Magnesium was first reported to be effective in preventing further convulsions in eclamptic women in 1925. The Collaborative Eclampsia Trial, reporting in 1995, confirmed that magnesium sulfate is significantly more effective than either diazepam or phenytoin in preventing recurrence of convulsions in eclamptic women.
The MAGPIE Trial, reporting in 2002, showed that magnesium sulfate was also effective in reducing (by about half) the incidence of eclampsia when given to pre-eclamptic women. However, since the incidence of eclampsia in the UK is low (~1-2% of pre-eclamptic cases), the number needed to treat (NNT) in order to prevent a single woman having a convulsion is ~110 in the UK. This has led to controversy about whether magnesium should be routinely given to all pre-eclamptics, especially since there was no overall effect on maternal and neonatal morbidity and mortality in the trial. In populations in which the incidence is higher, as in some African countries, or in those with severe pre-eclampsia, the NNT is lower, so administration to such cases is less controversial. However, it is impossible to predict which women will go on to develop eclampsia; as a result magnesium is now used frequently in cases of severe pre-eclampsia across the world, including in the UK, as a result of these two trials. These two studies have changed clinical practice around the world but especially in the UK, where magnesium used to be infrequently used for pre-eclampsia/eclampsia.
Magnesium sulfate is widely used in the USA as a tocolytic agent in preterm labour, but randomised trials have failed to confirm its efficacy for this purpose. Its beneficial effect as a neuroprotective agent in the premature fetus has, however, been established, and it has been shown to reduce the incidence of cerebral palsy in preterm neonates, although there is no evidence of a significant reduction in fetal mortality with its use.
Site of action
Magnesium is essential for potassium and calcium metabolism. It acts as a calcium antagonist, probably reducing systemic and cerebral vasospasm via action at calcium channels and intracellular sites. It is a cofactor in the sodium-potassium-ATPase system and is also an N-methyl-D-aspartate (NMDA) receptor antagonist; it is thought that its anticonvulsant action is mediated through these systems. Production of endothelial prostacyclin is increased by magnesium, and this may help to restore the thromboxane-prostacyclin imbalance that occurs in pre-eclampsia. Magnesium is also thought to reduce levels of circulating angiotensin-converting enzyme (ACE), which may contribute to its antihypertensive action.
Magnesium sulfate relieves the cerebral vasospasm associated with pre-eclampsia and eclampsia; transcranial Doppler studies have demonstrated an increase in cerebral blood flow.
Side effects
Magnesium sulfate has widespread effects, not all of which are beneficial. Its use has been associated with increased obstetric haemorrhage (presumably due to generalised vasodilatation and uterine atony), increased length of labour and increased rate of caesarean section. Prophylactic use of magnesium sulfate before induction of general anaesthesia for caesarean section (e.g. in severe pre-eclampsia) can prolong the effects of neuromuscular blocking agents; use of a peripheral nerve stimulator is mandatory.
Toxicity is possible during infusion, although this is unlikely at the usual dosage unless there is concomitant renal impairment. Symptoms and signs of toxicity occur as blood levels increase (Table 87.1). Magnesium toxicity is reversed by intravenous calcium gluconate (10 ml of 10% solution, given by slow intravenous injection), and calcium should always be available when magnesium therapy is given.
Dose
The Collaborative Eclampsia and MAGPIE trials used an intravenous loading dose of 4-5 g magnesium sulfate (given over 5-15 minutes) followed by either 5 g intramuscularly into each buttock and a further 5 g intramuscularly every 4 hours for 24 hours, or an intravenous infusion of 1-2 g/h after the intravenous loading dose.
There is controversy about whether an intravenous maintenance infusion of 1 g/h produces adequate plasma levels, with some studies suggesting that 3 g/h is required to guarantee therapeutic levels (4-8 mg/dl). The Collaborative Eclampsia group has stated that use of higher doses would increase the risk of toxicity without conferring proven benefit, and in the MAGPIE Trial side effects occurred in a quarter of cases.
Monitoring
If the regimen used in the two above trials is used, clinical monitoring is considered to be adequate. Assessment of respiratory rate and patellar tendon reflexes every 15 minutes, and monitoring of hourly urine output, should be performed. Monitoring of plasma levels is advisable if larger doses of magnesium sulfate are used, if there is impaired renal function, if symptoms/signs of toxicity occur or a convulsion occurs despite therapy.
Table 87.1 Signs and symptoms of magnesium toxicity at various blood levels
|
Symptoms |
Magnesium level |
|
|
mg/dl |
mmol/l |
|
|
Normal adult levels |
1.7-2.4 |
0.7-1.1 |
|
Therapeutic range |
4-8 |
2-4 |
|
Loss of patellar reflexes, warmth, flushing, somnolence |
9.5-12 |
4.2-5 |
|
Respiratory depression |
12-16 |
5-6.5 |
|
Muscle paralysis |
15-17 |
6.2-7 |
|
Cardiac conduction defects |
> 18 |
> 7.5 |
|
Cardiac arrest |
30-35 |
12.5-14.5 |
Key points
• Magnesium sulfate is the only drug proven to be effective in preventing recurrence of convulsions in eclampsia.
• In pre-eclampsia, magnesium sulfate reduces the incidence of eclamptic convulsions, but its use for this purpose is controversial because there is no reliable method of predicting eclampsia.
• Both intramuscular and intravenous regimens are effective, and clinical monitoring is adequate.
• Calcium gluconate should be available at the bedside of every woman receiving magnesium sulfate.
Further reading
Dean C, Douglas J. Magnesium and the obstetric anaesthetist. Int J Obstet Anesth 2013; 22: 52-63.
Duley L, Gulmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev 2010; (11): CD000025.
Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Syst Rev 2010; (10): CD000128.
Duley L, Henderson-Smart DJ, Walker GJ, Chou D. Magnesium sulphate versus diazepam for eclampsia. Cochrane Database Syst Rev 2010; (12): CD000127.
Duley L, Matar HE, Almerie MQ, Hall DR. Alternative magnesium sulphate regimens for women with pre-eclampsia and eclampsia. Cochrane Database Syst Rev 2010; (8): CD007388.