The case for magnesium sulfate in preeclampsia-eclampsia

lnfernamnal 0

Journal of Obstetric Anesrhesia (1992) 1, 167-175

1992 Longman Group UK Ltd

International Journal of Obstetric Anesthesia

The case for magnesium sulfate in preeclampsia-eclampsia B. M. Sibai, J. Ramanathan Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology and Department qf Anesthesiology University of Tennessee, Memphis, USA

gation and speculation. Reported abnormalities include vasospasm, activation of the coagulation system, abnormal hemostasis, disturbed hemodynamics, altered thromboxane to prostacyclin ratio, endothelial cell injury, mitochondrial injury, and uteroplacental ischemia. Recent evidence suggests that endothelial cell injury plays a central role in the pathogenesis of preeclampsia.4*5 Indeed, endothelial cell injury results in altered balance between the release of potent vasodilating substances such as prostacyclin and endothelium derived relaxing factor (EDRF) and potent vasoconstricting substances such as endothelin. In addition, there are several studies that have reported an imbalance in the production of the two biologically active eicosanoids (prostacyclin and thromboxane) in preeclamptic pregnancies. Abnormal production of these eicosanoids has been found in maternal tissues, uteroplacental vasculature, and in placental tissues. ‘*’ The findings of these studies suggest that the balance between thromboxane and prostacyclin production is tipped heavily in favor of thromboxane, thus promoting a state of vasoconstriction and increased platelet aggregation. A combination of endothelial cell injury, vasoconstriction, and increased platelet aggregation may lead to pathophysiologic vascular lesions within multiple organ systems including the uteroplacental vascular beds, kidneys, liver, and brain. The vascular lesions may be localized or diffuse and these lesions can explain all the clinical signs and symptoms reported in preeclampsia-eclampsia. Women with preeclampsia-eclampsia exhibit an increased sensitivity to vasoactive substances such as angiotensin II and catecholamines.* Such women have generalized arteriolar vasospasm resulting in increased peripheral vascular resistance, reduced plasma volume, hemoconcentration, and increased blood viscosity. In addition, eclamptic women have low central venous pressure, and the pulmonary capillary wedge pressure is in the low part of normal range (O-7 mmHg).’

Preeclampsia-eclampsia is a syndrome of unknown etiology that is unique to human pregnancy. During the past century, numerous theories regarding its etiology have been suggested, but most have not withstood the test of time. Some of the theories that are still under consideration include abnormal placentation, cardiovascular maladaptation, immunologic intolerance between maternal and fetal tissues, genetic and dietary deficiencies. This syndrome complicates about 7% of all pregnancies; however, it remains a major cause of maternal and perinatal morbidity and mortality worldwide.’ In addition, the incidence of preeclampsia-eclampsia varies according to the population studied and the criteria used for establishing the diagnosis. The incidence is significantly increased in nulliparous women, in women with multiple gestation, and in those with previous preeclampsiaeclampsia and in women with underlying vascular or renal disease. Eclampsia is defined as the development of convulsions or coma during pregnancy or postpartum in patients with signs and symptoms of preeclampsia. In recent years the reported incidence of eclampsia ranged from 1 in 110 to 1 in 3448 pregnancies.2 The incidence reaches 3.6% in women with twin pregnancy.3 The extremely low incidence reported from some countries indicates that appropriate prenatal care, astute medical judgement, and early hospitalization of patients with preeclampsia will prevent most cases of eclampsia.2 PATHOPHYSIOLOGY The pathophysiologic abnormalities of preeclampsiaeclampsia have been the subject of extensive investiBalm M. Sibai MD, Jaya Ramanathn MD, Division of Maternal-

Fetal Medicine, Department of Obstetrics and Gynecology, and Department of Anesthesiology, University of Tennessee, Memphis, USA. Correspondence to Dr Baha M. Sibai, 853 Jefferson Suite E102. Memphis, Tennessee 38103, USA. 167

168 International Journal of Obstetric Anesthesia

Eclampsia may result in functional derangement of multiple organ systems. The diagnosis is not dependent on any specific laboratory data. Laboratory findings in eclampsia are similar to those seen in preeclampsia except that they are more frequently and more abnormal. Abnormal liver function tests are seen in about 25% of cases and significant abnormalities in renal function tests are seen in about 50%.’ Thrombocytopenia (platelet count <100x log/liter) is seen in about lo-15% of the cases, while the full spectrum of disseminated intravascular coagulopathy is present in 5% of the cases.’ In addition, the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) is seen in 10% of eclamptic women.2 The precise pathogenesis of eclamptic seizures remains an enigma. Reported mechanisms have included vasospasm, hypertensive encephalopathy, ischemia, cerebral edema, infarction, and hemorrhage. lo Overall, the results of autopsy findings, clinical studies, and neurodiagnostic findings in eclamptic women suggest that diffuse vasoconstriction and cerebral vasospasm play a central role in the etiology of eclamptic convulsions. ‘l-l4 Indeed, cerebral vasospasm with resultant ischemia can explain most of the clinical changes in preeclamptic women that serve as warning symptoms before the onset of convulsions. These symptoms include severe and persistent headaches, blurred vision and photophobia, blindness, irritability, and transient mental changes.

ROLE OF HYPERTENSION

IN ECLAMPSIA

The clinical features of eclampsia include hypertension, cerebral symptoms, nausea and vomiting, and convulsions. These features are also characteristic of hypertensive encephalopathy - an acute clinical condition which results from abrupt severe hypertension and subsequent severe increases in intracranial pressure. Eclampsia and hypertensive encephalopathy also exhibit similar findings in pathology material as well as on computed tomography and magnetic resonance imaging of the brain. lo Based on these findings, Donaldson suggested that the cerebral manifestations of eclampsia are due to hypertensive encephalopathy. In addition, he suggested that ‘effective antihypertensive therapy is the most effective anticonvulsant’.’ However, eclampsia can develop at blood pressure levels that are significantly lower than those seen in hypertensive encephalopathy.2 Sibai found that 23% of 254 eclamptic women had diastolic blood pressure values below 90 mmHg at time of convulsions.2 Further, Milliez et all6 compared computed tomographic findings of the brain in women with eclampsia (n =44), women with severe hypertension in pregnancy (n= 13), and normotensive pregnant control (n = 10). The mean systolic and diastolic blood press-

ures in the hypertensive group were similar to the respective values in the eclamptic group. However, none of the hypertensive women had evidence of hypertensive encephalopathy on CT scan, while 3 eclamptic women displayed signs of cerebral hemorrhage or thrombosis, and 6 women (14%) showed areas of focal hypodensity located in the cortical lobes and the subcortical white matter. Sibai et ali7 found that abnormal EEG findings in eclamptic women do not correlate with the degree of maternal blood pressure elevation. These findings do not support an association between hypertensive encephalopathy and eclampsia. Moreover, papilledema and retinal hemorrhages (common clinical findings in hypertensive encephalopathy) are rarely seen in eclamptic women.

PREVENTION AND CONTROL ECLAMPTIC CONVULSIONS

OF

Eclamptic convulsions can develop antepartum, intrapartum, or postpartum. About 50% of cases develop antepartum, 20% during labor, and the rest in the postpartum period.2 Thus, it is necessary that anticonvulsive prophylaxis be used intrapartum and postpartum in all women with diagnosed preeclampsia. Since about 7% of pregnant women might require such prophylaxis, it follows that the drug to be chosen should be both clinically efficacious and safe for the mother, fetus, and newborn. The properties of an ideal agent for this purpose are summarized in Table 1. The author will present evidence to indicate that parenteral magnesium sulfate is the ideal anticonv&ant in preeclampsia-eclampsia.

MAGNESIUM

SULFATE

Parenteral magnesium sulfate is commonly used to prevent and treat eclamptic convulsions in North America.‘* However, its use for this indication was criticized as being empiric, dogmatic, and without scientific validation.‘5*‘g*20 A detailed history of the use of magnesium sulfate in preeclampsia-eclampsia was extensively reviewed by Chesley.” In this review, the author notes that the drug was first used for this purpose in 1906 by Horn, who injected it intrathecTable 1. Properties of the ideal anticonvulsant l l l l l l l l

Rapidly effective Reliable and predictable duration of action Wide safety margin Non-depressive to both mother and baby Non-toxic to both mother and baby Ease of reversibility Familiarity with drug Management without serum levels

MgS04 in preeclampsia-eclampsia

ally. The first intravenous regimen was reported by Lazard in 1925** and an intramuscular regimen was then reported by Dorsett in 1926.23 Since then, various regimens and methods for giving the drug have been devised.24 Currently, the two most widely used regimens of magnesium sulfate administration are the intramuscular regimen popularized by Pritchard” and the continuous intravenous regimen recommended by Zuspan.*‘j Sibai et al27 compared serum levels of magnesium achieved with the above two regimens and suggested increasing the maintenance dose of the intravenous regimen to 2 g/h. More recently, Sibai suggested increasing the loading dose to 6 g to be followed by a maintenance dose of 2 g/h. This regimen has been used at the University of Tennessee, Memphis since 1985.*

PHARMACOLOGY

AND TOXICITY

Normal plasma magnesium levels in pregnancy range between 1.5 and 2.5 mg/dl (0.6-l mmol/liter). The recommended ‘therapeutic levels’ range between 4.3 and 8.4 mg/dl (1.8-3.5 mmol/liter). Maternal magnesium plasma levels following parenteral administration generally depend on volume of distribution and renal excretion of the magnesium ion. Volume of distribution is usually increased during pregnancy, especially in preeclamptic-eclamptic patients who retain more extracellular fluid. In addition, renal clearance may be decreased in women with severe preeclampsia-eclampsia. In the presence of severe oliguria or renal failure, plasma magnesium levels must be monitored closely to avoid toxicity. Administration of a loading dose of 4-6 g intravenously results in an immediate maternal plasma level of 5-9 mg/dl (2-3.7 mmol/liter). A subsequent maintenance dose either intramuscularly or by continuous infusion results in plasma magnesium levels of 4-8 mg/dl (l-6-3.3 mmol/liter).24,27 Loss of patellar reflexes, which usually occurs at levels of 9-12 mg/dl (3.75-5 mmol/liter) is the first sign of magnesium toxicity. Other early manifestations of magnesium toxicity include a feeling of warmth, flushing, double vision, nausea, somnolence, slurred speech, and muscular weakness. These symptoms usually develop at plasma levels of 9-12 mg/dl (3.75-5 mmol/liter) also. Hence, any protocol for giving magnesium sulfate should include monitoring for these symptoms, and discontinuation of the maintenance dose if any is present. Subsequent management will then depend on plasma magnesium level. Muscular paralysis and respiratory arrest usually develop at plasma levels of 15- 17 mg/dl (6-7 mmol/ liter). These findings indicate that with careful administration and monitoring, magnesium sulfate has a wide margin of safety. Additionally, during its administration the patient can be monitored clinically with-

169

out the need for plasma magnesium levels. Moreover, in the event of muscular paralysis or respiratory arrest, an antidote (1 g of calcium gluconate or chloride) is available to reverse this effect. In case of cardiorespiratory arrest, the patient should be intubated immediately and managed with assisted ventilation until resumption of spontaneous respirations.28

MECHANISM

OF ACTION

The mechanism of action of the magnesium ion in the control of eclamptic convulsions is still unresolved. Some authors believe its action is peripheral at the neuromuscular junction, with minimal to no central effects. Experimental studies in normal humans29 and some animals30-31 have failed to demonstrate a central nervous system depressant effect even though the serum magnesium was adequate to paralyze skeletal muscles. In addition, experimental studies in cats and subhuman primates revealed conflicting results. 32,33 Hibbard and Rosen34 suggested that the primary mode of action of parenteral magnesium sulfate is neuromuscular blockade at the periphery, and apparent central effects may be the result of hypoxia or altered cerebral perfusion. On the other hand, Pritchard3’ cites the remarkable clinical response to parenteral magnesium sulfate over a short period of time in all their severe preeclampticeclamptic patients as strong evidence for a central nervous system action. In addition, the therapeutic levels of magnesium reported in the literature as being sufficient to control or prevent eclamptic convulsions are below the levels needed to produce complete neuromuscular blockade (15- 17 mg/dl or 6-7 mmol/ liter).*’ It is interesting to note that Sibai et all7 found that abnormal EEG findings in patients with preeclampsia-eclampsia were not influenced by magnesium levels achieved in their clinical management. These findings were taken to suggest that magnesium does not have a central nervous system effect. However, abnormal EEG findings were present in 4 patients with eclampsia managed by Sibai despite therapeutic levels of both phenytoin and phenobarbital. Sibai also observed abnormal EEG findings in two additional eclamptic women after receiving therapeutic doses of diazepam. Moreover, abnormal EEG tracings may be present in patients with epilepsy, with adequate control of seizures with various anticonvulsant medications. Thus, the electroencephalogram might be an insensitive method of evaluating the clinical effects of anticonvulsant drugs. There are multiple other physiologic actions of magnesium sulfate that may have beneficial effects on numerous pathophysiologic abnormalities that are reported in preeclampsia-eclampsia. Magnesium has vasodilating effects in vascular beds including the cerebral vessels by competing with calcium at binding

170 International Journal of Obstetric Anesthesia

sites or by changing the flux of calcium across cell membranes.36 In addition, magnesium sulfate administration in preeclamptic women was found to attenuate the vascular response to pressor substances, and to decrease plasma renin activity as well as plasma angiotensin-converting enzyme levels.37p38 Further, magnesium was reported to increase prostacyclin release by endothelial cells, to reduce platelet aggregation, and to produce bronchodilation in asthmatic patients. 39*40 Moreover, magnesium sulfate was found effective in the treatment of selected cases of cerebral ischemia and seizures41 These findings suggest that magnesium may prevent eclamptic seizures by increasing cerebral blood flow and influencing neuronal cellular excitability through its ability to block cation channels involved in the N-methyl-Daspartate (NMDA) receptor systems.42

CLINICAL EFFICACY

The efficacy of magnesium sulfate can be measured by its prophylactic effects in women with preeclampsia as well as its effects in preventing the onset of further convulsions in women presenting with eclampsia. It is generally accepted that preeclamptic women are at increased risk for convulsions as compared to normotensive pregnant women. The risk for convulsions depends on the severity of the preeclamptic process. Women with gestational hypertension (absent proteinuria) are at lower risk than those with proteinuric hypertension, and the highest risk is usually in women with severe preeclampsia, particularly those remote from term.43 Unfortunately, the exact incidence of eclampsia in preeclamptic women not receiving magnesium sulfate is unknown. However, there are limited reports describing such an incidence; all but one were published almost 40 years ago (Table 2).44-46 It is apparent from this table that the incidence is extremely low in the well-managed preeclamptic patient.46 However, this latter study included all

Table 2. Incidence of eclampsia without using magnesium sulfate Authors

Preeclampsia n

Eastman and Steptoe” (1939-1943) White Black

1072

15

(1.4)

512 560

2 13

(0.4) (2.3)

1911 373

16 45

(0.84) (12)

527 216

2 6

Walker& (1981-1989)

3885

7

(0.38) (2.8) (0.18)

Total

9056

106

NelsorF (1938-1950) Mild disease Severe disease (1951-1953) Mild disease Severe disease

Eclampsia n (“/)

(1.2)

women with hypertension in pregnancy and might not apply to women with severe preeclampsia. For many years, authorities in the USA have recommended using magnesium sulfate prophylaxis during labor and postpartum in all women with diagnosed preeclampsia. As a result, there are no data in the recent obstetric literature describing the incidence of eclampsia in preeclamptic women not receiving such therapy. However, eclamptic convulsions rarely develop after the administration of standard regimens of magnesium sulfate. Zuspan states that he has ‘never seen a patient who has been adequately treated with magnesium sulfate have a seizure during the infusion of the intravenous drug.‘47 In addition, the results of two large clinical studies indicate that eclamptic convulsions rarely develop in preeclamptic women receiving parenteral magnesium sulfate (Table 3). 48 It is important to note that the differences in the rate of eclampsia between these two studies may be related to differences in the populations studied (higher number of women with proteinuric hypertension and severe preeclampsia in Sibai’s study). Interestingly, the overall rate of eclampsia in these two studies is not different from the rate reported by Walker from Scotland46 without the use of magnesium sulfate. Thus, the efficacy of magnesium sulfate as prophylaxis against eclamptic convulsions in women with preeclampsia remains unresolved. This issue needs to be addressed in a randomized trial comparing magnesium sulfate to a saline infusion in a large number of preeclamptic women, particularly those with proteinuric hypertension or severe disease. 49 Such a trial will require a sample size of at least 5000 women. The efficacy of magnesium sulfate in the control of eclamptic convulsions has been well documented in several clinical reports (Table 4).50-55 Approximately 10% of women with eclampsia will have a second convulsion after receiving the loading dose of magnesium sulfate. However, most of these women will remain free of seizures after an additional 2-4 g of magnesium sulfate. It is important to note that most of these women will have evidence of cerebral pathology (edema, hemorrhage, infarct) on computerized axial tomography.53

Table 3. Incidence of convulsions in preeclamptic women receiving magnesium sulfate No. of women studied Cunningham and Leveno (1983-1985)48f Sibai (1977-1991)” Total

Eclampsia n

(%)

4726

7

(0.15)

9198

29

(0.32)

13924

36

(0.26)

* Intramuscular regimen. **Intravenous regimen, unpublished data.

MgS04 in preeclampsia-eclampsia Table 4. Subsequent convulsions in eclamptic women receiving magnesium sulfate Eclampsia n

Seizures after MgSO, n 3

(%)

Pritchard et al (1975)50 Gedekoh et al (1981)51 Pritchard et al (1984)52 Dunn et al (1986)53 Dommisse (1990)54 Crowther ( 1990)55 Sibai (1991)*

85 52 83 13 100 24 315

10 5 3 5 41

(12) (38) (3) (21) (13)

Total

672

68

(IO)

1

(4)

(2)

*Unpublished data.

SAFETY OF MAGNESIUM

SULFATE

A review of the obstetric literature in the USA indicates that magnesium sulfate is an extremely safe drug to use in pregnancy. Its use has been standardized, which has made it simple to administer, as well as to monitor clinically its effects and side-effects. All physicians and nurses working in obstetric units are familiar with at least one regimen for its administration, dose, and clinical monitoring of potential side-effects.l* In addition, medical personnel are usually familiar with its pharmacokinetics as well as pharmacodynamics. The current standard regimens have been tested in thousands of patients over the years and have proved to have predictable duration of action. When used in the clinical setting, it is unnecessary to monitor serum levels. Further, the established clinical regimens have a wide margin of safety and have been demonstrated to be safe for both mother and newborn when used in preeclampsia or in women with premature labor.” The drug does not cause any significant maternal or neonatal depression when used properly.24*26 During its administration the mother is awake and alert with intact laryngeal reflexes, which helps to protect against aspiration in case of convulsions. Some studies have reported low Apgar scores, respiratory depression, hyporeflexia, and hypocalcemia in the neonates of mothers receiving intravenous magnesium sulfate.56-58 These effects were reported in premature infants in association with fetal growth retardation and after bolus doses of magnesium sulfate just prior to delivery. Such complications may be present in these infants without the use of magnesium sulfate, as reported by McGuinness et al.” In addition, several studies found no such effects in term infants.24v26*60 Some studies have reported decreased fetal heart rate variability, decreased uterine activity and prolonged labor, and excessive blood loss after vaginal delivery in preeclamptic women receiving parenteral magnesium sulfate during labor. The reported effects on fetal heart rate variability and uterine activity are conflicting. 61-64 It is the authors’ experience that

171

magnesium sulfate will inhibit uterine contractions when given early in premature labor (cervical dilatation 12 cm). During the latent phase of labor, most preeclamptic women usually receive oxytocin for induction or stimulation of labor. Thus, the use of magnesium sulfate during this period will have minimal to no effect on uterine activity. In addition, magnesium sulfate is ineffective in suppressing uterine activity during the active phase of labor.62 Moreover, in a prospective study in 30 preeclamptic women receiving magnesium sulfate and oxytocin and 30 women receiving oxytocin induction only, Oakley and Sibai (unpublished data) found no difference in the amount of blood loss at delivery between the two patient groups. Some studies have shown that patients receiving magnesium sulfate show markedly increased sensitivity to the administration of both depolarizing and non-depolarizing muscle relaxants due to the effect of the magnesium ion at the myoneural junction.65 Ghoneim and Long66 reported 2 cases in which prolonged paralysis resulted when the usual doses of curare were used during surgery in patients receiving magnesium sulfate. Ramanathan and associates67 studied neuromuscular transmission in preeclamptic women receiving magnesium sulfate. They found that the degree of neuromuscular blockade correlated significantly with increased magnesium levels and decreased serum calcium levels. These findings suggest that preeclamptic women receiving magnesium sulfate require smaller doses of muscle relaxants during cesarean section.

MATERNAL-PERINATAL

OUTCOME

The syndrome of preeclampsia-eclampsia is a major cause of serious maternal morbidity and is still the leading cause of maternal mortality worldwide.2 Complicated and mismanaged cases are responsible for most maternal deaths, which are usually due to intracerebral hemorrhage, severe cerebral ischemia, pulmonary edema, or renal, hepatic, or respiratory failure.68v6g In addition, severe preeclampsiaeclampsia is usually associated with high perinatal mortality and morbidity. The main causes of perinatal mortality and neonatal morbidity are preterm delivery, fetal growth retardation, and abruptio placentae. The maternal and perinatal mortality and morbidity rates in women with eclampsia treated by magnesium sulfate are superior to the respective outcomes in such pregnancies reported from any other place in the world.2*46.52This excellent maternal and perinatal outcome is attributed to the experience of the physicians managing these patients, the use of standardized protocol for preeclampsia-eclampsia, and the availability of appropriate maternal and neonatal intensive care facilities. Thus, it is very

172 International Journal of Obstetric Anesthesia

difficult to evaluate the role of magnesium sulfate in improving outcome in such pregnancies. However, it is important to note that serious maternal and neonatal morbidities were encountered in eclamptic women receiving phenobarbital, diazepam, and phenytoin for control of eclamptic convulsions in some of these women.’ A review of the obstetric literature in eclampsia indicates that magnesium sulfate is safer and superior to other anticonvulsants in the management of eclamptic convulsions.‘*’

OTHER ANTICON WLSANTS In many centers outside the USA, magnesium sulfate is rarely used to prevent or treat eclamptic convulsions. During the past 60 years numerous anticonvulsant drugs have been introduced and replaced because of dissatisfaction with the results. These drugs have included bromethol, chloral, paraldehyde, phenothiazines, lytic cocktails, barbiturates, chlormethiazole, and clonazepam. The overzealous use of these drugs in eclampsia has been associated with significant matemalneonatal central nervous system and respiratory depression.” The use of barbiturates and chlormethiazole in anticonvulsant doses may depress maternal laryngeal reflexes, thus increasing the likelihood of aspiration during convulsions. Intravenous phenobarbital may produce laryngospasm and circulatory and respiratory depression. ” In addition, the use of chlormethiazole was associated with deep sedation, respiratory depression, obstruction, and death.” Further, chlormethiazole crosses the placenta resulting in hypotonia, sedation, and respiratory depression in the infants for up to 5 days after delivery.‘l Moreover, the use of clonazepam in eclampsia has been associated with feeding difficulties, jitteriness, and drowsiness in the neonate.

and maternal levels equalize within minutes. The use of large doses of diazepam (> 30 mg) during labor is associated with loss of beat to beat fetal heart rate variability, and significant neonatal morbidity (respiratory depression, apnea, hypotonia, cold stress, and poor feeding). 72,73 In addition, the use of diazepam in eclampsia is associated with significant maternal morbidity. 47*55 In the mother, large doses cause excessive sedation and depression of laryngeal reflexes thus increasing the risks of respiratory depression and aspiration of gastric contents. In fact, The Confidential Enquiry into Maternal Deaths in England and Wales in 1979-198 1 suggested that some of the deaths in women with eclampsia were due to excessive sedation and respiratory arrest rather than to eclampsia itself. Crowther,55 in a randomized controlled trial, compared magnesium sulfate and diazepam as anticonvulsants in 5 1 eclamptic patients. Twenty four women received magnesium sulfate and 27 intravenous diazepam. Recurrence of convulsions developed in 5 (21%) women receiving magnesium sulfate and in 7 (26%) women treated with diazepam. One woman developed respiratory depression and 3 women developed pneumonia in the diazepam group. These complications were attributed to heavy sedation from diazepam. There was one maternal death in the magnesium group which occurred in a patient who was moribund on admission. This patient also received diazepam and death was attributed to severe hypoxia from cardiorespiratory arrest. The incidence of low Apgar scores and neonatal morbidity was higher (not significant) in the diazepam group. The author concluded that magnesium sulfate was associated with less serious morbidity in the mother and infant. However, she emphasized that ‘the trial is small and should be replicated on a larger scale.’ Such a trial is currently in progress in South America.

PHENYTOIN DIAZEPAM Diazepam is a proven anticonvulsant in the control of status epilepticus in both pregnant and nonpregnant subjects. ” It is commonly used as first-line treatment to terminate eclamptic seizures in Europe and other countries. When administered in intravenous doses of lo-20 mg, diazepam effectively abolishes convulsions. The mode of action is believed to be facilitation of the actions of inhibitory neurotransmitters such as gamma aminobutyric acid (GABA) and glycine. In animals, diazepam abolishes electrically induced seizures and prevents the spread to other areas of the brain from the original seizure focus. In addition to being an anticonvulsant, diazepam is also a sedative, and a skeletal muscle relaxant. It rapidly crosses the placental and fetal

The efficacy of phenytoin as an epileptic drug has been proven for many years. It is the drug of choice in the treatment of epileptic seizures in non-pregnant and pregnant subjects. 2o The mode of action, pharmacokinetics, dosage, and side-effects when used in epileptic patients are extensively documented. Recently, phenytoin has been advocated for the prevention and treatment of eclamptic convulsions in several parts of the world. Slater et al” evaluated a regimen of phenytoin based on maternal weight in only 26 patients (7 had severe preeclampsia, 17 had mild disease, and 2 had eclampsia). They reported no seizures after the initiation of phenytoin (7501250 mg intravenously at a rate of I 25 mg/min), they noted no major maternal or neonatal side-effects. Moosa and El-Zayat74 studied 100 women (98 with preeclampsia and 2 with eclampsia); 50 women

MgS04 in preeclampsia-eclampsia

received diazepam, furosemide and hydralazine and the other 50 received an additional dose of phenytoin 300 mg/d. They reported favorable effects on maternal blood pressure and edema in the 50 women receiving phenytoin, and none had convulsions. They suggested that phenytoin has favorable effects on the ‘underlying pathophysiology of preeclampsia and eclampsia.’ Ryan et a175 reported their clinical experience with phenytoin prophylaxis in 104 patients (99 had preeclampsia and 5 had eclampsia before treatment). The authors used various doses of phenytoin according to maternal weight. They emphasized that the serum unbound (active) fraction of phenytoin is inversely related to serum albumin level, and maternal toxicity may occur if standard doses are given to all patients. They noted that one preeclamptic patient receiving phenytoin developed convulsions due to underdose. However, they had one additional patient subsequent to the study who developed convulsions despite an adequate dose. Friedman et al compared the use of phenytoin (n= 23) to that of intravenous magnesium sulfate (n = 22) in 45 women (43 had preeclampsia and 2 had eclampsia). Both eclamptic women were randomized to phenytoin. There were no convulsions in any of the women receiving either drug for preeclampsia. However, subsequent convulsions developed in both eclamptic women receiving phenytoin. Both women had areas consistent with ischemia or infarct on computed axial tomography or magnetic resonance imaging. In addition, they reported fewer side effects (prolonged labor and excess postpartum bleeding) and better acceptance in the phenytoin-treated group. Tuffnell et a176*77reported that 3 (17%) of 18 patients with preeclampsia-eclampsia had a further convulsion after the administration of the phenytoin dose recommended by Slater et a17’ Two of the 3 women were receiving phenytoin for eclampsia and the other was receiving phenytoin for severe preeclampsia. Phenytoin serum levels were measured in 2 of the 3 patients and were in the therapeutic range in both. In addition, focal intracranial lesions were not present in any of the 3 patients. In a subsequent report, Slater et a17s reported their experience in 70 patients (62 had preeclampsia and 8 had eclampsia) who were treated with phenytoin. None of the 62 preeclamptic women developed convulsions while 2 of the 8 eclamptic women developed a single seizure after the start of phenytoin. One of the latter 2 women had an intracerebral vascular malformation on computed tomography. Dommisse54 reported on 22 eclamptic women who were randomly allocated to receive intravenous phenytoin (n= 11) or intravenous magnesium sulfate (n = 11). None of the 11 women managed with magnesium sulfate had further seizures, while 4 of 11 women treated with phenytoin had further seizures. These

173

Table 5. Subsequent convulsions in eclamptic women receiving phenytoin Eclampsia n

Seizures after phenytoin n

W)

Slater et al (1989)” Tufnell et al ( 1989)76 Friedman et al (1989)64 Ryan et al (1989)75 Dommisse ( 1990)54 Coyaji and Otiv ( 1990)79 Sibai (1991)’

8 2 2 5 11 33 8

2 2 , 0 4 12 4

(25) (lo@ (100) (0) (36) (36) (50)

Total

69

26

(38)

latter women were subsequently treated effectively with magnesium sulfate. No side-effects occurred in either group. The author suggested that magnesium sulfate is a more effective anticonvulsant than phenytoin in eclampsia. Recently, Coyaji and 0tiv79 reported the use of a single 900 mg dose of phenytoin in 33 consecutive women admitted with eclampsia in India. These women were classified into either mild eclampsia (n = 17) or severe eclampsia (n = 16) according to maternal findings at onset of therapy. Four of the 17 women in the mild group (23.5%) and 8 of 16 in the severe group (50%) had convulsions after phenytoin administration. There were no maternal deaths in the mild group, but 2 women died in the severe group. As would be expected in an eclamptic population in India, the perinatal mortality rate was high. Interestingly, the authors stated that there were no maternal or neonatal side-effects from using phenytoin. A review of the above studies indicates that a total of 247 women received phenytoin prophylaxis in preeclampsia. Two women (0.8%) developed convulsions while receiving such therapy. This incidence is higher than the incidence reported with the use of magnesium sulfate in similar women (0.26%). In addition, Table 5 summarizes the incidence of subsequent convulsions in eclamptic women receiving phenytoin. The incidence of convulsions among 69 women was 38% which is considerably higher than the 10% rate reported with magnesium sulfate. These findings suggest that magnesium sulfate is more effective than phenytoin in the prevention and control of eclamptic convulsions. However, there is limited experience with the use of phenytoin in preeclampsiaeclampsia and the populations managed with this drug and those managed with magnesium sulfate may not be similar. Thus, there is a definite need for a large randomized clinical trial comparing the safety and efficacy of these drugs in a homogeneous group of women with severe preeclampsia-eclampsia. CONCLUSIONS

A review of the obstetric literature indicates that magnesium sulfate satisfies all the criteria needed for

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an ideal anticonvulsant in preeclampsia-eclampsia. Its clinical safety and efficacy for this purpose have been well documented in more than 100000 patients over the years. Its use is not empiric any more since its clinical efficacy has been proven against proven anticonvulsants in clinical trials in eclamptic women.

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