Souza_Choice of Anticonvulsants in Management of PEE

8/2/2019 Souza_Choice of Anticonvulsants in Management of PEE

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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


2/20

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


3/20

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


4/20

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


5/20

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.


6/20

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)


7/20

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


8/20

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


9/20

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.


10/20

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


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


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


11/20

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)


12/20

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


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



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


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


13/20

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


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


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


14/20

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


15/20

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


16/20

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


17/20

http://www.who.int/publications/guidelines/en/
http://www.who.int/publications/guidelines/en/http://www.who.int/publications/guidelines/en/


18/20

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)


19/20

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/

Souza_Choice of Anticonvulsants in Management of PEE

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