AHFS Class:

• Anticonvulsants, Miscellaneous 28:12.92

Generic Name(s):

• Magnesium Sulfate

Parenteral magnesium sulfate exhibits anticonvulsant properties.

Prevention and Control of Seizures

Magnesium sulfate is used parenterally as an anticonvulsant for the prevention and control of seizures in severe toxemias (preeclampsia or eclampsia) of pregnancy and in various other conditions.58,67,91,95

Preeclampsia and Eclampsia

Magnesium sulfate generally is considered the drug of choice for the prevention and control of seizures in severe preeclampsia or in eclampsia.58,59,60,61,104 The American College of Obstetricians and Gynecologists (ACOG) strongly recommends the administration of intrapartum/postpartum magnesium sulfate in women with severe preeclampsia to prevent eclampsia.58 In a systematic review of 6 randomized clinical studies that compared magnesium sulfate with placebo or no anticonvulsant therapy in more than 11,000 women with preeclampsia, prophylactic use of magnesium sulfate was associated with an approximate 50% reduction in the rate of eclampsia.58,103 While routine use of magnesium sulfate is not recommended in women with preeclampsia who do not have severe features (e.g., systolic blood pressure of 160 mm Hg or higher, diastolic blood pressure of 110 mm Hg or higher, thrombocytopenia, impaired liver or renal function, pulmonary edema, new-onset cerebral or visual disturbances), the decision to initiate therapy in these patients should be individualized based on the presence of certain warning signs and symptoms of imminent seizures (e.g., headache, altered mental state, blurred vision, scotomata, clonus, right upper quadrant pain).58 Because the clinical course of preeclampsia can change rapidly and unexpectedly during labor, patients with mild disease at presentation should be monitored closely and magnesium sulfate therapy should be initiated if progression to severe disease occurs.58

ACOG strongly recommends the administration of parenteral magnesium sulfate in women with eclampsia; treatment should be continued for at least 24 hours after the last seizure.58 Clinical studies have demonstrated that magnesium sulfate is superior to phenytoin for the prevention of eclampsia, and superior to phenytoin and diazepam for the treatment and further prevention of eclamptic seizures.58,101,102,104

Other Seizure Etiologies

Parenterally administered magnesium sulfate may be useful in controlling seizures associated with epilepsy, glomerulonephritis, or hypothyroidism.67

Magnesium sulfate also has been used for the immediate control of life-threatening seizures associated with acute nephritis in children.95

Prevention and Treatment of Hypomagnesemia

Magnesium sulfate is used parenterally to correct or prevent hypomagnesemia in patients receiving total parenteral nutrition.67 In such patients, magnesium sulfate usually is added to the nutrient admixture to correct or prevent hypomagnesemia, which can arise during the course of therapy.67

Magnesium sulfate also is used in the treatment of acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia.67 In such cases, serum magnesium concentrations usually are below the lower limits of normal (1.5-2.5 mEq/L) and the serum calcium concentrations are either normal (4.3-5.3 mEq/L) or elevated.67

Preterm Labor and Fetal Neuroprotection

Magnesium sulfate has been used in pregnant women to inhibit uterine contractions in preterm labor (tocolysis)† and thus prolong gestation when such prolongation of intrauterine life would be expected to benefit pregnancy outcome; however, efficacy and safety of magnesium sulfate for this use have not been established and the drug is not labeled by the FDA for this use.14,67,69,75,91 ACOG and the Society for Maternal-Fetal Medicine support the short-term (up to 48 hours) obstetric use of magnesium sulfate for appropriate conditions and durations of therapy.91 This includes the use of magnesium sulfate for short-term (i.e., up to 48 hours) prolongation of pregnancy to allow for the administration of antenatal corticosteroids in women who are at risk of preterm delivery within 7 days; corticosteroid administration prior to anticipated preterm birth is strongly associated with decreased neonatal morbidity and mortality.73,91,92 However, there currently is no evidence that tocolytic therapy has a direct favorable effect on neonatal outcomes or that any prolongation of pregnancy provided by tocolytic agents translates into substantial neonatal benefit.28,69,71,72,74 (See Antenatal Use in Preterm Labor under Uses: Complications of Prematurity, in the Corticosteroids General Statement 68:04.)

While short-term use of magnesium sulfate injection may effectively delay delivery,28,69,71,72,74 prolonged administration of the drug (i.e., beyond 5-7 days) has been associated with hypocalcemia and bone abnormalities (e.g., skeletal demineralization, osteopenia, fractures) in the developing fetus and is never indicated according to ACOG obstetric use guidelines.67,75,77,78,79,80,81,82,83,84,85,86,91 (See Cautions: Pregnancy and Lactation.) Certain maternal or fetal conditions may contraindicate tocolytic therapy (e.g., nonreassuring fetal status, chorioamnionitis, fetal demise, lethal congenital or chromosomal abnormalities, maternal bleeding with hemodynamic instability, severe preeclampsia or eclampsia, preterm premature rupture of membranes [may consider use in the absence of maternal infection for maternal transport and/or corticosteroid administration]) in general and magnesium sulfate specifically (e.g., myasthenia gravis).69

Few placebo-controlled studies have evaluated the tocolytic efficacy of magnesium sulfate.13 Instead, most studies have compared the efficacy and toxicity profile of magnesium sulfate with those of other tocolytic agents.13,14,15,17,18 Clinical studies indicate that IV magnesium sulfate (4-6 g infused IV over 20 minutes as a loading dose, followed by maintenance infusions of 2-4 g per hour for 12-24 hours after contractions cease) generally appears to be as effective as IV ritodrine,17,18 sublingual and/or oral nifedipine,15 or rectal or oral indomethacin14 for the short-term management of preterm labor.13,14,15,16,17,18 Magnesium sulfate-induced prolongation of pregnancy is less successful when preterm labor is complicated by premature rupture of membranes.24,26 Some clinicians have suggested that the lack of efficacy observed in some studies with magnesium sulfate tocolysis may be the result of subtherapeutic dosing regimens.13,16,21,22,23 Substitution of another tocolytic agent in patients experiencing failure with a given drug may result in effective tocolysis.13,16,17,18

ACOG guidelines for the management of preterm labor state that maintenance treatment with tocolytic drugs is not effective for preventing preterm birth and improving neonatal outcomes and is not recommended.69 Limited data indicate that combination therapy with magnesium sulfate and another tocolytic agent may be more effective in arresting preterm labor than a single tocolytic agent; however, combination therapy also may be associated with an increased risk of adverse maternal effects.19,24,25,27,69β-Adrenergic agonists and calcium-channel blocking agents should be used with caution in combination with magnesium sulfate because of the risk of potentially serious maternal complications; concurrent use of magnesium sulfate and nifedipine may be particularly risky.32,69 (See Drug Interactions.) Additional study and experience are needed to confirm the safety and efficacy of combined tocolytic therapy and to establish the role, if any, of such therapy.19,24,25,27

In addition to magnesium sulfate's efficacy in delaying delivery, data from several population-based observational studies and large clinical trials have indicated an association between the predelivery use of magnesium sulfate and a reduction in the incidence and severity of cerebral palsy among surviving infants if the drug is administered when birth is anticipated before 32 weeks of gestation.28,29,69,89 Based on these findings, ACOG recommends the use of magnesium sulfate for fetal neuroprotection† before anticipated preterm birth (less than 32 weeks of gestation).91 A possible mechanism for the neuroprotective effect of magnesium sulfate may be that the drug reduces the incidence of neonatal intraventricular hemorrhage, which is a risk factor for the development of these neurodevelopmental defects.28,29 If magnesium sulfate is being used in the preterm labor setting for fetal neuroprotection and the patient is still experiencing preterm labor, ACOG recommends that a different tocolytic agent be considered for short-term use.69 ACOG also recommends that hospitals that use magnesium sulfate for fetal neuroprotection† develop uniform and specific guidelines for such use, including inclusion criteria, treatment regimens, concomitant use of tocolytic agents, and patient monitoring, in accordance with one of the larger clinical trials.69,89

Arrhythmias

IV magnesium sulfate has been used successfully for the treatment of life-threatening arrhythmias such as atypical ventricular tachycardia† (torsades de pointes).8,9,10,94,400,401 IV magnesium sulfate is considered one of several preferred drugs in the treatment of polymorphic ventricular tachycardia suspected of being torsades de pointes† in patients in whom initial attempts at correcting or managing potential precipitating factors (e.g., ischemic cardiac events, electrolyte imbalance, drugs known to prolong the QT interval) have not been successful.64,94,401 Because polymorphic ventricular tachycardias other than torsades de pointes generally are unresponsive to magnesium therapy, use of β-adrenergic blocking agents or IV amiodarone generally is preferred in patients in whom polymorphic ventricular tachycardia (not suspected of being torsades de pointes) may be precipitated by myocardial ischemia.401

Antiarrhythmic drugs are used during cardiac arrest to facilitate the restoration and maintenance of a spontaneous perfusing rhythm in patients with refractory (i.e., persisting or recurring after at least one shock) ventricular fibrillation or pulseless ventricular tachycardia; however, there is no evidence that these drugs increase survival to hospital discharge when given routinely during cardiac arrest.400 High-quality cardiopulmonary resuscitation (CPR) and defibrillation are integral components of advanced cardiovascular life support (ACLS) and the only proven interventions to increase survival to hospital discharge.400,401 Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.400,401 The principal goal of pharmacologic therapy during cardiac arrest is to facilitate return of spontaneous circulation (ROSC), and epinephrine is the drug of choice for this use.400,401 (See Uses: Advanced Cardiovascular Life Support and Cardiac Arrhythmias, in Epinephrine 12:12.12.) If an antiarrhythmic agent is needed for the treatment of ventricular fibrillation or pulseless ventricular tachycardia during cardiac resuscitation, experts generally recommend the use of amiodarone (or lidocaine).400,401,403 In several randomized controlled studies, administration of magnesium sulfate during cardiac arrest did not improve rates of ROSC, survival to hospital discharge, or neurologic outcome for any presenting rhythm.400 The American Heart Association (AHA) therefore states that IV magnesium sulfate should not be used routinely during cardiac arrest; however, the drug may be considered when the arrest rhythm is associated with torsades de pointes.400,401,402,403

IV magnesium sulfate also has been used in the management of paroxysmal atrial tachycardia when other measures have failed and when there is no evidence of myocardial damage.67

Acute Myocardial Infarction

Magnesium sulfate has been administered IV as adjunctive therapy to reduce cardiovascular morbidity and mortality (e.g., through reduction in ventricular arrhythmias and/or limitation of infarct size and reperfusion injury) associated with acute myocardial infarction (MI)†;2,6,7,34,35,36,37,38,39,64 however, contradictory evidence of such beneficial effects has been reported.34,44,45,46,47,64

Pooled analyses42,43,64 of several small, controlled studies2,6,35,36,37,38,39,49,64 and results of a few other randomized, controlled studies40,50,51,52,53,64 have indicated a reduction in ventricular arrhythmias and/or mortality with early IV magnesium administration in patients with acute MI; in some studies, mortality rates in magnesium-treated patients have been similar to those reported with thrombolytic therapy.50 In a randomized, placebo-controlled study (the Second Leicester Intravenous Magnesium Intervention Trial; LIMIT-2) in more than 2000 patients with suspected acute MI and baseline serum magnesium concentrations in the normal range, adjunctive therapy with magnesium sulfate administered as a single IV injection (2 g) within 24 hours of onset of symptoms, followed by continuous IV infusion of the drug (16 g) over the next 24 hours, was associated with a reduction in all-cause mortality of 24% at 4 weeks (7.8% mortality) compared with that in placebo recipients (10.3% mortality).40,64 Approximately one-third of patients in the LIMIT-2 study also received a thrombolytic agent, and two-thirds received concomitant aspirin.40 Patients receiving IV magnesium had a 25% lower rate of congestive heart failure during hospitalization and a 21% reduction in ischemic heart disease-related mortality during long-term follow-up of at least 4.5 years.34,40,45,64 The benefit of IV magnesium therapy in this study was consistent with data from several previous, smaller, controlled studies in patients with acute MI in whom thrombolytic agents, aspirin, or β-blockers were not administered routinely;2,6,35,36,37,38,39,49 subsequent analysis of pooled data from these studies42,43 and the LIMIT-2 study indicated an overall reduction in early mortality of approximately 35% in patients who received IV magnesium treatment generally within 12 hours following infarction.54,55

In contrast to these findings, in the Fourth International Study of Infarct Survival (ISIS-4), a randomized, multicenter study in more than 58,000 patients, administration of IV magnesium sulfate in a regimen similar to that used in the LIMIT-2 study (single 2-g IV dose followed by 18 g infused over 24 hours) was not associated with a reduction in mortality or other appreciable benefit on cardiac function at 5 weeks in patients with acute MI.41,64 While the reasons for these discrepant results remain to be elucidated, some clinicians suggest that differences in the timing of IV magnesium administration in relation to onset of symptoms of MI and different patient characteristics may have accounted for the opposing outcomes of these studies.34,64 In the LIMIT-2 study, magnesium was administered concomitantly with thrombolytic therapy and randomization to treatment occurred within a median of 3 hours from the onset of chest pain; in ISIS-4, thrombolytic therapy was initiated before IV magnesium and the corresponding time to treatment randomization was a median of 8 hours.34,40,41 Since data in animals with experimentally induced MI indicate that elevated magnesium concentrations must be present prior to or shortly (e.g., within 1 hour) after the onset of coronary artery reperfusion in order for substantial myocardial salvage to occur, the lack of benefit on mortality reduction in the ISIS-4 study has been attributed to the late initiation of magnesium treatment in these patients relative to that in the LIMIT-2 study.34,56,57,64 In addition, it has been suggested that the low (7.2%) mortality rate in the control group in ISIS-4 may have been indicative of a relatively low-risk patient population in whom any additional mortality-reducing effects of IV magnesium (i.e., beyond those associated with the concurrently administered fibrinolytic and antiplatelet therapy) would have been difficult to detect.34,44,53,64

In a more recent randomized controlled study (the Magnesium in Coronaries [MAGIC] trial) that was designed to evaluate the effects of early administration of IV magnesium sulfate in high-risk patients with acute ST-elevation MI (STEMI), there was no difference in 30-day mortality (the primary end point) between patients who received magnesium sulfate and those who received placebo.106 Based on the currently available evidence, routine prophylactic administration of magnesium sulfate in patients with acute MI is not recommended; since there is no apparent harm associated with its use, however, magnesium may still be used in patients with documented magnesium deficiency or torsades de pointes-type ventricular tachycardia.105,106

Acute Asthma

Magnesium sulfate has been used parenterally in the management of acute asthma† in both pediatric patients and adults.96,98,99,100,196 There is some evidence indicating that the drug may modestly improve bronchodilation and pulmonary function when given in conjunction with standard bronchodilating agents (e.g., nebulized β-adrenergic agents) and corticosteroids; patients with the most severe exacerbations of asthma appear to derive the most benefits.99,196 In one randomized, placebo-controlled, double-blind study in children with severe persistent asthma (peak expiratory flow rate less than 60% of predicted) who failed to respond to an adequate trial of conventional therapy (3 doses of albuterol administered via nebulization), use of IV magnesium sulfate (25 mg/kg up to 2 g) substantially improved pulmonary function in such children as compared with those who received placebo.66 Children who received IV magnesium sulfate also were less likely to be hospitalized for treatment than those who received placebo.66 The benefit of IV magnesium sulfate therapy in this study was consistent with data from similarly designed controlled studies in adults and children in whom IV infusion of magnesium sulfate (2 g over 20 minutes) produced a beneficial effect only in the most severely ill patients.66 A systematic review of 7 randomized controlled studies in adults and pediatric patients with acute asthma found that magnesium sulfate improved pulmonary function (peak expiratory flow rate and forced expiratory volume in 1 second) and reduced hospitalizations in patients with the most severe exacerbations.99,196 In another systematic review of 14 randomized controlled studies in adults presenting to the emergency department with acute asthma, treatment with a single IV infusion of magnesium sulfate (1.2 or 2 g) reduced hospital admissions and improved lung function in patients who were unresponsive to conventional therapy.100 Although the currently available evidence does not support routine use of IV magnesium sulfate in all patients with acute asthma, the drug may be beneficial, and thus may be considered, in some patients with severe exacerbations.98,99,100,196

Other Uses

Magnesium sulfate has been administered IV to counteract the intense muscle stimulating effects of barium poisoning.67

Parenteral magnesium sulfate also has been used in the management of other clinical situations including cerebral edema (as an osmotic agent) and tetanus. The efficacy of parenteral magnesium sulfate therapy in these situations has not been conclusively demonstrated.

Although some evidence suggests an association between lower dietary intake of magnesium and higher blood pressure,63 there currently are no convincing data to justify increased magnesium intake as a means of lowering blood pressure.1200

For use of magnesium sulfate as a cathartic, see Saline Laxatives 56:12.

Administration

Magnesium sulfate is usually administered IV or IM.67,68,95

Magnesium sulfate also has been administered by intraosseous (IO) infusion† in the setting of advanced cardiovascular life support (ACLS), generally when IV access is not readily available;401,403 onset of action and systemic concentrations of the drug are comparable to those achieved with venous administration.403

When used in pregnant women for conditions other than those labeled by the FDA, such as for the prevention of preterm labor†, magnesium sulfate injection should be administered only by trained obstetric personnel in a hospital setting with appropriate obstetrical care facilities.67,75

IM Administration

For IM administration in adults, magnesium sulfate solution in concentrations of 250 mg/mL (25%) or 500 mg/mL (50%) is generally used. For IM use in infants and children, the drug concentration usually should not exceed 200 mg/mL (20%);67 however, higher concentrations (e.g., 50%) have been used.95

IV Administration

For IV administration, the concentration of magnesium sulfate should not be greater than 200 mg/mL (20%) and the rate of injection generally should not exceed 150 mg/minute (e.g., 1.5 mL/minute of a 10% concentration or equivalent) except in patients with seizures associated with severe eclampsia.67

Magnesium sulfate 50% injection must be diluted prior to IV administration;67 alternatively, a commercially available prediluted solution of magnesium sulfate in 5% dextrose injection or sterile water for injection may be used.68,97

Standardize 4 Safety

Standardized concentrations for magnesium sulfate have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care.250 Multidisciplinary expert panels were convened to determine recommended standard concentrations.250 Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label.250 For additional information on S4S (including updates that may be available), see [Web].250

Dosage

Dosage of magnesium sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.67

Clinicians should use caution when switching between different formulations of magnesium sulfate injection to ensure that patients receive the correct dose.90

Prevention and Control of Seizures

Preeclampsia and Eclampsia

Various dosing regimens for magnesium sulfate have been recommended for the management of preeclampsia or eclampsia.58,67,68,103,104 IV infusions of dilute solutions of magnesium sulfate (1-8%) are often given in combination with IM injections of 50% magnesium sulfate.68 In severe preeclampsia or eclampsia, the manufacturer states that the total initial dose of magnesium sulfate is 10-14 g.67,68 An initial IV dose of 4-5 g of magnesium sulfate in 250 mL of 5% dextrose injection or 0.9% sodium chloride injection may be given simultaneously with IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution of magnesium sulfate administered into each buttock).67 Alternatively, the initial IV dose of 4 g may be given by diluting the 50% magnesium sulfate injection to a concentration of 10 or 20% and the diluted solution (40 mL of a 10% solution or 20 mL of a 20% solution) injected IV over a period of 3-4 minutes; subsequent doses of 4-5 g (8-10 mL of the undiluted 50% magnesium sulfate injection) may then be administered IM into alternate buttocks every 4 hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.67 After the initial IV dose, some clinicians administer a maintenance IV infusion of 1-2 g/hour.58,68,104 For the prevention or treatment of eclamptic seizures, the American College of Obstetricians and Gynecologists (ACOG) recommends an IV loading dose of 4-6 g of magnesium sulfate, followed by a maintenance IV infusion of 1-2 g/hour for at least 24 hours.58

Therapy should continue until paroxysms cease.67 A serum magnesium concentration of 6 mg per 100 mL is considered optimal for control of seizures.67 The manufacturer states that total dosage of magnesium sulfate should not exceed 30-40 g daily.67 In the presence of severe renal insufficiency, frequent serum magnesium concentrations must be obtained and the maximum dosage of magnesium sulfate is 20 g per 48 hours.67

Other Seizure Etiologies

For controlling seizures associated with epilepsy, glomerulonephritis, or hypothyroidism, the usual adult dose is 1 g administered IM or IV.67

Hypomagnesemia

Prevention

Maintenance requirements for magnesium in total parenteral nutrition are not precisely known.67 As a part of total parenteral nutrition, adults are usually given 8-24 mEq of magnesium daily and infants are usually given 2-10 mEq of magnesium sulfate daily.67 (See Chemistry and Stability: Chemistry.)

Treatment

For the treatment of mild magnesium deficiency, the usual adult dosage of magnesium sulfate is 1 g (8.12 mEq or 2 mL of the 50% solution of magnesium sulfate) administered IM every 6 hours for 4 doses.67 For deficiency that is not severe in adults and older children, some manufacturers have recommended a magnesium sulfate dosage of 1 g (2 mL of the 50% solution) once or twice daily by IM injection using serum magnesium values to guide continued dosing.95 In patients with severe hypomagnesemia, as much as 250 mg (2 mEq or 0.5 mL of the 50% solution) of magnesium sulfate per kg of body weight may be administered IM within a 4-hour period if necessary.67 For severe hypomagnesemia, some manufacturers have recommended a daily magnesium sulfate dose of 1-5 g (2-10 mL of the 50% solution) given in divided doses by IM injection.95 Alternatively, 5 g of magnesium sulfate (approximately 40 mEq) may be added to 1 L of 5% dextrose injection or 0.9% sodium chloride injection and administered by slow IV infusion over a 3-hour period.67 In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.67

For the treatment of hypomagnesemia in pediatric patients, some experts recommend a magnesium sulfate dosage of 25-50 mg/kg (maximum single dose of 2 g) every 4-6 hours for 3-4 doses by IV or IM injection; doses may be repeated as needed.96

Preterm Labor and Fetal Neuroprotection

For use as a tocolytic agent in the management of preterm labor†, the rate and duration of magnesium sulfate infusion should be carefully adjusted according to the patient's response, as indicated by uterine response, and the maternal and fetal tolerance.13,14,15,16,17,18 Monitoring serum magnesium concentrations may be useful in minimizing the risk of magnesium toxicity (e.g., respiratory depression, cardiotoxicity, maternal tetany, muscular paralysis, hypotension) and in determining the maximum safe infusion rate.13,33 For acute tocolytic therapy, IV magnesium sulfate dosages of 4-6 g infused over 20 minutes as a loading dose, followed by maintenance infusions of 2-4 g per hour for 12-24 hours as tolerated after contractions cease, have been used.13,14,15,16,17,18,69 However, prolonged administration of the drug (i.e., more than 5-7 days) for tocolysis has been associated with hypocalcemia and bone abnormalities in the developing fetus.67,75,77,78,79,80,81,82,83,84,85,86 (See Cautions: Pregnancy and Lactation.) Monitoring the amount of administered IV fluids and the rate of administration is necessary to avoid circulatory fluid overload.13 Patients should be observed for signs and symptoms of pulmonary edema.13 (See Cautions: Adverse Effects.)

Hospitals that use magnesium sulfate for fetal neuroprotection† should develop uniform and specific guidelines for such use, including inclusion criteria, treatment regimens, concomitant use of tocolytic agents, and patient monitoring in accordance with one of the larger clinical trials.69,89

Arrhythmias

Ventricular Tachycardia

In adults with polymorphic ventricular tachycardia associated with QT interval prolongation (torsades de pointes†), some experts recommend an IV magnesium sulfate dose of 1-2 g administered over 15 minutes.401 A dose of 1-6 g of magnesium sulfate (8.1-48.6 mEq) administered over several minutes also has been used, followed in some cases by IV infusion of the drug at a rate of approximately 3-20 mg/minute for 5-48 hours depending on patient response and serum magnesium concentrations.8,9,10,64 For cardiac arrest associated with torsades de pointes†, some experts recommend an adult IV or IO† bolus dose of 1-2 g of magnesium sulfate, diluted in 10 mL of 5% dextrose injection.401

When used in pediatric advanced life support (PALS) for the treatment of torsades de pointes or suspected hypomagnesemia, some experts recommend an IV or IO† magnesium sulfate dose of 25-50 mg/kg (maximum single dose of 2 g) over 10-20 minutes (or faster in torsades de pointes).403

Paroxysmal Atrial Tachycardia

When magnesium sulfate was used in the management of paroxysmal atrial tachycardia, the usual dose was 3-4 g (e.g., 30-40 mL of a 10% solution) administered IV over 30 seconds with extreme caution. 67

Acute Asthma

For the management of severe refractory asthma† in adults, some experts state that the standard magnesium sulfate dose of 2 g may be given by IV infusion over 20 minutes.96,196

In children with moderate to severe exacerbation of reactive airway disease, a single magnesium sulfate dose of 25-75 mg/kg (maximum 2 g) over 20 minutes by IV infusion has been recommended.96

Barium Poisoning

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1-2 g given IV.67

Dosage in Geriatric Patients

Geriatric patients often require a reduced dosage of magnesium sulfate because of renal impairment.67 In geriatric patients with severe renal impairment, dosage of the drug should not exceed 20 g in a 48-hour period; serum magnesium concentrations should be monitored in such patients.67

Adverse Effects

Adverse effects associated with parenteral magnesium sulfate therapy are caused by magnesium intoxication. Signs of hypermagnesemia, which may begin at serum magnesium concentrations of 4 mEq/L, include neurologic symptoms (e.g., muscular weakness, flaccid paralysis, ataxia, drowsiness, confusion, depression of reflexes), flushing, sweating, vasodilation, hypotension, hypothermia, depression of cardiac function, bradycardia, cardiac arrhythmias, circulatory collapse, hypoventilation, and CNS depression.70 These symptoms can proceed to fatal respiratory paralysis. Hypocalcemia with signs of tetany secondary to magnesium sulfate therapy for eclampsia has been reported.

To minimize the risk of magnesium toxicity (e.g., respiratory depression, cardiotoxicity, maternal tetany, muscular paralysis, hypotension) during tocolytic therapy, serum magnesium concentrations should be monitored.13,21,22,23 In addition to the usual cautions and precautions of magnesium sulfate therapy, tocolytic therapy with the drug is associated with some risk of maternal pulmonary edema.13,69 The etiology of pulmonary edema associated with tocolytic therapy remains to be more fully elucidated.13 Maternal risk factors for its development include excessive hydration, multiple gestation, occult sepsis, and underlying cardiac disease.13 Although adjunctive corticosteroid therapy also has been suggested as contributing to the risk of developing pulmonary edema, most evidence suggests that this is not an important risk factor.13 The risk of maternal pulmonary edema associated with tocolytic therapy may be reduced by limiting fluid intake to 2.5-3 L daily, limiting sodium intake, and maintaining maternal pulse below 130 beats/minute.13 Development of pulmonary edema during the initial 24 hours of tocolytic therapy is uncommon.13

Precautions and Contraindications

Patients receiving parenteral magnesium sulfate should be observed carefully, and serum magnesium concentration should be monitored to avoid overdosage. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of magnesium intoxication. When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional magnesium should be given until they return. In addition, the respiration rate should be at least 16 per minute prior to parenteral administration of each dose of magnesium sulfate, and therapy should not be continued unless urine output is 100 mL or more during the 4 hours preceding each dose. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be given IV. Clinically important hypocalcemia including hypocalcemic tetany has occurred following parenteral magnesium sulfate therapy for eclampsia. Changes in calcium and phosphorus balance should be anticipated in each case of parenteral magnesium administration.

In adults, IV administration of 5-10 mEq of calcium (e.g., 10-20 mL of 10% calcium gluconate) will usually reverse respiratory depression or heart block caused by magnesium intoxication.

Magnesium sulfate should be administered with caution to patients with impaired renal function because of the danger of magnesium intoxication.

Some preparations of magnesium sulfate contain aluminum; aluminum accumulation and associated toxicity (e.g., CNS and bone toxicities) can occur with prolonged parenteral administration of the drug in patients with impaired renal function.67 Premature neonates are at particularly high risk of aluminum toxicity.67

Parenteral administration of magnesium sulfate is contraindicated in patients with heart block or myocardial damage.67

For precautions and contraindications associated with tocolytic use of magnesium sulfate, see Uses: Preterm Labor and Fetal Neuroprotection and also see Cautions: Adverse Effects.

Geriatric Precautions

Geriatric patients often require a reduced dosage of magnesium sulfate because of renal impairment.67 (See Dosage and Administration: Dosage in Geriatric Patients.)

Pregnancy and Lactation

Pregnancy

The neonate is usually not compromised by excess magnesium when IM magnesium sulfate is administered to the toxemic mother; however, when magnesium sulfate therapy is administered by continuous IV infusion (especially if for more than 24 hours preceding delivery), the possibility that the neonate may show signs of magnesium toxicity, including neuromuscular or respiratory depression, is increased. In addition, prolonged use of parenteral magnesium sulfate during pregnancy has been associated with fetal hypocalcemia and skeletal abnormalities.67,75,77,78,79,80,81,82,83,84,85,86 IV magnesium should not be given during the 2 hours preceding delivery. Management of the neonate with hypermagnesemia may require resuscitation and assisted ventilation via endotracheal intubation and/or intermittent positive-pressure ventilation, as well as IV calcium. For additional information on the risks of tocolysis with magnesium sulfate, see Cautions: Adverse Effects.

Epidemiologic studies and case reports indicate that prolonged use (i.e., longer than 5-7 days) of magnesium sulfate injection during pregnancy may cause hypocalcemia and related skeletal abnormalities (e.g., osteopenia, bone demineralization, fractures) in the developing fetus.67,75,77,78,79,80,81,82,83,84,85,86,87,88 Such bone abnormalities have been described in case reports of neonates exposed in utero to magnesium sulfate; as of May 30, 2013, 18 cases were identified in the FDA's Adverse Event Reporting System (AERS).75 All of these cases were previously described in the medical literature.75,77,78,79,80,85,86,88 In these case reports, magnesium sulfate was parenterally administered for prolonged periods for the prevention of preterm labor (tocolysis)†, which is not an FDA-labeled indication for the drug.75,77,78,79,80,85,86,88 According to an FDA analysis of data obtained from AERS, the average duration of in utero exposure to magnesium sulfate was 9.6 weeks (range: 8-12 weeks).75 Complete or near complete resolution of the bone abnormalities occurred in cases where outcomes were reported.75,77,78,80,85 Results of several epidemiologic studies, most of which were retrospective chart reviews, also have indicated an increased incidence of skeletal abnormalities in infants born to mothers who had received IV magnesium sulfate for prolonged tocolysis (more than 5-7 days).67,75,77,81,82,83 Some of these studies also reported changes in serum biochemistry related to bone metabolism (e.g., hypermagnesemia, hyperphosphatemia, hypocalcemia, increased alkaline phosphatase concentrations) and radiographic changes consistent with the bone abnormalities observed; however, the long-term consequences of such findings are not known.75,77,83,84 Although a causal relationship has not been conclusively established,88 FDA states that the available evidence to date supports an association between prolonged (i.e., longer than 5-7 days) maternal administration of IV magnesium sulfate therapy and neonatal hypocalcemia and skeletal abnormalities.75

Magnesium sulfate injection should be used during pregnancy only if clearly needed.67,75 If magnesium sulfate is administered to a pregnant woman for the prevention of preterm labor, the patient should be informed that efficacy and safety of such use have not been established and that use of the drug for more than 5-7 days in this setting may cause fetal harm; the shortest duration of use that can result in fetal harm is not known.67,75

Lactation

Since magnesium is distributed into milk during parenteral magnesium sulfate administration, the drug should be used with caution in nursing women. However, magnesium sulfate generally is considered to be compatible with breastfeeding.87 Milk concentrations of magnesium are increased for only about 24 hours after discontinuance of parenteral magnesium sulfate therapy; the amount of magnesium ingested by a nursing infant during this period is probably too small to be of clinical importance.

-Adrenergic Agonists

Although limited data indicate that combination therapy with magnesium sulfate and another tocolytic agent may be more effective in arresting preterm labor† than a single tocolytic agent alone,19,24,25,27,69 American College of Obstetricians and Gynecologists (ACOG) guidelines currently state that β-adrenergic agonists should be used with caution in combination with magnesium sulfate because of the risk of potentially serious maternal complications.69

Calcium-channel Blocking Agents

Although limited data indicate that combination therapy with magnesium sulfate and another tocolytic agent may be more effective in arresting preterm labor† than a single tocolytic agent alone,19,24,25,27,69 concurrent use of magnesium sulfate and calcium-channel blocking agents (e.g., nifedipine) may be particularly risky and is potentially harmful (e.g., reduced heart rate, contractility, and left ventricular systolic pressure; neuromuscular blockade).32,69 ACOG guidelines currently state that calcium-channel blocking agents should be used with caution in combination with magnesium sulfate because of the risk of potentially serious maternal complications.69

CNS Depressants

When barbiturates, opiates, general anesthetics, or other CNS depressants are administered concomitantly with magnesium sulfate, dosage of these agents must be carefully adjusted because of the additive central depressant effects.

Neuromuscular Blocking Agents

Excessive neuromuscular blockade has occurred in patients receiving parenteral magnesium sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly only with caution.

Cardiac Glycosides

Magnesium salts should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat magnesium toxicity.

Pharmacology

Magnesium is the fourth most abundant cation in the body and is essential for the function of important enzymes, including those related to the transfer of phosphate groups, all reactions involving ATP, and every step related to the replication and transcription of DNA and the translation of mRNA. Magnesium also is required for cellular energy metabolism and is involved in membrane stabilization, nerve conduction, iron transport, and calcium-channel activity.

When administered parenterally in doses sufficient to produce hypermagnesemia (serum magnesium concentrations greater than 2.5 mEq/L), the drug may depress the CNS and block peripheral neuromuscular transmission, producing anticonvulsant effects. The exact mechanism of this depressant activity is not fully known; however, excess magnesium appears to decrease the amount of acetylcholine liberated by the motor nerve impulse. When serum concentrations of magnesium exceed 4 mEq/L, deep-tendon reflexes may be depressed. At serum concentrations of 10 mEq/L, deep-tendon reflexes may disappear and respiratory paralysis may occur. Serum magnesium concentrations in excess of 12 mEq/L may be fatal. Complete heart block can also occur at high serum concentrations of magnesium (approximately 10 mEq/L). Animal studies suggest that the effect of magnesium ions on cardiac muscle is to slow the rate of the sinoatrial node impulse formation and prolong conduction time. Limited data in patients with no evidence of heart disease indicate that IV infusion of magnesium prolongs PR interval, H (atria-His bundle) interval, antegrade AV nodal effective refractory period, and sinoatrial conduction time. Available data also suggest that magnesium produces systemic and coronary vasodilatation, possesses antiplatelet activity, suppresses automaticity in partially depolarized cells, and protects myocytes against calcium overload under conditions of ischemia by inhibiting calcium influx especially at the time of reperfusion. However, the clinical benefit of administering magnesium in patients with acute myocardial infarction has not been fully determined. (See Uses: Acute Myocardial Infarction.) Magnesium also acts peripherally, producing vasodilation. Moderate doses produce flushing and sweating, and higher doses lower blood pressure. Both the CNS depression and the peripheral neuromuscular transmission blockade produced by hypermagnesemia can be antagonized by administration of excess calcium.

Pharmacokinetics

When magnesium sulfate is administered IV, the onset of action is immediate and the duration of action is about 30 minutes. Following IM administration of the drug, the onset of action occurs in about 1 hour and the duration of action is 3-4 hours. As an anticonvulsant, effective serum concentrations of magnesium have been reported to range from 2.5-7.5 mEq/L.

Magnesium readily crosses the placenta and is distributed into milk following parenteral administration of magnesium sulfate. Milk concentrations of magnesium are increased for only about 24 hours after discontinuance of parenteral magnesium sulfate therapy; the amount of magnesium ingested by a nursing infant during this period is probably too small to be of clinical importance.

Magnesium sulfate is excreted by the kidneys at a rate that varies from one patient to another but that is directly proportional to the serum concentration and glomerular filtration.

Chemistry and Stability

Chemistry

Parenteral magnesium sulfate exhibits anticonvulsant properties.

Stability

Magnesium sulfate injection and magnesium sulfate in 5% dextrose injection should be stored at 20-25°C; freezing should be avoided.67,68,97

Magnesium sulfate is converted to the monohydrate when heated to 150-160°C. Magnesium sulfate is incompatible with alkali hydroxides (forming insoluble magnesium hydroxide), with alkali carbonates (forming basic carbonates), and with salicylates (forming basic salicylates). The drug reacts with arsenates, phosphates, and tartrates, precipitating the corresponding magnesium salts. Lead, barium, strontium, and calcium react with magnesium sulfate resulting in precipitation of the respective sulfates. Specialized references should be consulted for specific compatibility information. Following withdrawal of a dose from one of the solutions which do not contain preservatives, any unused portion should be discarded.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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