Management of complicated preeclampsia

Management of Complicated Preeclampsia James W. Van Hook

The complicated preeclamptic patient represents a challenge for the clinician faced with her antepartum or postpartum care. The most serious sequelae of preeclampsia account for a significant portion of maternal morbidity and mortality. Severe preeclampsia also results in an appreciable portion of perinatal morbidity and mortafity. In this review, developing trends in the treatment of severe preeclampsia are discussed. Expectant treatment of the patient remote from term, anesthesia choices, and delivery route are reviewed. Developing trends in the pharmacological approach to complicated preeclampsia are discussed. New concepts in the treatment of cerebrovascular preeclampsia and hepatic rupture are outlined and reviewed.

Copyright 9 1999 by W.B. Saunders Company evere preeclampsia presents many unique

S challenges to the obstetric care provider. Because severe preeclampsia may manifest as a multisystem disease, several unique therapies have been directed at the multisystem treatment of severe preeclampsia. In this review, we discuss several developing issues in the treatment of severe preeclampsia. We outline advances in several investigational therapies. We also evaluate new concepts in relation to traditionally held beliefs in the antepartum and postpartum care of the patient with severe preeclampsia and HELLP syndrome (severe preeclampsia syndrome of hemolysis, thrombocytopenia and hepatic involvement). We also review current analyses of delivery options and discuss the issue of expectant m a n a g e m e n t of the preterm patient with severe preeclampsia.

Expectant Management C u n n i n g h a m et al I precisely outlined the ultimate goals sought after in the care of any patient with severe preeclampsia: "termination of pregnancy with the least possible trauma to mother and fetus, birth of an infant who subsequently thrives, and complete restoration of health to the mother." Any treatment used on the patient From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX. Address repnnt requests to James W. Van Hook, M.D, Assistant Professor, Maternal Fetal Medicine, University of Texas Medical Branch at Galveston, Department of Obstetrics and Gynecology, 301 University Blvd, Galveston, TX 77555-0587. Copyright 9 1999 by W.B. Saunders Company 0146-0005/99/2301-0009510. 00/0

with severe preeclampsia must have those three goals in mind. Because the only known cure for preeclampsia is delivery, any delay in delivery must be underscored by a clear picture of whatever benefits are to be gained by delay in delivery. With those ideas in mind, several investigations have been made regarding the feasibility of delayed (expectant) delivery of the patient with severe preeclampsia remote from term. Sibai and Frangieh 2 were early proponents of expectant management. In 1990, Sibai reported outcome in 109 patients between 24 and 28 menstrual weeks' gestation. Patients were selected for expectant m a n a g e m e n t based on the precise nature of their disease. Subjects with severe thrombocytopenia, fetal indications for delivery, or accelerated disease were not treated expectantly. The expectantly managed cohort received daily antenatal testing. Any patient less than 24 weeks' gestation was not treated expectantly but was counseled strongly concerning interruption of pregnancy. Compared with a control group of source preeclamptic patients who delivered either immediately or after corticosteroid administration, the expectantly managed group had a significantly higher perinatal survival rate (76.4% v 35%) and lower perinatal morbidity. Interestingly, maternal morbidity was not significantly different between the control group and the expectantly managed c o h o r t / Sibai's results were appreciably better than those of several other early studies. 4-6 Moodley et al 7 reported in 1993 less than favorable results with expectant management. Others have reported similar findings. 8 In review of these findings, the clear difference between the more favorable resuits appear to occur in circumstances in which

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selection for expectant m a n a g e m e n t is m o r e particular and in potentially viable gestational age patients in whom delayed delivery might r e d u c e fetal or neonatal morbidity and mortality (ie, after 24 weeks' gestation, but in fetuses of less than 1,500 grams). 9 As an additional end o r s e m e n t of expectant management, at least one study evaluating the 2-year neurodevelopm e n t o f expectantly managed offspring showed n o increased risk from expectant management. Neurodevelopmental risk in delivered and expectantly managed cohorts was most related to prematurity. 1~ More recently, Visser and Wallenburg 11 rep o r t e d successful results in the expectant mana g e m e n t of patients with severe preeclampsia between 20 and 32 weeks' gestation. Maternal morbidity and mortality rates were not increased in comparison with historical controls. Further work by Sibai et aP 2 evaluated expectant mana g e m e n t at 28 to 32 weeks' gestation. Patients were selected randomly to delivery immediately (after corticosteroid treatment if possible) or to expectant management. Once again, worsening thrombocytopenia, neurological symptoms, uncontrolled hypertension, fetal considerations, or increasing liver enzymes were end points for delivery in the expectant care group. Neonatal complications were significantly lower in the expectant care cohort, with n o appreciable difference in maternal outcome. 12 An important consideration made repeatedly by Sibai et aP 2 was the issue of tertiary care evaluation for any patient treated expectantly. T h e issues of fetal monitoring, amniotic fluid volume, and degree of proteinuffa have also b e e n addressed. Chaff et a113 evaluated fetal monitoring in expectantly treated patients. Daily antenatal testing was u n d e r t a k e n by nonstress testing or biophysical profile testing. In their relatively small stud}, (n = 68), no stillbirths o c c u r r e d in the tested patients. Chaff et al, 13 therefore, r e c o m m e n d e d daily antenatal testing of expectantly treated severe preeclamptic patients. To assess the usefulness o f amniotic fluid evaluation in the expectantly treated patient, Schucker et aP 6 reviewed perinatal outcome in relation to amniotic fluid volume (as measured by amniotic fluid index). Schucker et al n o t e d that, although an amniotic fluid index of less than 5 cm was somewhat predictive o f intrauterine growth delay, there was no association be-

TaMe 1. Important Points for Expectant Management of Severe Preeclampsia Issue

Gestational age Location Antenatal testing Delivery endpoints

Comment

Not recommended for <24 weeks' or >34 weeks' gestation Tertiary care center Daily (Type?) Cerebral preeclampsia Abnormal fetal testing HELLP Risk-benefit issues

tween the amniotic fluid index status and frequency of cesarean section for fetal distress or nonreassuring fetal testing. 14 Results of an earlier study at the same institution showed similar findings. 15 It is currently unclear as to the relationship between the degree of maternal proteinuria and maternal or fetal o u t c o m e in those patients with severe preeclampsia treated expectantly. At least two recent investigations do not show a relationship between outcome and the a m o u n t of proteinuria, a6,17 In review of the data just presented, several considerations come to light (Table 1). The first important point involves careful patient selection. As stated earlier, the immature (less than 24 weeks) and the relatively mature fetus (>32 t o 3 4 weeks' gestation) generally do not benefit from expectant management. T h e gravida who is 24 weeks or less with severe preeclampsia represents a c o h o r t in which a 1- to 2-week delay in delivery often does not impact favorably on neonatal survival. Pregnancies o f greater than 32 to 34 weeks' gestation generally also do not benefit neonatally from delay in delivery. Because maternal risks are present, the careful assessment of whatever realistically expected potential neonatal gains n e e d to be considered in any patient with expectantly treated severe preeclampsia. Also, because o f the severe ramifications of maternal cerebral disease or hepatic rupture, patients with consistently present neurological signs or symptoms or patients with worsening hepatic or hematologic consequences n e e d to be considered for delivery. Another issue involves daily antenatal testing. It appears to be advisable to perform fetal and maternal evaluations daily on patients treated expectantly. It is still not clear as to the potential

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superiority of one type of antenatal fetal surveillance as compared with others. The daily performance of testing, whatever the type (nonstress testing, biophysical profile testing, or contraction stress testing), is probably more important than the test used. As stated above, amniotic fluid volume assessment probably is not the most important testing modality in expectantly treated patients with severe preeclampsia. A final important issue mentioned above is one of tertiary care transfer. Because of the complexities involved in the care of obstetric patients with severe preeclampsia expectantly treated, tertiary care transfer and the resulting m a n a g e m e n t by clinicians experienced in the treatment of preeclampsia is advisable.

Route of Delivery With Severe Preeclampsia Once the decision to initiate delivery in the severe preeclamptic patient becomes clear, considerations regarding the route of delivery need to be evaluated. Issues related to induction of labor also need to be considered. It is important to emphasize that there is no one correct delivery method for the patient with severe preeclampsia. Consideration of maternal disease state, fetal tolerance, and the usual obstetric issues germane to labor and delivery all need to be addressed in each patient individually. Nonetheless, several investigations into delivery route or induction methodology have been undertaken in women with severe preeclampsia. Most authorities agree that, if possible, vaginal delivery should be attempted. One of the larger evaluations published in 1984 by Pritchard et al ia supports vaginal delivery. The American College of Obstetricians and Gynecologists encourages an attempt at vaginal delivery, even in cases of severe preeclampsiaA 9 Of course, as stated previously, careful consideration of the obstetric issues involved in any given patient may modify one's choice of delivery route. Fetal intolerance of labor, malpresentation, previous obstetric history, and other factors all generally should play a role in the delivery route selected in the patient with severe preeclampsia. The decision to induce the nonlaboring patient who has severe preeclampsia has received some investigation. A traditionally held belief

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regarding preeclampsia is the thought that patients with preeclampsia are either in labor or are easily induced. ~~ That belief has persisted despite outcome studies that report higher uncorrected rates of cesarean delivery in preeclamptic patients. ~,5 Recently, Edwards and Witter 23 compared the duration of labor and incidence of cesarean section in nulliparous patients with preeclampsia and uncomplicated nulliparous gravidas. Even when controlled for confounding variables, both the length of labor and the incidence of cesarean delivery were higher in the preeclamptic subsetY 2 Xenakis et a123 recently reported a fourfold higher induction failure rate and a twofold higher cesarean section rate in preeclamptic compared with nonpreeclamptic subjects. It is important to note, however, that the majority of preeclamptic patients that were induced did deliver vaginally. Xenakis et al 2a suggested that an integrative approach, using prostaglandin cervical ripening, early amniotomy, and oxytocin administration was the most successful induction plan in patients with severe preeclampsia. Cervical ripening with prostaglandin E 2 gel is supported by the American College of Obstetricians and Gynecologists. 24 Cervical ripening with prostaglandin E 1 methyl analogue also has been reported as successful in patients with severe preeclampsia remote from term. 25 Finally, induction appears to be a reasonable option in the carefully selected pregnancy complicated by preeclampsia with the very low birth weight infant. ~6 From the above investigations, one can surmise that induction of labor with attempted vaginal delivery is a reasonable option in the patient requiring delivery. Once again, other obstetric consideration needs to be evaluated. Preliminary data suggest that both prostaglandin E 2 gel and prostaglandin E 1 methyl analogue may have a place for cervical ripening in the preeclamptic patient needing delivery. It must be realized that in some individual cases, a seriously ill patient with an unfavorable cervix who is remote from delivery, may be better served by cesarean delivery. Clinical circumstances ultimately must dictate the delivery route. 19 Choice of anesthetic technique is another controversial issue relating to the intrapartum care of preeclampsia. Traditionally, use of regional anesthesia (spinal and epidural) was discouraged in patients with severe preeclampsia.

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TaMe 2. Limitations of Labor Anesthetic Techniques in Preeclampsia Technique

General anesthesia Epidural anesthesia Parenteral analgesia

Limitations

Airway issues, induction hypertension Intravascular volume issues, thrombocytopenia Efficacy

Concerns over precipitation of hypotension, complications from preanesthetic volume preload therapy, and issues surrounding thrombocytopenia all were and are potential concerns over the use of regional techniques for pain relief during labor and cesarean delivery. 1s,27,28As low-dose, lowconcentration epidural techniques were developed, other authorities advised epidural anesthesia for labor pain relief and for cesarean section anesthesia in patients with severe preeclampsia. It was felt that epidural anesthesia served to reduce vasospasm and hypertension (while increasing uteroplacental blood flow) in such patients. 29-32 For cesarean section, additional risks found in patients with preeclampsia (other than those usually described with general endotracheal anesthesia) included hypertension, intracranial hemorrhage, pulmonary edema, and laryngeal edema. 33-35 T o address the issues described, Wallace et a136 randomized anesthetic technique in pregnancies complicated by severe preeclampsia in which cesarean delivery was performed. Wallace et a136 c o n c l u d e d that, provided a careful approach was u n d e r t a k e n to address the complications described above, regional and general anesthetic techniques both have appropriate use. To that end, the American College of Obstetricians and Gynecologists suggests that epidural anesthesia (or parenteral analgesia) is suitable for labor pain relief, and regional or general anesthesia is acceptable for cesarean delivery, d e p e n d i n g on the individual clinical circumstances. 19 Conclusions can be drawn from the above information. All anesthetic and analgesic choices carry some risks and exhibit some shortcomings (Table 2). Individual patient concerns, clinical circumstances, resource availability, and operator experience should all play a part in the choice o f anesthetic technique. Thrombocytopenia, for example, probably would be a contraindication to regional anesthesia. In contradistinc-

tion, airway issues might favor a regional approach. Complications are not avoidable, even with p r o p e r technique. However, careful selection of the best technique for a particular given patient will minimize whatever risks are present.

The Pulmonary Artery Catheter and Severe Preeclampsia The pulmonary artery catheter is (debatably) an important central hemodynamic adjunct in the treatment o f critically ill patients. Pulmonary artery catheters were first described as being used in preeclampsia approximately 20 years ago. Early m e a s u r e m e n t o f central hemodynamics in severe preeclampsia suggested hyperdynamic myocardial contractility, elevated systemic vascular resistance (SVR), absence of interrelated pulmonary hypertension, and p o o r correlation between central venous pressure and p u l m o n a r y artery occlusion (wedge) pressure (PAWP)fl 7-39 Eclamptic patients afforded a similar clinical pattern. 4~ When a larger n u m b e r of patients were studied, a somewhat more variable hemodynamic picture became apparent. Cardiac o u t p u t (CO) was f o u n d to be variable. PAWP could be low, normal, or elevated. Ventricular function usually was hyperdynamic, albeit in patients with markedly elevated SVR, contractility could be depressed. 41 Overall, the hemodynamics of severe preeclampsia may be variable. A complete review and discussion notwithstanding, pulmonary artery catheters provide several basic pieces o f hemodynamic information. Because CO can be measured directly via thermodilution, ventricular function can be measured. More importantly, relative myocardial performance can be related to left ventricular diastolic volume through the pressurevolume interrelation inferred from PAWP measurement. Also, by knowing mean arterial blood pressure and measuring CO, vascular resistance may be calculated. Finally, if arterial oxygen content is known, CO m e a s u r e m e n t allows calculation o f total body oxygen delivery. Oxygen consumption may also be derived. 42 The a f o r e m e n t i o n e d hemodynamic information may be used diagnostically or clinically. Oliguria and pulmonary e d e m a can be characterized and treated, comorbid medical complications can be managed, the technique may afford a degree of

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hemodynamic safety during the delivery of anesthesia, and refractory hypertension can be addressed. The American College of Obstetricians and Gynecologists essentially lists the circumstances as just described as indications for pulmonary artery catheter use during pregnancy. 19 It should be emphasized that all patients with severe preeclampsia do not need pulmonary artery catheters. Excellent clinical results in the care of pregnancies complicated by severe preeclampsia have been published in which pulmonary artery catheters were not used routinely, is In the diagnosis and treatment of oliguria, Clark et al 4s described three hemodynamic subsets. The first and largest subset displayed hyperdynamic ventricular function, low PAWP, and moderately elevated SVR. The diagnosis of hypovolemia produced this clinical picture. Effective treatment consisted of volume expansion. Clark et al's second hemodynamic cohort exhibited normal or increased PAWP, normal CO, and normal SVR. This group was not volume depleted but exhibited severe renal arterial spasm. Renal dose dopamine or mild afterload reduction was the treatment of choice. Finally, a third hemodynamic profile exhibited elevated PAWP, elevated SVR, and depressed ventricular function. Such patients were volume overloaded with a massive increase in systemic afterload. Aggressive afterload reduction and volume restriction were tenets of treatment. 4s Clark et al's 43 work suggests that the majority of patients with oliguria are volume depleted. However, in patients who either do not respond to volume therapy, or in those who cannot safely receive volume therapy (such as the patient with hypoxemia), the/pulmonary artery catheter can be useful in the hemodynamic stratification of the therapy used to treat the oliguria. Pulmonary edema may be hydrostatic, oncotic, or caused by membrane capillary defects. Pulmonary edema in the preeclamptic patient is often multifactorial in etiology. Benedetti et al's 44 classic description of all three subsets when central hemodynamics were applied to severe preeclamptic patients with pulmonary edema suggests some role for central hemodynamic monitoring. Once again, indications for pulmonary artery catheter monitoring in preeclampsia complicated by pulmonary edema may be in the care of the patient with disease unresponsive to a simple trial of diuresis, to treat the patient with

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coexisting oliguria, or in the treatment of the worsening patient who requires intubation and mechanical ventilation. Large studies do not exist concerning the use of central hemodynamic monitoring for treatment of refractory preeclampsia-associated hypertension. Pulmonary artery catheters are used for this indication in the nonpregnant patient with severe hypertension. 42,45 Selective use of specific hemodynamically active antihypertensives may be categorically applied through the use of a pulmonary artery catheter. Noninvasive hemodynamic stratification of hypertension has been described. Easterling and Benedetti 46 developed a Guytonian model in a description of the variable hemodynamic picture associated with hypertension during pregnancy. High CO, high SVR, and mixed hemodynamic subsets were described. Crossover to a high resistance state appeared to be a late finding. The implications of this intriguing model are not yet fully clear. Another interesting hemodynamic concept that may relate to severe preeclampsia is the disease's effect on oxygen consumption. As related above, global oxygen delivery can be calculated as the produce of oxygen content and cardiac output. Global oxygen consumption can be derived as the product of cardiac output and the difference between arterial and mixed venous oxygen content. 45 Normally, global oxygen delivery is well in excess of tissue oxygen consumption. In many disease states (such as sepsis), oxygen consumption is diminished. Increasing oxygen delivery increases oxygen consumption. In such a state, oxygen consumption is described as being "oxygen delivery dependent. "47 In severe preeclampsia, Belfort et al 4s studied oxygen consumption and delivery. They used pulmonary artery catheters to hemodynamically calculate oxygen delivery, oxygen consumption, and the oxygen extraction ratio (oxygen consumption/oxygen delivery). Belfort et al 4s found that severe preeclampsia is a state of abnormal (elevated) oxygen extraction indicative of delivery-dependent consumption. Belfort and Saade 49 also showed a relationship between ophthalmic artery diastolic velocity and impaired oxygen delivery. Therapeutic interventions have been directed at supranormalizadon of oxygen delivery in nonpregnant patients with abnormal supply depen-

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TaMe 3. Pulmonary Artery Catheter Indications in Severe Preeclampsia Refractory oliguria Refractory hypoxemia Hypertensive crisis management Management of comorbid conditions

dent oxygen consumption. In the treatment of trauma, optimization of oxygen content and pharmacotherapy directed at increasing cardiac output has been used to favorably impact outcome. 5~ Although more recent investigations in n o n p r e g n a n t patients with sepsis have not been so encouraging, the application of oxygen delivery therapy to pregnant patients with severe preeclampsia remains an interesting concept. Wheeler et a152 demonstrated increased calculated base deficit in severe preeclampfic patients with impaired oxygen delivery. Wheeler et a152 questioned the potential relationship between mounting oxygen debt, base deficit and end organ damage. 25 At this time, the use of oxygen delivery therapy in severe preeclampsia remains highly investigational. Nonetheless, the implications of impaired oxygen debt in severe preeclampsia may hold future promise. Pulmonary artery catheters may have indications in the care of specific subsets of patients with severe preeclampsia (Table 3). Refractory oliguria, unresponsive pulmonary edema, coexisting medical disease, and (perhaps) hemodynamically-directed treatment of intrapartum or intraoperative hypertension may be potential indications for the technology. Future research may yield new indications for the use of pulmonary artery catheters in preeclampsia. That research notwithstanding, pulmonary artery catheters are not, in themselves, therapeutic. Furthermore, the majority of patients with preeclampsia can be safely treated without them.

Investigational Pharmacotherapies of Severe Preeclampsia Despite our unfortunate lack of a clear understanding as to the precise etiology of preeclampsia, inroads into the pharmacological treatment of severe preeclampsia have been made. In addition to seizure prophylaxis and treatment of hypertension, several investigative therapies may

offer future promise in the prevention or amelioration of the disease. Plasmapheresis, a process in which varying amounts of the noncellular portion of a given patient's circulating blood volume is replaced with donor plasma, has been useful in the treatm e n t of n o n p r e g n a n t patients with a variety of autoimmune disorders. Specifically, plasmapheresis has been used in the treatment of thrombotic thrombocytopenia purpura (TTP), hemolytic uremic syndrome (HUS), systemic lupus erythematosus, and other autoimmune renal diseases. 53,~4 Because of both the possible autoimmune etiology of preeclampsia and the fact that severe preeclampsia often is clinically confused with (and possibly related to) TTP and HUS, plasmapheresis has been investigated in pregnancy complicated by severe preeclampsia. Several case reports and small series show variable results with the antepartum treatment of severe preeclampsia or HELLP with plasmapheresis. 5~-57 It is interesting to note that these early investigations do not clearly discern the diagnosis of HELLP from that of TTP. Needless to say, the antepartum treatment of severe preeclampsia by plasmapheresis has not been wholly successful. More favorable results have been garnered from the postpartum treatment of subjects with persistent HELLP syndrome. Katz et al 5s reported the successful treatment of refractory postpartum HELLP syndrome with plasmapheresis. The three patients reported on over a 2-year period were begun on plasmapheresis by postpartum day 4 to 5 if the usually expected postpartum clinical improvement with HELLP was not seen. Katz et al 5s used the clinical signs of persistent thromobocytopenia or persistent hemolysis as the key indications for plasmapheresis. In a larger postpartum series, Martin et a159 treated 18 patients with persistent HELLP. The criteria used to institute plasmapheresis were persistent or worsening hypertension, hemolytic anemia, or hepatic preeclampsia that had not resolved after 72 postpartum hours of expectant management. Recalcitrant multisystern dysfunction was also an indication for exchange. Martin et al's findings were interesting in that those patients without other mulfiorgan involvement responded rapidly to one or two daily 3-L plasma exchanges. In patients with other organ involvement, the response was variable. Two maternal deaths occurred in this latter

Management of ComplicatedPreeclampsia

group (neither directly related to plasmapheresis) .59 Plasmapheresis has also been used successfully in conjunction with other treatments for T T P and HUS during pregnancy and in the postpartum period. 6~ Plasmapheresis has been used in both antepartum and postpartum patients with severe preeclampsia. The antepartum use o f plasmapheresis (for preeclampsia) is not well founded. More data exist on the use of the modality postpartum. If plasmaapheresis is to be used, most authorities r e c o m m e n d it be used after conventional treatments have failed. Because plasmapheresis is probably useful in patients with HUS or TTP, it may be indicated in some postpartum patients in whom the precise diagnosis is unclear (TTP versus HUS versus HELLP). Also owing to traditional treatment o f autoi m m u n e disorders in n o n p r e g n a n t individuals is the use of corticosteroids in severe preeclampsia. Clark et al 6x reported an early description o f reversal o f hematologic abnormalities associated with HELLP syndrome. At least one o t h e r small series suggested the use o f corticosteroids for the treatment of HELLP syndrome. 6~ More frequently, as a result of analysis of the use of corticosteroids to accelerate fetal lung maturity, Magann et a163 noted what appeared to be a positive impact on maternal o u t c o m e in pregnancies complicated by severe preeclampsia in which corticosteroids were administered. Subsequently, Martin et a164 published a retrospective analysis concerning the use of pharmacological doses of dexamethasone in postpartum patients with refractory HELLP syndrome. Patients with refractory postpartum disease were given intravenous dexamethasone (10 mg every 12 hours) until clinical improvement began. T h e dose was then reduced by one half and summarily discontinued. Despite being significantly more ill than the comparative control group, those patients who received dexamethasone had quicker resolution of hematologic and hepatic sequelae, less morbidity, and shorter hospitalizations. 64 At least one other group of investigators r e p o r t e d similar findings, albeit with less i m p r o v e m e n t of hypertension and hepatic sequelae. 65 These preliminary findings suggest that there might be a place for corticosteroid treatment o f resistant postpartum HELLP syndrome. Further investigation in this area certainly is warranted. A n o t h e r area of investigative therapy used in

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severe preeclampsia is in the administration of various vascular active mediators. Intravenous prostacyclin has been advocated in the treatm e n t o f severe preeclampsia. Its potential efficacy is based on the now less popular prostaglandin etiologic pathogenesis of preeclampsia. deBelder and Weston 66 r e p o r t e d the use of a continuous infusion of epoprostenol (prostacyclin) as a treatment adjunct in HELLP and T T P during pregnancy. Moodley and Gouws 67 evaluated the antihypertensive effects of epoprostenol and f o u n d the effects similar to intravenous hydralazine. H u b e r et a168 described a single case o f refractory HELLP thought to improve through the use of epoprostenol. Clarification of the indications and efficacy o f prostacyclin in severe preeclampsia await further study. Nitric oxide (NO), also known as endothelialderived relaxation factor (EDRF) is a n o t h e r mediator that has been investigated regarding its relationship to preeclampsia. NO is a highly effervescent free radical gas p r o d u c e d by vascular endothelium. EDRF works as a transcellular messenger by activating guanylate cyclase, an enzyme that catalyzes the production of cyclic guanosine m o n o p h o s p h a t e . Cyclic guanosine m o n o p h o s p h a t e activates cellular protein kinases, leading to dephosphorylation and relaxation of smooth muscle. NO is p r o d u c e d by enzymatic synthesis from L-arginine, L-arginine analogues such as 2~methyl-L-arginine (LNMMA), and N~nitro-L-arginine methyl ester (LNAME) .69 In normal pregnancy, NO seems to be involved in refractoriness to the pressor effects of angiotensin II, the regulation o f uteroplacental blood flow, and inhibition of uterine contractility. 70"72 Because o f its diverse effects on endothelial cells and the effects just listed, NO may play an important role in the pathogenesis of preeclampsia. 7~ In at least one animal model, LNAME inhibition o f NO synthesis p r o d u c e d a clinical syndrome similar to preeclampsia. 7~ T h e administration of the N O d o n o r glyceryl trinitrate to p r e g n a n t h u m a n s at high risk for the development of preeclampsia p r o d u c e d an increase in uterine artery blood flow. TM Hardy et a175 showed that platelets from preeclamptic donors are m o r e sensitive to the effects o f NO than are the platelets of normal p r e g n a n t controls. Gonzalez et a176 recently investigated the effects of various nitrovasodilators on uterine and pla-

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cental vessels from normal and preeclamptic donors. NO production through nitrovasodilator administration, produced effects that were equivalent in both cohorts. Areas of ongoing research on the interaction and effects of NO on pregnancy complicated by preeclampsia include L-arginine supplementation, use of sulfhydryl group donors, and use of NO donors (such as nitroprusside and nitroglycerine). 60 Although not yet clinically useful, research may identify important uses for NO therapy in the managem e n t or prevention of preeclampsia.

Management Options for Complications of Severe Preeclampsia Despite appropriate care, the diagnosis of severe preeclampsia places the antepartum or postpartum patient with the disorder at appreciable risk for serious sequelae. In other sections of this issue, developing trends in the care of several of those complications are discussed. We, therefore, limit our discussion to the diagnosis and m a n a g e m e n t of cerebrovascular accident and hepatic rupture as they relate to severe preeclampsia.

Cerebrovascular Accident In addition to eclampsia and the other more commonly seen central nervous system (CNS) manifestations of preeclampsia (photophobia, amaurosis, headache), cerebral edema, coma or cerebral hemorrhage may occur as complications of preeclampsia. Cerebral edema and hemorrhage are two major causes of maternal mortality in preeclampsia. The combination of coagulopathy and hypertension may result in cerebral hemorrhage (PIH chapter in crit care book). Cerebral edema can occur through several mechanisms. In severe preeclampsia/eclampsia, the process most likely occurs either as a result of loss of normal cerebral autoregulation or hypoxic encephalopathy. 77 Mechanistically, cerebral edema is most likely vasogenic (from direct vascular damage), but the precise mechanism currently is not known. Primary cerebral hemorrhage from preeclampsia usually is in patients with underlying hypertension. A minority occurs as a result of previously undiagnosed cerebral vascular malformations. 1

Several interesting features of cerebral physiology and pathophysiology may aid our understanding of acute and secondary brain injury in preeclampsia. Cerebroautoregulation normally maintains a fairly constant cerebral blood flow over mean arterial blood pressures of 50 to 150 m m Hg. In n o n p r e g n a n t patients with chronic hypertension, autoregulation is skewed. 7s Precisely how cerebral autoregulation is altered during normal pregnancy is not known. The hyperventilation normally seen during pregnancy may also affect cerebral autoregulation. In nonpregnant subjects, hyperventilation acutely reduces cerebral blood flow, with maximal effect occurring in the 26 to 28 m m Hg Paco 2 range. 79 Because pregnancy is a state of chronic hyperventilation, the intrinsic impact this hyperventilation has on cerebral autoregulation is unclear. Also, the effects of forced hyperventilation (above the normal physiological hyperventilation of pregnancy) are not known. The traditional model of focal CNS injury involves the death of directly involved cells, an ischemic penumbra of damaged neurons, and a surrounding population of healthy cells. The reduction of secondary injury in the minutes to days after a primary insult is thought to reduce healthy cell injury and ischemic penumbra cell death. Attempts to limit secondary injury constitute the philosophy behind most therapies for cerebrovascular accident (CVA) in the nonpregnant population. 7s An evolving idea in the pathophysiology of CVA is the possibility that some neurons may survive longer periods of low or absent cerebral blood flow.s~ In any case, limitation of secondary injury and reperfusion of injured areas are both mainstays of modern CVA treatment. The underlying vascular abnormality most associated with severe preeclampsia-eclampsia is vasospasm. Several recent findings have suggested that cerebral vasospasm may be present in severe preeclampsia or eclampsia, Giannina et al sl suggested that vasoconstriction persisted postpartum by observing changes in retinal artery velocimetry. Using transcranial Doppler velocimetry, Williams and Wilson s2 found significantly higher middle cerebral artery velocity in posteclamptic seizure patients as compared with nonseizing severe preeclampfic controls. Qureshi et al s3 reported similar results. Interestingly, the measurements of Qureshi et al s3 in

Managementof ComplicatedPreeclampsia

Table 4. Potential Treatments of Cerebral Edema Osmotic therapy Fluid restriction Controlled hyperventilation

nonseizing preeclamptic patients were comparable with normal pregnant controls. It was only in eclamptic patients that Doppler evidence of vasospasm existed. Cerebral blood flow itself was found to be increased in patients at high risk for preeclampsia, with the increase found long before any symptoms of preeclampsia developed. 84 The above findings suggest that focal or diffuse cerebral vasospasm may play at least some role in the cerebrovascular sequelae of preeclampsia. Cerebral blood flow may be increased, with vasospasm as a late finding (or as a precursor to eclampsia). If that supposition is correct, then some of the treatments and strategies used in the care of n o n p r e g n a n t patients with cerebral vasospasm may offer future promise in preeclampsia-eclampsia. Magnesium sulfate, recently endorsed as efficacious in both prevention and treatment of eclampsia, may have as a mechanism of action the reduction of cerebral vasospasm. 85,86 Although not as effective as other therapies (such as the cerebroactive calcium channel blocking agent nimodipine) in the treatment of subarachnoid hemorrhage-induced vasospasm, magnesium sulfate has cerebral antispasmodic activity. Other treatments for vasospasm may one day have a role in treatment or prevention of elcampsia. Current strategies for the treatment of cerebral edema includes osmotic therapy, controlled hyperventilation, intravenous fluid restriction, and intracranial pressure monitoring (Table 4) .78.79 It is not known if such treatments, primarily developed for n o n p r e g n a n t patients with cerebral edema, are effective in edema caused by preeclampsia. Some modalities, such as intracranial pressure monitoring, may not be possible because of the concomitant presence of coagulopathy. Magnesium sulfate should probably remain a mainstay of the underlying treatment of eclampsia. Traditional treatment of seizure activity should be considered in patients with secondary injury or anoxia-induced seizure activity. Control of hypertension, without overtreatment, may also have some protective or therapeutic benefit if brain injury mechanisms in preeclamp-

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sia-eclampsia are analogous to those found in n o n p r e g n a n t patients with CVA. s~

Hepatic Rupture In severe preeclampsia, subcapsular h e m a t o m a (and hepatic rupture) probably occurs as a result of vasospasm-induced hepatic infarction. A biphasic pattern of presentation has been described, with epigastric pain and gastrointestinal symptoms preceding frank hemorrhage and vascular collapse, s7 Traditionally, mortality and morbidity rates were both reported as approximately 60%.ss Elevations of serum transaminases may precede the clinical development of the disease. In some cases, confusion with other diagnoses such as hepatitis or cholecystitis may make the diagnosis of hepatic severe preeclampsia initially confusing. 2s When suspected antepartum, the presence of a subcapsular h e m a t o m a usually is an indication for p r o m p t delivery. If necessary, cesarean section in conjunction with exploration of the upper abdomen and liver should be undertaken. The comorbid circumstances of thrombocytopenia and hypertension may make the treatment of the patient with subcapsular h e m a t o m a particularly challenging. If diagnosed postpartum, individualization regarding laparotomy may be reasonable (because the underlying disease should regress) 23.87.89 If hepatic rupture and hemorrhage are identified at laparotomy, the m a n a g e m e n t choices include surgical packing, use of topical hemostatic agents, vascular ligation, and lobectomy. Conservative m a n a g e m e n t through the use of packing and topical hemostatic agents resulted in improved outcome in at least one series. Smith et a189 reported an analysis of 35 cases of hepatic rupture. Survival was over three times higher (82% v 25%) in patients treated conservatively, as compared with vascular ligation or resection. Although selection bias may have influenced the dramatic difference in outcome between the two m a n a g e m e n t styles (was the decision to manage conservatively influenced by the severity of the hepatic involvement?), the findings of Smith et al s9 suggest an initial role for surgical conservatism. Many patients with hepatic rupture hemorrhage profoundly and are near death at diagnosis. Gravity trousers have been attempted as a heroic measure. 9~ At least

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one case of liver transplant has been reported. Hunter et a191 described a case of massive hepatic rupture in which various conservative and aggressive measures failed. The patient underwent a total hepatectomy, After being anhepatic for 14 hours, she underwent an orthotopic liver transplant and ultimately survived. Hepatic rupture is a potentially life-threaten9 ing complication of severe preeclampsia. Conservative therapy, if possible, is probably initially advisable. The patient with massive hemorrhage from hepatic rupture may not be saved, despite the provision of appropriate care. Prompt recognition and early treatment may reduce the risk of mortality, although the diagnosis initially may be confusing.

Conclusion Severe preeclampsia represents a management challenge for the clinician faced with the diagnosis. Despite ongoing research into the treatm e n t of severe preeclampsia, the most serious sequelae of preeclampsia may result in significant maternal and fetal morbidity. Furthermore, despite the rendering of appropriate, care, the complication s of severe preeclampsia represent some of the leading causes of maternal mortality. Several innovative therapies may soon be available for the antepartum and postpartum treatment of severe preeclampsia. Recognition of advances in the treatment of similar diseases in the n o n p r e g n a n t population may offer treatment options in difficult cases. Early consultation or tertiary care transfer of the particularly complicated patient with severe preeclampsia often is advisable.

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