Magnesium sulfate given according to Zuspan regimen safe in Women with Preeclampsia: Study

Preeclampsia is a hypertensive disease affecting 2-8% of all pregnancies with associated edema, placental insufficiency, kidney and liver dysfunction, hemolysis, coagulopathy, and seizures—referred to as eclampsia. Eclampsia is a rare, but potentially fatal complication of preeclampsia.

Diagnostic criteria for preeclampsia have changed from elevated blood pressure and proteinuria to a less strict definition of hypertonia and any of several organ dysfunctions, such as anaemia or thrombocytopenia, elevated liver enzymes, central nervous symptoms, proteinuria or elevated creatinine, or foetal growth restriction. Magnesium sulfate treatment is described as early as 1933. In the last decades of the 20th century, magnesium sulfate treatment became less common, due to concerns of magnesium toxicity, and the belief that anticonvulsant drugs were equally efficacious in preventing eclampsia. The mechanism behind neuroprotection in magnesium treatment is not fully understood but is believed to stem from calcium antagonism, blocking overactivationof NMDA receptors and inhibiting inflammatory cytokine response—both factors in a second phase of brain insults.

During the 1950s, Zuspan in Ohio, USA, and Pritchard in Texas, USA, introduced standardised magnesium sulfate treatments. Zuspan advocated a regime of intravenous bolus and maintenance treatment, whilst Pritchard favoured intramuscular bolus and repeat injections. These regimens persist today—Zuspan in high-resource settings and Pritchard in low-resource settings. The tentative therapeutic range of serum magnesium (2.0–3.0 mM) stems from measurements in successful cases of this era, whilst the threshold of toxicity as measured by loss of patellar reflex (3.5 mM) was established in 1940. In the 2002 Magpie trial (MAGnesium sulfate for Prevention of Eclampsia), designed to evaluate the effects of magnesium sulfate on pregnant women with preeclampsia and their babies, there was a marked reduction in seizures for mothers given magnesium sulfate rather than placebo, regardless of whether treatment is started before or after delivery and irrespective of any previous anticonvulsant therapy.

Since 2002, obesity rates have soared worldwide and are expected to continue to increase. Increased weight increases distribution volume, and thus time to achieve steady state concentration. Obesity is a pronounced risk factor for developing preeclampsia, making it imperative to ascertain that obese women receive adequate magnesium treatment.

The body mass index among women giving birth in authors’ health care region is lower than the population used in developing the pharmacokinetic model. Thus, they hypothesised that body weight is lower among women treated with magnesium sulfate in their region and therefore sought to perform an external validation of the PK model. Since preeclampsia is a major cause of preterm delivery and they do not treat extremely preterm neonates, there might also be a difference in patient selection causing gestational age at treatment to start to be higher in our population. The rationale for validating this particular model is that it used a mixed model—decreasing the risk of overfitting model to data, and that the population is well-characterised. A secondary aim of the study was to evaluate the proportion of women in historical cohort reaching the target serum magnesium of >2 mM.

Women with preeclampsia undergoing magnesium sulfate treatment. Subjects initially received Zuspan treatment (4 g bolus and 1 g/h maintenance dose), commonly increased by individual titration. Main Outcome measures included difference in mean between measured and predicted magnesium concentration and proportion of women reaching target concentration (>2 mM) in 25 h.

56 women were included, with 356 magnesium measurements available. Mean magnesium concentration was 1.82 mM. The prediction model overestimated magnesium concentration by 0.10 mM (CI 0.04–0.16) but exhibited no bias for weight, creatinine, or treatment duration. Weighted mean infusion rate was 1.22 g/h during 30 hours. Overall success rate in reaching target concentration was 54%, decreasing to 40% in women > 95 kg. Overall success rate at 8 hours was 11%. No toxic concentrations were found.

This study found a good predictive capability of the pharmacokinetic model. There was a statistically significant difference in prediction vs outcome of +0.10 mM; however, the study was not designed nor powered to evaluate its clinical impact. In a clinical setting, when using a potentially very toxic drug. Overestimation is preferable to underestimation. The model performed well at all concentrations, and without any bias identified.

In this historical cohort, magnesium sulfate treatment with using a 4 g bolus and a minimum maintenance dose of 1 g/h produced no toxic concentration and thus did not necessitate additional monitoring with respect to magnesium sulfate treatment. On the contrary, only 54% of treated women reached target concentration > 2 0 mM within 25 hours, falling even lower among women with high body weight or low creatinine. Calculating individual bolus and maintenance doses could be used to improve treatment outcomes and simultaneously decrease blood sampling. Further, the cohort of 56 cases with 356 magnesium measurements validated an external pharmacokinetic model for magnesium sulfate treatment, proving that individualised treatment is feasible—only requiring body weight and serum creatinine level.

Source: Erik Holmström Thalme 1 and Magnus Frödin-Bolling; Hindawi Journal of Pregnancy Volume 2024, Article ID 1178220, 8 pages https://doi.org/10.1155/2024/1178220

Dr Nirali Kapoor has completed her MBBS from GMC Jamnagar and MD Obstetrics and Gynecology from AIIMS Rishikesh. She underwent training in trauma/emergency medicine non academic residency in AIIMS Delhi for an year after her MBBS. Post her MD, she has joined in a Multispeciality hospital in Amritsar. She is actively involved in cases concerning fetal medicine, infertility and minimal invasive procedures as well as research activities involved around the fields of interest.