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8/2/2019 Souza_Choice of Anticonvulsants in Management of PEE
1/20
Choice of Anticonvulsant for Prevention
and Management of Eclamptic Seizures
J.P. SouzaMedical Officer, Maternal and Perinatal Health UnitDepartment of Reproductive Health and Research
World Health Organization
Geneva, Switzerland
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Background
PE/E accounts for significant maternal and perinatalmorbidity and mortality particularly in the developingcountries
Stopping the progression of PE to E is key to improvingoutcome
Making the right choice of anticonvulsant is important foroptimal care
Substandard care in management persists despiteoverwhelming evidence on effective interventions
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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
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Anticonvulsants for PE/E: diazepam
A benzodiazepine
First suggested for eclampsia in the 1960s
A traditional anticonvulsant also used for a wide rangeof conditions
Common side effects: drowsiness, confusion andamnesia
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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.
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Anticonvulsants for PE/E: lytic cocktail
Usually a combination of chlorpromazine (antipsychotic)promethazine (H1 histamine antagonist) and pethidine (opioidanalgesic)
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)
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WHO Guideline Development Process
Prioritization survey
Requests from Member States Controversies around practices
Assessment of need for guideline
IBP-KG discussion Scoping for relevant PICOT questions &
critical outcomes
Stakeholders consultation to prioritizecritical issues
Secretariat to identify number and typeof systematic reviews and other studies
Establish clear timeline withindividual/groups to retrieve evidence
Evidence synthesis Reviews of effectiveness (GRADE appr.)
Quality of evid+ Strength of recommendatn
Public (electronic) consultations
Final recommendation expert panelmeeting
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
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Critical outcomes for WHO recommendationson PE/E
Outcomes Proxy
Eclampsia PE (if it is an intervention forpreventing PE); Severe hypertension;Severe PE/HELLP
Recurrence of convulsions --
Severe maternal morbidity Organ failureMaternal death --
Perinatal death Stillbirth, neonatal death, any babydeath
Admission to neonatal intensive care
unit
--
Apgar scores at 5 < 7 --
Adverse events of intervention Toxicity (as defined); Calciumgluconate administration for MgSO4
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Evidence summaries: prevention ofeclampsia
A Cochrane review of 15 RCTs investigated the relativeeffects 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.
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Magnesium sulfate and other anticonvulsants for prevention of eclampsia
EvidenceSource
Eclampsia Any seriousmaternalmorbidity
Respiratoryarrest
Maternaldeath
Anyreportedsideeffects
Toxicity (resp.depr. + absenttendonreflexes
Calciumgluconategiven
5 Apgar
score < 7Admissionto NICU
Stillbirth orneonataldeath
Magnesium sulfate versus placebo or no anticonvulsants
6 RCTs,11,444women
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)
EvidenceQuality
HIGH HIGH HIGH HIGH HIGH MODERATE HIGH HIGH HIGH HIGH
Magnesium sulfate versus phenytoin
4 RCTs,
2343women
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)
EvidenceQuality
MODERATE MODERATE MODERATE MODERATE
Magnesium sulfate versus diazepam
2 RCTs,66women
2 RCTs,n=66; RR3.00, (0.13-69.31)
-- -- -- -- -- --
EvidenceQuality
VERY LOW
Magnesium sulfate versus nimodipine
1 RCT,1650women
1 RCT,n=1650;RR 0.33,(0.14-0.77)
-- -- -- -- -- --
EvidenceQuality
LOW
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Evidence summaries: treatment of eclampsia
Three Cochrane reviews separately investigated theeffects of magnesium sulfate compared to:
Diazepam (Duley et al, 2000)
Phenytoin (Duley et al, 2010a)
Lytic cocktail (Duley et al, 2010b)
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Magnesium sulfate and other anticonvulsants for treatment of eclampsia
- maternal outcomesEvidenceSource
Recurrence
ofconvulsions
Maternaldeath
Anyseriousmorbidity
ICUadmission
Renal failure Pulm.oedema
Resp. depr. Mech.ventilation
CVA Cardiacarrest
Coma >24hours
Magnesium sulfate versus diazepam
Cochranereview7 RCTs,1396women
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 to2.07)
3 RCTs,n=1025;RR 0.86(0.57 to1.30)
3 RCTs,n=1025;RR 0.73,(0.45 to1.18)
4 RCTs,n=1225;RR 0.62,(0.32-1.18)
4 RCTs,n=1085;RR 0.80(0.41 -1.54)
--
EvidenceQuality
HIGH MODERATE MODERATE MODERATE MODERATE MODERATE MODERATE MODERATE
Magnesium sulfate versus phenytoin
Cochranereview6 RCTs,972women
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)
--
EvidenceQuality
HIGH MODERATE MODERATE HIGH MODERATE MODERATE MODERATE MODERATE
Magnesium sulfate versus lytic cocktail
Cochranereview3 RCTs,397women
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)
EvidenceQuality
MODERATE MODERATE LOW MODERATE
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Magnesium sulfate and other anticonvulsants for treatment of eclampsia
- fetal outcomes
Evidence Source Stillbirth Neonatal death Perinatal death Admission to Specialcare Nursery
5 Apgar score < 7
Magnesium sulfate versus diazepam
Cochrane review7 RCTs, 1396women
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 review6 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 review3 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
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Alternative magnesium sulfate regimens fortreatment of pre-eclampsia and eclampsia
Evidence derived from a Cochrane review of 6 RCTsinvolving 866 women (Duley et al, 2010c)
2 RCTs (451 women) compared regimens for eclampsia
4 RCTs (415 women) compared regimens for PE
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Alternative magnesium sulfate regimens for treatment of PE and E
EvidenceSource
Eclampsia Maternaldeath
Recurrence ofconvulsions
Anyseriousmorbidity
Renalfailure
Resparrest
Toxicity(Respdepr.
Calciumgluconategiven
Any sideeffects
Stillbirthorneonataldeath
Admission to SCBU
5 Apgar
score < 5
Loading dose alone versus loading dose plus maintenance regimen for women with eclampsia
1 RCT,401women
N/A 1 RCT,n=401; RR0.89(0.37-2.14)
1 RCT,n=401;RR 1.13(0.42-3.05)
-- -- -- -- -- -- Stillbirth:1 RCTn=401;RR 1.13(0.66-1.92)
-- --
Quality VERY LOW VERY LOW VERYLOW
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)
-- Absenttendonreflexes:
1 RCT,n=50;RR 0.250.06-1.06
-- -- -- -- --
Quality VERY LOW VERYLOW
VERY
LOW
Intravenous versus standard intramuscular maintenance regimen for 24 hours for women with pre-eclampsia
1 RCT,17 women
1 RCT,n=17; RRNot
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 VERYLOW
VERYLOW
VERYLOW
Short versus standard (24 hours) duration of postpartum maintenance regimen for women with pre-eclampsia
3 RCTs,398women
3 RCTs,n=394; RRNotestimable
-- -- -- -- -- 1 RCT,n=196;RR Notestimable
-- -- -- -- --
Quality LOW LOW
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Evidence Interpretation
Evidence supports the use of magnesium sulfate in severe PE toprevent progression to eclampsia
Clear evidence that magnesium sulfate treatment in eclampsiareduces the incidence of further fits
Clear evidence that magnesium sulfate is more effective thandiazepam, phenytoin and lytic cocktail in preventing furthereclamptic fit
No clear evidence on which MgSO4 dosage regimen is better thanthe other
Most trials providing the evidence used clinical monitoring inwomen undergoing treatment and none used serum monitoring
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http://www.who.int/publications/guidelines/en/
http://www.who.int/publications/guidelines/en/http://www.who.int/publications/guidelines/en/8/2/2019 Souza_Choice of Anticonvulsants in Management of PEE
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WHO Recommendations
Magnesium sulfate is recommended for the prevention of eclampsiain women with severe pre-eclampsia in preference to otheranticonvulsants. (High Quality Evidence, Strong Recommendation)
Magnesium sulfate is recommended for the treatment of womenwith eclampsia in preference to other anticonvulsants. (ModerateQuality Evidence, Strong Recommendation)
The full intravenous or intramuscular magnesium sulfate regimensare recommended for the prevention and treatment of eclampsia.(Moderate Quality Evidence, Strong Recommendation)
For settings where it is not possible to administer the fullmagnesium sulfate regimen, the use of magnesium sulfate loadingdose followed by immediate transfer to a higher level health-carefacility is recommended for women with severe pre-eclampsia andeclampsia. (Very low Quality Evidence, Weak Recommendation)
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Implications for clinical practice
Magnesium sulfate is the drug of choice for preventing and treatingconvulsions in severe PE & E (WHO 2003. Managing Complications inPregnancy 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 IVevery hour by continuous infusion
For recurrent convulsions: 2 g of 50% magnesium sulfate IV over 5 min
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http://www.who.int/publications/guidelines/en/
http://www.who.int/publications/guidelines/en/http://www.who.int/publications/guidelines/en/