is being driven by hypomagnesemia, repletion of magnesium may help substantially.
- About half of patients with hypokalemia are also hypomagnesemic. (29610664) Consider empiric administration of magnesium along with potassium to treat hypokalemia.
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References
- 29610664 Hansen BA, Bruserud Ø. Hypomagnesemia in critically ill patients. J Intensive Care. 2018 Mar 27;6:21. doi: 10.1186/s40560-018-0291-y [PubMed]
- 30220246 Van Laecke S. Hypomagnesemia and hypermagnesemia. Acta Clin Belg. 2019 Feb;74(1):41-47. doi: 10.1080/17843286.2018.1516173 [PubMed]
- 36872194 Rosner MH, Ha N, Palmer BF, Perazella MA. Acquired Disorders of Hypomagnesemia. Mayo Clin Proc. 2023 Apr;98(4):581-596. doi: 10.1016/j.mayocp.2022.12.002 [PubMed]
- 38372687 Adomako EA, Yu ASL. Magnesium Disorders: Core Curriculum 2024. Am J Kidney Dis. 2024 Jun;83(6):803-815. doi: 10.1053/j.ajkd.2023.10.017 [PubMed]
- 38838313 Touyz RM, de Baaij JHF, Hoenderop JGJ. Magnesium Disorders. N Engl J Med. 2024 Jun 6;390(21):1998-2009. doi: 10.1056/NEJMra1510603 [PubMed]