Choice of Anticonvulsant for Prevention and Management of Eclamptic Seizures

FFemi Oladapoemi Oladapo

Maternal and Fetal Health Research Unit,Maternal and Fetal Health Research Unit,Department of Obstetrics & Gynaecology,Department of Obstetrics & Gynaecology,

Olabisi Onabanjo University, Olabisi Onabanjo University, Sagamu, NigeriaSagamu, Nigeria

On behalf of the Guideline Development Group for theOn behalf of the Guideline Development Group for theWHO Recommendations on Preeclampsia and EclampsiaWHO Recommendations on Preeclampsia and Eclampsia

Outline

• Background

• Anticonvulsants for PE/E

• WHO guideline development process

• Evidence summary on clinical effectiveness

• Interpretation of evidence

• Implications for clinical practice

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

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

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

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.

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)

WHO Guideline Development Process

Critical outcomes for WHO recommendations on PE/E

Outcomes ProxyEclampsia PE (if it is an intervention for

preventing PE); Severe hypertension; Severe PE/HELLP

Recurrence of convulsions --

Severe maternal morbidity Organ failure

Maternal death --

Perinatal death Stillbirth, neonatal death, any baby death

Admission to neonatal intensive care unit

--

Apgar scores at 5’ < 7 --

Adverse events of intervention Toxicity (as defined); Calcium gluconate administration for MgSO4

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.

Magnesium sulfate and other anticonvulsants for prevention of eclampsiaEvidence Source

Eclampsia Any serious maternal morbidity

Respiratory arrest

Maternal death

Any reported side effects

Toxicity (resp. depr. + absent tendon reflexes

Calcium gluconate given

5’ Apgar score < 7

Admission to NICU

Stillbirth or neonatal death

Magnesium sulfate versus placebo or no anticonvulsants

6 RCTs, 11,444 women

6 RCTs, n=11,444; RR 0.41, (0.29- 0.58)

2 RCTs, n=10,332; RR 1.08, (0.89-1.32)

1 RCT, n= 10,110; RR 2.50, (0.49-12.88)

2 RCTs, n=10,795; RR 0.54, (0.26-1.10)

1 RCT, n= 9992; RR 5.26, (4.59-6.03)

3 RCT, n=10,899; RR 5.96 (0.72-49.40)

2 RCTs, n=10,795; RR 1.35, (0.63-2.88)

1 RCT, n=8260;RR 1.02, (0.85-1.22).

1 RCT, n=8260; RR 1.01, (0.96-1.06)

3 RCTs, n=9961; RR 1.04, (0.93-1.15)

Evidence Quality

HIGH HIGH HIGH HIGH HIGH MODERATE HIGH HIGH HIGH HIGH

Magnesium sulfate versus phenytoin

4 RCTs, 2343 women

3 RCTs, n=2291; RR 0.08, (0.01-0.60)

-- -- -- -- -- -- 1 RCT, n=2141; RR 0.58,

(0.26-1.30)

1 RCT, n=2141; RR 1.00,

(0.63-1.59)

1 RCT, n=2165; SB:

RR 0.62, (0.27-1.41)/

ND: RR 0.26, (0.03-2.31)

Evidence Quality

MODERATE MODERATE MODERATE MODERATE

Magnesium sulfate versus diazepam

2 RCTs, 66 women

2 RCTs, n=66; RR 3.00, (0.13-69.31)

-- -- -- -- -- --

Evidence Quality

VERY LOW

Magnesium sulfate versus nimodipine

1 RCT, 1650 women

1 RCT, n=1650;RR 0.33, (0.14-0.77)

-- -- -- -- -- --

Evidence Quality

LOW

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)

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

Evidence Source

Recurrence of convulsions

Maternal death

Any serious morbidity

ICU admission

Renal failure Pulm. oedema

Resp. depr. Mech. ventilation

CVA Cardiac arrest

Coma >24 hours

Magnesium sulfate versus diazepamCochrane review 7 RCTs, 1396 women

7 RCTs, n=1390; RR 0.43, (0.33-0.55)

6 RCTs, n=1336; RR 0.59, (0.38-0.92)

2 RCTs, n=956; RR 0.88, (0.64-1.19)

3 RCTs, n=1034;RR 0.80 (0.59, 1.07)

5 RCTs, n=1164; RR 0.85 (0.53-1.36)

3 RCTs, n=1013; RR 0.86 (0.35 to 2.07)

3 RCTs, n=1025; RR 0.86 (0.57 to 1.30)

3 RCTs, n=1025;RR 0.73, (0.45 to 1.18)

4 RCTs, n=1225; RR 0.62, (0.32-1.18)

4 RCTs, n=1085; RR 0.80 (0.41 -1.54)

--

Evidence Quality

HIGH MODERATE MODERATE MODERATEMODERATE MODERATE MODERATE MODERATEMODERATE MODERATE

Magnesium sulfate versus phenytoin

Cochrane review 6 RCTs, 972 women

6 RCTs, n=972; RR 0.34 (0.24-0.49)

3 RCTs, n=847;RR 0.50 (0.24-1.05)

1 RCT, n=775; RR 0.94 (0.73-1.20)

1 RCT, n=775; RR 0.67 (0.50-0.89)

3 RCTs, n=902;RR 1.52 (0.98-2.36)

3 RCTs, n=902; RR 0.92 (0.45-1.89)

1 RCT, n= 775;RR 0.71 (0.46-1.09)

2 RCTs, n=825; RR 0.68 (0.50-0.91)

1 RCT, n=775;RR 0.54, (0.20-1.46).

1 RCT, n=775; RR 1.16, (0.39-3.43)

--

Evidence Quality

HIGH MODERATE MODERATE HIGH MODERATE MODERATE MODERATE MODERATE

Magnesium sulfate versus lytic cocktail

Cochrane review 3 RCTs, 397 women

3 RCTs, n=397; RR 0.06 (0.03-0.12)

3 RCTs, n=397; RR 0.14 (0.03-0.59)

-- -- 2 RCTs, n=307; RR 0.64 (0.22-1.85)

-- 2 RCTs, n=198; RR 0.12 (0.02-0.91)

1 RCT, n=90; RR 0.20 (0.01-4.05)

1 trial, n=108;RR 0.22 (0.01-4.54).

2 RCTs, n=307; RR 0.26 (0.03-2.34)

1 RCT, n=108; RR 0.04 (0.00-0.74)

Evidence Quality

MODERATE MODERATE LOW MODERATE

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

Evidence Source Stillbirth Neonatal death Perinatal death Admission to Special care Nursery

5 ‘ Apgar score < 7

Magnesium sulfate versus diazepam

Cochrane review 7 RCTs, 1396 women

5 RCTs, n=799; RR 0.97 (0.70-1.34)

4 RCTs, n=759; RR 1.18 (0.75-1.84)

4 RCTs, n=788 ;RR 1.04 (0.81-1.34)

3 RCTs, n=634;RR 0.92 (0.79-1.06)

3 RCTs, n=643; RR 0.70 (0.54-0.90)

Evidence Quality MODERATE HIGH HIGH

Magnesium sulfate versus phenytoin

Cochrane review 6 RCTs, 972 women

2 RCTs, n=665;RR 0.83 (0.61-1.13)

2 RCTs, n=665;RR 0.95 (0.59-1.53)

2 RCTs, n=665; RR 0.85 (0.67-1.09)

1 RCT, n=518; RR 0.73 (0.58-0.91)

1 RCT, n=518; RR 0.86 (0.52-1.43)

Evidence Quality MODERATE MODERATE MODERATE HIGH MODERATE

Magnesium sulfate versus lytic cocktail

Cochrane review 3 RCTs, 397 women

2 RCTs, n=177; RR 0.33 (0.01-7.16)

2 RCTs, n=177; RR 0.37 (0.14-1.00).

Any baby death: 2 RCTs, n=177; RR 0.35 (0.05-2.38)

-- --

Evidence Quality VERY LOW VERY LOW VERY LOW

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

Alternative magnesium sulfate regimens for treatment of PE and EEvidence Source

Eclampsia Maternal death

Recurrence of convulsions

Any serious morbidity

Renal failure

Resp arrest

Toxicity (Resp depr.

Calcium gluconate given

Any side effects

Stillbirth or neonatal death

Admission to SCBU

5’ Apgar score < 5

Loading dose alone versus loading dose plus maintenance regimen for women with eclampsia1 RCT, 401 women

N/A 1 RCT, n=401; RR 0.89 (0.37-2.14)

1 RCT, n=401; RR 1.13 (0.42-3.05)

-- -- -- -- -- -- Stillbirth: 1 RCT n=401; RR 1.13 (0.66-1.92)

-- --

Quality VERY LOW VERY LOW VERY LOW

Lower dose regimens versus standard dose regimens over 24 hours for women with eclampsia

1 RCT, 50 women

N/A -- 1 RCT, n=50RR 3.00, (0.13-70.30).

-- Oliguria: 1 RCT, n=50, RR 0.20 (0.03-1.59)

-- Absent tendon reflexes: 1 RCT, n=50;RR 0.25 0.06-1.06

-- -- -- -- --

Quality VERY LOW VERY LOW

VERY LOW

Intravenous versus standard intramuscular maintenance regimen for 24 hours for women with pre-eclampsia1 RCT, 17 women

1 RCT, n=17; RR Not estimable

-- -- -- 1 RCT, n=17; RR 3.33 (0.15-71.90)

-- 1 RCT, n=17; RR 3.33 (0.15-71.90)

-- -- 1 RCT, n=17; RR 1.25 (0.09-17.02)

-- --

Quality VERY LOW VERY LOW

VERY LOW

VERY LOW

Short versus standard (24 hours) duration of postpartum maintenance regimen for women with pre-eclampsia3 RCTs, 398 women

3 RCTs, n=394; RR Not estimable

-- -- -- -- -- 1 RCT, n=196; RR Not estimable

-- -- -- -- --

Quality LOW LOW

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

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

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