Magnesium Sulfate and Eclampsia

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CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a totalof 36 AMA/PRA category 1 creditsTM can be earned in 2006. Instructions for how CME credits can be earned appear on the

last page of the Table of Contents.

Cerebral Hemodynamics inPreeclampsia: Cerebral Perfusion and

the Rationale for an Alternative toMagnesium Sulfate

Michael A. Belfort, MD, PhD,* Steven L. Clark, MD,†and Baha Sibai, MD‡

*Professor, St. Marks Hospital and University of Utah School of Medicine, Salt Lake City, Utah; †Director of Maternal–Fetal Medicine, St. Marks Hospital, Salt Lake City, Utah; and ‡Professor, University of Cincinnati,

Cincinnati, Ohio

Preeclampsia and eclampsia continue to be major causes of maternal death. Currently, approximately

18% of U.S. maternal deaths are attributed to hypertensive disorders and eclampsia, and several hundred

women die from eclampsia and its complications every year. In the United States, preeclamptic women

have received magnesium sulfate as a seizure prophylaxis agent for 3 decades, and this practice is

becoming more widely accepted internationally. In addition to a recognized failure rate, there are financial,

logistic, and safety concerns associated with the universal administration of magnesium sulfate. Many

institutions in the developing world lack the necessary equipment and expertise to administer the medica-tion, and many preeclamptic patients thus do not receive magnesium sulfate before their first seizure. As

effective as it has been in reducing mortality from eclampsia, magnesium sulfate is also associated with

appreciable morbidity and mortality from administration errors and magnesium toxicity. The availability of

an easily administered, cheap, safe, and orally administered alternative to magnesium sulfate would be

welcomed in the developing world and would provide an extremely useful alternative therapy to the current

standard of care. Recent advances in the understanding of the pathophysiology of preeclampsia and

eclampsia, primarily related to cerebral perfusion and blood flow, could allow us to reduce the seizure rate

in treated preeclamptic women even further than what is currently reported. This article deals with the

rationale behind the use of labetalol as an alternative to magnesium sulfate for the prevention of eclampsia.

Target Audience: Obstetricians & Gynecologists, Family Physicians

Learning Objectives: After completion of this article, the reader should be able to recall that hypertensive

diseases of pregnancy contribute a significant portion of today’s maternal mortality, explain that methods of

preventing eclampsia are not applicable worldwide, and state that understanding of the pathophysiology ofpreeclampsia/eclampsia may assist in developing safe and effective medications that can be used universally.

Preeclampsia and eclampsia continue to be majorcauses of maternal death (1,2). It is conservatively es-

timated that in the United States (3), over 100,000women are treated for preeclampsia per year.

Dr. Belfort was a member of the speakers’ bureau for Symposia

Medicus and the Medical Intelligence Corporation. All other authors

have disclosed that they have no financial relationships with or interests

in any commercial companies pertaining to this educational activity.

The authors have disclosed that labetalol has not been approved by

the U.S. Food and Drug Administration for use in the prevention of

eclampsia. Consult product labeling for the approved use of this drug.

Lippincott Continuing Medical Education Institute, Inc. has

identified and resolved all faculty conflicts of interest regarding

this educational activity.

Reprint requests to: Michael A. Belfort, MD, PhD, Maternal–Fetal

Medicine, St. Marks Hospital, 1140E 3900S, Suite 390, Salt Lake City,

UT 84124. E-mail: [email protected].

CME REVIEWARTICLE Volume 61, Number 10

OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright © 2006

by Lippincott Williams & Wilkins 28

655



Approximately 21,000 women develop severe pre-eclampsia. Currently, approximately 18% of mater-nal deaths in the United States are attributed tohypertensive disorders and eclampsia, and severalhundred women die from eclampsia and its compli-cations every year (3).

In the United States, preeclamptic women havereceived magnesium sulfate as a seizure prophylaxisagent for over 3 decades (4), and the introduction of this drug has been associated with a significant re-duction in maternal mortality. With demonstratedefficacy in the treatment of eclampsia, and the pre-vention of eclampsia in women with severe pre-eclampsia, magnesium sulfate (MgSO4) currentlyrepresents the standard of care for seizure preventionin the United States. Many obstetricians also use thisdrug in patients with mild preeclampsia despite a

lack of robust evidence to support a clear benefit, anda guideline from ACOG that specifically excludesmild preeclampsia (5). Based on available data (6,7),it appears that the incidence of seizures in untreatedseverely preeclamptic women is approximately 3%to 4%, whereas for those receiving magnesium sul-fate, the rate is generally thought to be just under 1%(8). Given an estimated prevalence of eclampsia of 1% in women with preeclampsia who are receivingmagnesium sulfate prophylaxis, and an estimated100,000 women per year with preeclampsia in theUnited States, approximately 1000 women a year

will convulse despite our current best efforts. Of these patients, an unknown number will experienceaspiration, asphyxia, cerebrovascular complications,and death.

Since publication of the MAGPIE Study, whichshowed a significant reduction in the rate of eclamp-sia in preeclamptic women treated with MgSO4 (9),there has been a worldwide increase in the use of MgSO4 for seizure prophylaxis in women with pre-eclampsia. The MAGPIE trial (9) involved 10,110women with preeclampsia in 175 hospitals in 33countries and revealed a significant reduction in the

rate of eclampsia in women assigned to MgSO4. Thisbenefit was primarily found in women enrolled indeveloping countries, and there was no significantreduction in the rate of eclampsia in women fromindustrialized countries (relative risk, 0.67; 95% con-fidence interval, 0.19–2.37). However, the number of women enrolled from industrialized countries wassmall and the lack of significance may simply rep-resent insufficient statistical power. Even so, it isperhaps ironic that the majority of the increased useof MgSO4 since the MAGPIE trial has occurred inindustrialized countries as opposed to nonindustrial-

ized ones, many of which still have significant finan-cial, logistic, and safety concerns associated with theuniversal administration of MgSO4 to all preeclampticwomen. Magnesium sulfate is not without risks; everyyear, a significant number of women die, experiencesevere morbidity, or experience permanent disabilityfrom administration errors and magnesium toxicity. It isextremely difficult to assess this number accurately as aresult of underreporting (or an assumption that the out-come was the result of the underlying condition itself).Conversely, in many maternal transport situations,MgSO4 is withheld from patients until they are admittedto a center where adequate facilities and personnel areavailable for the safe administration and monitoring of the infusion. Some of these women convulse en routeand may die from aspiration, hypoxia, or other compli-cations related to the seizure. Thus, the availability of an

easily administered, inexpensive, safe alternative toMgSO4 would be welcomed in this and other countriesand would provide an extremely useful alternative ther-apy to the current standard of care. From a globalperspective, the availability of such an eclampsia pro-phylactic agent would be of even greater benefit. Inmany developing countries, MgSO4 is not available orpractical as a management modality because of ex-pense, logistics, lack of trained personnel, and lack of resources. It is estimated that in these situations, sei-zures may occur in more than 4% of severely pre-eclamptic patients, and in some settings, as many as

15% of eclamptic women will die (10).

PATHOPHYSIOLOGY OF PREECLAMPSIA/

ECLAMPSIA

The etiology of eclamptic convulsions is unclear.Cerebral vasospasm, hypertensive encephalopathy(from cerebral overperfusion), excitation of brainreceptors, and a hyperactive sympathetic nervoussystem have all been implicated (11–14). We andothers have shown that both vasospasm (15) andhypertensive encephalopathy (16,17) may be associ-

ated with seizures, but that in most cases, preeclamp-tic women have cerebral overperfusion rather thanischemia (18–20). The results of the NimodipineStudy (8) (in which women with severe preeclampsiawere randomly assigned to receive a selective cere-bral vasodilator—nimodipine—vs MgSO4) supportthis by showing that deliberate cerebral vasodilata-tion, which interfered with protective physiologicalvasoconstriction, actually increased the eclampsiarate in women with severe preeclampsia over thatseen in women treated with MgSO4 (2.6% vs 0.8%).The resulting 2.6% eclampsia rate is not statistically

656 Obstetrical and Gynecological Survey



different from the approximately 3% rate of seizuresseen in untreated preeclamptic women.

In eclampsia, secondary vasospasm is thus morelikely to be the result of prolonged and untreatedhypertensive encephalopathy rather than the primarypathology. Theoretically, either of these 2 perturba-tions (overperfusion or underperfusion) may result inbrain receptor stimulation and excitation of ectopicfoci to cause seizures. The relative contribution of vasospasm versus cerebral barotrauma (20) and hy-pertensive encephalopathy as the primary mechanismof eclampsia are discussed in more detail subse-quently. Before detailing these arguments, however,an overview of the current literature regarding cere-bral perfusion in normal and preeclamptic pregnancywill be helpful to allow the reader to fully considerthe arguments to follow.

Data from both normal pregnant (18) and preeclamp-tic women (21–23) studied with Doppler ultrasoundhave outlined a picture of the cerebral hemodynamics inboth normal pregnancy and preeclampsia. In normalpregnancy, the systolic velocity and resistance index inthe middle cerebral artery both decrease approximately20% over gestation (18), whereas the cerebral perfusionpressure (CPP) increases by 50% from early pregnancyto term (Fig. 1) (18). Cerebral perfusion, expressed asthe cerebral blood flow index (CFI) was shown toincrease approximately 10% from early pregnancy toterm (18,19). These Doppler derived data have recently

been confirmed by magnetic resonance imaging studiesthat show that the middle and posterior cerebral artery

diameters remain static during normal late pregnancy,whereas the flow (which in this instance is proportionalto the velocity) decreases by approximately 20% (17).

Cerebral autoregulation is very efficient duringpregnancy and despite a significant increase in per-fusion pressure the cerebral blood flow changes by amuch smaller percentage. A small decrease in cere-bral resistance is seen in normal pregnancy as bloodpressure increases within the normal range, and thisis believed to be the result of prostacyclin release asthe vessel walls are distended. However, as pressureincreases out of the normal range (in preeclampticwomen without headache; left panel in Fig. 2), aphysiological increase in cerebral resistance occurs tolimit perfusion (21), and this should not be regarded (aswas the case before normative data becoming available)as a pathologic change.

Many studies performed before the publication of normative data assumed that in preeclamptic patients, adecrease in the middle cerebral artery resistance indexafter delivery, or after treatment with MgSO4, was in-direct evidence of recovery from cerebral vasospasm. Inretrospect, many of those patients had initial resistanceindex (RI) values that were well within the normalrange for pregnancy, and the change in resistance sim-ply reflected a vasodilator effect of fluids and antihy-pertensive drugs used in treatment of the hypertension/ eclampsia. The newer indices that incorporate bloodpressure (CPP [24], resistance area product [RAP] [25],

and CFI [26]) and the availability of normative data forpregnancy (18) now allow a much better perception of

Fig. 1. Normal pregnancy Doppler derived cerebral hemodynamic parameters (18).

Cerebral Hemodynamics in Preeclampsia Y CME Review Article 657



the state of cerebral perfusion than the RI or pulsatilityindex that were previously used.

Using these indices, Belfort et al (19) compared ce-rebral perfusion (as depicted by CFI) in 72 women withmild preeclampsia and 120 patients with severe pre-eclampsia (Fig. 3) and found that in most cases, itremains within the normal limits. In severe preeclamp-sia, if cerebral blood flow is abnormal, it may be eitherincreased (14% of the patients) or decreased (10% of the patients), whereas in mild preeclampsia, almost allabnormal CFI (25% of the patients) is lower than nor-

mal. In those cases with low or normal cerebral bloodflow, severe preeclampsia is associated with a signifi-cantly higher perfusion pressure (CPP), RAP, and meanarterial pressure (MAP) than mild preeclampsia (P .05), whereas the CFI is not significantly different. Asignificant proportion of severe preeclamptics havehigh perfusion pressure (52%) versus only a minority of mild preeclamptics (13%) (Fig. 3). Overall, in severepreeclampsia, the resistance (RAP) is abnormally high,whereas it is within the normal range in women withmild preeclampsia. Magnetic resonance imaging datafrom Zeeman et al (27) are consistent with the Doppler

data (19).In most preeclamptic women with high CPP and

resistance, there is normal flow. However, the factthat the flow is usually normal does not negate thepotential for damage from a high CPP. Under thesecircumstances, a high middle cerebral artery (MCA)perfusion pressure, in and of itself, may well lead tovascular damage of the MCA and its branches, al-though the flow distal to the MCA may be adequateto maintain brain function for a long period of time.Depending on the time that the vessel is subjected toabnormally high CPP, there may or may not be

Fig. 3. Failure of autoregulation in preeclamptic women with

headache as shown by failure to increase middle cerebral artery

resistance index in response to increasing mean arterial pressure

(21,29).

Fig. 2. Cerebral flow index and cerebral perfusion pressure index data from women with mild and severe preeclampsia are shown on

a background of median and 95% prediction limits for normal pregnancy (19).




endothelial damage, vasogenic edema, or muscularisdysfunction. Abnormally high resistance will almostalways result in a low flow state with reduced per-fusion, and very low resistance will usually result inhigh flow state and overperfusion. By using the com-bination of these parameters (CPP, CFI, and RAP),we are allowed a much more complete understandingof what is taking place in the brain than with anysingle parameter in isolation.

One of the fundamental differences between mildand severe preeclampsia is the degree of cerebralperfusion pressure to which the middle cerebral ar-teries are subjected. Because most preeclampticwomen, regardless of their degree of severity, have anormal CFI (19), it appears that autoregulation isgenerally intact until quite late in preeclampsia.However, in those preeclamptic women who develop

headache, it can be seen that autoregulation in themiddle cerebral artery fails and there is no compen-satory increase in MCA RI in response to increasingblood pressure (Fig. 2, right panel) (21). It is quiteeasy to hypothesize that the combination of 1) failedcerebral autoregulation and 2) increased CPP canlead to an overperfusion state in some small num-ber of severely preeclamptic women. The fact thatwomen with severe preeclampsia and a headache aremore likely to have failed autoregulation and highCPP support the current conviction that severe pre-eclamptics are more prone to cerebral catastrophe

than those with mild disease. We contend that this is,at least in part, related to very elevated CPP, whichmay cause barotrauma and vessel damage with hy-pertensive encephalopathy and overperfusion injury.These findings underline the fact that therapeuticstrategies that ensure reduction of the CPP withmaintenance of cerebral perfusion seem most likelyto prevent the cerebral injuries (over- or underperfu-sion) that cause seizures/death in women withpreeclampsia/eclampsia.

CEREBRAL BAROTRAUMA AND

HYPERTENSIVE ENCEPHALOPATHY

As outlined previously, the data strongly suggest thatin preeclampsia, the proximal cerebral vasculature is ina state of protective vasoconstriction that is autoregu-lated and which maintains normal blood flow in thethinner-walled distal vessels. This autoregulation doesnot come without a price, however. The increased per-fusion pressure proximal to the areas of protective va-soconstriction subjects the arterial/arteriolar wall to ashear force that, if persistent, can result in vascularbarotrauma, leakage of fluid into the interstitium, vaso-

genic (16) (and sometimes cytotoxic) edema (28)around the blood vessels, disruption of the blood–brainbarrier allowing stimulatory substances into the cerebralextravascular compartment, and, in some cases, vaso-spasm (19). Damage to the vessel wall may result infailure of autoregulation and an overperfusion state inwhich flow increases and overwhelms distal capillaries.Abnormal autoregulation has been shown to occur inboth the cerebral and renal circulations of preeclampticwomen (29–31). Because most eclamptic seizures orig-inate from the MCA distribution, the abnormal re-sponse in this vessel may indicate failure of localautoregulation. A similar response, failure to protect anorgan from excessive blood pressure, has been reportedby Kublickas et al (31), who showed decreased resis-tance in the renal artery in preeclampsia despite increas-ing perfusion pressure. Others have shown differential

vascular abnormalities in the occipital lobes in eclamp-tic women, a finding that is in concert with the fre-quently encountered visual disturbances and occasionalreversible blindness seen in this disease (32–34). Thesedata support the theory that in some preeclamptic pa-tients, as a result of abnormal cerebral autoregulation,overperfusion of the brain may occur with resultinghypertensive encephalopathy. This might explain thefailure of prophylactic medications that tend to increasecerebral perfusion (eg, nimodipine) and perhaps en-courage the persistent seizures seen in some eclampticwomen.

What actually causes eclamptic seizures is still un-known. Seizures may occur early in the process, beforethe development of vasospasm, and be the result of thevasogenic/cytotoxic edema with breakdown of theblood–brain barrier. In some cases, hypertensive en-cephalopathy alone may be enough to set off an ectopicelectrical focus leading to seizure activity. In othercases, this may not be sufficient, and the ensuing inter-ference with endothelial production of vasodilators anddamage to the arteriolar muscularis may be required tobring about a pathologic state of extreme and unrelent-ing vasoconstriction with resulting ischemia. This

ischemia may be the trigger required to start seizureactivity. The fact that vasospasm is present within hoursof the seizure may simply be an epiphenomenon afterinitial hypertensive encephalopathy, or it may be thecause of the seizure. In either case, vasospasm will bepresent after the seizure.

THE CHOICE OF AN IDEAL AGENT FOR

THE PREVENTION OF ECLAMPSIA

From the data presented previously, it is assumedthat most women with preeclampsia (by blood pres-




sure criteria) will have normal cerebral perfusion,whereas some will be overperfused (hypertensiveencephalopathy) and a very small minority will beunderperfused (ischemic) (Fig. 3). Women with hy-pertensive encephalopathy will most likely benefitfrom a drug that predominantly causes peripheralvasodilatation (leading to reduction in CPP) but thatmaintains cerebral blood flow within the normalrange. The few preeclamptic women with cerebralischemia are more likely to benefit from a drug withpredominant cerebral vasodilator effect.

MAGNESIUM SULFATE

Magnesium sulfate has been extensively used inthe management and prevention of eclamptic sei-zures in the United States (4,35). It has been shown

to be superior to both diphenylhydantoin and diaze-pam in the prevention of recurrent seizures ineclamptic patients (36). Lucas et al (37) addressedthe prophylactic use of magnesium sulfate in gesta-tional hypertension and preeclampsia and showedthat MgSO4 is more effective in preventing an initialseizure than diphenylhydantoin. The recently pub-lished MAGPIE study (9) supported the use of MgSO4

as a prophylactic agent for eclampsia and demonstrateda significant reduction in seizures when compared withplacebo. However, in this study, despite MgSO4, 0.8%of women with preeclampsia (mild or severe) still de-

veloped eclampsia. Likewise, our own Nimodopinestudy (8) of approximately 1600 severe preeclampticsshowed that 0.8% of women developed eclampsia de-spite MgSO4. Although the MAGPIE study did notprovide insight into the mechanism of eclampsia, theNimodipine study suggests that eclampsia is unlikely tobe the result of severe vasospasm.

The mechanism of action of MgSO4 is still unde-fined. We, and others, have suggested that MgSO4

has a cerebral (and retinal) vasodilator effect inwomen with preeclampsia (38–47), although the rel-ative contribution of this effect to the prophylactic

and/or treatment efficacy is unknown. Hatab et al(48) have recently contradicted this theory with mag-netic resonance imaging data showing no vasodilatoreffect of MgSO4 in severe preeclampsia. Their pa-tients were, however, a select group and they ex-cluded those with blood pressure 160/110 mm Hgand those with symptoms of cerebral irritation, andthe applicability of their findings to all severely pre-eclamptic women may be questioned. Although theirstudy does not rule out a microvascular effect, it doesmake it less likely that the predominant antiseizureaction of MgSO4 is at the level of blood flow regu-

lation in the larger brain arteries (middle cerebral,anterior cerebral, or posterior cerebral arteries).

Despite conflicting data on the vasodilator effect of MgSO4, our previously held opinion that it actspredominantly through vasodilatation of constrictedcerebral vessels by opposing calcium-dependent ar-terial vasospasm is placed into doubt by the findingsof the Nimodipine study (8). The fact that MgSO4

dilates arterioles distal to the MCA in preeclampticwomen does not mean that these arterioles werevasospastic to start with. They may be demonstratingprotective vasoconstriction (normal autoregulatorystate) or, as a result of aberrant autoregulation, theymay not be vasoconstricted at all. In some cases of severe preeclampsia and eclampsia in which the re-sistance is low or “normal,” forced vasodilatation of the downstream vasculature without simultaneous re-

duction in blood pressure/cerebral perfusion pressuremay actually be deleterious. We have shown thatMgSO4 reduces the CPP in preeclamptic patients(49), whereas nimodipine increases it.

We have also shown that in some patients, MgSO4

has a sustained systemic (up to 6 hours) antihyperten-sive effect (in up to 30% of women with an admissionMAP 126 mm Hg) (8). One can perhaps explainsome of the prophylactic anticonvulsive action of MgSO4 on the basis of a combination of its cerebralvasodilator and simultaneous peripheral antihyperten-sive effects as well as an as yet unidentified membrane-

stabilizing action. An agent that provides more rapidand effective peripheral vasodilatation than cerebralvasodilatation will decrease CPP and potentially pre-vent hypertensive encephalopathy. The combination of simultaneous (but proportionately greater) systemicblood pressure reduction with reliable cerebral vasodi-latation is possibly the key to effective seizure prophy-laxis with MgSO4. Magnesium sulfate may reduce thecerebral perfusion pressure and decrease the risk of cerebral barotrauma (both by diminishing the physicaldistention of the blood vessels and by antagonizing theincrease in the intracellular calcium concentration

caused by sustained vasoconstriction) (38,39) and inthis way maintain normal cerebral blood flow.

LABETALOL

Labetalol is a rather unique substance in that it hasboth selective, competitive alpha-1 and nonselective,competitive beta-adrenergic-blocking actions (50). Inhumans, the ratio of the alpha and beta blockade isestimated to be approximately 1:3 and 1:7 for the oraland intravenous compounds, respectively (50). Athigher doses than required for adrenoreceptor block-




ade, labetalol has been shown to be a membranestabilizer (51).

Labetalol produces rapid dose-dependent decreasesin blood pressure without reflex tachycardia or sig-nificant reduction in heart rate. Hemodynamic effectson cardiac output are minimal, and the predominanteffect appears to be a decrease in peripheral vascularresistance (52). Satisfactory blood pressure controlhas been achieved with either intravenous or oraladministration. In fact, oral labetalol has been usedfor acute control of severe preeclampsia and has beenfound to be comparable to hydralazine (53). Mabieand coworker (54) compared bolus-dose intravenouslabetalol with intravenous hydralazine in the acutetreatment of severe hypertension. They found thatlabetalol had a quicker onset of action and did notresult in reflex tachycardia (54). In terms of fetal

effects, blood pressure reduction with labetalol doesnot result in fetal distress (54,55) unlike acute bloodpressure reduction with hydralazine in which 15% of fetuses will exhibit distress frequently requiring im-mediate cesarean section for delivery (56).

Despite reduced maternal blood pressure, labetaloldoes not decrease uteroplacental blood flow (57,58). Aswith all beta-blockers, labetalol has been associatedwith hypoglycemia, bradycardia, and hypotension, butneonatal outcome is uniformly good (54,59,60).

In pregnant women with hypertension, the peak serum level of labetalol has been shown to occur

within 20 to 60 minutes after a 100-mg oral dose witha terminal elimination half-life of 1.7 0.27 hours(61). The elimination half-life after intravenous ad-ministration in pregnant hypertensive patients is sim-ilar to that seen with oral administration (62). Theelimination half-life at steady state is significantlyless than that seen in nonpregnant individuals (6–8hours) (63), and for this reason, more frequent dosingis recommended in pregnancy (4–6 hours). Rogers etal reported a fetal/maternal serum ratio of 0.5 0.15and an amniotic fluid/maternal serum ratio of 0.16 0.13 (61).

Labetalol has some interesting and potentially impor-tant nonantihypertensive effects that may be beneficialin preeclampsia. Among these are an antiplatelet aggre-gation action (64), a thromboxane-reducing effect (65),and a fetal lung maturation-accelerating influence (66).

Labetalol has been successfully used for manyyears in pregnant women with severe preeclampsia,and although hydralazine is more commonly used forthe management of acute hypertension in preeclamp-sia in the United States, labetalol has been shown tobe equally effective (54) and is currently a first-linerecommendation of ACOG for blood pressure con-

trol in preeclampsia (5). Of great interest are the datareported by Walker (67) on the experience at theGlasgow Royal Maternity Hospital in Scotland. Overa 10-year period, he and his colleagues managed over36,000 pregnancies with a 10% rate of hypertensionin pregnancy (67). They had only one patient developeclampsia out of a total of 555 women who werereceiving treatment for their hypertension, and inthis patient, the hypertension was inadequately con-trolled. Fewer than 100 of these 555 patients receivedMgSO4, and labetalol was the drug of choice forhypertension control. Thus, their rate of seizures onlabetalol was on the order of one in 455 (0.2%).

LABETALOL LOWERS CEREBRAL

PERFUSION PRESSURE IN

PREECLAMPSIA: CURRENT DATA

We have recently published our findings on the ce-rebral hemodynamic effects of labetalol in pregnanthypertensive women (23). Labetalol reduced the CPP(Fig. 4) as well as the systolic, diastolic, and meanblood pressure significantly at 60 and 180 minuteswithout significantly affecting the heart rate, MCA ve-locities, RAP, or CFI (23). Labetalol effectively reducesCPP, without affecting cerebral perfusion, and this isthought to be primarily by a decrease in systemic bloodpressure. We recently compared the CPP effects of MgSO

4

and labetalol and showed that labetalol is amore reliable CPP-lowering agent than MgSO4 (68).

RATIONALE FOR THE USE OF

LABETALOL AS AN ANTICONVULSANT

AGENT IN PREECLAMPSIA

We hypothesize that if reduction of CPP is an impor-tant part of the antiseizure prophylactic mechanism of action of MgSO4 in preeclampsia, then the use of amore specific, less toxic agent that can be administered

orally such as labetalol may greatly simplify the man-agement of preeclamptic patients while at the same timeproviding equivalent or improved efficacy. In addition,the ease of administration, reduced risk of respiratoryand cardiac depression, lack of need for intensive mon-itoring of blood magnesium levels, suitability for use byprimary care personnel, safety, and low cost of theregimen give labetalol very attractive risk/benefit andcost/benefit ratios. We have demonstrated (23,68) thatlabetalol has some important characteristics that maymake it an ideal agent to limit cerebral overperfusion,control blood pressure, and prevent seizures in pre-




eclampsia. This drug has been in use for over 2 decadesand thousands of preeclamptic women and their babies

have been safely treated with it. The potential advan-tages of using labetalol as a blood pressure-controllingagent, as well as a seizure prophylaxis agent, in pre-eclamptic women are wide reaching. By adopting labe-talol, if it is proven to be as (or more) effective asMgSO4, there will be a simplification of the currentsystem in this country and a significant cost savings.Given the potential risks of MgSO4, it is possible thatthe use of labetalol will reduce maternal mortality fromMgSO4 toxicity. Patients who might not otherwise re-ceive seizure prophylaxis (with MgSO4) as a result of logistic, personnel, safety, or training issues will be in a

position to have treatment started earlier. This is be-cause the administration of a tablet (with known safetyand no need for monitoring of blood levels) beforetransport of a patient is simply easier and more acceptedby nursing staff and primary caregivers.

ETHICS OF NOT TREATING WOMEN

WITH PREECLAMPSIA WITH

MAGNESIUM SULFATE

In many European and Scandinavian countries,MgSO4 is used sparingly, if at all, in the prophylaxis of

eclampsia, and the only agents used are those for bloodpressure control. Even after the MAGPIE study, therehas not been a significant change in many developedEuropean countries. Magnesium sulfate is used in casesin which there is “imminent eclampsia” and not in casesof mild preeclampsia or even severe preeclampsia if thepatient is not deemed to have cerebral irritation. Thereported eclampsia rate in these countries is no differentfrom that reported from countries with almost universaluse of MgSO4 in preeclampsia in the United States.This statistic is borne out by the MAGPIE study (9) inwhich the majority of the adverse outcomes and all of

the maternal mortality occurred in developing coun-tries. It is felt in the developed European countries,

control of hypertension with drugs such as hydralazineand labetalol provides sufficient protection againsteclampsia, and there is evidence to support this. Someauthors have theorized that MgSO4 is no more effec-tive in the prevention of seizure activity than antihy-pertensive medication alone (hydralazine or labe-talol) (67,69).

Sibai, on the basis of a review of the MAGPIE data,calculated that in developed countries, 385 preeclamp-tic women need to be treated to prevent one case of eclampsia and concluded that because of the rare caseof aspiration or hypoxia associated with eclampsia,

magnesium sulfate prophylaxis may be justified inwomen with severe preeclampsia, but that the evidenceto date does not justify routine use of magnesium sul-fate prophylaxis in women with mild preeclampsia(70,71).

Finally, one of the principal reasons for observingwomen with preeclampsia during labor is to monitortheir blood pressure. Although MgSO4 has some effecton blood pressure (8), it is not a primary antihyperten-sive agent. The use of a primary antihypertensive drug(labetalol) to treat preeclamptic women during laborwill certainly reduce the number of women who may

need emergency addition of an antihypertensive agent.

PRELIMINARY DATA FROM THE

LABETALOL VERSUS MAGNESIUM

SULFATE STUDY

Between 2002 and 2005, we conducted a pilotstudy of labetalol versus magnesium sulfate (72).Three hundred twenty-two patients were enrolled, of which 175 women received labetalol and 147 pa-tients MgSO4. Demographics, blood pressure on ad-mission, and laboratory results were similar between

Fig. 4. Labetalol significantly reduces cerebral perfusion pressure while maintaining a normal cerebral flow index (23).




the 2 groups. Two patients in each group developed

eclampsia (labetalol 1.1% vs MgSO4 1.4%, P .7).One patient in the labetalol group died as a result of

pulmonary fat emboli and was diagnosed at autopsyas having had fatty liver of pregnancy. There were nodifferences in the rates of abruptio placentae (2.6%for labetalol vs 0% for MgSO4), cesarean section forfetal distress (35% for labetalol vs 46% for MgSO4),postpartum hemorrhage (2.0% for labetalol vs 0.5%for MgSO4), or postpartum pulmonary edema (0.5%for labetalol vs 0% for MgSO4).

The MgSO4 group required significantly more ad-ditional antihypertensive therapy. Blood pressure

control in the labetalol group was characterized bysignificantly lower postpartum systolic and diastolicblood pressures (Fig. 5). Intrapartum blood controlwas similar between the 2 groups. There were nosignificant differences in terms of the other recordedparameters between the 2 groups: headache, diplopia,scotomata, hypotension, nausea, vomiting, allergicreaction, and respiratory depression. There were alsono significant differences in intra-/postpartum com-plications or neonatal outcomes. The mean heart ratewas significantly lower in the labetalol group duringboth antepartum and postpartum time periods.

Routine administration of labetalol to patients whowere not hypertensive after the first dose did notresult in hypotension or fetal compromise.

The neonatal outcomes were similar with no sig-nificant differences being detected. In particular,neonatal bradycardia and hypoglycemia were notseen. The nursing staff and doctors were very recep-tive to the protocol and preferred using labetalol,which they found easier, less time-consuming, andmore comfortable for their patients than standardMgSO4 therapy. Obviously, the numbers in this pre-liminary study are not sufficient to completely ad-

dress the issue of safety, and the preliminary study

was undertaken to test the protocol suitability for themulticenter study, to identify any potential logisticproblems, and to assess the satisfaction of the pa-tients, nurses, and physicians with the study. Thesafety issues have been addressed by others, and wefeel comfortable that labetalol is both safe and effi-cacious for hypertension control in preeclampsia.ACOG (5) has recommended this drug as an alter-native to hydralazine, and Walker (67) has amassedsufficient data to show that the drug is safe as a singleagent in preeclampsia and chronic hypertension.Most units around the country use labetalol as either

their primary or secondary agent for the control of hypertension in preeclampsia, and no safety issueshave been raised over the many years that this drughas been in use.

THE LAMPET STUDY

On the basis of our pilot study, we have initiatedthe LAMPET (Labetalol versus Magnesium Sulfatefor the Prevention of Eclampsia Trial) study, a mul-ticenter, randomized, controlled clinical trial compar-ing the antiseizure effect of parenteral and/or oral

labetalol (n 4000) versus parenteral (intravenousor intramuscular) MgSO4 (n 4000) with mild orsevere preeclampsia who are deemed to be atsufficient risk to warrant seizure prophylaxis withMgSO4. Patients receiving labetalol will either begiven a 20-mg intravenous loading dose followed bya 200-mg oral dose every 6 hours from the time of inclusion in the study until 24 hours postpartum orwill receive only the 200-mg oral dose every 6 hoursfrom inclusion. Whether or not an intravenous doseis necessary will be decided by the clinician incharge. Only patients thought to be at sufficient risk

Fig. 5. Antepartum (left panel) and postpartum (right panel) blood pressures for the labetalol and MgSO4 groups. The postpartum

systolic and diastolic blood pressures were significantly lower in the labetalol group than in the MgSO4 group (72).




to warrant immediate antihypertensive therapy willreceive the initial intravenous dose. Patients random-ized to the MgSO4 group will receive intravenousMgSO4 as a 4- or 6-g loading dose over 20 minutesfollowed by a 1- or 2-g per hour continuous infusionuntil 24 hours postpartum. The exact MgSO4 proto-col used will be determined by the protocol in use ateach institution. We have previously shown in theNimodipine study (as have others with the MAGPIEstudy) that there is no difference in seizure ratesbetween protocols that use 1-g per hour and 2-g perhour maintenance infusions.

Patients on the labetalol arm of the study whoconvulse will be treated with MgSO4. Patients on theMgSO4 arm who convulse will continue to receiveMgSO4. All patients who convulse will be man-aged per the unit’s standard protocol for eclampsia

treatment.All patient data will be recorded in an Internet-

based interactive computer database. The URL is www.labetalol.org and a testing/training program can beaccessed by interested parties using the URL www.medscinet.com/labetaloltest/, login name: training, pass-word: training. This will allow the potential site princi-pal investigator to review the training web site. Thedatabase satisfies all HCA, HIPPA, FDA CRF 21 Part11, and NIH security protocols. We are currently recruit-ing sites and any interested parties can contact the studycoordinator [email protected].

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Magnesium Sulfate and Eclampsia