Prevent Recurrent Eclamptic Seizures With Magnesium Sulfate, an Unconventional Anticonvulsant

[Drug & Ther Perspect 16(1):6-8, 2000. © 2000 Adis International Limited]

Introduction

Eclampsia is among the leading causes of maternal mortality worldwide. The cornerstone of therapy for this multisystem disorder is delivery of the baby, but the prevention of recurrent seizures is also an essential component of management. Magnesium sulfate, while not conventionally regarded as an anticonvulsant agent, is the drug of choice for preventing recurrent seizures in women with eclampsia. It is more effective than either diazepam or phenytoin for this indication. The main concern associated with the use of magnesium sulfate is that of overdose which may lead to cardiopulmonary arrest. Close monitoring for signs of hypermagnesaemia (e.g. reduced respiratory rate and loss of knee-jerk reflex) is important.

Eclampsia is a Life-Threatening Condition...

Eclampsia is the occurrence of a seizure in association with pre-eclampsia (characterised by hypertension and proteinuria).[1] Eclampsia complicates approximately 1 in 2000 pregnancies in developed countries and, although uncommon, is one of the leading causes of maternal mortality in both industrialised and developing countries.[1]

The condition is characterised by the occurrence of 1 or more seizures during pregnancy, delivery or up to 10 days postpartum. By definition, 2 or more of the following features must also be present within 24 hours of the seizure:[2]

...But is Hard to Predict

Unfortunately, it is extremely difficult to predict which women with pre-eclampsia will develop eclamptic seizures.[1,3] Consequently, it is almost impossible to devise strategies for seizure prophylaxis in pre-eclamptic women,[3] and the routine use of anticonvulsant prophylaxis in all women with pre-eclampsia is controversial.[1] In women with eclampsia, delivery of the infant is the only way to restore health. However, supportive management, including anticonvulsant therapy,[3] is also required.

Prevent Recurrent Seizures With MgSO4

The aim of anticonvulsant therapy is to stop any convulsion that is present and to prevent recurrent seizures (see Patient care guidelines). If the patient is experiencing a seizure, intravenous diazepam can be used to stop the convulsion.[1] Magnesium sulfate is generally accepted as the treatment of choice for preventing recurrent eclamptic seizures,[1,3] following the results of the landmark Collaborative Eclampsia Trial.[6] Magnesium sulfate significantly reduced the number of subsequent seizures compared with either diazepam or phenytoin in this large randomised trial of 1680 women with eclamptic seizures. There were also fewer deaths among women randomised to receive magnesium sulfate, although the difference between treatment groups was not statistically significant.[6] These results were confirmed by 2 meta-analyses by the Cochrane Collaboration.[7,8] Although not widely used in the UK and Europe prior to the Collaborative Eclampsia Trial, magnesium sulfate has been used in eclampsia, at least in the US, for several decades.[3]

fig1

But Not for Everyone

Magnesium sulfate should be used with caution in women with impaired renal function because of the risk of magnesium intoxication.[4] Parenteral administration is contraindicated in patients with a heart block or myocardial damage including a history of cardiac ischaemia.[4,5]

How Does it Work?

Magnesium sulfate is not a conventional anticonvulsant agent and its mechanism of action in eclampsia is not well understood. Eclampsia is thought to occur secondary to ischaemia caused by cerebral vasospasm.[3] Magnesium sulfate is a potent vasodilator, particularly in the cerebral vasculature.[5] In women with pre-eclampsia, magnesium sulfate has been shown to improve cerebral arterial circulation, and preclinical evidence suggests possible neuroprotective effects.[3,5]

Cardiopulmonary Arrest is a Risk in Overdose

The greatest concern with the use of magnesium sulfate is that of overdose which may lead to cardiopulmonary arrest and death. The overall tolerability profile of magnesium sulfate is well established and maternal adverse effects include flushing, increased warmth, headaches, blurred vision, nausea, nystagmus, lethargy, hypothermia, urinary retention and faecal impaction.[5] In general, these adverse events most commonly develop at serum magnesium levels of 3.8 to 5.0 mmol/L,[5] whereas the therapeutic range is approximately 2.0 to 4.0 mmol/L.[3,5] Respiratory paralysis can occur at serum levels of 5 to 6.5 mmol/L,[5] cardiac conduction is affected at serum levels >7.5 mmol/L, and cardiac arrest is associated with serum levels >12.5 mmol/L.[5] The majority of toxicities occur when there is deviation from established protocols.

Magnesium sulfate readily crosses the placenta, and neonatal hypermagnesaemia can occur.[3,5] Respiratory depression and hyporeflexia have been reported in a small group of newborn infants of mothers treated with magnesium sulfate, but such effects appear to be uncommon.[5]

And Careful Monitoring is Required

Close monitoring for clinical signs of hypermagnesaemia, such as reduced respiratory rate, reduced urinary output and depression of tendon reflexes, is essential.[1,3,5] Monitoring of serum magnesium levels is also recommended,[3,5] particularly in women with renal disease or low urine output, since magnesium sulfate is excreted by the kidneys.[1] The first clinical warning of impending toxicity in the mother is usually loss of the patellar reflex, typically at serum magnesium levels between 3.5 and 5 mmol/L.[5]

Be on the Lookout for Drug Interactions

Magnesium sulfate can interact with various other drugs. For example, it can potentiate the activity of both depolarising and nondepolarising neuromuscular blocking agents.[5] These and other drug interactions are summarised in table 1.

Choose Between Dosage Regimens

There is no consensus on the optimal dosage and concentration of magnesium sulfate for the management of eclamptic seizures.[5] The most commonly used regimens are the so-called Pritchard's and Zuspan's regimens (see table 2).[3,5] Both of these regimens are effective and were used in the Collaborative Eclampsia Trial, the choice being at the discretion of doctors and midwives participating in the study.[6] Intramuscular administration of magnesium sulfate, which is used in the Pritchard's regimen, can be very painful and this should be taken into consideration when a specific regimen is selected. Dosage is adjusted according to patient response, clinical signs of toxicity and serum magnesium levels (aim to achieve levels of approximately 2 to 4 mmol/L). Various modifications of these regimens are also used.[4]

Table 1. Drug interactions with magnesium sulfate[4,5]

AgentEffectRecommendation
Depolarising/nondepolarising neuromuscular blockersActivity of these agentsMay require dosage reduction of neuromuscular blocking agents; administer with caution
CNS depressants (e.g. opioids, barbiturates, general anaesthetics)Additive CNS depressionMay require dosage reduction of CNS depressants
NifedipineHypotensionaAdminister with caution and adjust nifedipine dosage if necessary

aRisk appears to be low.

Table 2. Pritchard's and Zuspan's regimens for magnesium sulfate administration in eclampsia[1,3-5]

Pritchard's regimen
Loading dose: 4g IV (administered over 5 to 10min; concentration not to exceed 20%a ) plus 10g IM (using undiluted 50% solution)Maintenance dose: 5g IM q4h x >/=24h after the last seizure (using undiluted 50% solution administered in alternate buttocks)
Zuspan's regimen
Loading dose 4g IV (administered over 5 to 10min; concentration not to exceed 20%a)Maintenance dose: 1 to 2 g/h by controlled infusion pump x >/=24h after the last seizure (concentration not to exceed 20%a )

aLower concentrations, e.g. 10%, are preferred.
Abbreviations: h = hour(s); IM = intramuscularly; IV = intravenously; min = minutes; q4h = every 4 hours.

References

  1. Salha O, Walker JJ. Modern management of eclampsia. Postgrad Med J 1999; 75: 78-82
  2. Munro PT. Management of eclampsia in the accident and emergency department. J Accid Emerg Med 2000 Jan; 17 (1): 7-11
  3. Gaffney G. Eclamptic seizures: treatment guidelines. CNS Drugs 1999 Aug; 12 (2): 111-117
  4. AHFS Drug Information. Bethesda: American Society of Health-System Pharmacists, Inc., 1999: 1882-5
  5. Lu JF, Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia. Clin Pharmacokinet 2000 Apr; 38 (4): 305-14
  6. Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995; 345: 1455-63
  7. Duley L, Henderson-Smart D. Magnesium sulphate versus diazepam for eclampsia. Cochrane Database Syst Rev 2000; 2: CD000127
  8. Duley L, Henderson-Smart D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Syst Rev 2000; 2: CD000128


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