Choice of Anticonvulsant for Prevention and Management of Eclamptic Seizures

1. Choice of Anticonvulsant for Prevention and Management of Eclamptic Seizures Femi OladapoMaternal and Fetal Health Research Unit,Department of Obstetrics & Gynaecology,OlabisiOnabanjo University, Sagamu, Nigeria On behalf of the Guideline Development Group for the WHO Recommendations on Preeclampsia and Eclampsia

2. Outline • Background • Anticonvulsants for PE/E • WHO guideline development process • Evidence summary on clinical effectiveness • Interpretation of evidence • Implications for clinical practice

3. Background • PE/E accounts for significant maternal and perinatal morbidity and mortality particularly in the developing countries • Stopping the progression of PE to E is key to improving outcome • Making the right choice of anticonvulsant is important for optimal care • Substandard care in management persists despite overwhelming evidence on effective interventions • Uncertain pathophysiology and associated multisystemic complications raise safety concerns regarding drug treatment

4. Anticonvulsants for PE/E: magnesium sulfate • First introduced for eclampsia in the 1920s • Not a traditional anticonvulsant • Mechanism of action is poorly understood • Dosage regimens have evolved over the years • Side effects: • Common: flushing • Less common: nausea, vomiting, muscle weakness, thirst, headache, drowsiness and confusion • Rare: respiratory depression, respiratory and cardiac arrest

5. Anticonvulsants for PE/E: diazepam • A benzodiazepine • First suggested for eclampsia in the 1960s • A traditional anticonvulsant also used for a wide range of conditions • Core medicine in the World Health Organization's 'Essential Drugs List‘ • Common side effects: drowsiness, confusion and amnesia

6. Anticonvulsants for PE/E: phenytoin • Suggested for eclampsia in the 1980s • Widely used for acute and long-term control of seizures • Acts as anticonvulsant without causing sedation • Prevents onset of but not useful for aborting seizures • Side effects: hypotension, cardiac arrhythmias, nystagmus and ataxia.

7. Anticonvulsants for PE/E: lytic cocktail • Usually a combination of chlorpromazine (antipsychotic) promethazine (H1 histamine antagonist) and pethidine (opioid analgesic) • First introduced and used to be standard treatment in India • Individual component has sedative effects on the CNS • No longer in widespread use • Side effects: • cardiac arrhythmias (chlorpromazine) • hallucinations, incoordination (promethazine), • seizures (chlorpromazine, promethazine and pethidine)

8. WHO Guideline Development Process • Cochrane systematic reviews • Other studies (RCTs, observational) • New systematic reviews? • Updating of existing reviews? • Online technical consultation on recomm. • Virtual global consultation • Agreement on recommendations • Implementation plan & update

9. Critical outcomes for WHO recommendations on PE/E

10. Evidence summaries: prevention of eclampsia • A Cochrane review of 15 RCTs investigated the relative effects of anticonvulsants for prevention of eclampsia (Duley et al, 2010) • Magnesium sulfate versus placebo or no anticonvulsants • Magnesium sulfate versus phenytoin • Magnesium sulfate versus diazepam • Magnesium sulfate versus nimodipine • Magnesium sulfate versus isosorbide • Magnesium chloride with methyldopa.

11. Magnesium sulfate and other anticonvulsants for prevention of eclampsia

12. Evidence summaries: treatment of eclampsia • Three Cochrane reviews separately investigated the effects of magnesium sulfate compared to: • Diazepam (Duley et al, 2000) • Phenytoin (Duley et al, 2010a) • Lytic cocktail (Duley et al, 2010b)

13. Magnesium sulfate and other anticonvulsants for treatment of eclampsia- maternal outcomes

14. Magnesium sulfate and other anticonvulsants for treatment of eclampsia- fetal outcomes

15. Alternative magnesium sulfate regimens for treatment of pre-eclampsia and eclampsia • Evidence derived from a Cochrane review of 6 RCTs involving 866 women (Duley et al, 2010c) • 2 RCTs (451 women) compared regimens for eclampsia • 4 RCTs (415 women) compared regimens for PE

16. Alternative magnesium sulfate regimens for treatment of PE and E

17. Evidence Interpretation • Evidence supports the use of magnesium sulfate in severe PE to prevent progression to eclampsia • Clear evidence that magnesium sulfate treatment in eclampsia reduces the incidence of further fits • Clear evidence that magnesium sulfate is more effective than diazepam, phenytoin and lytic cocktail in preventing further eclamptic fit • No clear evidence on which MgSO4 dosage regimen is better than the other • Most trials providing the evidence used clinical monitoring in women undergoing treatment and none used serum monitoring

18. Implications for clinical practice • Development of WHO Recommendations on PE & E is currently underway • Magnesium sulfate is the drug of choice for preventing and treating convulsions in severe PE & E (WHO 2003. Managing Complications in Pregnancy and Childbirth) • Magnesium sulfate schedules for severe PE and eclampsia (WHO MCPC): Loading dose • 4 g of 20% magnesium sulfate solution IV over 5 min • Plus10 g of 50% magnesium sulfate solution IM (5 g in each buttock) Maintenance dose • 5 g of 50% magnesium sulfate solution IM into alternate buttock every four hours • If 50% solution is not available, give 1 g of 20% magnesium sulfate solution IV every hour by continuous infusion • For recurrent convulsions: 2 g of 50% magnesium sulfate IV over 5 min

19. THANK YOU