What is the toxic dose and lethal of IV magnesium sulfate when given as a bolus.

Comment by InpharmD Researcher

There is limited literature defining a specific toxic or lethal dose of IV magnesium sulfate when administered as a bolus. No definitive dose has been established, with severe toxicity reported across a wide range of doses and administration rates; acute exposures of approximately 12–50 g have resulted in respiratory or cardiac arrest, although recovery has also occurred after similarly large doses (Tables 1–5). Serum magnesium concentrations may therefore provide more useful guidance for assessing toxicity than a specific administered dose, with loss of patellar reflexes reported at approximately 3.5–5 mmol/L, respiratory paralysis at 5–6.5 mmol/L, altered cardiac conduction at >7.5 mmol/L, and cardiac arrest at >12.5 mmol/L. Overall, available evidence suggests that dose, administration rate, renal function, and patient-specific factors contribute to toxicity; consequently, a definitive toxic or lethal IV bolus dose has not been established.

Background

A 2000 review examines the pharmacokinetics, clinical use, and toxicity of magnesium sulfate in women with preeclampsia or eclampsia. Therapeutic concentrations are consistently achieved following a 4-g IV loading dose administered over 15 minutes, and an additional 2–4 g bolus over 5 minutes is recommended for ongoing or recurrent convulsions. The first warning of impending maternal toxicity is loss of the patellar reflex at plasma magnesium concentrations of 3.5–5 mmol/L; respiratory paralysis occurs at 5–6.5 mmol/L, cardiac conduction is altered at >7.5 mmol/L, and cardiac arrest is expected at >12.5 mmol/L. Maximum serum magnesium concentrations during therapy depend on the rate of infusion rather than the total dose administered or duration of infusion after a plateau is reached. [1]

A 2004 patient-safety article examines obstetric accidents involving intravenous magnesium sulfate and summarizes a database of 52 accidental overdoses, along with magnesium toxicity, monitoring considerations, and patient-safety recommendations. The article describes magnesium sulfate toxicity as dose dependent and reports a therapeutic serum magnesium range of 4.8–9.6 mg/dL. Reported toxicity thresholds include loss of patellar reflexes at 8–12 mg/dL, respiratory difficulty or depression at 12–16 mg/dL, muscular paralysis at 15–17 mg/dL, altered cardiac conduction at >18 mg/dL, and cardiac arrest at 30–35 mg/dL. The authors note that untreated respiratory arrest may progress to cardiac arrest at magnesium concentrations below those associated with direct cardiotoxicity. Across the reported overdose cases, outcomes ranged from no adverse effects to respiratory arrest, persistent vegetative state, and death with varying administered doses and infusion rates. Therapeutic and toxic serum concentrations were noted to vary between patients, with renal function identified as an important determinant of magnesium tolerance. Please refer to Table 1 for individual overdose exposures and associated outcomes. [2]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the toxic dose and lethal of IV magnesium sulfate when given as a bolus.

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-5 for your response.

Cases of magnesium sulfate accidents
Design	Case series
Case 1	A woman in preterm labor receiving IV magnesium sulfate experienced a precipitous delivery, after which magnesium sulfate was inadvertently infused at a rapid rate instead of oxytocin. She received approximately 22 g of magnesium sulfate and was found nonresponsive and not breathing approximately 30 minutes later. Resuscitation required three defibrillations and 9 minutes to restore her heart rate. Despite aggressive resuscitation, calcium chloride, and intensive care, she did not regain consciousness and remained in a persistent vegetative state.
Case 2	A woman with preeclampsia receiving IV magnesium sulfate at 2 g/hour was transferred to a postpartum unit approximately 12 hours after delivery. An unlabeled 1-L bag containing 40 g of magnesium sulfate was inadvertently administered as maintenance fluid in addition to the prescribed magnesium sulfate infusion; the additional infusion was running at 300 mL/hour rather than the intended 125 mL/hour. Approximately 1.5 hours after her previous assessment, she was found nonresponsive and not breathing. Resuscitation was initiated, but she did not regain consciousness and remained in a persistent vegetative state. The total amount of magnesium sulfate received was not reported.
Case 3	A woman with preeclampsia receiving IV magnesium sulfate at 2 g/hour was transferred to a tertiary care center. During transport, the prescribed 2 g/hour infusion was misinterpreted as 7 g/hour and the infusion rate was increased accordingly. On arrival, the patient had a respiratory rate of 10 breaths/minute. The dosing error was identified, calcium gluconate was administered, and her respiratory status improved quickly.
Case 4	A woman with preeclampsia receiving IV magnesium sulfate had her solution concentrated to 40 g/L for fluid restriction, with an intended infusion rate of 2 g/hour. Because the increased concentration was not documented or labeled, the infusion rate was subsequently increased to 100 mL/hour, resulting in administration of 4 g/hour. Hourly assessments showed progressively decreasing respirations, deep tendon reflexes, and level of consciousness, and the serum magnesium concentration was 12 mg/dL. The dosing error was identified and magnesium sulfate was discontinued until the symptoms of toxicity resolved.
Case 5	A woman with severe preeclampsia was prescribed a 4-g IV magnesium sulfate loading dose followed by 2 g/hour. The loading dose was inadvertently administered twice, with the second 4-g dose given over 20 minutes while the maintenance infusion was running. Her serum magnesium concentration was 9.6 mg/dL, and no adverse effects were reported.
Case 6	A woman with preeclampsia presented for labor induction and was prescribed a 4-g IV magnesium sulfate loading dose over 30 minutes followed by 2 g/hour. The infusion was prepared at 80 g/L instead of the intended 40 g/L, resulting in administration of approximately 12 g over 25 minutes. She developed feeling very hot, nausea, difficulty moving her extremities, shallow respirations, and absent deep tendon reflexes, with continued deterioration in respiratory status. Magnesium sulfate was discontinued and calcium gluconate was ordered, after which she improved quickly; her serum magnesium concentration was 12.8 mg/dL.
Case 7	A woman with preterm labor was prescribed a 6-g IV magnesium sulfate loading dose followed by 3 g/hour. Due to switched IV bag labels, she subsequently received magnesium sulfate at 12 g/hour for 3 hours instead of the intended mainline fluids. During this period, she developed flushing, nausea, and a respiratory rate of 10 breaths/minute and later became deeply unresponsive. She was subsequently found not breathing and without a palpable pulse; resuscitation was initiated but was unsuccessful.
Case 8	A woman with preterm labor was prescribed a 6-g IV magnesium sulfate loading dose over 20 minutes followed by 3 g/hour. The infusion was not reduced to the maintenance rate after the loading dose, resulting in administration of 18 g over 1 hour. She became difficult to arouse and had a respiratory rate of 8 breaths/minute, with a serum magnesium concentration of 11.4 mg/dL. Calcium gluconate and an 800-mL IV bolus of lactated Ringer solution were administered, after which her condition improved rapidly.
Case 9	A woman with twins and a history of kidney disease and kidney transplantation was receiving IV magnesium sulfate at 2.5 g/hour for preterm labor. Eight hours after transfer to an antepartum/postpartum unit, she was difficult to arouse, had a respiratory rate of 8 breaths/minute, and had absent deep tendon reflexes. Magnesium sulfate was discontinued and calcium gluconate was administered; because her respiratory status did not improve, she was transferred to the intensive care unit (ICU) and received ventilatory assistance for several hours. She recovered completely after 2 additional days in the ICU.
Case 10	A woman presenting with symptoms of preterm labor was prescribed IV magnesium sulfate at 4 g/hour. The written order was misinterpreted as 42 g/hour, and the infusion was administered at that rate. After transfer to a tertiary care center, she experienced respiratory arrest and received calcium gluconate during resuscitation. Her serum magnesium concentration was 16.8 mg/dL 30 minutes after the code, and she recovered after 24 hours in the ICU.
Case 11	A woman 4 hours postpartum with mild preeclampsia was receiving IV magnesium sulfate at 2 g/hour. After her mobility was assessed as adequate, she was instructed to assist herself to the bathroom while moving the infusion pump. She fainted while going to the bathroom and fell, sustaining skull and wrist fractures. She required an additional 6-day hospitalization and ultimately made a full recovery.
Case 12	A woman 4 days postpartum presented to the emergency room with severe headache, blurred vision, epigastric pain, a blood pressure of 168/110 mmHg, and 4+ pitting edema. She was prescribed a 2-g IV magnesium sulfate loading dose followed by 1 g/hour, but an incorrect pump rate resulted in administration of 25 g over 2.5 hours. She subsequently developed weakness and inability to move. Calcium gluconate was administered, after which she rapidly improved.
Study Author Conclusions	IV magnesium sulfate treatment has become routine practice in obstetrics, but vigilance in its use is required for safe care for mothers and babies. Implementing the recommendations provided in this article will promote patient safety and decrease the likelihood of an accidental overdose as well as increase the chances that an error is identified before a significant adverse outcome occurs.

Table 1 References:
[3] Simpson KR, Knox GE. Obstetrical accidents involving intravenous magnesium sulfate: recommendations to promote patient safety. MCN Am J Matern Child Nurs. 2004;29(3):161-171. doi:10.1097/00005721-200405000-00006

Accidental intravenous infusion of a large dose of magnesium sulphate during labor: A case report
Design	Case report
Case presentation	A 28-year-old primigravida with a dichorionic diamniotic twin pregnancy complicated by severe preeclampsia was receiving IV magnesium sulfate and subsequently delivered both infants vaginally. Following delivery, she developed postpartum hemorrhage and later became increasingly short of breath and somnolent, with progressive respiratory depression requiring intubation. Her serum magnesium concentration was 8.6 mmol/L, and magnesium toxicity was considered the cause of her respiratory arrest and neurologic suppression. Investigation identified an empty magnesium sulfate bag that had presumably been administered instead of oxytocin, resulting in administration of 40 g of magnesium sulfate as an IV push. She received calcium, respiratory support, and treatment to reduce magnesium levels; her magnesium concentration returned to the therapeutic range by early evening, and after extubation she was alert, oriented, and asymptomatic.
Study Author Conclusions	MgSO4 is among one of the most frequently used drugs in obstetric practice. However, despite years of use and provider familiarity, the administration of MgSO4 occasionally results in accidental overdose and patient harm. Color coding of premixed bags, use of color‑coded tags on lines, and vigilance in its use is required for safe care of mothers and babies.

Table 2 References:
[4] Kumar K, Al Arebi A, Singh I. Accidental intravenous infusion of a large dose of magnesium sulphate during labor: A case report. J Anaesthesiol Clin Pharmacol. 2013;29(3):377-379. doi:10.4103/0970-9185.117105

IATROGENIC MAGNESIUM OVERDOSE: TWO CASE REPORTS
Design	Case series
Case 1	A 43-year-old male presented to the emergency department after being found unresponsive at a drug and alcohol detoxification center. He was prescribed 2 g of IV magnesium sulfate but inadvertently received 20 g over 10 minutes. Within 1 minute of completing the infusion, he developed asystole and required cardiopulmonary resuscitation and intubation, with return of spontaneous circulation after 18 minutes. His serum magnesium concentration was 6.0 mmol/L 80 minutes after the infusion and returned to normal within 27 hours. He recovered rapidly and was neurologically intact 36 hours after admission.
Case 2	A 52-year-old male presented to the emergency department from a drug and alcohol detoxification center with possible gastrointestinal hemorrhage while being treated for mild alcohol withdrawal. He was prescribed 2 g of IV magnesium but inadvertently received 20 g of magnesium sulfate over 45 minutes. Five minutes after transfer to the observation unit, he was found pulseless and apneic, initially with ventricular fibrillation and subsequently asystole. Return of spontaneous circulation occurred 8 minutes after resuscitation began; no post-arrest serum magnesium concentration was obtained. The patient died 3 days later after supportive care was withdrawn.
Study Author Conclusions	Hypermagnesemia is a rare but potentially life-threatening complication of magnesium therapy. The major effects primarily involve the cardiovascular and neuromuscular systems. Cardiac manifestations include progressive conduction defects leading to asystole with increasingly higher serum concentrations, as well as a less predictable hypotension. Neurologic sequelae begin with diminished deep tendon reflexes and progress to apnea and coma. The treatment consists of discontinuation of the exogenous source, intravenous calcium, supportive care and, in some cases, dialysis. Recognizing the potential drug errors associated with iatrogenic overdoses may prevent this complication. Written orders must be precise regarding doses, concentrations, and the duration of the infusion. A particular hazard with intravenous magnesium is the variety of units of measurement used in written orders and on the labels, leading to misinterpretation and errors in calculation. With the increased utilization of magnesium in the emergency department, it is essential to be aware of the dosing forms available, to be clear and precise in ordering magnesium and, ideally, to use units that are consistent with those on the drug vial. Acute iatrogenic magnesium toxicity should be considered in any patient who manifests symptoms consistent with hypermagnesemia despite having been given a presumed benign dose of IV magnesium.

Table 3 References:
[5] Vissers RJ, Purssell R. Iatrogenic magnesium overdose: two case reports. J Emerg Med. 1996;14(2):187-191. doi:10.1016/0736-4679(95)02115-9

latrogenic Magnesium Overdose in a Patient With Suspected Acute Myocardial Infarction
Design	Case report
Case presentation	A 73-year-old man presented to the emergency department with substernal chest pain, shortness of breath, and nausea and was treated for suspected acute myocardial infarction with congestive heart failure. He was prescribed 2 g of IV magnesium sulfate but inadvertently received two 25-g vials, for a total of 50 g. Approximately 45 minutes after the magnesium sulfate infusion began, he reported feeling hot and developed nausea and vomiting, followed by profound bradycardia, hypotension, and apnea requiring intubation. His serum magnesium concentration was 7.0 mg/dL 5.5 hours after the infusion was discontinued and 5.9 mg/dL 10 hours after discontinuation. He was alert and successfully extubated 10 hours after the magnesium sulfate infusion was stopped.
Study Author Conclusions	This case of iatrogenic, parenteral magnesium overdose in a patient with suspected acute myocardial infarction and congestive heart failure demonstrates a hazard of intravenous magnesium therapy. As the role for magnesium expands in the acute management of medical illness, the potential for witnessing its toxic effects increases. Educating and training ED staff on the available formulations, dosing regimens, and toxicity of magnesium salts will hopefully prevent the recurrence of this error. Caution must be exercised when using magnesium salts in the ED.

Table 4 References:
[6] Frohna WJ. Iatrogenic magnesium overdose in a patient with suspected acute myocardial infarction. Am J Emerg Med. 1995;13(4):436-437. doi:10.1016/0735-6757(95)90134-5

Deterioration of Ventricular Tachycardia to Ventricular Fibrillation after Rapid Intravenous Administration of Magnesium Sulfate
Design	Case report
Case presentation	A 65-year-old man presented with an extensive anterior myocardial infarction complicated by severe left ventricular dysfunction and subsequently developed recurrent sustained monomorphic ventricular tachycardia. During an episode of ventricular tachycardia, he received a 2-g IV magnesium sulfate bolus over 5 seconds. The ventricular tachycardia initially slowed, followed by progressive QRS widening and electrical alternans, culminating in ventricular fibrillation within 3 minutes. He was successfully resuscitated with a single 300-J shock and remained in sinus rhythm for several hours. He later experienced additional episodes of ventricular tachycardia and died of cardiogenic shock 2 days later.
Study Author Conclusions	The mechanism of deterioration of VT to VF in our patient is unclear. Marked widening of the QRS complex and slowing of the ventricular rate before VF induction reflect a strong negative dromotropic effect, similar to that of class 1 antiarrhythmic drugs. Such effect could be due to the rate of drug administration. Magnesium sulfate has not been shown to affect intraventricular conduction and refractoriness significantly when infused slowly (infusion rates of 1 g/min). On the other hand, blockade of conduction over accessory bypass tracts may occur with faster infusion rates (2 g of magnesium sulfate over 15 s or less). Also, decreased intraventricular conduction following magnesium administration has been observed during rapid ventricular pacing. Regardless of the mechanism involved, and as interest in the clinical use of magnesium sulfate increases, a word of caution against its rapid intravenous administration, even during resuscitation for ventricular arrhythmias, is in order.

Table 5 References:
[7] Viskin S, Belhassen B, Laniado S. Deterioration of ventricular tachycardia to ventricular fibrillation after rapid intravenous administration of magnesium sulfate. Chest. 1992;101(5):1445-1447. doi:10.1378/chest.101.5.1445