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Magnesium Treatment in Pediatric Patients

      Pediatric patients may require magnesium replacement to treat life-threatening emergencies such as torsades de pointe or asthma exacerbations, as well as for the general replacement of magnesium in patients with hypomagnesemia. Clinicians must be aware of recommendations for magnesium administration as the route, dose, timing of administration, and formulation of magnesium can differ for each indication. It is imperative for clinicians to ensure that magnesium is appropriately administered to effectively treat the presenting indication and avoid adverse effects.

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      • 1.
        State the physiology and associated symptoms of magnesium derangements.
      • 2.
        Describe the role of magnesium in the treatment of children with Torsades de Pointe and asthma.
      • 3.
        Describe the pharmacologic treatment of hypomagnesemia.
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      INTRODUCTION

      Magnesium is the second most abundant intracellular cation in the body and the fourth most abundant cation. Sixty percent of total body magnesium is stored in bone, 20% is located in skeletal muscle, and the remaining 20% is distributed in various organ tissues, including the kidney, liver, and heart (
      • Grober U.
      • Schmidt J.
      • Kisters K.
      Magnesium in prevention and therapy.
      ). Approximately 0.3% of magnesium is found in the serum (
      • Grober U.
      • Schmidt J.
      • Kisters K.
      Magnesium in prevention and therapy.
      ). Therefore, the determination of the serum magnesium concentration remains the best readily available test for magnesium deficiency, although it provides only an estimate of total body magnesium stores.
      Magnesium homeostasis is primarily regulated through passive absorption in the gastrointestinal (GI) tract and through excretion and reabsorption by the kidneys (
      • Grober U.
      • Schmidt J.
      • Kisters K.
      Magnesium in prevention and therapy.
      ). When serum magnesium levels decline, the kidneys reabsorb more magnesium to maintain serum levels, whereas high serum levels will result in an increase in magnesium excretion (
      • Grober U.
      • Schmidt J.
      • Kisters K.
      Magnesium in prevention and therapy.
      ). Magnesium is a cofactor in many enzymatic reactions, including many adenosine triphosphate (ATP)-generating reactions. Through its role in ATP generation, magnesium plays key roles in muscle contraction and relaxation, cell membrane stabilization, heart rhythm, and vascular tone (
      • Hansen B.A.
      • Bruserud O.
      Hypomagnesemia in critically ill patients.
      ;
      • Jahnen-Dechent W.
      • Ketteler M.
      Magnesium basics.
      ). In addition, magnesium has been found to be a regulator of immune function (
      • Hansen B.A.
      • Bruserud O.
      Hypomagnesemia in critically ill patients.
      ). Hypomagnesemia may result from a lack of absorption and intake through GI losses, malnutrition, or malabsorption. Certain drug therapies, such as loop and thiazide diuretics, aminoglycosides, cisplatin, pentamidine, and cyclosporine, may also lead to a loss of magnesium through renal wasting (
      • Siddappa F
      • Dandinavar S.D.
      • Ratageri V.H.
      • Wari P.K.
      Prevalence of hypomagnesemia in children admitted to pediatric intensive care unit and its correlation with patient outcome.
      ). Hypomagnesemia may potentiate further electrolyte derangements, such as hypokalemia and hypocalcemia, and disturbances to the cardiac conduction system leading to dysrhythmias. Patients with severe hypomagnesemia may experience neuromuscular hyperexcitability (
      • Grober U.
      • Schmidt J.
      • Kisters K.
      Magnesium in prevention and therapy.
      ). Furthermore, hypomagnesemia in critically ill pediatric patients has been associated with an increased mortality rate and increased length of pediatric intensive care unit stay (
      • Siddappa F
      • Dandinavar S.D.
      • Ratageri V.H.
      • Wari P.K.
      Prevalence of hypomagnesemia in children admitted to pediatric intensive care unit and its correlation with patient outcome.
      ). This review article provides an overview of key disease states in pediatric patients in which magnesium is part of the treatment. The treatment of hypomagnesemia and hypermagnesemia will be described, with a review of dosing and timing of magnesium administration.

      TORSADES DE POINTE

      Torsades de pointe is a ventricular tachycardia characterized by the QRS complexes twisting around the isoelectric baseline. Torsades de pointe results from a prolonged repolarization phase and early afterdepolarizations (
      • Cohagan B.
      • Brandis D.
      Torsade de pointes.
      ;
      • Thomas S.H.
      • Behr E.R.
      Pharmacological treatment of acquired QT prolongation and torsades de pointes.
      ). The prolonged repolarization phase typically results from either medications or congenital conditions inhibiting the potassium channel of myocardial cells (
      • Banai S.
      • Tzivoni D.
      Drug therapy for torsade de pointes.
      ;
      • Cohagan B.
      • Brandis D.
      Torsade de pointes.
      ). Bradycardia and electrolyte imbalances, particularly potassium and magnesium, can also increase the risk of developing torsades de pointe. Although torsades de pointe may be self-limiting, it can lead to further arrhythmias such as ventricular tachycardia or ventricular fibrillation (
      • Banai S.
      • Tzivoni D.
      Drug therapy for torsade de pointes.
      ).
      According to case reports, torsades de pointe is typically seen with pediatric patients taking medications that cause QT prolongation with additional risk factors (e.g., structural heart disease, left ventricular dysfunction, starvation, hypokalemia, and renal or hepatic failure;
      • Esch J.J.
      • Kantoch M.J.
      Torsades de Pointes ventricular tachycardia in a pediatric patient treated with fluconazole.
      ). Congenital factors, such as acquired long QT syndrome, a syndrome that functionally inhibits the influx of potassium into the cardiac membrane, may also put a pediatric patient at risk for torsades de pointe (
      • Hanash C.R.
      • Crosson J.E.
      Emergency diagnosis and management of pediatri arrhythmias.
      ). Magnesium is used in the management of torsades de pointe to stabilize the cardiac membrane through facilitating potassium influx, as magnesium is a cofactor for the sodium-potassium-ATPase (
      • Cohagan B.
      • Brandis D.
      Torsade de pointes.
      ;
      • Thomas S.H.
      • Behr E.R.
      Pharmacological treatment of acquired QT prolongation and torsades de pointes.
      ). Magnesium may function to suppress early afterdepolarizations through blockage of the calcium channel in myocardial cells (
      • Kaye P.
      • O'Sullivan I
      The role of magnesium in the emergency department.
      ).
      The dosing of magnesium for the treatment of torsades has been more commonly evaluated in adult patients (
      • Banai S.
      • Tzivoni D.
      Drug therapy for torsade de pointes.
      ;
      • Perticone F.
      • Adinolfi L.
      • Bonaduce D
      Efficacy of magnesium sulfate in the treatment of torsade de pointes.
      ) with small studies and case reports evaluating magnesium sulfate treatment in pediatric patients. In a study of six pediatric patients (average age 64 months, range 0–109 months) presenting with torsades de pointe, torsades de pointe stopped with a magnesium sulfate bolus of 6.1 ± 4.2 mg/kg (range, 2.3–12 mg/kg;
      • Hoshino K.
      • Ogawa K.
      • Hishitani T.
      • Isobe T.
      • Eto Y.
      Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome.
      ). One patient required an additional bolus to receive 30 mg/kg to completely abolish the rhythm (
      • Hoshino K.
      • Ogawa K.
      • Hishitani T.
      • Isobe T.
      • Eto Y.
      Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome.
      ). In this study, the patients also were given a magnesium infusion ranging from 0.3 to 1.0 mg/kg/hr after the bolus for a minimum of 48 hr (
      • Hoshino K.
      • Ogawa K.
      • Hishitani T.
      • Isobe T.
      • Eto Y.
      Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome.
      ). The American Heart Association Pediatric Advanced Life Support guideline recommends magnesium sulfate 50 mg/kg/dose (maximum 2 g/dose) infused over 10 min in pediatric patients with torsades de pointe (
      • de Caen A.R.
      • Berg M.D.
      • Chameides L.
      • Gooden C.K.
      • Hickey R.W.
      • Scott H.F.
      • Sutton R.M.
      • Tijssen J.A.
      • Topjian A.
      • van der Jagt É.W.
      • Schexnayder S.M.
      • Samson R.
      Pediatric advanced life support.
      ).

      ASTHMA

      Recent literature has postulated the use of intravenous (IV) magnesium to treat acute asthma exacerbations, and the 2019 Global Initiative for Asthma guideline recommends the administration of IV magnesium sulfate in patients with severe asthma exacerbations with an inadequate response to intensive initial treatment (). Magnesium is proposed to be beneficial in patients with asthma exacerbations through the blockage of calcium channels resulting in bronchial smooth muscle relaxation (
      • Wong J.J
      • Lee J.H.
      • Tuener D.A.
      • Rehder K.J.
      A review of the use of adjunctive therapies in severe acute asthma exacerbation in critically ill children.
      ). Magnesium may also play a role as an antiinflammatory agent through attenuating neutrophil activity (
      • Cairns C.B.
      • Kraft M.
      Magnesium attenuates the neutrophil respiratory burst in adult asthmatic patients.
      ). A Cochrane review assessed the outcomes of pediatric patients receiving IV magnesium sulfate in the emergency department (ED) and found a 68% reduction in the hospital admission rate in patients given magnesium sulfate (odds ratio = 0.32, 95% confidence interval = [0.14, 0.74]), this result; however, had statistically significant heterogeneity (I2 = 63%, p = .07) and only included three studies with 115 patients (
      • Griffiths B.
      • Kew K.M.
      Intravenous magnesium sulfate for treating children with acute asthma in the emergency department.
      ).
      A wide range of dosing strategies for IV magnesium to treat asthma exacerbations have been used in clinical trials. A retrospective review that assessed prescribing patterns of IV magnesium for acute asthma exacerbations in pediatric patients at four hospitals found the median magnesium sulfate dose was 40 mg/kg over an average of 20 min; with doses ranging from 20 to 50 mg/kg over 20–180 min
      • Kokotajlo S.
      • Degnan L.
      • Meyers R.
      • Siu A.
      • Robinson C.
      Use of intravenous magnesium sulfate for the treatment of an acute asthma exacerbation in pediatric patients.
      ). A randomized double-blinded, placebo-controlled trial by
      • Ciarallo L.
      • Sauer A.H.
      • Shannon M.W.
      Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial.
      assessed 31 pediatric patients (aged 6–18 years) being treated for an acute asthma exacerbation with either magnesium sulfate or a saline solution (
      • Ciarallo L.
      • Sauer A.H.
      • Shannon M.W.
      Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial.
      ). Patients treated with IV magnesium sulfate were found to have greater improvement in short-term pulmonary function tests than the placebo group. Magnesium sulfate was dosed at 25 mg/kg (maximum 2 g) over 20 min (
      • Ciarallo L.
      • Sauer A.H.
      • Shannon M.W.
      Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial.
      ). A follow-up study assessed a higher magnesium sulfate dose with randomization of 30 pediatric patients with a moderate to severe asthma exacerbation to receive either magnesium sulfate 40 mg/kg (maximum 2 g) or placebo (
      • Ciarallo L.
      • Brousseau D.
      • Reinert S.
      Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma.
      ). This higher-dose strategy resulted in similar improvements in pulmonary function tests and quicker improvement than the previously used lower-dosing strategy (
      • Ciarallo L.
      • Brousseau D.
      • Reinert S.
      Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma.
      ).
      • Gürkan F.
      • Haspolat K.
      • Bosnak M.
      • Dikici B.
      • Derman O.
      • Ece A.
      Intravenous magnesium sulphate in the management of moderate to severe acute asthmaticchildren nonresponding to conventional therapy.
      randomized 20 children experiencing a moderate to severe asthma exacerbation to either placebo or magnesium sulfate 40 mg/kg (maximum 2 g) over 20 min, and patients in the IV magnesium group had significantly improved peak expiratory flow rates. A higher dosing strategy of magnesium sulfate 100 mg/kg over 35 min was assessed in a randomized, double-blind, placebo-controlled study (
      • Devi P.R.
      • Kumar L.
      • Singhi S.C.
      • Prasad R.
      • Singh M.
      Intravenous magnesium sulfate in acute severe asthma not responding to conventional therapy.
      ). This study assessed 47 children presenting to an ED with acute severe asthma and found magnesium sulfate (in addition to aminophylline) to improve peak expiratory flow rates. The higher dose of magnesium sulfate 100 mg/kg over 35 min only had minimal adverse effects, providing some evidence to support a higher dosing strategy for magnesium sulfate in the treatment of acute asthma exacerbations (
      • Devi P.R.
      • Kumar L.
      • Singhi S.C.
      • Prasad R.
      • Singh M.
      Intravenous magnesium sulfate in acute severe asthma not responding to conventional therapy.
      ).
      Magnesium administration as a high-dose continuous infusion has also been studied. As higher magnesium serum concentrations result in increasing renal clearance, this strategy is thought to maintain maximum serum levels of magnesium over an extended period (
      • Irazuzta J.E.
      • Chiriboga N.
      Magnesium sulfate infusion for acute asthma in the emergency department.
      ). This strategy had positive results in a study of 38 patients randomized to either magnesium sulfate 50 mg/kg over 1 hr (bolus group) or magnesium sulfate 50-mg/kg/hr over 4 hr (continuous infusion group). The study found significantly more patients in the continuous infusion group to be discharged home at 24 hr (
      • Irazuzta J.E.
      • Paredes F.
      • Pavlicich V.
      • Domínguez S.L.
      High-dose magnesium sulfate infusion for severe asthma in the emergency department: efficacy study.
      ).
      More recently, interest has grown in the use of inhaled nebulized magnesium sulfate in the setting of acute severe asthma. (
      • Su Z.
      • Li R.
      • Gai Z.
      Intravenous and nebulized magnesium sulfate for treating acute asthma in children. A systematic review and meta-analysis.
      ) performed a meta-analysis of clinical trials using either IV magnesium sulfate or nebulized magnesium sulfate. Ten randomized and quasi-randomized trials (six IV and four nebulized) were included (
      • Su Z.
      • Li R.
      • Gai Z.
      Intravenous and nebulized magnesium sulfate for treating acute asthma in children. A systematic review and meta-analysis.
      ). They concluded that
      IV magnesium sulfate is an effective treatment in children, with the pulmonary function significantly improved and hospitalizations and further treatments decreased. But nebulized magnesium sulfate showed no significant effect on respiratory function or hospital admission and further treatments were needed (
      • Su Z.
      • Li R.
      • Gai Z.
      Intravenous and nebulized magnesium sulfate for treating acute asthma in children. A systematic review and meta-analysis.
      ).
      A recent Cochrane review published in 2017 reviewed 25 clinical trials (
      • Knightly R.
      • Milan S.J.
      • Hughes R.
      • Knopp-Sihota J.A.
      • Rowe B.H.
      • Normansell R.
      • Powell C.
      Inhaled magnesium sulfate in the treatment of acute asthma.
      ). Nine trials involved adults, four included adult and pediatric patients, and eight studies enrolled pediatric patients, and they concluded that well-designed clinical trials using nebulized magnesium have failed to demonstrate clinically important benefits; however, it is not associated with an increase in adverse events (
      • Knightly R.
      • Milan S.J.
      • Hughes R.
      • Knopp-Sihota J.A.
      • Rowe B.H.
      • Normansell R.
      • Powell C.
      Inhaled magnesium sulfate in the treatment of acute asthma.
      ).
      The

      National Heart, Lung and Blood Institute (2007), National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. https://www.nhlbi.nih.gov/sites/default/files/media/docs/EPR-3_Asthma_Full_Report_2007.pdf. Accessed June 29, 2021.

      asthma guidelines recommend a magnesium sulfate dose of 25–75 mg/kg/dose (maximum 2 g/dose) infused over 20 min for patients with moderate to severe asthma. The 2019 Global Initiative for Asthma asthma guidelines recommends 40–50 mg/kg/dose (maximum 2 g/dose) infused over 20 min in children age 2 years or greater with severe asthma exacerbations. Recent inhaled magnesium sulfate studies have failed to demonstrate benefit compared with administration of IV magnesium sulfate. A Cochrane review demonstrated a 68% reduction in hospital admission in pediatric patients administered magnesium sulfate for acute severe asthma; improvements in ED management of severe asthma could have a significant economic impact in the treatment of pediatric asthma (
      • Griffiths B.
      • Kew K.M.
      Intravenous magnesium sulfate for treating children with acute asthma in the emergency department.
      ). Well-designed ED asthma management pathways, including the use of magnesium sulfate for severe patients, may facilitate early discharge, reduce hospitalization rates, and is cost-effective.

      HYPOMAGNESEMIA TREATMENT

      Hypomagnesemia typically occurs because of either GI or renal magnesium loss. Gastrointestinal losses may be the result of diarrhea, malabsorption, or steatorrhea. Renal magnesium loss can result from medications, including cisplatin, loop diuretics, thiazide diuretics, aminoglycosides, amphotericin B, calcineurin inhibitors, cyclosporine, or pentamidine (
      • Kaplinsky C.
      • Alon U.S.
      Magnesium homeostasis and hypomagnesemia in children with malignancy.
      ;
      • Martin K.J.
      • González E.A.
      • Slatopolsky E.
      Clinical consequences and management of hypomagnesemia.
      ). Congenital cases of hypomagnesemia have been reported because of a mutation in the TRPM6 gene, resulting in decreased intestinal magnesium absorption. Gitelman and Bartter syndromes have been associated with renal magnesium wasting (
      • Martin K.J.
      • González E.A.
      • Slatopolsky E.
      Clinical consequences and management of hypomagnesemia.
      ). Pediatric patients with malignancies are prone to hypomagnesemia as hypomagnesemia may result from several oncological medications and result from GI losses and poor nutrition, both of which are commonly experienced in these patients.
      Symptoms of hypomagnesemia are summarized in Table 1. Clinicians should be aware of concomitant electrolyte disturbances associated with hypomagnesemia. The most common disturbance is hypokalemia occurring in 40%–60% of cases (
      • Grober U.
      • Schmidt J.
      • Kisters K.
      Magnesium in prevention and therapy.
      ). Hypokalemia is caused in part by the underlying cause of hypomagnesemia, such as diuretic therapy and diarrhea. However, there is evidence that the hypomagnesemia itself may cause increased potassium secretion in the loop of Henle and the cortical collecting tubule.
      TABLE 1Symptoms of hypomagnesemia
      Symptom categorySymptoms
      Neuromuscular irritabilityHyperactive deep tendon reflexes

      Muscle cramps

      Muscle fibrillation

      Trousseau and Chvostek signs

      Dysarthria and dysphagia from esophageal dysmotility
      CNS hyperexcitabilityIrritability and combativeness

      Disorientation

      Psychosis

      Ataxia

      Nystagmus

      Vertigo

      Seizures (levels < 1 mEq/L)
      Cardiac arrhythmiasParoxysmal atrial and ventricular arrhythmias

      Torsades de pointes
      NeonatesApnea

      Weakness

      Seizures

      Jitteriness
      Electrolyte disordersHypocalcemia

      Hypokalemia
      Note. CNS, central nervous system.
      Hypokalemia is thought to occur because the sodium-potassium-ATPase pump is dependent on adequate circulating magnesium to function properly. Potassium secretion into the loop of Henle and cortical collecting tubule is mediated by ATP-inhibitable potassium channels. The reduction in cellular magnesium leads to a decline in ATP activity and a concomitant increase in potassium channels. This leads to enhanced urinary potassium losses. Hypokalemia in this setting is relatively refractory to potassium supplementation. Serum magnesium must be replaced before administering potassium replacement for potassium replacement to be successful. Hypocalcemia associated with severe hypomagnesemia (< 1 mg/100 mL) is thought to occur because the calcium cannot be properly mobilized from the bone without the action of parathyroid hormone, which is dependent on circulating magnesium.
      Serum magnesium levels less than 1.5 mg/100 mL are considered low and may warrant replacement, particularly if the patient is symptomatic. Magnesium can be replaced orally unless the patient has severely low magnesium levels (Mg < 1.0 mg/100 mL), malabsorption is suspected as the cause of the hypomagnesemia, or the patient has symptoms of hypomagnesemia, in which case the IV route of replacement is preferred. Magnesium oxide is typically used for oral replacement at a dose of 10–20 mg/kg/dose of elemental magnesium (maximum 2 g) up to four times per day. However, magnesium oxide is only commercially available as a 140 mg capsule and 400 mg tablet. Therefore, in pediatric patients, other salt forms may be used to provide the same 10–20 mg/kg/dose of elemental magnesium (Table 2). Magnesium hydroxide is commonly used to treat infants and small children requiring oral magnesium replacement, as it is a liquid that is both sold over the counter and inexpensive. Caution should be used in administering oral magnesium in patients with diarrhea as oral magnesium may worsen diarrhea and not be optimally absorbed. For IV replacement, magnesium sulfate is typically used and can be given as 25–50 mg/kg/dose (maximum 2 g/dose) of magnesium sulfate every 4–6 hr (every 8 hr in neonates) as needed to replete serum magnesium levels (
      • Kaplinsky C.
      • Alon U.S.
      Magnesium homeostasis and hypomagnesemia in children with malignancy.
      ). As renal impairment can lead to magnesium accumulation, these dosing recommendations should be decreased by 50% in patients with renal insufficiency. In patients experiencing life-threatening symptoms from dangerously low magnesium levels (i.e., seizures), a more aggressive replacement is warranted. In these cases, magnesium sulfate should be given magnesium sulfate 50 mg/kg (maximum 2 grams/dose) IV push over 1−5 min. Then, assuming the patient has total body depletion of magnesium, they should receive magnesium sulfate 125 mg/kg/day over 24 hr, then 75 mg/kg/day for 3–5 days. Rapid administration of magnesium sulfate is not very helpful in restoring total body deficits. The acute increase in the serum magnesium concentration after a rapid administration exceeds the renal threshold, and rapid renal excretion of magnesium occurs. Therefore, if the patient is not symptomatic, slower administration of magnesium may improve uptake in the body. Suggested rates for optimal magnesium retention are 25 mg/kg (maximum 1 g) per hr (
      • Kraft M.D.
      • Btaiche I.F.
      • Sacks G.S.
      • Kudsk K.A.
      Treatment of electrolyte disorders in adult patients in the intensive care unit.
      ). The maximum concentration of magnesium sulfate to be given in a peripheral IV is 60 mg/mL, and the maximum amount of magnesium sulfate to be given via a central line is 200 mg/mL. Serum magnesium levels should be monitored daily in patients receiving IV replacement.
      TABLE 2
      Elemental magnesium per 1 g of saltCommercially available formulations
      Magnesium saltmmolmgmEqAmounts of elemental magnesium
      Magnesium oxide24.8603.2549.64140 mg capsule = 84 mg or 7 mEq

      200 mg tablet = 120.5 mg = 9.9 mEq

      400 mg tablet = 241 mg or 19.8 mEq

      Miscellaneous: 420 and 500 mg tablets
      Magnesium gluconate2.22544.44200 mg/mL = 10.8 mg/mL or 0.96 mEq/ml

      Tablet: 500 mg (27 mg el)
      Magnesium/aluminum hydroxide (Maalox Plus or Mylanta II)17412.53480 mg/mL = 33 mg/ml or 2.75 mEq/mL
      Magnesium hydroxide (milk of magnesia)17412.53480 mg/ml = 33 mg/mL or 2.75 mEq/mL
      Magnesium sulfate (parenteral)4.0698.78.12IV solution (50%): 2, 10, 20, or 50 mL

      Premade bags: 1, 2 and 4 g

      Capsules: 70 and 140 mg
      Magnesium carbonate10.5254.7721Liquid: 54 mg/5 mL
      Magnesium citrate6.5916013.71.745 g/30 mL; 296 mL bottle
      Note. IV, intraveneous.

      ADVERSE REACTIONS

      Although normal magnesium levels are 1.5–2.2 mg/100 mL in pediatric patients, children typically do not experience symptoms of hypermagnesemia until serum levels are greater than or equal to 4 mg/dL. Once serum magnesium levels are greater than 4 mg/dL, patients may start to experience symptoms such as nausea, vomiting, flushing, and headaches. As serum magnesium levels increase above 6 mg/dL, patients may begin to experience more serious adverse reactions such as loss of deep tendon reflexes, hypotension, electrocardiogram changes, and muscle paralysis (
      • Jhang W.K.
      • Lee Y.J.
      • Kim Y.A.
      • Park S.J.
      • Park Y.S
      Severe hypermagnesemia presenting with abnormal electrocardiographic findings similar to those of hyperkalemia in a child undergoing peritoneal dialysis.
      ;
      • Kraft M.D.
      • Btaiche I.F.
      • Sacks G.S.
      • Kudsk K.A.
      Treatment of electrolyte disorders in adult patients in the intensive care unit.
      ). These high serum levels are most common in patients with renal failure taking supplemental magnesium; however, case reports exist of pediatric patients experiencing fatal overdoses of magnesium without known renal impairment (
      • McGuire J.K.
      • Kulkarni M.S.
      • Baden H.P
      Fatal hypermagnesemia in a child treated with megavitamin/megamineral therapy.
      ). A summary of magnesium levels and associated symptoms can be located in Table 3.
      TABLE 3Manifestations of altered serum magnesium concentrations
      Magnesium level
      Mg/dLmEq/LMmol/LManifestations
      < 1.2< 1< 0.5Tetany

      Seizures

      Arrhythmias
      1.2–1.81–1.50.5–0.75Neuromuscular irritability

      Hypocalcemia

      Hypokalemia
      1.8–2.51.5–2.10.75–1.05Normal magnesium level
      2.5–52.1–4.21.05–2.1Typically asymptomatic
      5–74.2–5.82.1–2.9Lethargy

      Drowsiness

      Flushing

      Nausea and vomiting

      Diminished deep tendon reflexes
      7–125.8–102.9–5Somnolence

      Loss of deep tendon reflexes

      Hypotension

      ECG changes
      > 12> 10> 5Complete heart block

      Cardiac arrest

      Apnea

      Paralysis

      Coma
      Note. ECG, electrocardiogram.
      Oral magnesium is generally well tolerated when given within a normal dosing range, with the most common adverse effect being gastrointestinal disturbances (
      • Taketomo C.K.
      • hodding J.H.
      • Kraus D.M.
      Pediatric dosage handbook:Including neonatal dosing, drug administration, and extemporaneous preparations.
      ). For IV administration of magnesium, most studies assessing high-dose IV magnesium infusions have shown few adverse effects. Out of 53 patients receiving an IV magnesium sulfate infusion in a retrospective review by
      • Kokotajlo S.
      • Degnan L.
      • Meyers R.
      • Siu A.
      • Robinson C.
      Use of intravenous magnesium sulfate for the treatment of an acute asthma exacerbation in pediatric patients.
      , only one patient (receiving 40 mg/kg over 1 hr) experienced an adverse reaction. This patient became hypotensive; however, once the IV infusion rate was subsequently decreased from 1 to 5 hr, the hypotension resolved (
      • Kokotajlo S.
      • Degnan L.
      • Meyers R.
      • Siu A.
      • Robinson C.
      Use of intravenous magnesium sulfate for the treatment of an acute asthma exacerbation in pediatric patients.
      ). In another study assessing a higher dosing strategy in asthma patients, magnesium sulfate 100 mg/kg over 35 min only resulted in minor adverse effects of epigastric warmth (12.5%), pain (16.6%), and tingling and numbness (12.5%) at the infusion site. Each of these side effects started within 2–3 min after initiating the infusion and then subsided soon after the infusion started. No other significant side effects (hypotension or respiratory depression) were noted in this study (
      • Devi P.R.
      • Kumar L.
      • Singhi S.C.
      • Prasad R.
      • Singh M.
      Intravenous magnesium sulfate in acute severe asthma not responding to conventional therapy.
      ). Another study by
      • Pruikkonen H
      • Tapiainen T
      • Kallio M.
      • Dunder T.
      • Pokka T.
      • Uhari M.
      • Renko M.
      Intravenous magnesium sulfatfe for acute wheezing in young children: a randomized double-blind trial.
      assessed magnesium sulfate 40 mg/kg over 20 min versus placebo in pediatric patients with severe wheezing. Out of 31 patients receiving magnesium sulfate, only one patient experienced a minor adverse effect of facial redness and infusion site erythema (Prukkoinen et al., 2018). Finally, in a study by
      • Irazuzta J.E.
      • Paredes F.
      • Pavlicich V.
      • Domínguez S.L.
      High-dose magnesium sulfate infusion for severe asthma in the emergency department: efficacy study.
      in which patients received high-dose magnesium infusions up to 50 mg/kg/hr over 4 hr (maximum 8,000 mg/4 hr), no adverse effects, including hypotension, were reported (
      • Irazuzta J.E.
      • Paredes F.
      • Pavlicich V.
      • Domínguez S.L.
      High-dose magnesium sulfate infusion for severe asthma in the emergency department: efficacy study.
      ).

      FORMULATIONS

      When using different formulations of magnesium, it is imperative to know how much elemental magnesium the patient is receiving. In addition, when interpreting dosing recommendations, it is crucial to know whether the provided dose is referencing total milligrams of the formulation or milligrams or milliequivalents of elemental magnesium. Table 2 contains a list of common formulation of magnesium and their respective amounts of elemental magnesium.

      HYPERMAGNESEMIA

      Hypermagnesemia is defined as a serum magnesium concentration greater than 2.4 mg/dL. Elevated magnesium is rare; the most common causes are renal insufficiency and iatrogenic causes such as over-replacement, treatment of eclampsia, laxative abuse, and lithium toxicity. Adrenal insufficiency and hyperparathyroidism may also contribute to hypermagnesemia. Common symptoms of hypermagnesemia (Table 3) include nausea, vomiting, paresthesia, dysarthria, loss of deep tendon reflexes, altered mental status, and seizures. Treatment of hypermagnesemia depends on the underlying cause. For asymptomatic end-stage renal disease patients who have missed a treatment session (hemodialysis) or have been nonadherent with home peritoneal dialysis, the initial treatment is magnesium restriction, loop diuretics, and dialysis. In severe hypermagnesemia, administration of IV calcium can reverse the loss of deep tendon reflexes, hypotension, and respiration depression. IV calcium can be given as either calcium chloride (20 mg/kg/dose; maximum dose 1 g) or calcium gluconate (100 mg kg/dose; maximum 3 g/dose) intravenously over 5–10 min. Doses may be repeated every 10 min until symptoms resolve (
      • Taketomo C.K.
      • hodding J.H.
      • Kraus D.M.
      Pediatric dosage handbook:Including neonatal dosing, drug administration, and extemporaneous preparations.
      ).
      Magnesium is an essential element as it plays an important role in muscle contraction and relaxation, cell membrane stabilization, heart rhythm, vascular tone, and a cofactor in many enzymatic reactions (
      • Hansen B.A.
      • Bruserud O.
      Hypomagnesemia in critically ill patients.
      ). Magnesium replacement is warranted in pediatric patients that show symptoms of hypomagnesemia or with serum magnesium levels < 1.5 mEq/L. Pediatric patients may also receive magnesium for torsades de pointe and asthma exacerbations. As the amount of elemental magnesium varies among differing magnesium formulations, it is imperative for the provider to ensure that the amount of elemental magnesium being given aligns with the dosing recommendation. Correction of magnesium deficits should precede attempts to correct hypocalcemia or hypokalemia. Hypermagnesemia is rare, but its causes are frequently iatrogenic. Stopping the offending agent and administration of rescue doses of IV calcium allow for renal elimination of magnesium, or the use of renal replacement therapies can be used in patients with renal dysfunction if medically necessary.

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      Biography

      Sarah Anderson, Pharmacy Resident, New Hanover Regional Medical Center, Wilmington, NC.
      Elizabeth Farrington, Clinical Pharmacist, Pediatrics, New Hanover Regional Medical Center, Wilmington, NC.