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
