Management of Eclampsia

As reviewed by Chesley (1978), it has been long recognized in American obstetrics that magnesium sulfate is highly effective in preventing convulsions in women with preeclampsia and in stopping them in those with eclampsia. He cited observational data by Pritchard and colleagues (1955, 1975) from Parkland Hospital and from his own institution, Kings County Hospital in Brooklyn. At that time, most eclampsia regimens used in the United States adhered to a similar philosophy still in use today, and the tenets of which include the following: 1. Control of convulsions using an intravenously administered loading dose of magnesium sulfate. This is followed by a continuous infusion of magnesium sulfate 2. Intermittent administration of an antihypertensive medication to lower blood pressure whenever it is considered dangerously high 3. Avoidance of diuretics unless there is obvious pulmonary edema, limitation of intravenous fluid administration unless fluid loss is excessive, and avoidance of hyperosmotic agents 4. Delivery of the fetus to achieve a cure.

Magnesium Sulfate to Control Convulsions

In more severe cases of preeclampsia, as well as in eclampsia, magnesium sulfate administered parenterally is an effective anticonvulsant that avoids producing central nervous system depression in either the mother or the infant. It may be given intravenously by continuous infusion or intramuscularly by intermittent injection (Table 34-13). The dosages for severe preeclampsia are the same as for eclampsia. Because labor and delivery is a more likely time for convulsions to develop, women with preeclampsia-eclampsia usually are given magnesium sulfate during labor and for 24 hours postpartum. Magnesium sulfate is almost universally administered intravenously, and in most units, the intramuscular route has been abandoned. Of concern, magnesium sulfate solutions, although inexpensive to prepare, are not readily available in all parts of the developing world. And even when the solutions are available, the technology to infuse them may not be. Therefore, it should not be forgotten that the drug can be administered intramuscularly and that this route is as effective as intravenous administration. In a recent report from India, Chowdhury and colleagues (2009) showed that the two regimens were equivalent in preventing recurrent convulsions and maternal deaths in 630 women with eclampsia. Magnesium sulfate is not given to treat hypertension. Based on a number of studies cited subsequently, as well as extensive clinical observations, magnesium most likely exerts a specific anticonvulsant action on the cerebral cortex. Typically, the mother stops convulsing after the initial 4-g loading dose. By an hour or two, she regains consciousness sufficiently to be oriented to place and time. The magnesium sulfate dosages presented in Table 34-13 usually result in plasma magnesium levels illustrated in Figure 34-20. When magnesium sulfate is given to arrest eclamptic

seizures, 10 to 15 percent of women have a subsequent convulsion. If so, an additional 2-g dose of magnesium sulfate in a 20percent solution is slowly administered intravenously. In a small woman, this additional 2-g dose may be used once, but it can be given twice if needed in a larger woman. In only five of 245 women with eclampsia at Parkland Hospital was it necessary to use supplementary medication to control convulsions (Pritchard and associates, 1984). An intravenous barbiturate such as amobarbital or thiopental is given slowly. Midazolam or lorazepam may be given in a small single dose because prolonged use is associated with a higher mortality rate (Royal College of Obstetricians and Gynaecologists, 2006). Maintenance magnesium sulfate therapy is continued for 24 hours after delivery. For eclampsia that develops postpartum, magnesium sulfate is administered for 24 hours after the onset of convulsions. Ehrenberg and Mercer (2006) studied abbreviated postpartum magnesium administration in 200 women with mild preeclampsia. Of 101 women randomized to 12-hour treatment, seven had worsening preeclampsia, and treatment was extended to 24 hours. None of these 101 women and none of the other cohort of 95 given the 24-hour magnesium infusion developed eclampsia. This abbreviated regimen needs further study before being routinely administered for severe preeclampsia or eclampsia. Pharmacology and Toxicology. Magnesium sulfate USP is MgSO47H2O and not simple MgSO4. Parenterally administered magnesium is cleared almost totally by renal excretion, and magnesium intoxication is unusual when the glomerular filtration rate is maintained or only slightly decreased. Adequate urine output usually correlates with preserved glomerular filtration rates. That said, magnesium excretion is not urine flow dependent, and urinary volume per unit time does not, per se, predict renal function. Thus, serum creatinine levels must be measured to detect signs of declining glomerular filtration rate. Eclamptic convulsions are almost always prevented or arrested by plasma magnesium levels maintained at 4 to 7 meq/L, 4.8 to 8.4 mg/dL, or 2.0 to 3.5 mmol/L. Although laboratories typically report total magnesium levels, free or ionized magnesium is the active moiety for suppressing neuronal excitability. Taber and associates (2002) found that there is a poor correlation between total and ionized levels. Further studies are necessary necessary to determine if either measurement provides a superior method for surveillance. As shown in Figure 34-20, after a 4-g intravenous loading dose, magnesium levels observed with the intramuscular regimen and those observed with the maintenance infusion of 2 g per hour are similar. In our experience with the infusion, a number of women require 3 g/hr to maintain effective plasma levels of magnesium. That said, most do not recommend routine magnesium level measurements (American College of Obstetricians and Gynecologists, 2002a; Royal College of Obstetricians and Gynaecologists, 2006). Patellar reflexes disappear when the plasma magnesium level reaches 10 meq/Labout 12 mg/dLpresumably because of a curariform action. This sign serves to warn of impending magnesium toxicity. When plasma levels rise above 10 meq/L,

breathing becomes weakened, and at 12 meq/L or more, respiratory paralysis and respiratory arrest follow. Somjen and colleagues (1966) induced marked hypermagnesemia in themselves by intravenous infusion and achieved plasma levels up to 15 meq/L. Predictably, at such high plasma levels, respiratory depression developed that necessitated mechanical ventilation, but depression of the sensorium was not dramatic as long as hypoxia was prevented.

Corticosteroids
The National Institutes of Health Consensus Development Conference (2000) recommended a single course of antenatal corticosteroids for women with preterm membrane rupture before 32 weeks and in whom there was no evidence of chorioamnionitis. Since then, a number of meta-analyses have addressed this issue, and according to the American College of Obstetricians and Gynecologists (2007), single-dose therapy is recommended from 24 to 32 weeks. There is no consensus regarding treatment between 32 and 34 weeks. They are not recommended prior to 24 weeks. Corticosteroid Therapy to Enhance Fetal

Lung Maturation
Glucosteroids will accelerate lung maturation in preterm sheep fetuses, and thus Liggins and Howie (1972) evaluated them to treat women. Corticosteroid therapy was effective in lowering the incidence of respiratory distress and neonatal mortality rates if birth was delayed for at least 24 hours after initiation of betamethasone. Remarkably, infants exposed to corticosteroids in these early studies have been now followed to age 31 years with no ill effects detected. The work by Liggins and Howie (1972) has stimulated more than 35 years of fetal lung research. In

1995, a National Institutes of Health Consensus Development Panel recommended corticosteroids for fetal lung maturation in threatened preterm birth. In a follow-up meeting, the National Institutes of Health Consensus Development Conference (2000) concluded that data were insufficient to assess the effectiveness of corticosteroids in pregnancies complicated by hypertension, diabetes, multifetal gestation, fetal-growth restriction, and fetal hydrops. It concluded, however, that it was reasonable to administer corticosteroids for these complications. Roberts and Dalziel (2006) reviewed antenatal corticosteroids for accelerating fetal lung maturation. The issue of the fetal and infant safety with single versus repeat courses of corticosteroids for lung maturation has been the topic of two major trials. Although both found repeated courses to be beneficial in reducing neonatal respiratory morbidity rates, the long-term consequences were much different. Specifically, Crowther and colleagues (2007) studied outcomes in 982 women from the Australian Collaborative Study. These women were given a single weekly dose of 11.4 mg of betamethasone. These investigators found no adverse effects in the infants followed to age 2 years. Wapner and colleagues (2007) studied infants born to 495 women in a Network study who were randomized to receive two weekly 12mg betamethasone doses given 24 hours apart. They were concerned by their finding of a nonsignificant increase in cerebral palsy rates in infants exposed to repeated courses. The twice-as-large betamethasone dose in the Network study was worrisome because there is some experimental evidence to support the view that adverse corticosteroid effects are dose dependent. Bruschettini and colleagues (2006) studied the equivalent of 12-mg versus 6-mg betamethasone given to pregnant cats. They reported that the lower dose had less severe effects on somatic growth without affecting cell proliferation in the fetal brain. Stiles (2007) summarized the Australian and American studies as early gain, long-term questions. We agree, and at Parkland Hospital, we follow the recommendation for single-course therapy by the American College of Obstetricians and Gynecologists (2008a).

Rescue Therapy

This refers to administration of a repeated corticosteroid dose when delivery becomes imminent and more than 7 days have elapsed since the initial dose. The 2000 Consensus Development Conference recommended that rescue therapy should not be routinely used and that it should be reserved for clinical trials. The first randomized trial reported by Peltoniemi and colleagues (2007) allocated 326 women to placebo or 12-mg betamethasone single-dose rescue regimens. Paradoxically, they found that the rescue dose of betamethasone increased the risk of respiratory distress syndrome! Subsequently, the American College of Obstetricians and Gynecologists (2008a) also recommended such therapy for trials. Most recently, in a multicenter study of 437 women _ 33 weeks who were randomized to rescue therapy or placebo, Kurtzman and associates (2009) reported

significantly decreased rates of respiratory complications and neonatal composite morbidity with rescue corticosteroids. There were, however, no differences in perinatal mortality rates and other morbidities. In another trial, McEvoy and co-workers (2009) showed that treated infants had improved respiratory compliance.

Which Corticosteroid?

As summarized by Murphy (2007), there is a 10-year question as to whether betamethasone is superior to dexamethasone for fetal lung maturation. Elimian and co-workers (2007) randomized 299 women between 24 and 33 weeks in a double-blinded trial of betamethasone versus dexamethasone. These two drugs were comparable in reducing the rates of major neonatal morbidities in preterm infants.