Clinical pharmacokinetic properties of magnesium sulphate in women with pre‐eclampsia and eclampsia

Abstract

BackgroundThe pharmacokinetic basis of magnesium sulphate (MgSO 4) dosing regimens for eclampsia prophylaxis and treatment is not clearly established.ObjectivesTo review available data on clinical pharmacokinetic properties of MgSO 4 when used for women with pre‐eclampsia and/or eclampsia.Search strategy MEDLINE, EMBASE, CINAHL, POPLINE, Global Health Library and reference lists of eligible studies.Selection criteriaAll study types investigating pharmacokinetic properties of MgSO 4 in women with pre‐eclampsia and/or eclampsia.Data collection and analysisTwo authors extracted data on basic pharmacokinetic parameters reflecting the different aspects of absorption, bioavailability, distribution and excretion of MgSO 4 according to identified dosing regimens.Main resultsTwenty‐eight studies investigating pharmacokinetic properties of 17 MgSO 4 regimens met our inclusion criteria. Most women (91.5%) in the studies had pre‐eclampsia. Baseline serum magnesium concentrations were consistently <1 mmol/l across studies. Intravenous loading dose between 4 and 6 g was associated with a doubling of this baseline concentration half an hour after injection. Maintenance infusion of 1 g/hour consistently produced concentrations well below 2 mmol/l, whereas maintenance infusion at 2 g/hour and the Pritchard intramuscular regimen had higher but inconsistent probability of producing concentrations between 2 and 3 mmol/l. Volume of distribution of magnesium varied (13.65–49.00 l) but the plasma clearance was fairly similar (4.28–5.00 l/hour) across populations.ConclusionThe profiles of Zuspan and Pritchard regimens indicate that the minimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted level. Exposure–response studies to identify effective alternative dosing regimens should target concentrations achievable by these standard regimens.Tweetable abstractMinimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted therapeutic level.

Population Pharmacokinetic Modeling to Evaluate Standard Magnesium Sulfate Treatments and Alternative Dosing Regimens for Women With Preeclampsia

“…For example, loss of the patella tendon reflex was reported to occur at concentrations of 3.5 to 5 mmol/L, and alteration in cardiac conduction and possible cardiac arrest may occur at concentrations of >7.5 and 12.5 mmol/L, respectively. 8 Respiratory depression has also been reported at concentrations of approximately 12 mmol/L. Our simulations indicated that the magnesium concentrations of the standard Zuspan and Pritchard regimens were below the safety margin of 3.5 mmol/L.…”

“…4 A serum magnesium concentration of at least 2 mmol/L has generally been cited as the potential minimum therapeutic concentration. 8 However, a systematic review of 28 studies investigating magnesium sulfate in women with preeclampsia and eclampsia concluded that the minimum effective serum magnesium concentration for eclampsia prophylaxis may be lower than 2 mmol/L. 8 Using our model, simulated magnesium profiles for the standard Zuspan and Pritchard regimens demonstrated slightly lower magnesium concentrations, especially for women with higher body weight and lower creatinine.…”

“…8 However, a systematic review of 28 studies investigating magnesium sulfate in women with preeclampsia and eclampsia concluded that the minimum effective serum magnesium concentration for eclampsia prophylaxis may be lower than 2 mmol/L. 8 Using our model, simulated magnesium profiles for the standard Zuspan and Pritchard regimens demonstrated slightly lower magnesium concentrations, especially for women with higher body weight and lower creatinine. These simulations were consistent with the findings of a recently completed randomized trial that aimed to compare intravenous and intramuscular regimens of magnesium with 300 women at risk for eclampsia.…”

Clinical practice patterns on the use of magnesium sulphate for treatment of pre‐eclampsia and eclampsia: a multi‐country survey

“…This may reflect healthcare providers' familiarity with intravenous administration of MgSO 4 and a belief that higher dosage may result in greater clinical efficacy, as previously suggested in some old studies . In the absence of standard dose–exposure studies on minimum effective concentration of MgSO 4 , this variation in clinical practice is likely to persist for some time due to conflicting views on the optimal dosing regimen to prevent eclamptic seizures. The systematic review of small‐scale randomised trials and observational studies on several alternative MgSO 4 regimens in recent years have concluded that there is still insufficient evidence on their benefits to justify their introduction into clinical practice …”

Safety and efficacy of low dose intramuscular magnesium sulphate (MgSO4) compared to intravenous regimen for treatment of eclampsia

“…The pharmacokinetic basis of MgSO4 dosing regimens for eclampsia prophylaxis and treatment is not clearly established . Minimum effective serum magnesium concentrations for eclampsia prophylaxis are lower than the generally accepted therapeutic level …”