Acute Hypertensive Crisis in Pregnancy

Medical Problems in Pregnancy

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Acute Hypertensive Crisis in Pregnancy Helayne M. Silver, MD*

The management of hypertensive disorders during pregnancy is greatly complicated by the presence of a fetus in whose interests our care may directly oppose those of the mother. An additional problem is the difficulty in distinguishing those cases where the hypertension precedes pregnancy from those induced by pregnancy. This distinction is important, as the pathophysiology is different, the prognosis for mother and fetus is different and, therefore, our management is different. Many studies of the use of antihypertensive agents during pregnancy have included both types of patients, making interpretation of results difficult. The classification recommended by the American College of Obstetricians and Gynecologists is as follows: (1) pre-eclampsia-eclampsia or pregnancy-induced hypertension; (2) chronic hypertension; (3) chronic hypertension with superimposed pre-eclampsia; and (4) late or transient hypertension. Pre-eclampsia is defined as the onset of hypertension with proteinuria, edema, or both, at greater than 20 weeks' gestational age. Hypertension is defined as a rise in systolic blood pressure of greater than 30 mm Hg or diastolic blood pressure greater than 15 mm Hg or a blood pressure of greater than 140/90 mm Hg on more than two occasions 6 hours apart. Eclampsia is the occurrence of seizures in a patient with pre-eclampsia. Severe preeclampsia is diagnosed when one of the following criteria are found: (1) blood pressure greater than 160 mm Hg systolic or greater than llO mm Hg diastolic on two occasions more than 6 hours apart; (2) proteinuria greater than 5 g per 24 hours or 3 to 4 + on dipstick; (3) oliguria less than 400 ml per 24 hours; (4) cerebral or visual disturbances; and (5) pulmonary edema or cyanosis. Chronic hypertension is diagnosed prospectively when the prepregnant blood pressure is known to be greater than 140/90 mm Hg or is detected prior to 20 weeks' gestation. When hypertension persists beyond 6 weeks postpartum, a diagnosis of chronic hypertension can be made retrospectively. Pre-eclampsia is said to be superimposed on chronic hypertension when

*Assistant

Professor, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of California-Davis, Sacramento, California

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there is an exacerbation of hypertension of greater than 30 mm Hg systolic or 15 mm Hg diastolic, plus the appearance of significant proteinuria or generalized edema. Transient hypertension is the development of hypertension during pregnancy without other signs of pre-eclampsia. The importance of the distinction between chronic hypertension and pre-eclampsia lies in the very different prognosis for an ongoing pregnancy and, therefore, in a very different plan of management. While conservative management of mild pre-eclampsia remote from term is the rule, delivery of the severe pre-eclamptic is always in the best interest of the mother. Temporizing by aggressive antihypertensive therapy to prolong the pregnancy in the interest of the preterm fetus is fraught with dangers for the mother and is not likely to benefit the fetus. In a recent study, Sibai and colleagues60 reviewed the results of conservative management of 60 patients with severe pre-eclampsia at 18 to 27 weeks' gestation. If the patient had a good response to initial stabilization with parenteral hydralazine therapy, the patient was then treated with oral methyldopa and, if necessary, oral hydralazine to maintain a diastolic blood pressure of 90 to 100 mm Hg. Maternal morbidity was high with 21. 7 per cent of patients developing abruptio placentae, 20 per cent thrombocytopenia, 8.3 per cent disseminated intravascular coagulopathy, 16.7 per cent eclampsia, 5 per cent acute renal failure, 3 per cent hypertensive encephalopathy, and one patient each ruptured subcapsular hematoma of the liver and intracranial hemorrhage due to a ruptured aneurysm. While complete statistics are not available on maternal morbidity in severe pre-eclampsia with delivery effected immediately, the reported incidence of eclampsia is 2 per cent,16 of coagulation abnormalities is 10 per cent, 55 and of pulmonary edema is 2 per cent.·5 While the rationale for conservative therapy in the face of extreme prematurity was to decrease perinatal mortality, the outcome was extremely poor with a perinatal mortality rate of 87 per cent.60 In contrast, treatment of severe chronic hypertension will allow prolongation of pregnancy, improvement of perinatal mortality from 50 per cent untreated,16 to no higher than the general population if superimposed pre-eclampsia does not develop. While therapy aimed at prolonging the severely pre-eclamptic pregnancy is not warranted, therapy is required to reduce maternal complications while effecting delivery and awaiting spontaneous resolution. Complications are the result of the altered hemodynamics of severe pre-eclampsia, that can result in underperfusion and damage to maternal organ systems, including the uteroplacental system and, consequently, the fetus. All these complications are the result of the primary vasospastic process that, when not fully compensated, will lead to tissue hypoxia and organ damage. The heart will attempt to compensate for this decrease in flow by increasing its output. This can be done by increasing heart rate or by increasing stroke volume (SV). SV may increase by increasing preload or contractility. An increase in heart rate will decrease diastolic filling time, which may result in a decrease in preload and, therefore, a decrease in Sv. It will also decrease coronary perfusion and increase myocardial oxygen consumption leading to ischemia. Therefore, this compensation could actually lead to further decompensation. When SV is increased by an increased preload making use of the Frank-Starling mechanism, cardiac function improves. When the heart

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dilates to such a degree that further stretching of the myocardial fibers offers no further mechanical benefit and wall tension increases compromising coronary perfusion and increasing myocardial oxygen consumption, the limit of preload reserve is then said to have been reached. 57 When SV is increased by an increase in con tractility by an increase in adrenergic drive, the cost is increased ventricular work, increased myocardial oxygen consumption, and increased afterload that may result in a vicious cycle. Therefore, preeclampsia represents a state of acute increase in afterload secondary to a primary vasospastic process, which requires compensatory adaptations to maintain adequate blood flow and more essentially, delivery of oxygen to vital organs. It follows that the hemodynamic status of the untreated severe preeclamptic would offer much insight into the compensatory mechanisms used in this process and would greatly aid in guidance of therapy. Many studies have been published of the hemodynamic findings in severe pre-eclampsia derived from pulmonary artery catheters (PAC); however, only limited information is available about untreated severe pre-eclampsia. A study of 10 untreated severe pre-eclamptics, not in labor, demonstrated tachycardia, low pulmonary capillary wedge pressures (PCWP), elevated systemic vascular resistance (SVR), and low cardiac output (CO) for pregnancy. 23 These findings suggest the acute pressure load cannot be compensated by an increase in preload because of the limitations of hypovolemia. Intravascular volume depletion is an often described component of pre-eclampsia, with increasing severity as the severity of the disease increases. Sufficient data are not presented in this study to construct left ventricular (LV) function curves, but the data suggest there is an increase in adrenergic drive, although not sufficient to compensate for the afterload mismatch. Increase in sympathetic tone will further increase SVR, and thus a vicious cycle may begin, culminating in LV failure-a not uncommon complication of severe preeclampsia. LV failure in this setting may be purely mechanical but there may also be a metabolic component secondary to tissue hypoxia and acidosis both locally, in the myocardium, and systemically secondary to poor peripheral tissue perfusion. A recent abstract l l examined the hemodynamic findings in 45 severe pre-eclamptics receiving minimal intervention prior to obtaining initial hemodynamic measurements. The patients demonstrated low central venous pressures (CVP), normal PCWPs, elevated SVRs, and minimal tachycardia. Construction of Starling curves revealed 44 per cent of patients to have hyperdynamic, 49 per cent normal, and 7 per cent depressed cardiac function. In those patients with elevated cardiac indexes (Cl), this was due to an increase in SV, not increased heart rate. This study suggests a large number of patients maintain adequate CO by use of the Frank-Starling mechanism. As PCWP is but an indirect measurement of end-diastolic volume (EDV), this is speculative. The discrepancies between these two studies may be explained by some major differences in management and study design. In the first study, the patients had been salt-restricted and may have been unusually hypovolemic. In the second study, it is not specified whether patients are in labor. In normal patients, labor will result in a progressive rise in CO, peaking at 80

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per cent over baseline immediately postpartum. 70 Therefore, it is difficult to interpret the specificity of the finding of a large number of hyperdynamic patients. No study has been performed on the hemodynamic effects oflabor in untreated severe pre-eclamptics, and there is a relative dearth of serial studies of treated patients during labor. One study, by Phelan,49 of four treated patients suggests an increase in CO and LV stroke work index (LVSWI) during active labor. However, these same findings may have occurred as a result of a decrease in SVR secondary to adequate therapy. A study of 10 severe pre-eclamptics in labor by Benedetti and colleagues 4 did not demonstrate a similar rise in LVSWI; these patients, however, were not volume-resuscitated. If little is known about the compensatory mechanisms in untreated severe pre-eclamptics, even less is known of milder pre-eclamptics who rarely require invasive monitoring. These patients have been studied echocardiographically, but again, the results have been conflicting. In normal pregnancy, the heart adapts to the physiologic volume overload by eccentric hypertrophy. This means the heart is dilated but with normal wall thickness, which allows an increase in SV and CO by the Frank-Starling mechanism. :1l.57 However, as the pregnant heart may already be functioning at the limit of preload reserve, an acute increase in afterload might not be compensated by the Frank-Starling mechanism. Veille 71 examined by echo cardiogram the hearts of 23 mild pre-eclamptics and demonstrated concentric hypertrophy typical of chronic hypertension (increase in LV wall thickness to radius ratio). However, unlike nonpregnant patients with chronic hypertension, there was also increased LV end-diastolic dimension and SV of the same magnitude as in normal pregnancies, suggesting these patients may also have limited remaining preload reserve. In contrast, Kuzniar and colleagues 33 .39 examined echocardiographically 42 pre-eclamptics and found no increase in LV wall thickness, normal con tractility but low Cl, and low SV for pregnancy secondary to a relatively low EDY. Of nine patients with severe pre-eclampsia, three also had decreased myocardial con tractility. This study suggests that these patients have a fixed preload secondary to hypovolemia, are not utilizing an increase in adrenergic drive and, therefore, are not hemodynamically compensated. The results of these two groups of investigators are quite disparate, but the groups of patients studied are not comparable. Veille studied mild preeclamptics with a mean arterial pressure (MAP) of 102 ± 8 mm Hg. Some patients had received magnesium sulfate (n = 3) and some, diuretics (n = 2). He does not state whether patients were in labor, a circumstance with tremendous hemodynamic consequences. Kuzniar's patients were sicker, with a mean MAP of 122 ± 11 mm Hg, were untreated, and not in labor. From the results of these noninvasive studies, it is difficult to judge the adequacy of compensatory mechanisms and indeed, it is unclear what mechanisms are in use. One point that is clear is that undertreatment of hypertension is associated with serious complications. Computed tomographic (CT) scans suggest the seizures of eclampsia are the result of vasogenic cerebral edema. 32.52 The etiology is most likely endothelial permeability defects that result from the loss of the protective vasospasm of cerebral autoregulation. The MAP at

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which this occurs varies individually, depending on the patient's normal baseline blood pressure. The normal MAP limits for cerebral autoregulation are 60 to 150 mm Hg, but in a young patient whose normal MAP may be 70 to 80 mm Hg, a MAP of 120 to 130 mm Hg may result in a loss of autoregulation. 17 This explains the frequently observed uncertain relationship between the severity of hypertension and the occurrence of eclampsia, and the importance of adequate blood pressure control. A severe afterload mismatch may culminate in LV failure. Pure cardiogenic pulmonary edema will begin to manifest clinical symptoms at a PCWP of approximately 20 to 25 mm Hg. If the patient also has a low colloid oncotic pressure (COP), as is common with severe pre-eclampsia, pulmonary edema may manifest earlier. Doppler flow studies of the arcuate arteries in the placental bed have demonstrated abnormal flow in the majority of patients with severe hypertension. 68 In addition to the chronic problems associated with decreased placental perfusion such as growth retardation, an acute worsening of vasospasm may further compromise uterine blood flow, precipitating fetal distress. Moreover, untreated hypertension is associated with an increased incidence of abruptio placentae. As there is confusion about the mechanism of physiologic adaptation to the hypertension of pre-eclampsia, it is not surprising that there is also some disagreement as to therapy. Because of the life-threatening complications described, many believe the cardiovascular disturbances of severe preeclampsia warrant intensive therapy. Current treatment strategies usually include a combination of volume expansion and vasodilators. Judicious hydration has been shown by some investigators to significantly decrease MAP, heart rate, and SVR. 23 Others have shown an increase in Cl, oxygen delivery, and a decrease in SVR. 15 Potent vasodilators can be safely used to decrease blood pressure if proper monitoring is performed. Epidural anesthesia will decrease sympathetic tone and has also been advocated as a safe and effective vasodilator that will at least maintain and possibly improve placental perfusion. 29 Vasodilators have also been shown to increase placental blood flow in hypertensive sheep,54 although this has not been consistently confirmed in humans. On the other hand, many physicians are reluctant to treat intensively for fear of complications of therapy. When treating without the benefits of hemodynamic monitoring, complications of therapy are more likely to occur. Reported complications of hydration of severe pre-eclamptics include cerebral edema3 and both cardiogenic and noncardiogenic pulmonary edema. 6 . 66 Vasodilation in the face of hypovolemia may precipitate hypotension and fetal distress. 28 ,51 Hemodynamic monitoring with a CVP line is insufficient as there may be a large disparity in the function of the right and left ventricles in acutely ill patients including severe pre-eclamptics. 13 ,66 Reliable information on LV function can only be obtained by CO determinations, most conveniently by PAC monitoring. Reliable information on volume status can only be obtained by echo cardiographic measurement ofEDY. PCWP reflects LV end-diastolic pressure (EDP), and is used as an indirect assessment of LVEDV, the parameter of interest in assessment of volume status. The relationship of EDP and EDV is nonlinear secondary to decreasing compliance with progressive filling. In acutely ill patients, PCWP correlates

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poorly with LVEDV and is only a minor determinant of SVlO Measurement of plasma volume with the Evans blue dye dilution technique is of questionable significance in the face of capillary leak syndromes, such as preeclampsia. Even when a minimalist approach to therapy is taken, treatment of diastolic blood pressure of greater than 110 mm Hg is felt to be mandatory in prevention of intracranial hemorrhage. When this approach is taken, the usual choice of antihypertensive agent is parenteral hydralazine. When a more intensive therapeutic approach is undertaken, numerous agents have been used. The more commonly employed antihypertensive agents appropriate for therapy of a hypertensive crisis are discussed.

SPECIFIC THERAPY OF ACUTE HYPERTENSIVE DISORDERS IN PREGNANCY Diuretics In the 1960s, diuretics were widely prescribed to treat the physiologic edema of pregnancy. This was felt to be useful in the prevention of preeclampsia73 as well as for therapy. Because pre-eclampsia is a volume-contracted state, initiation of diuretic therapy for the treatment of hypertension in pre-eclampsia is contraindicated. Diuretic therapy is occasionally indicated for treatment of specific complications such as pulmonary edema, where the agent of choice would be parenteral furosemide. The use of thiazide diuretics in pregnancy is controversial. There have been case reports of neonatal thrombocytopenia in association with prenatal thiazide exposure. 56 These fetuses had been exposed to multiple other drugs including amphetamines, prochlorperazine, chlorpheniramine, aspirin, caffeine, and phenacetin; however, thiazide diuretics were the only drugs common to all six cases. The mothers were tested for evidence of antiplatelet antibodies and none were found. In patients with chronic hypertension maintained on thiazide diuretics throughout pregnancy, the physiologic plasma volume expansion of pregnancy was significantly less than that of chronic hypertensives not on diuretic therapy.61 There appears to be little role for thiazide diuretics in pregnancy. SYMPATHOLYTIC AGENTS

Clonidine The experience with clonidine in pregnancy has been much more limited than that of the closely related methyldopa. It has been used successfully in the treatment of hypertensive emergencies in nonpregnant patients. 2.5 Oral administration effects a graded reduction in blood pressure with onset in 30 to 60 minutes and maximum effect at 2 to 4 hours. It has the advantages of ease of administration, gradual reduction of blood pressure, and absence of reflex tachycardia. These characteristics invite a trial of use in treatment of the acute hypertension of severe pre-eclampsia. However, studies of use in pregnancy to date have been in the treatment of chronic hypertension or

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mild pre-eclampsia in ongoing pregnancies. In a study by Horvath and colleagues,26 the therapy of mild pre-eclamptics was randomized to clonidine or methyldopa. Results in both groups were equivalent with equal control of hypertension, no difference in the incidence of fetal growth retardation, fetal distress, low Apgar scores, low umbilical cord pHs, or neonatal hypotension. There has been only one study on the long-term effects of prenatal exposure to clonidine. A retrospective study identified 22 children ages 3 to 9.5 years exposed in utero to chronic clonidine therapy.27 When matched to children of untreated hypertensive pregnancies, an excess of sleep disturbances such as night terrors and somnambulism was found in the clonidine group. Clonidine has been shown to suppress REM sleep in animal studies. 43 The relevance of this finding to short-term therapy as required in severe pre-eclampsia is questionable. Labetalol Over the last several years, there has been much interest in the use of labetalol for control of the hypertension of pre-eclampsia. Although circulating levels of catecholamines are not elevated in pre-eclampsia, these patients have an abnormal sensitivity to a standardized dose of angiotensin n. 21 Indeed, this abnormality is demonstrable prior to the onset of clinical disease, and this differential has been advocated as an early diagnostic test. During labor without analgesia, catecholamine levels are elevated and, frequently, pre-eclampsia is exacerbated. Therefore the alpha-adrenergic antagonist activity oflabetalol is physiologically desirable. The direct beta2 -agonist activity combined with beta 1-antagonist activity to control the reflex tachycardia induced by the vasodilation is also physiologically desirable. In a study of eight severe pre-eclamptics monitored with P ACs, with doses of intravenous (IV) labetalol that elicited a 21 per cent reduction in MAP there was no decrease in Cl, no tachycardia, and an 8 per cent increase in stroke index (SI) that did not achieve statistical significance. 39 Another desirable quality is that with chronic use of orallabetalol and acute exposure of pre-eclamptics to IV labetalol, radionuclide studies of uteroplacental blood flow have shown no decrease despite significant decreases in blood pressure, suggesting a decrease in uteroplacental vascular resistance. 30..38.47 The use in pregnancy of nonspecific beta-adrenergic antagonists such as propranolol has been controversial. While not a consistent finding, multiple studies have shown a decrease in birth weight and an increase in small for gestational age (SGA) infants with chronic use of propranolol. 37 Additionally, there have been reports of prolonged neonatal apnea following IV administration immediately prior to delivery.69 These adverse findings have not been reported with the use oflabetalol,53 with the exception of one study by Sibai and colleagues,62 where an excess of SGA babies was found in a group of mild pre-eclamptics randomized to oral labetalol as compared to a similar group maintained on bedrest without the use of antihypertensive agents. One difficulty with the use of IV labetalol in severe pre-eclampsia has been variable efficacy. While in some reports the ability to achieve a diastolic blood pressure of less than 100 mm Hg with labetalol reaches 90 per cent (36 of 40),40 in others this goal was obtainable in only 40 per cent (4 of 10).2

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In the first study, the drug was administered as increasing boluses from 20 to 80 mg, while in latter it was administered as a continuous drip to a maximum of 160 mg per hour. However, in another study using a continuous drip to the same maximum dose, control was achieved in 83 per cent (5 of 6).22 In all studies, there were no cases of maternal hypotension, and therefore, no iatrogenic fetal distress as is commonly seen with direct vasodilators. Overall, the results with labetalol are promising and, as experience with use in pregnancy is gained, this may become a first-line antihypertensive for treatment of pre-eclampsia. Trimethaphan Trimethaphan is a short-acting ganglionic blocking agent that has some limited usage in pregnancy. Enthusiasm for this agent waned following a case report of interaction with succinylcholine leading to prolonged neuromuscular blockade and prolonged intubation in a severe pre-eclamptic delivered by cesarean section under general anesthesia. 50 This interaction was due to noncompetitive inhibition of plasma cholinesterase. This patient was documented to have normal cholinesterase activity 6 weeks postpartum. Since operative deliveries (frequently of an emergent nature) are common in this group of patients, this agent has little role in obstetrics. VASODILATORS

Hydralazine

In the United States, hydralazine is the antihypertensive most widely used in the treatment of pre-eclampsia. Its popularity stems from ease of administration, being used mainly in intermittent boluses without intraarterial monitoring, and in the vast experience with use during pregnancy. In theory, it has some advantage over other vasodilators in these hypovolemic patients because its effect is predominantly on arterial vessels with minimal effect on the capacitance vessels. In practice, many patients will have precipitous drops in blood pressure and resultant fetal distress. Hemodynamic studies of severe pre-eclamptics treated with hydralazine show a significant increase in Cl due in the most part to the reflex increase in heart rate and, in some studies, to a small degree, an increase in SI.14,3,5 One of the major concerns in the treatment of hypertensive pregnant patients is that the decrease in blood pressure, therefore, the driving force, will decrease placental perfusion if the uterine arteries are not affected at least to the same degree as other arterial beds. The increase in Cl is felt to be desirable, as it may offset the diversion of blood flow. Indeed, its effect on uteroplacental blood flow is variable with some patients showing an increase and others a decreaseY This may vary with the individual state of hydration. In pregnant ewes made hypertensive with phenylephrine, hydralazine sufficient to normalize blood pressure was only able to improve uterine blood flow from 35 per cent below baseline to 20 per cent below baseline. 54 In practice, hydralazine frequently precipitates fetal distress with reported rates as high as 58 per cent. 64,72 This rate varies directly with the incidence of hypotension and, in this setting, without prehydration, this may occur with any diastolic

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blood pressure less than 90 mm Hg. With intermittent doses of 5 mg every 10 minutes, the incidence of precipitated fetal distress was 10 per cent (2 of 20) and in both cases the diastolic blood pressure was reduced below 90 mm Hg (78 and 89 mm Hg).40 Hydralazine is frequently administered by infusion. This is, however, hazardous because hydralazine is a long-acting drug with a relatively long time to maximum effect (20 minutes) and, therefore, is difficult to titrate and control. When given as a continuous infusion, the rate offetal distress is reported to be higher, with 14 of 24 patients (58 per cent) showing signs of distress and 9 of 24 (38 per cent) of patients requiring cesarean sections for that indication compared to 5 of 77 (9 per cent) when no antihypertensive therapy was given. 64 The clinical protocol was to decrease the diastolic blood pressure to 100 to 110 mm Hg and to discontinue the infusion when the diastolic blood pressure was less than 100 mm Hg. However, 9 of 14 (64 per cent) of those patients developing fetal distress had the infusion continued for at least 30 minutes after the diastolic blood pressure was below 100 mm Hg while this was the case in only 2 of 10 (10 per cent) patients not developing fetal distress. No other adverse fetal outcomes have been associated with prenatal exposure. Therefore, while its use is not without hazard, the risks are well-defined and can be minimized by proper dosing (5 to 10 mg every 20 minutes to a diastolic blood pressure of approximately 100 mm Hg) and adequate hydration. Diazoxide Diazoxide is a nondiuretic thiazide that is a potent direct arterial vasodilator. Like hydralazine, it has little effect on the capacitance vessels and no direct cardiac effects, although reflex tachycardia is the rule. Also like hydralazine, it frequently causes maternal hypotension and fetal distress. When initially introduced as an agent for treatment of hypertensive emergencies, the recommended dose was 300 mg given as a rapid IV bolus. Initial reports describe a high incidence of severe maternal hypotension, with two of four patients in clinical shock following a bolus of 300 mg.45 More recently, diazoxide has been administered in mini-boluses of30 to 75 mg. When given in doses of30 mg every I to 2 minutes, there were no instances of hypotension in 34 patients. 18 When administered in doses of 75 mg every 30 minutes, there were eight cases of hypotension in 45 patients (18 per cent).41 Therefore, it appears very small, frequent doses can safely reduce maternal hypertension. While no adverse fetal outcomes other than distress are associated with acute use of diazoxide, chronic use has been associated with alopecia in humans 42 and with fetal hyperglycemia and islet cell destruction in sheep.8

Sodium Nitroprusside Sodium nitroprusside (SNP) is an extremely potent vasodilator of both the resistance and capacitance blood vessels. It is delivered by continuous infusion with dosage easily titrated to the rapid blood pressure response. Its duration of action is 3 to 5 minutes. Because of these qualities, intra-arterial blood pressure monitoring is required. SNP combines with hemoglobin to form methemoglobin and cyanide. The cyanide is metabolized in the liver to thiocyanate that is excreted in the urine. Cyanide can accumulate if there

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is either increased production due to large doses or prolonged administration, or if there is decreased metabolism in the liver. Reported experience in obstetrics has been limited because of concerns raised by a study in sheep and concern that the fetus may have a decreased capacity to metabolize the cyanide due to relative immaturity of the hepatic enzyme systems. In the animal study of concern, pregnant ewes were given SNP to decrease the MAP to 20 per cent below baseline for 1 hour. 44 Five of eight ewes developed tachyphylaxis and required increasingly large doses of SNP to maintain the decreased blood pressure. The mean dose required was 25 f.Lg per kg per minute. All five fetuses died within .30 minutes, all mothers within 1 hour. The three ewes and fetuses that did not develop tachyphylaxis suffered no ill effects. Other animal studies have used a different design where SNP has been used to correct pharmacologically induced hypertension. 19,54,74 In these studies, the doses required were within the range used clinically and there were no instances of maternal or fetal cyanide toxicity. These studies were designed to explore the effects of SNP on uterine blood flow, and the results varied by the agent chosen to induce hypertension. When phenylephrine was used to increase the MAP by 20 per cent, SNP corrected the blood pressure to baseline but did not reverse the 35 per cent reduction in uterine blood flow. M In two studies, norepinephrine was the hypertensive agent and in both cases SNP partially corrected the deficit in uterine blood flow. 14 ,74 When SNP was given alone to decrease the MAP by 20 to 25 per cent, there was no decrease in uterine blood flow. 74 There have been a few case reports of use in severe pre-eclamptics with complicating pulmonary edema. In the four cases reported by Stempel and colleagues,65 there was a marked decline in the PCWP that paralleled the decrease in MAP. Three of these patients had previously failed therapy with hydralazine that had no effect on the PCWP. Cyanide levels were obtained in one neonate and in two mothers, and cyanide was not detectable. In a single case report of a patient with severe pre-eclampsia complicated by mitral stenosis and regurgitation, a total dose of 3.5 mg per kg was administered. 59 Tissue levels in the liver of a previable stillborn fetus were less than 10 f.Lg per ml, well below the toxic range. In 58 neonates treated with SNP for various clinical indications, the mean dose required was 3.6 f.Lg per kg per minute for a mean duration of 44 hours. 7 There were no cases of cyanide toxicity. While concerns about the use of this potent agent are warranted, with proper usage and careful monitoring this agent can be used safely to great advantage in resistant or complicated cases of severe pre-eclampsia. Because of the precarious state of hydration in these patients, infusion should be started at the lowest dose of 0.25 f.Lg per kg per minute. Nitroglycerin Nitroglycerin (NTG) is a direct vasodilator of both resistance and capacitance blood vessels, but the effect on the latter is more pronounced. As such, it is well suited to use in pre-eclampsia complicated by pulmonary edema. It is not advisable for use in an uncomplicated pre-eclamptic without prior volume resuscitation. Like SNP, it has a very rapid onset and short duration of action allowing easy titration of a continuous infusion to the

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desired blood pressure. Intra-arterial monitoring is required. Clinical reports of use in severe pre-eclampsia have been limited to small studies '2.'s and to a case report of control of the exacerbation of hypertension with tracheal intubation. 63 Aside from the iatrogenic fetal distress that can be a complication of any of the vasodilators, the only specific concern about use of NTG in treatment of pre-eclampsia has been about the possibility of further elevation of intracranial pressure (ICP). NTG will cause an elevation of ICP in normotensive dogs as well as an elevation of an already elevated ICP in dogs made hypertensive by norepinephrine infusion. 75 In clinical practice, NTG is frequently used during tracheal intubation, and an increased incidence of intracranial hemorrhage has not been reported. The effects on uterine blood flow are similar to that of SNP, with partial correction of the deficit caused by pharmacologically induced hypertension in gravid ewes. 74 In a study of three patients with pulmonary edema with a 20 per cent reduction in MAP, there was a prompt and significant decline in the PCWP with no change in the maternal heart rate, Cl, SVRI, or oxygen transport. There was a significant increase in oxygen consumption and oxygen extraction, and a significant decrease in the shunt fraction, suggesting perfusion of previously underperfused vascular beds. 12 In six patients with uncomplicated severe pre-eclampsia, NTG was infused to decrease the MAP 20 per cent both before and after volume expansion with 5 or 25 per cent salt poor albumin. IS Prior to volume expansion, NTG caused a significant decrease in MAP, PCWP, Cl, SI, and oxygen transport with a mean dosage of 1.2 fLg per kg per minute. Two patients developed fetal bradycardias associated with maternal hypotension, but these changes resolved within 10 minutes. Following volume expansion to a PCWP of 10 mm Hg, the desired MAP reduction of 20 per cent could not be achieved with a mean MAP decrease of 15 per cent with doses as high as 35 fLg per kg per minute. There was a Significant reduction of SVRI and no change in Cl, SI, oxygen transport, or consumption. There were no fetal heart rate changes in this phase of the study. Because of the limitations in efficacy in the hydrated pre-eclamptic and the danger of use in the nonhydrated patient, it appears that use of NTG will remain limited to the setting of patients with pulmonary edema and for short-term control of the hypertension associated with tracheal manipulation. Calcium Channel Blockers There are several advantages to the use of a calcium channel blocker as an antihypertensive agent. It is easily administered in oral form with a rapid onset of action and a duration of action of 3 to 5 hours. The induced decrease in MAP is proportional to the baseline blood pressure and, therefore, hypotension is rare. It causes coronary artery vasodilation and improves subendocardial perfusion. However, the use of calcium channel blockers in the treatment of pre-eclampsia has been limited by concerns raised by several animal studies. Fifteen ewes made hypertensive with angiotensin 11 were normalized with an infusion of nicardipine. 48 Evaluation of fetal arterial blood gases revealed a significant decrease in pH and an increase in PC0 2 • Within 60 minutes of the start of the nicardipine infusion, five of the fetuses died. Long-term administration of nicardipine to pregnant rabbits reduced the

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uterine blood flow as a per cent of the CO, and acute administration decreased the total uterine blood flow as well as the ratio of placental to total uterine flow. 24 When nifedipine was used to reverse norepinephrine induced hypertension in gravid ewes, there was not any recovery of the 50 per cent decline in uterine blood flow. 46 There are also several concerns of a theoretical nature. Magnesium sulfate is the standard agent used in pre-eclampsia for seizure prophylaxis and is also a calcium antagonist. The combination of magnesium sulfate and a calcium channel blocker may be additive or synergistic and cause significant increases in serious side effects such as cardiac arrest. Another concern is that of effect on platelet function in these patients who are not infrequently thrombocytopenic. In patients given nitrendipine 2 to 4 hours prior to elective abortion, there was no increase in blood loss or change in platelet function 36 but these patients are not comparable to severe pre-eclamptics. There have been a few small studies of use in preeclampsia with no apparent adverse maternal or fetal effects.l Experience, however, is inadequate to justify antepartum use at this time. These agents are, nevertheless, quite useful in the treatment of hypertension in the postpartum period. Angiotensin-converting Enzyme Inhibitors While in theory these agents are attractive since pre-eclampsia is characterized by an abnormal sensitivity to angiotensin II, in practice these agents have been associated with adverse outcomes in both animal and human studies and are contraindicated for use during pregnancy. In pregnant rabbits with chronic exposure to captopril, fetal wastage was 86 per cent compared to 1 per cent in controls.20 In a case report58 of a patient on captopril, furosemide, and methyldopa for control of hypertension secondary to renal artery stenosis, the neonate displayed multiple dysmorphic features secondary to prolonged oligohydramnios, severe hypotension not responsive to pressors, and anuria for 1 week despite normal kidneys by ultrasound, perfusion scan, arteriogram, and biopsy. Oliguria persisted for 19 days until peritoneal dialysis was begun at which time urine output improved. The baby died of sepsis at 30 days of life. By increasing renal efferent arteriolar resistance, angiotensin II is required for the maintenance of glomerular filtration rate in the face of decreased renal perfusion pressure such as found normally in fetal life. Captopril may inhibit this compensation. In a similar case, chronic exposure to captopril in utero resulted in an SGA infant with intractable hypotension for the first 10 days of life. 9 There appears to be no role for these agents in the treatment of pre-eclampsia.

SUMMARY Severe pre-eclampsia is a state of acute afterload increase where compensation may be total by use of the Frank-Starling mechanism and/or increased adrenergic drive, or may be uncompensated in a patient with limited or exhausted preload reserve. As such, we are presented with a diverse group of patients and antihypertensive therapy ideally should be individualized. In reality we are dealing with a complex situation because of the

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presence of the fetus raising concerns both about direct effects on the fetus as well as on uteroplacental blood flow. This limits our choice of agents to those with extensive use in pregnancy except in complicated or resistant cases. For these reasons, hydralazine is the antihypertensive agent of choice for treatment of acute hypertensive emergencies in pregnancy. In the complicated case other agents such as sodium nitroprusside or nitroglycerin may be more appropriate and, in these cases, hemodynamic monitoring should be performed to allow not only greater safety, but also to tailor therapy to the individual hemodynamic profile.

REFERENCES 1. Alien J, Maigaard S, Forman A, et al: Acute effects of nitrcndipine in pregnancy-induced hypertension. Br J Obstet Gynaecol 94:222, 1987 2. Ashe RG, Moodley J, Richards AM, et al: Comparison of labetalol and dihydralazine in hypertensive emergencies of pregnancy. S Afr Med J 71:354, 1987 3. Benedetti TJ, Quilligan EJ: Cerebral edema in severe pregnancy induced hypertension. Am J Obstet Gynecol 137:860, 1980 4. Benedetti TJ, Cotton DB, Read JC, et al: Hemodynamic observations in severe preeclampsia with a flow-directed pulmonary artery catheter. Am J Obstet Gynecol 136:465, 1980 5. Benedetti TJ, Benedetti JK, Stenchever MA, et al: Severe preeclampsia-maternal and fetal outcome. Clin Exper Hypertens B1:401-416, 1982 6. Benedetti TJ, Kates R: Hemodynamic observations in severe preeclampsia complicated by pulmonaryedema. Clin Exp Hypertens B1:289, 1982 7. Benitz WE, Y!alachowski N, Cohen RS, et al: Use of sodium nitroprusside in neonates: Efficacy and safety. J Pediatr 106:102, 1984 8. Boulos BY!, Davis LE, Almond CH, et al: Placental transfer of diazoxide and its hazardous effect on thc newborn. J Clin Pharrnacol 1971, p 206 9. Boutroy MJ, Vert P, Hurault de Ligny B, et al: Captopril administration in pregnancy impairs fetal angiotensin converting enzyme activity and neon tal adaptation. Lancet 1:935, 1984 10. Calvin JE, Driedger AA, Sibbald WJ: Does the pulmonary capillary wedge pressure predict left ventricular preload in critically ill patients? Crit Care Med 9:437, 1987 11. Cotton DB, Lee W, Huhta JC, et al: Initial hemodynamic profile and left ventricular function in patients with severe pregnancy-induced hypertension [Abstract]. Society of Perinatal Obstetricians, 7th Annual meeting, Lake Buena Vista, Fla, 1982 12. Cotton DB, Jones MM, Longmire S, et al: Role of intravenous nitroglycerin in the treatment of severe pregnancy-induced hypertension complicated by pulmonary edema. Am J Obstet Gynecol 154:91, 1984 13. Cotton DB, Gonik B, Dorman K, et al: Cardiovascular alterations in severe pregnancyinduced hypertension: Relationship of central venous pressure to pulmonary capillary wedge pressure. Am J Ob stet Gynecol 151:762, 1985 14. Cotton DB, Gonik B, Dorman KF: Cardiovascular alterations in severe pregnancy-induced hypertension seen with an intravenously given hydralazine bolus. Surg Gynecol Obstet 161:240, 1985 15. Cotton DB, Longmire S, Jones M, et al: Cardiovascular alterations is severe pregnancyinduced hypertension: Effects of intravenous nitroglycerin coupled with blood volume expansion. Am J Obstet Gynecol 154:1053, 1986 16. Creasy RK, Resnik R (eds): Maternal-Fetal Medicine, Philadelphia, WB Saunders, 1984 17. Donaldson JO: Neurology of Pregnancy. Philadelphia, WB Saunders, 1978 18. Dudley DKL: Minibolus diazoxide in the management of severe hypertension in pregnancy. Am J Obstct GynecoI151:196, 1985 19. Ellis SC, Wheeler AS, James FM Ill, et al: Fetal and maternal effects of sodium nitroprusside used to counteract hypertension in gravid ewes. Am J Obstet GynecoI143:766, 1982

636

HELAYNE

M.

SILVER

20. Ferris TF, Weir EK: The effect of captopril on uterine blood flow and PGE synthesis in the pregnant rabbit. J Clin Invest 71:809, 1983 21. Gant NF, Chand S, vVhalley PJ, et al: The nature of pressor responsiveness to angiotension II in human pregnancy. Obstet Gynecol 43:854, 1974 22. Garden A, Davey DA, Dommisse J: Intravenous labetalol and intravenous dihydralazine in severe hypertension in pregnancy. Clin Exp Hypertens B1:371, 1982 23. Groendijk R, Trimbos JBMJ, Wallenberg HCS: Hemodynamic measurements in preeclampsia: Preliminary observations. Am J Obstet Gynecol 150:232, 1984 24. Holbrook RH, Katz M, Hendricks SK, et al: Maternal cardiovascular and uterine blood flow changes during acute and cbronic administration of nicardipine-HCI [abstract]. SGI, 33rd Annual Meeting, Toronto, Canada, 1985 25. Houston MC: Treatment of hypertensive emergencies and urgencies with oral clonidine loading and titration. Arch Intern Med 146:586, 19H6 26. Horvath JS, Phippard A, Korda A, et al: Clonidine hydrochloride-a safe and effective antihypertensive agent in pregnancy. Obstet Gynecol 66:634, 1985 27. Huisjes HI. Hadders-Algra M, Touwen BGL: Is clonidine a behavioural teratogen in the human? Early Human Devel 14:43, 1986 28. James F, Davies P: Maternal and fetal effects of lumbar epidural analgesia for labor and delivery in patients with gestational hypertension. Am J Obstet Gynecol 126:19.5, 1976 29. Jouppila R, Jouppila P, Hollmen A, et al: Epidural analgesia and placental blood flow during labor in pregnancies complicated by hypertension. Br J Ob stet Gynecol 86:969, 1979 30. Jouppila P, Kirkinen P, Koivula A, et al: Labetalol does not alter the placental and fetal blood flow or maternal prostanoids in pre-eclampsia. Br J Ob stet Gynaecol 93:543, 1986 31. Katz R, Karliner JS, Resnik R: Effects of a natural volume overload state (pregnancy) on left ventricular performance in normal human subjects. Circulation 58:434, 1978 32. Kirby JC, Jaindl JJ: Cerebral CT findings in toxemia of pregnancy. Radiology 151:114,1984 33. Kuzniar I. Piela A, Skret A, et al: Echocardiographic estimation of hemodynamics in hypertensive pregnancy. Am J Ob stet Gynecol 144:430, 1982 34. Kuzniar J, Piela A, Skret A: Left ventricular function in preeclamptic patients: An echocardiographic study. Am J Obstet Gynecol 146:400, 1983 35. Kuzniar J, Skret A, Piela A, et al: Hemodynamic effects of intravenous hydralazine in pregnant women with severe hypertension. Obstet Gynecol 66:453, 1985 36. Lawrence MR, Pipkin FB: Some observations on the effects of a calcium channel blocker, nitrendipine, in early human pregnancy. Br J Clin Pharmacol 23:683, 1987 37. Lieberman BA, Stirrat GM, Cohen SL, et al: The possible adverse effect of propranolol on the fetus in pregnancies complicated by severe hypertension. Br J Obstet Gynaecol 85:678, 1978 38. Lunell NO, Nylund L, Lewander R, et al: Acute effect of an antihypertensive drug, labetalol, on uteroplacental blood flow. Br J Ob stet Gynaecol 89:640, 1982 39. Mabie WC, Sibai BM, Gonzalez AR, et al: Hemodynamic effects of labetalol versus hydrazaline in the peripartum period. SGI 34rd Annual Meeting, Atlanta, GA, 1987 40. Mabie WC, Gonzalez AR, Sibai BM, et al: A comparative trial oflabetalol and hydralazine in the acute management of severe hypertension in complicating pregnancy. Obstet Gynecol 70:328, 1987 41. Michael CA: Intravenous labetalol and intravenous diazoxide in severe hypertension complicating pregnancy. Aust NZ J Obstet Gynaecol 26:26, 1986 42. Milner RD, Chouksey SK: Effects of fetal exposure to diazoxide in man. Arch Dis Child 47:537, 1972 43. Mirmiran M, Scholtens J, Van De Poll NE, et al: Effects of experimental suppression of active (REM) sleep during early development upon adult brain and behavior in the rat. Developmental Brain Res 7:277, 1982 44. Naulty I. Cefalo RC, Lewis PE: Fetal toxicity of nitroprusside in the pregnant ewe. Am J Obstet Gynecol 139:708, 1981 45. Neuman J, Weiss B, Rabello Y, et al: Diazoxide for the acute control of severe hypertension complicating pregnancy: A pilot study. Obstet Gynecol 53:50S, 1979 46. Norris MC, Rose JC, Dewan DM: Nifedipine or verapamil counteracts hypertension in gravid ewes. Anesthesiology 65:254, 1986

ACllTE HYPERTEl\SIVE emS IS l:--J PREC:--JANCY

637

47. Nyluncl L, Luncll NO, Lewander R, et al: Labetalol for the trcatmcnt of hypertension in pregnancy. Acta Obstct Gynecol Scand 118(suppl):71, 1984 48. Parisi VM, Salinas JK, Stockmar EJ: Fetal cardiorcspiratory response to maternal administration of nicardipinc in the hypertensive cwe [abstract]. Society of Perinatal Obstetricians. 6th Annual Meeting, San Antonio, TX, Jan 30-Fcb 1, 1986 49. Phelan JP, Yurth DA: Severe preeclampsia 1. Peripartum hemodynamic observations. Am J Obstet GynecoI144:17, 1982 .50. Pou\ton TJ, James FM Ill, Lockridge 0: Prolonged apnea following trimethaphan and succinylcholine. Anesthesiology .50:54, 1979 .51. Ra/l.erty LD, Berkowitz RL: Hemodynamics in paticnts with severe toxemia during labor and delivery. Am J Obstet Gynecol 138:263, 1980 .52. Richards AM, Moodley J, Graham 01, et al: Active management of the unconscious eclamptic patient. Br J Obstet Gynaecol 93:5.54, 1986 .53. Riley AJ: Clinical pharmacology oflabetalol in pregnancy. J Cardiovasc Pharmacol3(suppl 1):S53, 1981 .54. Ring G, Kramcs E, Shnider SM: Comparison of nitroprusside and hydralazine in hypertensive pregnant ewes. Obstet Gynecol .50:.598, 1977 .5.5. Roberts JM, May WJ: Consumptive coagulopathy in severc preeclampsia. Obstet Gynecol 48:163, 1976 .56. Rodriguez SU, Leikin SL, Hiller MC: Neonatal thrombocytopenia associated with antepartum administration of thiazide drugs. N Engl J Med 270:881, 1984 .57. Ross J: Afterload mismatch and preload reserve: A conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis 18:2.5.5, 1976 .58. Rothberg AD, Lorenz R: Can captopril cause fetal and neonatal renal failure? Pediatr Pharmacol 4:189, 1984 .59. Shoemaker CT, Meyers M: Sodium nitroprusside for control of severe hypertensive disease of pregnancy: A case report and discussion of potcntial toxicity. Am J Obstet Gynecol 149:171, 1984 60. Sibai BM, Taslimi M, Abdella TN, et al: Maternal and perinatal outcome of conservative management of severe preeclampsia in midtrimester. Am J Obstet Gynecol 1.52:32-37, 198.5 61. Sibai Byl, Grossman RA, Grossman HG: Effects of diuretics on plasma volume in pregnancies with long-term hypertension. Am J Obstet Gynecol 1.50:831, 198.5 62. Sibai BM, Gonzalez AR, .\1abie WC, et al: A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term. Obstet Gynecol 70:323, 1987 63. Snyder SW, Wheeler AS, James F~I Ill: The use of nitroglycerin to control severe hypcrtcnsion of pregnancy during cesarean section. Anesthcsiology.51:563, 1979 64. Spinnato JA, Sibai BM, Anderson GO: Fetal distress after hydralazine therapy for severe pregnancy-induced hypertension. South Med J 79:559, 1986 6.5. Stempel JE, O'Grady PJ, Morton MJ, et al: Use of sodium nitroprusside in complications of gestational hypertension. Obstet Gynecol 60:533, 1982 66. Strauss RG, Keeler R, Burke T, et al: Hemodynamic monitoring of cardiogenic pulmonary edema complicating toxemia of pregnancy. Obstet Gynecol 5.5:170, 1980 67. Suonio S, Saarikoski S, Tahvanainen K, et al: Acute e/l.ects of dihydralazine mesylate, furosemide, and metroprolol on maternal hemodynamics in pregnancy-induced hypertension. Am J Obstet Gynecol 155:122, 1986 68. Trudinger BJ, Gill's WB, Cook CM: Uteroplacental blood How velocity-time waveforms in normal and complicated pregnancy. Br J Oh stet Gynecol 92:39, 1985 69. Tunstall ME: The effect of propranolol on the onset of breathing at birth. Br J Anesthes 41:792, 1969 70. Ueland K, Hansen J\1: Maternal cardiovascular dynamics. Am J Obstet Gynecol 103:8, 1969 71. Veille JV, Hoseppud J, Morton MJ, et al: Cardiac sizc and fimction in pregnancy-induced hypertension. Am J Obstet Gynecol 1.50:443, 1984 72. Vink GJ, Moodley J, Philpott RH: E/l.ect of dihydralazine on the fetus in the treatment of maternal hypertension. Obstet Gynecol 55:519, 1980

638

HELAYC\!E

M.

SILVER

73. \Veseley AC, Douglas G\V: Continuous use of chlorothiazidc or prevention of toxemia of pregnancy. Oh stet Gynecol 19:355, 1962 74. Wheeler AS, James FM Ill, Meis PI. et al: Effects of nitroglycerin and nitroprusside on the uterine vasculature of gravid ewes. Anesthesiology .52:390, 1980 7.5. Writer WDR, James FM Ill, Stullken EH Jr, et al: Intracranial effects of nitroglycerin~ An obstetrical hazard? Anesthesiology .53:S309, 1980 Department of Obstetrics and Gynecology University of California- Davis 1621 Alhambra Boulevard Suite 2.500 Sacramento, CA 9.5816-70.51