Critical Care Obstetrics part 46 pot

Chronic hypertension Hypertension that is present before pregnancy or diagnosed before 20 weeks of gestation Pre - eclampsia – eclampsia Hypertension plus proteinuria usually occurrin

chronically stimulating autoregulatory mechanisms, thus

increas-ing vascular tone and producincreas-ing vascular hypertrophy These

changes then may impede pregnancy - induced plasma volume

expansion, which occurs in normal pregnancies, and result in

general circulatory maladaptation

One of the more striking clinical risk factors for the

develop-ment of pre - eclampsia is the antiphospholipid syndrome At the

University of Utah, Branch et al [44] studied 43 women who

presented with severe pre - eclampsia prior to 34 weeks of

gesta-tion and found 16% to have signifi cant levels of antiphospholipid

antibodies They recommended that women with early - onset

severe pre - eclampsia be screened for antiphospholipid antibodies

and, if detected, be considered for prophylactic therapy in

subse-quent pregnancies The same group [45] found a high incidence

of pre - eclampsia (51%) and severe pre - eclampsia (27%) in 70

women with antiphospholipid syndrome whose pregnancies

pro-gressed beyond 15 weeks of gestation, despite various medical

treatment protocols

An integrated model of pre - eclampsia pathophysiology has

been proposed by Romero et al [46] Abnormal placentation is

thought to be the fi rst step in the development of the disease,

possibly related to immune mechanisms Trophoblastic

prosta-cyclin, which may be important with respect to trophoblast

inva-sion and prevention of blood clotting in the intervillous space,

becomes defi cient A relative decrease in the prostacyclin –

thromboxane ratio allows platelet aggregation, thrombin

Table 34.1 Classifi cation of hypertensive diseases during pregnancy

Chronic hypertension

Hypertension that is present before pregnancy or diagnosed before 20 weeks of

gestation

Pre - eclampsia – eclampsia

Hypertension plus proteinuria usually occurring after 20 weeks of gestation or

earlier with trophoblastic diseases

Pre - eclampsia superimposed upon chronic hypertension

Chronic hypertension with signs and symptoms of pre - eclampsia such as:

Blood pressure ≥ 160/110 mmHg

Proteinuria ≥ 2.0 g/24 h

Serum creatinine > 1.2 mg/dL unless previously elevated

Thrombocytopenia

Persistent epigastric pain

Elevated hepatic transaminases

Persistent neurologic disturbances

Gestational hypertension

These are retrospective diagnoses If pre - eclampsia is not present at the time of

delivery and elevated blood pressure:

Transient hypertension of pregnancy: returns to normal by 12 weeks post

partum

Chronic hypertension: persists beyond 12 weeks

Modifi ed from the Working Group Report on High Blood Pressure in Pregnancy

National Heart, Lung, and Blood Institute NIH Publication No 00 - 3029, July 2000

Table 34.2 Complications of severe pregnancy - induced hypertension

Cardiovascular

Severe hypertension Pulmonary edema

Renal

Oliguria Renal failure

Hematologic

Hemolysis Thrombocytopenia Disseminated intravascular coagulopathy

Neurologic

Eclampsia Cerebral edema Cerebral hemorrhage Amaurosis

Hepatic

Hepatocellular dysfunction Hepatic rupture

Uteroplacental

Abruption Intrauterine growth retardation Fetal distress

Fetal death

Table 34.3 Risk factors for the development of pregnancy - induced

hypertension

Family history of pregnancy - induced hypertension 5

Revised from American College of Obstetricians and Gynecologists Hypertension

in Pregnancy ACOG Technical Bulletin 219 Washington, DC: American College

of Obstetricians and Gynecologists, 1996

tion, and fi brin deposition in systemic vascular beds Thrombosis and vasospasm develop and lead to multiorgan involvement, including renal, hepatic, neurologic, hematologic, and uteropla-cental dysfunction

necessitates careful evaluation, management in a tertiary care facility, and consideration for delivery [3]

General m anagement p rinciples for p re - eclampsia

On suspecting the diagnosis of pre - eclampsia, several steps are initiated simultaneously to treat and further evaluate the mother and her fetus A peripheral intravenous line is placed and fl uid therapy initiated These patients are often volume - depleted and benefi t from intravenous hydration, but are also susceptible to volume overload, so meticulous monitoring of intake and output

is recommended

Routine laboratory evaluation for pre - eclampsia (Table 34.5 ) includes complete blood count, platelet count, serum creatinine, and liver enzyme analyses [46,56 – 59] If delivery is not felt to be imminent, a 24 - hour collection of urine should be started for volume, creatinine clearance, and total protein excretion The patient should be placed in a lateral recumbent position and fetal assessment (ultrasound, non - stress test, or biophysical profi le) performed as indicated [60] Amniocentesis for fetal lung matu-rity may be considered in those cases in which fetal matumatu-rity is

in question and the disease process is not severe enough to mandate delivery

When severe pre - eclampsia is diagnosed, immediate delivery, regardless of gestational age, has generally been recommended [61] Conservative management has been proposed in select cases [62 – 64] ) Sibai and colleagues retrospectively reviewed 60 cases

of conservatively managed severe pre - eclampsia during the second trimester (18 – 27 weeks gestation) They found a high maternal morbidity rate, with complications such as abruptio placentae, eclampsia, coagulopathy, renal failure, hypertensive encephalopathy, intracerebral hemorrhage, and ruptured hepatic hematoma Additionally, an 87% perinatal morality rate was noted [65] In subsequent prospective studies, Sibai and col-leagues reported improved perinatal outcomes with no increased rate of maternal complications in a select group of women with severe pre - eclampsia between 24 – 27 weeks of gestation and

28 – 32 weeks of gestation [66] who were managed with intensive fetal and maternal monitoring under strict protocols in a tertiary care center In another randomized controlled trial, expectant management in selected severe pre - eclamptics between 28 and 34

Women with a previous pregnancy complicated by pre

eclampsia have an increased risk for recurrence in subsequent

pregnancies For severe pre - eclamptic women in an initial

preg-nancy, recurrence rates for pre - eclampsia are very high,

approach-ing 50% in some studies Furthermore, signifi cant maternal and

fetal complications are more common in recurrent pre - eclampsia

compared with an initial episode [47]

All of the preceding theories still do not allow accurate

predic-tion of which gravidas will develop pre - eclampsia, and an ideal

screening test is currently not available [19,48] Furthermore,

it is still not clear which process or processes separate mild

disease from the development of critical illness and multiorgan

dysfunction

Diagnosis of p re - eclampsia

The diagnosis of pre - eclampsia is often clinically confusing and

erroneous [49 – 52] Blood pressure (BP) criteria include a systolic

BP of at least 140 mmHg or a diastolic BP of at least 90 mmHg

The relative rise from baseline values in systolic pressure of

30 mmHg or diastolic pressure of 15 mmHg appears to be of

questionable value [53,54] Signifi cant proteinuria is defi ned as

at least 300 mg in a 24 - hour period Semiquantitative dipstick

analysis of urinary protein is poorly predictive of the actual

degree of proteinuria measured by 24 - hour urinary collections;

thus, classifi cation of pre - eclampsia based on proteinuria should

be confi rmed with a 24 - hour quantitative collection [55] Edema

and weight gain historically have been included in the diagnostic

triad (hypertension, proteinuria, edema) of pre - eclampsia, but

have been de - emphasized recently due to the ubiquitous nature

of edema during pregnancy [1] These changes usually occur after

20 weeks of gestation, except when there exist hydatidiform

changes of the chorionic villi, such as seen with hydatidiform

mole or hydrops fetalis

The signs and symptoms of severe pre - eclampsia are

summa-rized in Table 34.4 The development of these manifestations

Table 34.4 Diagnostic criteria for severe pre - eclampsia

Blood pressure > 160 – 180 mmHg systolic or > 110 mmHg diastolic

Proteinuria > 5 g/24 h

Oliguria defi ned as < 500 mL/24 h

Cerebral or visual disturbances

Pulmonary edema

Epigastric or right upper quadrant pain

Impaired liver function of unclear etiology

Thrombocytopenia

Fetal intrauterine growth retardation or oligohydramnios

Elevated serum creatinine

Grand mal seizures (eclampsia)

Revised from American College of Obstetricians and Gynecologists Hypertension

in Pregnancy ACOG Technical Bulletin 219 Washington, DC: American College

of Obstetricians and Gynecologists, 1996

Table 34.5 Laboratory evaluation for pre - eclampsia

Complete blood count Platelet count Liver function tests (ALT and AST) Renal function tests (creatinine, blood urea nitrogen, uric acid) Urinalysis and microscopy

24 - hour urine collection for protein and creatinine clearance Blood type and antibody screen

These investigators found that the only benefi t of such manage-ment was avoidance of sudden profound drops in systemic blood pressure and fetal distress during antihypertensive therapy The overall incidence of fetal distress in labor was not affected, however Because of a signifi cant requirement for pharmacologic diuresis to prevent pulmonary edema in the study group, these authors recommended that COP not be corrected with colloid unless markedly decreased (12 mmHg) or a prolonged negative COP – PCWP gradient was identifi ed While the infusion of col-loids has been shown to result in less of a decrease in COP when compared with crystalloids, there is no evidence of any clinical benefi t of colloids over crystalloids for the pregnant patient [81] Thus, in the absence of a fi rm clinical indication for colloid infu-sion, carefully controlled crystalloid infusions appear to be the safest mode of fl uid therapy in severe pre - eclampsia

A randomized clinical trial (n = 264) compared the postpar-tum management of pre - eclampsia with brief furosemide therapy (20 mg oral furosemide daily for 5 days with 20 mEq per day of oral potassium supplementation) versus no furosemide therapy, after spontaneous onset of postpartum diuresis and discontinu-ation of intravenous magnesium sulfate Only patients with severe pre - eclampsia appeared to benefi t from furosemide therapy, defi ned by more rapid normalization of blood pressure and reduction in the need for antihypertensive therapy Shortening

of hospitalization and reduction of delayed postpartum compli-cations were not observed

Seizure p rophylaxis for p re - eclampsia

Magnesium sulfate (MgSO 4 · 7H 2 O USP) has been used for the prevention of eclamptic seizures since the early 20th century [82 – 84] and has long been the standard treatment of pre - eclamp-sia – eclampeclamp-sia in the United States [85,86] The mechanism of action of magnesium sulfate remains controversial [87] Some investigators feel that magnesium acts primarily via neuromus-cular blockade, while others believe that magnesium acts centrally [88,89] Two separate investigations evaluating the effect of par-enteral magnesium sulfate on penicillin - induced seizure foci in cats report confl icting data [88,90] Koontz and Reid [90] postu-late that magnesium may be effective as an anticonvulsant only when the blood – brain barrier is disrupted Human data reveal that abnormal EEG fi ndings are common in pre - eclampsia – eclampsia, and they are not altered by levels of magnesium con-sidered to be therapeutic [91] In the rat model, Hallak et al [92] and Hallak [93] proposed that magnesium ’ s anticonvulsant mechanism of action was central, mediated through excitatory amino acid (N - methyl - d - aspartate) receptors In a randomized placebo - controlled study, Belfort et al [94] evaluated the effect

of magnesium sulfate on maternal retinal blood fl ow in pre eclamptics by way of Doppler blood fl ow measurements of central retinal and posterior ciliary arteries Their fi ndings suggested that magnesium sulfate vasodilates small vessels in the retina and pro-posed that this may refl ect similar changes occurring in the

cere-weeks of gestation was not associated with an increase in maternal

complications, but did result in a signifi cant prolongation of the

pregnancy, reduction of neonates requiring ventilation, and a

reduction in the number of neonatal complications [67]

The presence of pre - eclampsia does not guarantee accelerated

lung maturation, and a high incidence of neonatal respiratory

complications has been associated with premature delivery for

pre - eclampsia [68,69] In a stable maternal – fetal environment,

steroid therapy may be considered if amniocentesis reveals fetal

lung immaturity or the clinical situation is consistent with

prematurity Although delivery is generally indicated for severe pre

eclampsia regardless of gestational age, we feel that conservative

therapy in a tertiary care center is appropriate in select premature

patients with proteinuria exceeding 5 g/24 h, mild elevations of

serum transaminase levels, or borderline decreases in platelet

count and blood pressure that is controllable

Fluid t herapy for p re - eclampsia

Fluid management in severe pre - eclampsia consists of crystalloid

infusions of normal saline or lactated Ringer ’ s solution at 100 –

125 mL/h Additional fl uid volumes, in the order of 1000 –

1500 mL, may be required prior to use of epidural anesthesia or

vasodilator therapy to prevent maternal hypotension and fetal

distress [70]

Epidural anesthesia appears to be safe and is the anesthetic

method of choice in severe pre - eclampsia, if preceded by volume

preloading to avoid maternal hypotension [71 – 75] Likewise,

severely hypertensive patients receiving vasodilator therapy may

require careful volume preloading to prevent an excessive

hypo-tensive response to vasodilators Abrupt and profound drops in

blood pressure leading to fetal bradycardia and distress may

occur in severe pre - eclampsia when vasodilator therapy is not

accompanied by volume expansion [76 – 78]

Intravenous fl uids are known to cause a decrease in colloid

oncotic pressure (COP) in laboring patients [79] In addition,

baseline COP is decreased in patients with pre - eclampsia and may

decrease further postpartum as a result of mobilization of

inter-stitial fl uids This may be clinically relevant with respect to the

development of pulmonary edema in pre - eclamptic patients [80]

Therefore, close monitoring of fl uid intake and output,

hemody-namic parameters, and clinical signs must be undertaken to

prevent an imbalance of hydrostatic and oncotic forces that

potentiate the occurrence of pulmonary edema

Kirshon et al [77] placed systemic and pulmonary artery

cath-eters in 15 primigravid patients with severe pre - eclampsia during

labor A hemodynamic protocol requiring strict control of COP,

pulmonary capillary wedge pressure (PCWP), and mean arterial

pressure (MAP) throughout labor, delivery, and the postpartum

period was followed Low COP and PCWP were corrected with

the administration of albumin Severe hypertension was treated

as needed with intravenous nitroglycerin, nitroprusside, or

hydralazine Furosemide was administered for elevated PCWP

[61,69,99] , whereas in the United Kingdom and in a few US centers, conventional antiepileptic agents have been advocated [100 – 103] Recently, several important randomized clinical trials

of magnesium sulfate for prevention or control of eclamptic seizures have been published (Table 34.7 )

In a randomized trial comparing magnesium sulfate with phenytoin for the prevention of eclampsia, Lucas et al [104] found a statistically signifi cant difference (P = 0.004) in the devel-opment of seizures between the magnesium sulfate group (0/1049) and the phenytoin group (10/1089), with no signifi cant differences in eclampsia risk factors between the two study groups

The Eclampsia Trial Collaborative Group [105] enrolled 1,687 women with eclampsia in an international multicenter random-ized trial comparing standard anticonvulsant regimens of mag-nesium sulfate, phenytoin, and diazepam Women allocated magnesium sulfate had a 52% lower risk of recurrent convulsions than those allocated diazepam, and a 67% lower risk of recurrent convulsions than those allocated phenytoin Women allocated magnesium sulfate were less likely to require mechanical ventila-tion, to develop pneumonia, and to be admitted to intensive care than those allocated phenytoin Furthermore, the babies of mothers allocated magnesium sulfate were less likely to be intu-bated at delivery and less likely to be admitted to the newborn intensive care nursery when compared with babies of mothers treated with phenytoin The Eclampsia Trial Collaborative Group concluded that magnesium sulfate is the drug of choice for routine anticonvusant management of women with eclampsia, rather than diazepam or phenytoin, and recommended that other anticonvulsants be used only in the context of randomized trials Coetzee et al [106] conducted a blinded, randomized, con-trolled trial (n = 822) of intravenous magnesium sulfate versus placebo in the management of women with severe pre - eclampsia They found that use of intravenous magnesium sulfate signifi -cantly reduced the development of eclampsia (0.3% vs 3.2%, relative risk 0.09; 95% confi dence interval 0.01 – 0.69; P = 0.003) compared to placebo

Thus at present, magnesium sulfate is strongly endorsed as the agent of choice for eclampsia prophylaxis and treatment

bral circulation More recently, Belfort et al [95] showed that

magnesium sulfate reduces cerebral perfusion pressure while at

the same time maintaining cerebral blood fl ow This fi nding

sug-gests that at least in part, magnesium sulfate acts by preventing

or reducing hypertensive encephalopathy and barotrauma of the

cerebral microcirculation [96]

Magnesium sulfate regimens are illustrated in Table 34.6

Because a regimen of a 4 - g IV loading dose followed by a 1 – 2 - g/h

IV maintenance dose failed to prevent eclampsia in a signifi cant

number of pre - eclamptic women, Sibai et al [97] modifi ed this

regimen to a 4 - g IV loading dose followed by a 2 – 3 - g/h IV

main-tenance dose Sibai compared Pritchard ’ s regimen of a 4 - g IV and

10 - g IM loading dose followed by a 5 - g IM maintenance dose

every 4 hours, with a 4 - g IV loading dose followed by a 1 – 2 - g/h

continuous IV maintenance infusion The IV loading dose with

maintenance dose of 1 g/h did not produce adequate serum levels

of magnesium (4 – 7 mEq/L); thus, they recommended a 2 – 3 - g/h

maintenance dose [97] We employ a regimen of a 4 – 6 - g IV

loading dose over 20 minutes, followed by a 2 – 3 - g/h continuous

IV infusion The maintenance infusion may be adjusted

accord-ing to clinical parameters and serum magnesium levels Pruett

et al [98] found no signifi cant effects on neonatal Apgar scores

at these doses

Until relatively recently there remained considerable

contro-versy regarding the best agent for eclampsia prophylaxis In the

United States, magnesium sulfate has been the agent of choice

Table 34.6 Magnesium sulfate protocols

Loading dose Maintenance dose

Eclampsia 4 g IV and 10 g IM 5 g IM every 4 h

Severe pre - eclampsia None 1 g/h IV

Eclampsia 4 – 6 g IV over 5 – 10 min 1 g/h IV

Pre - eclampsia – eclampsia 6 g IV over 15 min 2 g/h

Table 34.7 Randomized trials comparing magnesium sulfate ( M g SO 4 ) with other agents in prophylaxis (preventing eclampsia in pre - eclamptics) and treatment

(preventing recurrent seizures) of eclampsia

Reference Study population n MgSO 4 Placebo Phenytoin Diazepam Lytic cocktail Nimodipine

Eclampsia Trial Collaborative Group [105] Eclamptics 905 13.2% – – 27.9% – –

Magpie Trial Collaborative Group [319] Mixed pre - eclamptics 10,141 0.8% 1.9% – – – –

Antihypertensive t herapy for s evere

p re - eclampsia

Pre - eclampsia is sometimes manifested by severe systemic hyper-tension Careful control of hypertension must be achieved to prevent complications such as maternal cerebral vascular acci-dents and placental abruption Medical intervention is usually recommended when the diastolic BP exceeds 110 mmHg [116,121,122] The degree of systolic hypertension requiring therapy is less certain, but most would treat for a level exceeding

160 – 180 mmHg, depending on the associated diastolic pressure

In the previously normotensive patient, cerebral autoregulation

is lost and the risk of intracranial bleeding increases when MAP exceeds 140 – 150 mm Hg, as illustrated in Figure 34.1 [123] Although many different antihypertensive agents are available,

we confi ne our discussion to those agents most commonly used for acute hypertensive crises in pregnancy (Table 34.8 )

Hydralazine h ydrochloride

Hydralazine hydrochloride (Apresoline) has long been the gold standard of antihypertensive therapy for use by obstetricians in the United States Hydralazine reduces vascular resistance via direct relaxation of arteriolar smooth muscle, affecting precapil-lary resistance vessels more than postcapilprecapil-lary capacitance vessels [124] Assali et al [125] noted the hypotensive effect to be marked and prolonged in pre - eclamptic patients, moderate in patients with essential hypertension, and slight in normotensive subjects Using M - mode echocardiography, Kuzniar et al [126] found an attenuated response to a 12.5 - mg IV dose of hydralazine in patients with pre - existing hypertension, compared with those with severe pre - eclampsia Cotton et al [127] studied the cardio-vascular alterations in six severe pre - eclamptics following

[1,107 – 110] The Cochrane Review of randomized clinical trials

found magnesium superior to lytic cocktail (chlorpromazine,

promethazine, pethidine), diazepam, and phenytoin for

preven-tion and/or treatment of eclampsia [111 – 114] The role of

mag-nesium sulfate seizure prophylaxis for mild pre - eclamptics is still

subject to debate

Plasma magnesium levels maintained at 4 – 7 mEq/L are felt to

be therapeutic in preventing eclamptic seizures [3] Patellar

refl exes usually are lost at 8 – 10 mEq/L, and respiratory arrest may

occur at 13 mEq/L [85,115] Urine output, patellar refl exes, and

respiratory rates should be monitored closely during magnesium

sulfate administration In those patients who have renal

dysfunc-tion, serum magnesium levels should be monitored as well

Calcium gluconate, oxygen therapy, and the ability to perform

endotracheal intubation should be available in the event of

mag-nesium toxicity [115] Calcium will reverse the adverse effects of

magnesium toxicity Calcium gluconate is administered as a 1 - g

dose (10 mL of a 10% solution) IV over a period of 2 minutes

[116]

Bohman and Cotton [117] reported a case of supralethal

magnesemia (38.7 mg/dL) with patient survival and no

adverse sequelae The essential elements in the resuscitation

and prevention of toxic magnesemia are: (i) respiratory

support as determined by clinical indicators; (ii) use of

continu-ous cardiac monitoring; (iii) infusion of calcium salts to

prevent hypocalcemia and the enhanced cardiotoxicity associated

with concurrent hypocalcemia and hypermagnesemia; (iv) use

of loop or osmotic diuretics to excrete the magnesium ion

more rapidly, as well as careful attention to fl uid and electrolyte

balances; (v) a consideration that toxic magnesium is neither

anesthetic nor amnestic to the patient; and (vi) assurance

that all magnesium infusions be administered in a buretrol - type

system or by intramuscular injection to prevent toxic

magnesemia

Magnesium sulfate is not an antihypertensive agent [85]

Administration produces a transient decrease in BP in

hyperten-sive, but not normotenhyperten-sive, non - pregnant subjects [118] Young

and Weinstein [119] noted signifi cant respiratory effects and a

transient fall in maternal BP in patients who received a 10 - g IM

loading dose of magnesium sulfate followed by maintenance push

doses of 2 g every 1 – 2 hours, but not in patients who received the

10 - g loading dose followed by a 1 - g/h continuous infusion [119]

Cotton et al [76] observed a transient hypotensive effect related

to bolus infusion, but not with continuous infusion in severe

pre - eclampsia

Duration of magnesium administration post - delivery for

seizure prophylaxis in severe pre - eclampsia has traditionally

been 24 hours in many centers A randomized clinical trial of 98

severe pre - eclamptics compared standard 24 - hour treatment

with discontinuation of magnesium upon the onset of maternal

diuresis, defi ned as urine output > 100 mL/h for 2 consecutive

hours [120] This study showed no untoward outcomes or need

for re - initiation of treatment with discontinuation of therapy at

diuresis

Normotensive

Previously Hypertensive

Mean Arterial Pressure

mm Hg

Figure 34.1 Cerebral blood fl ow remains constant over a wide range of

pressures in normotensive individuals This range is shifted to the right in individuals with chronic hypertension (Modifi ed from Zimmerman JL

Hypertensive crisis: emergencies and urgencies In: Ayers SM, ed Textbook of Critical Care Philadelphia: WB Saunders, 1995.)

tion (300 mg within 10 s), because the infusion method results in

a more gradual decline in BP and can be interrupted in cases of exaggerated drop in BP

Calcium c hannel b lockers

Calcium channel blockers such as nifedipine (Procardia, Adalat) lower BP primarily by relaxing arterial smooth muscle An initial oral dose of 10 mg is administered, which may be repeated after

30 minutes, if necessary, for the acute management of severe hypertension; 10 – 20 mg may then be administered orally every

3 – 6 hours as needed [121] Principal side effects in severe pre eclamptics include headache and cutaneous fl ushing Care must

be given when nifedipine is administered to patients receiving concomitant magnesium sulfate because of the possibility of an exaggerated hypotensive response [135] In a randomized clinical trial, 49 women with severe pre - eclampsia and severe hyperten-sion between 26 and 36 weeks of gestation were primarily treated with sublingual (then oral) nifedipine or intravenous (then oral) hydralazine [136] Effective control of BP (values consistently below 160/110 mmHg) was achieved in 96% of the nifedipine group and 68% of the hydralazine group (P < 0.05), with acute fetal distress occurring more commonly in the hydralazine group

A benefi cial effect may also be seen on urine output in women with severe pre - eclampsia treated with nifedipine [137,138] Other calcium channel blockers (nimodipine) have been studied

in the management of pre - eclampsia [139 – 142] and are the subject of ongoing investigation

Labetalol

Labetalol (Normodyne, Trandate) is a combined α - and β adrenoceptor antagonist that may be used to induce a controlled

venous administration of a 10 - mg bolus of hydralazine They

observed a signifi cant increase in maternal heart rate and cardiac

index (CI), with a decrease in MAP and systemic vascular

resis-tance (SVR) index There was a wide range of individual response

with respect to peak and duration Jouppila et al [128] measured

maternal – fetal effects with Doppler in severe pre - eclamptics

receiving dihydralazine and demonstrated a fall in maternal BP

with no change in intervillous blood fl ow and an increase in

umbilical vein blood fl ow Dihydralazine also has been shown to

cross the placenta to the fetus [129] The administration of

hydralazine may result in maternal hypotension and fetal distress

[130] For this reason, we recommend an initial dose of 2.5 –

5.0 mg IV, followed by observation of hemodynamic effects If

appropriate change in BP is not achieved, 5 – 10 mg IV may be

administered at 20 - minute intervals to a total acute dose of 30 –

40 mg Hypertension refractory to the preceding approach

war-rants the use of alternative antihypertensive agents [131,132]

Diazoxide

Diazoxide (Hyperstat) is a benzothiadiazine derivative that exerts

its antihypertensive effect by reducing peripheral vascular

resis-tance through direct relaxation of arterioles [133] The

com-monly used 300 - mg bolus injection to treat severe hypertension

may induce signifi cant hypotension with resultant morbidity

Minibolus diazoxide titration is clinically effective and relatively

free of side effects in non - pregnant, severely hypertensive adults;

a suggested dose would be 30 – 60 mg IV in 5 - minute intervals,

titrating to desired clinical response Thien et al [134]

recom-mended that diazoxide for the treatment of severe pre - eclampsia –

eclampsia be administered by the infusion method (15 mg/min;

total amount, 5 mg/kg body weight) rather than by bolus

Table 34.8 Pharmacologic agents for antihypertensive therapy in pre - eclampsia – eclampsia

Generic name Trade name Mechanism of action Dosage Comment

Hydralazine Apresoline Arterial vasodilator 5 mg IV, then 5 – 10 mg

IV/20 min up to total dose of

40 mg; titrated IV infusion

5 – 10 mg/h

Must wait 20 min for response between IV doses; possible maternal hypotension

Trandate

Selective α - and non - selective

β - antagonist

20 mg IV, then 40 – 80 mg IV/10 min to 300 mg total dose;

titrated IV infusion 1 – 2 mg/min

Less refl ex tachycardia and hypotension than with hydralazine

Adalat

Calcium channel blocker 10 mg PO, may repeat after 30 min Oral route only; possible exaggerated

effect if used with MgSO 4 Nitroglycerin Nitrostat IV

Tridil Nitro - Bid IV

Relaxation of venous (and arterial) vascular smooth muscle

5 µ g/min infusion; double every

5 min

Requires arterial line for continuous blood pressure monitoring; potential methemoglobinemia Nitroprusside Nipride

Nitropress

Vasodilator 0.25 µ g/kg/min infusion; increase

by 0.25 µ g/kg/min every 5 min

Requires arterial line for continuous blood pressure monitoring; potential cyanide toxicity Modifi ed from Dildy GA, Cotton DB Hemodynamic changes in pregnancy and pregnancy complicated by hypertension Acute Care 1988 – 89; 14 – 15: 26 – 46

may be an early sign of cyanide toxicity In non - pregnant sub-jects, sodium nitroprusside infusion rates in excess of 4 µ g/kg/ min led to red blood cell cyanide levels that after 2 – 3 hours of administration extended into the toxic range ( > 40 nmol/mL); infusion rates of less than 2 µ g/kg/min for several hours remained non - toxic [157] ) Treatment time should be limited because of the potential for fetal cyanide toxicity [158] Correction of hypo-volemia prior to initiation of nitroprusside infusion is essential

in order to avoid abrupt and often profound drops in BP

Angiotensin - converting e nzyme i nhibitors

Angiotensin - converting enzyme (ACE) inhibitors (captopril, enalapril) interrupt the renin – angiotensin – aldosterone system, resulting in a lowering of BP [159] The risk of inducing neonatal renal failure and other serious complications would contraindi-cate the use of ACE inhibitors during pregnancy [160 – 163] Fetal abortion has been reported in pregnant rabbits [164] Additionally, the ACE inhibitors as a class do not appear to be useful in acute treatment of severe hypertension because of a 1 – 4 - hour delay in achievement of peak serum levels after ingestion [159]

Severe h ypertension

We recommend labetalol for the initial management of severe hypertension in pre - eclampsia (BP 180 – 160/110 mmHg) Labetalol will be effective in restoring BP to a desired range (160 – 130/110 – 80 mmHg) in the majority of cases and has favorable cerebral hemodynamic effects with a minimum of adverse fetal effects Hydralazine is used if labetalol is ineffective and if maximum doses (up to 40 mg) have not corrected the severe hypertension, we then proceed to nifedipine Hydralazine in high doses has been associated with diversion of blood from the utero-placental ciculation and sudden - onset fetal decompensation In rare cases, these agents are ineffective, and we resort to intrave-nous infusion of nitroglycerin or nitroprusside, which requires

an intensive care setting

Analgesia – a nesthesia for p re - eclampsia

The use of conduction anesthesia in pre - eclampsia was, at one time, controversial Concerns have been voiced by some authors that the sympathetic blockade and peripheral vasodilation result-ing from epidural anesthesia may lead to hypotension and fetal distress in patients who are already volume contracted [3,86,165] However, induction of general endotracheal anesthesia is not without its own inherent risks General anesthesia has been shown to result in signifi cant rises in systemic arterial pressure in patients with severe pre - eclampsia An average increase in systolic arterial BP of 56 mmHg during endotracheal intubation of 20 patients with hypertension was reported by Connell et al [166] Hodgkinson et al [167] evaluated 10 severe pre - eclamptic – eclamptic patients undergoing general anesthesia using the pulmonary artery catheter They noted severe systemic and pulmonary hypertension during endotracheal intubation and

rapid decrease in BP via decreased SVR in patients with severe

hypertension [143] Reports on the effi cacy and safety of labetalol

in the treatment of hypertension during pregnancy have been

favorable ( [144 – 150] Mabie et al [149] compared bolus

intrave-nous labetalol with intraveintrave-nous hydralazine in the acute

treat-ment of severe hypertension They found that labetalol had a

quicker onset of action and did not result in refl ex tachycardia

Labetalol also may exert a positive effect on early fetal lung

matu-ration in patients with severe hypertension who are remote from

term [145,151] An initial dose of 10 mg is given and is followed

by progressively increasing doses (20, 40, 80 mg) every 10 minutes,

to a total dose of 300 mg Alternately, constant intravenous

infu-sion may be started at 1 – 2 mg/min until therapeutic goals are

achieved, then decreased to 0.5 mg/min or completely stopped

[121] Lunell et al [152] studied the effects of labetalol on

utero-placental perfusion in hypertensive pregnant women and noted

increased uteroplacental perfusion and decreased uterine

vascu-lar resistance Morgan et al [153] evaluated the effects of labetalol

on uterine blood fl ow in the hypertensive gravid baboon and

found that low doses (0.5 mg/kg) signifi cantly reduced MAP

without adversely affecting uterine blood fl ow Belfort et al have

shown that labetalol has a favorable profi le in terms of its cerebral

hemodynamic effects It reduces elevated cerebral perfusion

pres-sure while maintaining cerebral blood fl ow [154] This may be

important in its control of cerebral overperfusion and prevention

of hypertensive encephalopathy and associated pathology

Nitroglycerin

Nitroglycerin (Nitrostat IV, Nitro - Bid IV, Tridil) relaxes

pre-dominantly venous but also arterial vascular smooth muscle,

decreasing preload at low doses and afterload at high doses [155]

It is a rapidly acting potent antihypertensive agent with a very

short hemodynamic half - life Using invasive hemodynamic

mon-itoring, Cotton et al [131,156] noted that the ability to control

BP precisely was dependent on volume status Although larger

doses of nitroglycerin were required following volume expansion,

the ability to effect a smoother and more controlled drop in BP

required prevasodilator hydration [156] Nitroglycerin is

admin-istered via an infusion pump at an initial rate of 5 µ g/min and

may be doubled every 5 minutes Methemoglobinemia may result

from high - dose (7 µg/kg/min) intravenous infusion Patients

with normal arterial oxygen saturation who appear cyanotic

should be evaluated for toxicity, defi ned as a methemoglobin

level greater than 3% [155]

Sodium n itroprusside

Sodium nitroprusside (Nipride, Nitropress) is another potent

antihypertensive agent that may be used to control severe

hyper-tension associated with pre - eclampsia A dilute solution may be

started at 0.25 µ g/kg/min and titrated to the desired effect through

an infusion pump by increasing the dose by 0.25 µ g/kg/min every

5 minutes The solution is light sensitive and should be covered

in foil and changed every 24 hours [157] Arterial blood gases

should be monitored for developing metabolic acidosis, which

in Table 34.9 Hemodynamic fi ndings in non - pregnant women, normal third - trimester pregnancy, and severe pre - eclamptics are provided in Table 34.10

Current indications for the use of a pulmonary artery catheter

in pre - eclampsia are listed in Table 34.11 [132,174 – 176] Routine use of the pulmonary artery catheter in uncomplicated severe pre - eclampsia is not recommended In these cases, the potential morbidity of pulmonary artery catheterization does not appear

to be justifi ed Known complications of invasive monitoring at the time of insertion include cardiac arrhythmias, pneumotho-rax, hemothopneumotho-rax, injury to vascular and neurologic structures, pulmonary infarction, and pulmonary hemorrhage Later com-plications include balloon rupture, thromboembolism, catheter knotting, pulmonary valve rupture, and catheter migration into the pericardial and pleural spaces, with subsequent cardiac tam-ponade and hydrothorax [177 – 179] It should be noted, however, that Clark et al [174] observed no signifi cant complications from pulmonary artery catheterization in a series of 90 patients who underwent the procedure on an obstetrics – gynecology service A retrospective study of 115 pregnant women with severe pre eclampsia and eclampsia managed by pulmonary artery catheter-ization concluded that cathetercatheter-ization was subjectively benefi cial

in 93% of cases with an acceptable complication rate of 4% [180]

An alternate approach to the use of invasive monitoring is the use of echocardiography to determine central hemodynamic parameters [181 – 183] In almost all cases of severe pre - eclampsia

an initial echocardiogram will allow determination of cardiac function (cardiac output and ejection fraction), and central venous pressure This is generally all that is needed to make the important clinical decisions regarding fl uid management and antihypertensive drug choice It also allows rapid determination

of cardiac function and the potential for hypertensive cardiomy-opathy and diastolic dysfunction – two important complications frequently seen in severe hypertension in pre - eclampsia We have

extubation Ten patients undergoing epidural anesthesia with

0.75% bupivacaine for cesarean section maintained stable

sys-temic and pulmonary arterial pressures, with the exception of one

patient who developed systemic hypotension that responded

promptly to ephedrine

Newsome et al [75] demonstrated a drop in MAP and a slight

but insignifi cant decrease in SVR without change in CI,

periph-eral vascular resistance (PVR), central venous pressure (CVP), or

PCWP in 11 patients with severe pre - eclampsia undergoing

lumbar epidural anesthesia Jouppila et al [73] measured

inter-villous blood fl ow in nine patients with severe pre - eclampsia

during labor with lumbar epidural block and found a signifi cant

increase in uterine blood fl ow Ramos - Santos et al [168] studied

the effects of epidural anesthesia on uterine and umbilical artery

blood fl ow by way of Doppler velocimetry in mild pre - eclamptics,

chronic hypertensives, and normal controls during active term

labor In the pre - eclamptic group, the uterine artery systolic/

diastolic ratios decreased to levels similar to those of the control

group, suggesting a possible benefi cial effect in reducing uterine

artery vasospasm

Deleterious hypotension may be avoided by lateral maternal

tilt, thus preventing aortocaval occlusion, and preloading with

crystalloid solution to compensate for peripheral vasodilation

[73] Contraindications to epidural anesthesia include patient

refusal, fetal distress requiring immediate delivery, local

infec-tion, septicemia, severe spinal deformities, and coagulopathy

[74] If preceded by volume loading, epidural anesthesia appears

benefi cial and safe in severe pre - eclampsia [70 – 75,132] Clark

and Cotton [132] state, “ In skilled hands, a cautiously

adminis-tered epidural anesthetic is, in our opinion, not only justifi ed, but

the method of choice for anesthesia in cesarean section or for

control of the pain of labor in the patient with severe pre -

eclampsia ” The safety and effi cacy of neuraxial analgesia for severe pre

-eclamptics appears to be well supported by recent studies

[169,170] ) When general anesthesia is necessary, careful control

of maternal BP, especially around the time of induction and

awakening, is essential Small doses of nitroglycerin or other

similar agents are often useful in this regard

Hemodynamic m onitoring for p re - eclampsia

The pulmonary artery catheter, introduced over 30 years ago, has

been very useful in the management of critically ill patients [171]

In cases of severe pre - eclampsia, most clinicians have obtained

excellent results without invasive monitoring [69] Protocols

developed to study the central hemodynamic parameters of

severe pre - eclampsia have revealed interesting data, which are

sometimes confounded by differences in clinical patient

manage-ment prior to and at the time of catheterization [70]

Hemodynamic changes observed in normal pregnancies and

pregnancies complicated by hypertension are summarized by

Dildy and Cotton [172,173] Central hemodynamic fi ndings in

severe pre - eclampsia are summarized by Clark and Cotton [132]

Table 34.9 Hemodynamic fi ndings in severe pregnancy - induced hypertension

Cardiac output is variable Mean arterial pressure is elevated; systemic vascular resistance is normal (early)

or elevated (late) Central venous pressure is usually low to normal and does not correlate with pulmonary capillary wedge pressure

Pulmonary hypertension and pulmonary vascular resistance are not present, but low pulmonary artery pressure may occur in the presence of hypovolemia Pulmonary capillary wedge pressure may be low, normal or high

Oliguria may not refl ect volume depletion Ventricular function is usually hyperdynamic, but may be depressed in the presence of marked elevation in systemic vascular resistance Colloid oncotic pressure is usually low

Reproduced with permission from Clark SL, Cotton DB Clinical indications for pulmonary artery catheterization in the patient with severe preeclampsia Am J Obstet Gynecol 1988; 158: 453 – 458

Table 34.10 Hemodynamic profi les of non - pregnant women, normal women during the late third trimester, and severe pre - eclamptics

Normal Normal late non - pregnant

(n = 10) * (mean ± SD)

Normal/late third trimester (n = 10) * (mean ± SD)

Severe pre eclampsia (n = 45) †

(mean ± SEM)

Severe preeclampsia (n = 41) ‡ (mean ± SEM)

Mean arterial blood pressure (mmHg) 86.4 ± 7.5 90.3 ± 5.8 138 ± 3 130 ± 2

Pulmonary capillary wedge pressure (mmHg) 6.3 ± 2.1 7.5 ± 1.8 10 ± 1 8.3 ± 0.3 Pulmonary artery pressure (mmHg) 11.9 ± 2.0 § 12.5 ± 2.0 § 17 ± 1 15 ± 0.5

Systemic vascular resistance (dynes · sec · cm − 5 ) 1530 ± 520 1210 ± 266 1496 ± 64 1,226 ± 37 Pulmonary vascular resistance (dynes · sec · cm − 5 ) 119 ± 47 78 ± 22 70 ± 5 65 ± 3 Serum colloid osmotic pressure (mmHg) 20.8 ± 1.0 18.0 ± 1.5 19.0 ± 0.5 N/A

Body surface area (m 2

Systemic vascular resistance index (dynes · sec · cm − 5 · m 2 ) N/A N/A 2726 ± 120 2,293 ± 65 Pulmonary vascular resistance index (dynes · sec · cm − 5 · m 2 ) N/A N/A 127 ± 9 121 ± 7

Left ventricular stroke work index (g · m · M − 2 ) 41 ± 8 48 ± 6 81 ± 2 84 ± 2 Cardiac index (L · min − 1

· m 2

Data from * Cotton et al [176] , † Clark et al [195] , ‡ Mabie et al [318] ; § Clark et al., unpublished data

N/A, not available; SD, standard deviation; SEM, standard error of the mean

Table 34.11 Indications for use of pulmonary artery catheter in pregnancy

induced hypertension

Complications related to central volume status

Pulmonary edema of uncertain etiology

Pulmonary edema unresponsive to conventional therapy

Persistent oliguria despite aggressive volume expansion

Induction of conduction anesthesia in hemodynamically unstable patients

Medical complication that would otherwise required invasive monitoring

found that this approach is very useful and in all but the most

severe cases allows non - invasive management and avoids the

need for a pulmonary artery catheter

Cardiopulmonary c omplications of

p re - eclampsia

During normal pregnancy, plasma volume increases

approxi-mately 42% while red blood cell volume increases approxiapproxi-mately

24% [184] Earlier studies of cardiovascular changes in pre eclampsia revealed increased vascular resistance, decreased circu-latory volume, and decreased perfusion of various organ systems, most notably the renal and uteroplacental circulations, when compared with normal non - pregnant subjects [17,185] , In preg-nancies complicated by pre - eclampsia, a reduction in plasma volume with hemoconcentration occurs in proportion to the severity of the disease [184] Signifi cant plasma volume depletion and reduction in circulating plasma protein may occur prior to the clinical manifestations of pre - eclampsia [185 – 187] In sub-jects who developed hypertension during pregnancy, various degrees of increased cardiac output (CO) and/or SVR were noted [188]

Although the precise cause of these changes remains unknown, further insight into the exact cardiovascular parameters associ-ated with pregnancy - relassoci-ated disease states evolved around 1980, when obstetric and gynecologic indications for use of the pulmo-nary artery catheter were described, and measurements of CVP, pulmonary artery pressure (PAP), PCWP, CO, and mixed venous oxygen became available [178]

Rafferty and Berkowitz [189] studied three pre - eclamptic patients with a pulmonary artery catheter and noted an increased

Clark et al [195] documented for the fi rst time central hemo-dynamic parameters in normotensive late third - trimester preg-nant patients (see Table 34.10 ) They demonstrated that most reported patients with severe pre - eclampsia have SVR in the normal range for pregnancy, and that left ventricular function in normal pregnancy as assessed by LVSWI is not hyperdynamic This supports the model of an initially hyperdynamic hyperten-sion without vasospasm in pre - eclampsia This may be followed

by the development of elevated SVR associated with vasospasm and a secondary decline in CO and LVSWI Such a phenomenon has been documented in untreated non - pregnant patients with essential hypertension [196]

Pulmonary e dema

Sibai et al [197] reported a 2.9% incidence of pulmonary edema

in severe pre - eclampsia – eclampsia; 70% of these 37 cases devel-oped postpartum In 90% of the cases that develdevel-oped antepar-tum, chronic hypertension was identifi ed as an underlying factor

A higher incidence of pulmonary edema was noted in older patients, multigravidas, and patients with underlying chronic hypertension The development of pulmonary edema was also associated with the administration of excess infusions, either col-loids or crystalcol-loids

Reduction of COP, alteration of capillary membrane permea-bility, and elevated pulmonary vascular hydrostatic pressures may lead to extravasation of fl uids into the interstitial and alveo-lar spaces, resulting in pulmonary edema [192] Cotton et al [127] observed a negative COP – PCWP gradient in fi ve pre eclamptic patients who developed pulmonary edema Interestingly, Clark et al [175] compared the hemodynamic alterations in severe pre - eclamptics and eclamptics and suggested that the occurrence of eclamptic seizures may have also been associated with decreased COP rather than with the intensity of peripheral vasospasm

The etiology of pulmonary edema in pre - eclamptic patients appears to be multifactorial, as illustrated by Benedetti ’ s work involving 10 pre - eclamptic women with pulmonary edema [198]

Of these patients eight developed pulmonary edema in the post-partum period Five patients had an abnormal COP – PCWP gradient, three demonstrated increased pulmonary capillary permeability, and two suffered left ventricular failure Pulmonary edema secondary to capillary leak versus that due to increased hydrostatic pressure was distinguished by evaluating the ratio

of edema fl uid protein to plasma protein [199] The diagnosis of capillary leak was made in Benedetti ’ s study when the ratio of protein in pulmonary edema fl uid to serum protein was greater than 0.4 [198] Again, CVP was found not to correlate with PCWP A decreased COP – PCWP gradient has long been corre-lated with the development of pulmonary edema in non - preg-nant patients [199] Pregnancy is known to lower COP, and COP

is lower in pre - eclamptic patients than in normal pregnant patients COP decreases further postpartum, secondary to supine positioning, bleeding at the time of delivery, and intrapartum infusion of crystalloid solutions [200] In 50% of Benedetti ’ s

left ventricular stroke index (LVSWI) and normal pulmonary

artery resistance At delivery, the CI and PCWP increased in these

patients, probably secondary to increased venous return These

investigators noted an increased PCWP postpartum, which also

was felt to be secondary to increased circulatory volume These

fi ndings suggest that the pulmonary vasculature is not involved

in the vasospastic process and that pulmonary hypertension is not

present in severe pre - eclampsia

Observations made from pulmonary artery catheterization

in 10 patients with severe pre - eclampsia during labor showed

an increased LVSWI (suggesting hyperdynamic ventricular

function), normal PAP, and poor correlation between

CVP and PCWP [190] The poor correlation of PCWP and

CVP has been verifi ed by subsequent investigations

[127,158]

Hemodynamic studies have consistently demonstrated

hyper-dynamic left ventricular function in pre - eclamptic patients

[76,191,192] Phelan and Yurth [191] studied 10 severe pre

eclamptics and noted hyperdynamic cardiac function with

ele-vated CO and variable elevation of SVR Immediately postpartum,

a transient fall in left ventricular function with a rise in CVP and

PCWP was noted in 6 of 10 patients, possibly secondary to an

autotransfusion effect Hyperdynamic ventricular function

returned 1 hour postpartum One criticism of this study as it

related to CO is the fact that several of these patients received

intrapartum hydralazine, which could account for the elevated

CO

Groenendijk et al [193] noted a low CI, low PCWP, and high

SVR in pre - eclamptics prior to volume expansion Volume

expansion resulted in an elevation of PCWP and CI to normal

pregnant values, a drop in SVR, and no change in BP Vasodilation

using hydralazine then resulted in a further drop in SVR and BP,

with a rise in CI, and no change in PCWP

Eclamptics studied by Hankins et al [194] initially

demon-strated hyperdynamic left ventricular function and elevated SVR,

as well as low right and left ventricular fi lling pressures Following

labor management, consisting of fl uid restriction, magnesium

sulfate, and hydralazine, the authors observed a postpartum rise

in PCWP in patients who did not have an early spontaneous

diuresis This rise in PCWP was thought to be secondary to

mobi-lization of extravascular fl uids before the diuresis phase They

concluded that the hemodynamic status was infl uenced by

the severity and duration of the disease, other underlying

disease states, and therapeutic interventions such as epidural

anesthesia

Cotton et al [176] summarized the hemodynamic profi le in

45 patients with severe pre - eclampsia or eclampsia They observed

a wide variety of hemodynamic measurements in these patients;

however, the majority were found to have an elevated BP, variably

elevated SVR, hyperdynamic left ventricular function, normal to

increased PCWP, and low CVP They hypothesized that the

ele-vated PCWP with decreased CVP was secondary to eleele-vated left

ventricular afterload, combined with a hypovolemic state These

fi ndings are summarized in Table 34.9