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Nimodipine in the management of preeclampsia: Maternal and fetal effects
Nimodipine in the management of preeclampsia: Maternal and fetal effects Michael A. Belfort, MD, George R. Saade, MD, Kenneth J. Moise, Jr., MD, Arcadia Cruz, RVT, Karolina Adam, MD, Wayne Kramer, MD, and Brian Kirshon, MD Houston, Texas OBJECTIVE: Our purpose was to determine the effects of orally administered nimodipine on selected maternal and fetal parameters in patients with preeclampsia. STUDY DESIGN: Ten consecutive patients were given 30 mg of nimodipine orally every 4 hours from admission until 24 hours after delivery. Maternal and fetal cerebral blood velocity, umbilical artery blood velocity, fetal heart rate variability, maternal blood pressure and heart rate, and transplacental passage of the drug were studied. All 10 patients were delivered within 24 hours of the first dose of nimodipine. RESULTS: There was an acute and significant reduction in the pulsatility index in the smaller diameter maternal cerebral arteries (ophthalmic and central retinal) and in the fetal middle cerebral artery. The umbilical artery systolic/diastolic ratio was also significantly reduced. Maternal blood pressure was controlled without the need for other antihypertensive medication, and although there was an increase in heart rate after administration of the drug, it was well tolerated. Nimodipine reached significant maternal and fetal levels within 2 hours. CONCLUSIONS: Nimodipine is rapidly absorbed after oral administration and has significant maternal and fetal cerebral vasodilator activity. It is an effective, easily administered antihypertensive agent when used in patients with preeclampsia. (AM J OSSTET GVNECOL 1994; 171 :417-24.)
Key words: Nimodipine, cerebral blood flow, preeclampsia, antihypertensive
Preeclampsia is known to cause widespread vasoconstriction, and there is increasing evidence to suggest that eclampsia is associated with severe cerebral vasospasm. I The resultant cerebral ischemia could lower the threshold for seizure activity in affected regions of the brain. Magnesium sulfate, frequently given to patients with preeclampsia, reduces the pulsatility index in the middle cerebral and central retinal arteries ". " This may lead to improved cerebral perfusion with relief of cerebral ischemia, thereby preventing cell damage, cerebral edema, and convulsions. 4 Although the exact mechanism of action is unknown, there is evidence to suggest that magnesium sulfate acts by opposing calcium-dependent arterial vasoconstriction and by antagonizing the increase in the intracellular calcium concentration caused by ischemia.' Both of these mechanisms can reduce the potential for neuronal cell damage. h Given the significance of the calcium channel-blocking effect of magnesium sulfate, other drugs that have a similar From the DWlSlon oj Matnnal-Fetal MedlClne, Department of Obstet no and Gynecology, Baylor College oj Medlcme. Supported b~ a grant-m-md Ji'01l! the AII!erlcan HeUlt AssouatlOn. RerelVed for pllbltcatlOn Ortober 26, 1993; reCllled Feb1'llary 8, 199-1; accepted February 9, 1994. Reprint requests: Michael A. Be/jort, MD, DIViSIOn of Maternal-Fetal Medinne, Department oj ObstetriCS and Gynfcolog); One Baylor Plaza, HOllston. 1~,( 77030. Copynght © 199-1 by Mosby-Year Book. Inc 0002-9378/9-1 $3 00 + 0 6/1/55071
calcium antagonist action may be beneficial in preeclamptic patients. Of these, nimodipine, a dihydropyridine, appears to be the most selective cerebral vasodilator." In addition to its selective cerebral action, nimodipine has a less precipitate antihypertensive efl'ect than do the other dihydropyridine calcium antagonists. 6 The use of nimodipine in eclampsia ha5 resuILed in dramatic resolution of status eclampticus, a finding associated with retinal artery vasodilation. 7 We hypothesized that if calcium antagonism i~ an important mechanism in the cerebral vasodilator action of magnesium sulfate, then the use of a more specific, less toxic calcium channel blocker may simplify the management of preeclamptic patients. vVe therefore designed this study to investigate the maternal and tetal effects of nimodipine in patients with preeclampsia.
Material and methods The protocol for this study was approved by the Baylor College of Medicine Institutional Review Board for Human Investigation. All patients gave written informed consent. Patients with severe preeclampsia who were not in labor were entered into the study only after the decision to effect delivery had been made. The absence of fetal distress, as assessed by cardiotocography, was required for inclusion. Blood pressure was measured with an automated blood pressure monitor (Dinamap, Criticon, Tampa) with the patient at rest in 417
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Table I. Demographic data (yr) Parity
A~e
Ge~tational age (wk) Systolic. blood pressure (mm Hg) DIastolic blood pressure (mm Hg) Proteinuna (semIquantitative analysis) Hemoglobin (gmfdl) Platelets (X IO"/f,d) Aspartate transamina5e (U/L) Alanine transaminase (U/L) Uric acid (mg/dl) Urea (mg/dl) Creatinine (mg/dl) Lactate dehydrogenase (U/L)
27 ± 4 o (3)
38 ± 2 166 ± 15 102 ± 9
4 (0)
12.9 240 24 15 5.6 10 0.7 214
(5.1) (174) (114) (99) (4.6) (7) (2) (321)
Normally distributed data are presented as mean ± SD, and non-normally di~tributed data are prc;ented as median and range.
IS-degree lateral recumbency. Hypertension was confirmed by two elevated blood pressures over a 30minute period. Preeclampsia was defined by at least two elevated diastolic blood pressures > 90 mm Hg after admission to the labor suite, associated with proteinuria of ;::: 3 + (diagnosed by both dipstick and sulfosalicylic acid examination ofa catheter specimen of urine). Nine of the 10 patients had diastolic blood pressures that remained > 90 mm Hg from admission until the beginning ot the study, and one patient had a diastolic blood pressure that dropped from lOS mm Hg on admission to 89 mm Hg at the baseline measurement. Only patients with normal blood pressure ( < 140/90 mm Hg) and absence of proteinuria at the 6-week postpartum visit were included in the final analysis of the data. Women who had been given magnesium sulfate or any long-term antihypertensive medication or who had received > 1 L of intravenous crystalloid solution before evaluation for the study were excluded. After inclusion, baseline maternal transcranial (middle cerebral artery), extracranial (internal carotid artery), and orbital (central retinal artery and ophthalmic artery) Doppler ultrasonography was performed by standard techniques.'" R 9 Baseline fetal ultrasonography (biometry, biophysical profile, and amniotic fluid index), fetal heart rate (FHR) monitoring, and Doppler studies of the middle cerebral artery and umbilical artery were also undertaken. Patients were positioned in a semirecumbent position with a IS-degree lett lateral tilt. A 2 MHz pulsed, range-gated transcranial Doppler probe (Medasanies Cerebrovascular Diagnostic System, Fremont, Calif.) with a 10 mm sample volume wa5 used to insonate the M I portion of the middle cerebral artery by the trans temporal approach." A Siemens-Quantum (Quantum Medical Systems, Issaquah, Wash.) angiodynagraph system was used for all color flow Doppler studies. A 7.S MHz linear transducer with a 2 mm sample volume was used to study blood velocity in the remaining mater-
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nal vessels. A 3.S MHz curvilinear transducer with a 2 mm sample volume was used to study the umbilical and fetal middle cerebral arteries during a period of iCtal body and respiratory inactivity. At least IS successive waveforms, without visible pattern changes, were obtained at each examination. The maximum Doppler ultrasonic energy was 100 mW/cm", spatial peak temporal average. All calculations of mean velocity, pulsatility and systolic/diastolic (S/D) index values were performed by means of the software in the Medasonics and SiemensQuantum systems. A minimum of six waveforms were averaged for each parameter. The pulsatility index was used to present all data except for the fetal umbilical artery, where the conventional SID ratio was used. In those cases where both left and right vessels were insonated the average value was calculated. The FHR was recorded with a Sonicaid FM7 fetal monitor (Oxford/Sonicaid, Oxon, U.K.) and analyzed with an Oxford SOOO FHR computer (Oxford/Sonicaid). 10 This system was used to assess the baseline FHR in beats per minute, short-term beat-to-beat variability in milliseconds, and overall beat-to-beat variability in milliseconds and beats per minute. The Oxford SOOO fetal monitor did not have the capability for analyzing a signal from an internal scalp electrode, and all FHR data were acquired from an external Doppler transducer system. The advantage of such a computer analysis system is that an objective assessment of changes in FHR parameters is possible. A complete blood cell count, platelet count, coagulation profile, renal and liver function tests, and a nimodipine serum level were performed at baseline. The patient was then given a :~O mg nimodipine gelatin capsule orally with 10 ml of water. The FHR was continuously monitored for I hour, and then the maternal hemodynamic and the maternal and fetal Doppler examinations were repeated. The Doppler examinations were performed in the same order each time, with the transcranial measurements being obtained first. FHR analysis and maternal serum nimodipine level were repeated at the same time as the other I hour observations. Patients then underwent induction of labor or cesarean section as indicated and received one 30 mg nimodipine gelatin capsule orally every 4 hours from the time of the first dose until 24 hours after delivery. Maternal blood pressure, heart rate, and urine output were recorded hourly until 24 hours after delivery. Maternal venous blood and fetal umbilical cord blood (mixed arterial and venous specimen) were obtained at delivery for nimodipine levels. Umbilical cord blood was also taken for arterial and venous blood ga~ analysis. Patients were questioned hourly in a nondlrected fashion to determine the presence or absence of gastrointestinal, cardiovaslular, or other side effects. Blood specimem for nimodipine analysis were imme-
Belfort et al.
Volume 171, l\umber 2 Am J Obstet G) newl
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Table II. Maternal baseline and I-hour hemodynamic and Doppler data (mean ± SD) I'anable
Systolic blood pre,sure (mm Hg) Diastohc blood pressure (mm Hg) Heart rate (beats/min) Internal carotid artery systolic velocity (em/sec) Internal carotid artery dIastolic veloCIty (cm/sec) Internal carotid artery pulsatility index Middle cerebral arterv systohc velocity (em/sec) Middle cerebral artery diastolic velocity (em/sec) Middle cerebral artery pulsatility index Central retinal artery systolic velocitv (em/sec) Central retinal artery diastolic velocity (cm/sec) Central retinal artery pulsatility index Ophthalmic artery systolic veloeny (cm/sec) Ophthalmic artery diastolic velocity (cm/sec) Ophthalmic artery pulsatility index
*P
Baselme
166 102 81 41 17 1.16 99 50 0.77 13 5 1.09 42 13 1.4
± 15 ± 9 ± 14
± II
± 6 ± 0.29 ± 19 ± 15
± 0.13 ± ± ± ± ± ±
2
I 0.10 14 3 0.4
1 hI'
142 81 93 43 18 1.04
87
44 0.75 II 5 0.79 38 14 1.12
± 15* ± ± ± ± ± ±
± ± ± ± ±
±
8* 15* II 6 0.3 24 17 0.19 2* 2 0.19* J:)
± 3 ± 0.3*
< 0.05 compared with baseline value.
diately centrifuged at 5000 revolutions/min for 10 minutes and then frozen at - 70° C. The concentration of nimodipine in the serum was determined by the Clinical Pharmacology Department of Miles Inc. (Westhaven, Conn.). A capillary gas chromatograph (Varian 6000/6500) process similar to that used by the same laboratory for the analysis of nitrendipine was used. II All data sets were subjected to D'Agostino's test to confirm a normal distribution. Appropriate parametric and nonparametric tests for paired data were then used in the analysis. The maternal hemodynamic and Doppler data and FHR data were analyzed with a paired Student t test using the baseline and I hour values. The
signed-rank test was used for analysis of the fetal umbilical artery Doppler data. Regression analysis was used to examine the relationship between maternal and umbilical cord levels of nimodipine at birth. A probability value of < 0.05 was considered to indicate statistical significance. Results
Ten patients were enrolled in the study. Six were primiparous and four were multiparom. Nine of the 10 patients were Hispanic and one was of Asian-Indian origin. The demographic data of the study group IS presented in Table 1. Some of the patients were C'xpe-
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Table III. Fetal Doppler and heart rate analysis data
Fetal middle cerebral artery systohc velocity (em/sec) Fetal mIddle cerebral artery dIastolic velocity (cm/sec) Fetal middle cerebral artery pulsatility index Umbilical artery SID ratio FHR (beats/mm) Short-term beat-to-beat variabihty (msec) Overall beat-to-beat variabIlity (msec) Overall beat-to-beat vanability (beats/min)
Bmelzne
1 hr
Significance
49 ± 14 13 ± 5 1.43 ± 0.5 2.67 (3.68) 136 ± 10 7.8 ± 4.0 42.4 ± 23.4 14.1 ± 7
46 ± 13 16 ± 6 1.20 ± 0.4 2.52 (3.57) 134 ± 12 9.03 ± 3.2 51.2 ± 18.5 16.8 ± 5.2
NS NS P = 0.01 P = 0.01 NS NS NS NS
Normally distributed data are presented as mean ± SD, and non-normally distributed data are presented as median and range. NS, Not sigmficant.
riencing symptoms of severe preeclampsia at the time of admission (headache [71 = 5]. scotomas [71 = 3], right-up per-quadrant pain [71 = 2], and nausea and emesis [n = 1]). In all cases these symptoms resolved within 20 to 30 minutes of receiving nimodipine. There was a significant reduction in systolic and diastolic blood pressure after nimodipine administration (Table II, Fig. 1). This effect was evident within 15 minutes in most cases and was well established by 1 hour. No additional antihypertensive agents were required during the study period, and both antepartum and postpartum blood pressure control was excellent (Fig. 1). The maternal heart rate was significantly increased at 1 hour (Table II) and remained elevated throughout the first 24 hours post partum (Fig. 1). There were no significant changes in velocity in the maternal internal carotid and middle cerebral arteries 1 hour after nimodipine administration (Table II). There was a small decrease in the internal carotid artery pulsatility index with a similar trend seen in the middle cerebral artery pulsatility index, but no statistically significant differences were noted (power to detect a difference of this magnitude was < 20o/c with this sample size), possibly representing a type II statistical error. There were significant reductions in the pulsatility index in the central retinal artery and ophthalmic artery 1 hour after oral administration of 30 mg of nimodipine. The change in central retinal artery pulsatility index was associated with a significant reduction in the central retinal artery systolic velocity (13 ± 2 cm/sec to 11 ± 2 cm/sec, p < 0.02). Fetal Doppler and heart rate data at the baseline and 1 hour after nimodipine administration are presented in Table III. There was no change in FHR, short-term beat-to-beat variability, or overall beat-to-beat variability I hour after nimodipine administration. There was, however, a significant reduction in the umbilical artery SID ratio and fetal middle cerebral artery pulsatility index over the first hour after nimodipine administration (Table III). All fetuses appeared to tolerate the reduction in maternal blood pressure without any evidence of distress.
All patients were delivered within 24 hours of administration of the first dose of nimodipine. In those cases where repeated nimodipine doses were given ante partum. there was no adverse effect noted on either mother or fetus. In particular, there were no instances of maternal hypotension with our scheduled dosage regimen. In all cases the drug appeared to be well tolerated by the fetus, and there were no episodes of fetal stress or distress noted. Anesthesia was well tolerated, and there were no problems with hypotension. Two patients had general anesthesia, two had spinal anesthesia, and the remaining six had an epidural anesthetic. Those patients who received regional anesthesia had prior volume expansion with a bolus infusion of 1000 ml of lactated Ringer's solution. Four women had a cesarean section performed immediately after the I-hour observations were completed. Indications for surgery included previous classic cesarean section, prior cesarean section (unknown scar) for a transverse lie, syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) (hematocrit 38.5%, platelets 101 ,OOO/mm', aspartate transaminase 131 U/L, alanine transaminase 107 U/L), and transverse lie with oligohydramnios. Six patients underwent induction of labor (median initial cervical dilatation 2 cm). Of these six women three were delivered vaginally (mean duration of the active phase of labor 10 ± 3 hours). The mean rate of oxytocin infusion at delivery was 6 mIU/min. No patient experienced uterine atony or postpartum hemorrhage. Three patients required a cesarean section, two for failure to progress and one for a ruptured uterus. In the case of the patient with rupture of the uterus there was no maternal hypotension or shock, and the diagnosis was made at the time of cesarean section for sudden fetal distress. The average blood loss was 400 ml at vaginal delivery and 800 ml at cesarean section. The mean hematocrit on admission was 37% ± 8% and decreased to a mean of 30% ± 6% 24 hours after delivery. No patient had convulsions at any time during this study, and none experienced symptomatic hypotension. One of the 10 patients had facial flushing within 15
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Volume 171. l\'umber 2 Am J Obstet G}necol
minutes of administration of nimodipine. Two patients experienced emesis approximately 20 minutes after administration. One of these women was experiencing nausea and emesis before entry in the study. In her case the drug had been given sublingually. After delivery all patients tolerated the nimodipine well. Blood pressure control remained good in the postpartum period (Fig. 1) without need for additional antihypertensive medication. No patient experienced symptomatic or asymptomatic hypotension. Because the patient who experienced a rupture of her uterus was excluded from the study at that time, her postpartum blood pressure data were not included in the analysis. This patient was started on magnesium sulfate post partum without any evidence of adverse interaction with the nimodipine. There was no difference in the pattern of blood pressure control between those patients delivered vaginally and those who underwent a cesarean section. All patients received a maintenance infusion of 125 ml of crystalloid per hour after the I-hour study measurements. Before delivery urine output remained above 40 ml/hr (except in one patient who required a intravenous crystalloid bolus with prompt response). Post partum all patients maintained a urine output > 30 ml/hr, and by 12 hours the mean urine output was > 100 ml/hr, which this was maintained for the remainder of the study period. The median maternal nimodipine level 1 hour after administration was 15.8 (range 79.0) ng/ml. There was a positive correlation between the maternal and fetal nimodipine blood levels at delivery (r = 0.96, P < 0.001), indicating good transfer of nimodipine across the placenta (Fig. 2). The median maternal serum nimodipine concentration at delivery was 7.32 (range 27.0) ng/ml and the umbilical cord serum concentration was 2.6 (13) ng/ml. The maternal/fetal ratio was 2.4: 1. In the four women who underwent cesarean section immediately after the I-hour observation (within 2 hours of the first dose), maternal and umbilical cord serum levels of nimodipine were analyzed separately. In these four patiems the median maternal serum nimodipine concentration at delivery was 9.68 (range 11.7) ng/ml, and the umbilical cord serum concentration was 3.46 (range 5.94) ng/ml. The maternal/fetal ratio was 2.6: 1. There was a positive correlation (r = 0.6) between the maternal ~erum nimodipine level and the change in the central retinal artery pulsatility index, suggesting that the higher the maternal nimodipine level the greater the reduction seen in the central retinal artery pulsatility index. The neonatal data are presented, excluding that of the infant of one patient (No.9) who had a ruptured uterus with severe fetal distress (data presented separately). Apgar scores (median) at 1 and 5 minutes after
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delivery were 8 (range 6 to 10) and 9 (range 8 to 10), respectively. The umbilical arterial blood gases were as follows: pH 7.25 ± 0.07, base excess -5.7 ± 4.6, Peo:! 47.4 ± 6.0 mm Hg, and bicarbonate 21.0 ± 4.3 m Eq/L. The umbilical venous blood gases were as follows: pH 7.30 ± 0.04, base excess -4.0 ± 3.2, Pco:! 42.9 ± 4.4 mm Hg, and bicarbonate 20.6 ± 5.7 mEq/L. None of the nine neonates included in the group analysis were delivered with evidence of rlistre~s or metabolic derangement. At the 6-week follow-up visit all nine infants were thriving. Infant No.9 was assigned Apgar scores at 1 and 5 minutes of 1 and 5, respectively. Cord blood gas analysis revealed an arterial pH of 6.81, Peo:! of 123 mm Hg, P0 2 of 14 mm Hg, and base excess of -18. The infant recovered rapidly and was extubated within 3 hours. There was no evidence of organ failure and a follow-up computed tomographic ~can on day of life 3 was normal. The baby was discharged in good condition on day of life 15 without any evidence of residual damage. Nimodipine levels in the maternal serum and fetal umbilical cord blood at delivery were 0.70 ng/ml and 0.94 ng/ml, respectively. Follow-up at 6 weeks ~howed the infant to be deVeloping normally. Comment
There is increasing evidence that cerebral vasospasm plays a role in the pathogenesis of eclampsia. I. 7 Cere-
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Bellort et al.
bral vasoconstriction has been demonstrated in angiographic and magnetic resonance imaging studies of eclamptic patients, and there are Doppler data to suggest that in preeclampsia vasospasm distal to the middle cerebral and central retinal arteries may be related to cerebral ischemia. I-e. 12 Whatever the mechanism involved in the initiation of cerebral vasospasm. the contraction of cerebral arteries is ultimately induced by an increase in free intracellular calcium. This depends on the influx of extracellular Ca e + combined with the release of Ca ~ + from intracellular stores. 13 Thus there is a theoretic basis for the use of calcium channel blockers in the management of preeclampsia. The dihydropyridine calcium antagonists have been used in pregnancy, primarily in research studies dealing with blood pressure control in patients with preeclampsia H . I ' and for the treatment of premature labor. lfi Nimodipine may be especially appropriate for preeclamptic patients, not only because it is an effective antihypertensive agent but also because it has a more potent vasodilator action on human cerebral vessels than does magnesium sulfate. '7 One of the major concerns when blood pressure is reduced in the mother is the effect of the drug on uteroplacental circulation. There is good evidence that dihydropyridine calcium channel blockers (nifedipine. 14 nitrendipine,18 and isradipine l9 ) do not reduce uteroplacental blood flow in spite of a significant reduction in maternal blood pressure. The maternal hemodynamic effects of nimodipine in our study were characterized by a 14% reduction in systolic blood pressure, a 22% reduction in diastolic blood pressure, and a 15% increase in maternal heart rate within the first hour of administration. These changes appeared to be well tolerated by both mother and fetus, and there was no evidence of the abrupt hypotension sometimes seen with intravenous vasodilators. The antihypertensive effect of the drug was maintained post partum without evidence of a rebound effect or tachyphylaxis. In addition, postpartum administration of nimodipine did not result in hypotensive episodes, even when it was given to normotensive patients. Our fmdings are consistent with the data of others regarding calcium channel blockers in normal pregnancy and preeclampsia and in nonpregnant patients. 1<>-21 The increase in heart rate that we observed was well tolerated without symptoms and probably reflects a baroreceptor-mediated compensation to a decrease in total peripheral resistance. There was no evidence that nimodipine prolonged labor or increased the occurrence of uterine atony and postpartum hemorrhage. We have studied the Doppler index values in the central retinal artery longitudinally in a group of normal pregnant patients (n = 9), and preliminary data indicate that the pulsatility index decreases from a peak
Augmt 19'H Am J Ob.(ci Gvnccol
of approximately 0.98 at 20 weeks to 0.85 at term (unpublished data). The preeclamptic patients in this study had a mean central retinal artery pulsatility index of 1.09 ± 0.1, supporting the theory that preeclampsia is associated with vasospasm in the cerebral microcirculation. The central retinal and ophthalmic artery pulsatility index values decreased significantly within 1 hour of administration of nimodipine. In the central retinal artery the effect of the drug was dose dependent. The vasodilator effect of nimodipine was, however, not seen to the same extent in the larger cerebral vessels (internal carotid. middle cerebral, and ophthalmic arteries). This finding is consistent with the literature for nonpregnant patients, where it has been demonstrated that the principal effect of nimodipine is directed at vessels with a diameter of < 100 f..Lm. 22 In addition, nimodipine acts primarily on constricted vessels,27 and the major vasospasm in preeclampsia is present in the small resistance vessels (central retinal arteries) but not in the larger conducting vessels (internal carotid and middle cerebral arteries). Although no patient in our population experienced seizure activity, the issue of the anticonvulsant action of nimodipine in preeclampsia cannot be addressed by this study. Power analysis calculations indicate that > 2000 severely preeclamptic patients, randomized to receive either magnesium sulfate or nimodipine, will be needed to detect a 50% reduction in the current number of patients who have convulsions in spite of antiseizure prophylaxis with magnesium sulfate. The fact that there was resolution of headache and scotomas in two of our patients within 15 minutes of receiving nimodipine is encouraging and suggests that there is a clinically evaluable increase in cerebral perfusion in severe cases of preeclampsia. This statement is supported by a case report in which nimodipine was used to control status eclampticus and where a decrease in cerebrovascular resistance was seen.7 Orally administered nimodipine is almost completely absorbed from the gastrointestinal tract with maximum serum concentrations occurring within 30 to 60 minutes in nonpregnant subjects."" Levels ofnimodipine similar to those noted in our patients were reported in healthy volunteers taking a 30 mg capsule sublingually (mean 19 ng/ml, range 4.6 to 53.6 ng/ml)."' The dosing schedule we used, which was based on that for nonpregnant su~jects, appeared to be effective. Dihydropyridine calcium antagonists may, however, be more rapidly metabolized in pregnancy, and experience with nisoldipine has demonstrated the need for larger doses and more frequent administration in the postpartum period than for nonpregnant patients. I, Further experience with nimodipine will be required to determine the optimum dose and dosing schedule in the postpartum preeclamptic patient.
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In our patients there was no relationship between serum level and vomiting, and the widely distributed data may possibly be the result of liver metabolism and a first-pass eHect. Nimodipine is preferentially metabolized in the liver."" and its use in patients with severely compromised hepatic function should be cautioned against. It has, however, been shown to be safe in young patients with renal compromise.""' In our study renal output remained satisfactory throughout, and in only one case was an additional crystalloid bolus infusion required. These data are consistent with the known natriuretic effect of dihydropyridine calcium channel blockers in nonpregnant and pregnant patients. Placental transfer of nimodipine has been shown to be limited in pregnant animals, with maternal levels being approximately eight to 15 times greater than those seen in the fetus."" A higher rate of transplacental transfer was noted in our study, with a maternal/fetal ratio of 2.4: 1. Dihydropyridine calcium channel blockers have not been demonstrated to reduce placental blood flow in either animal or human studies; this appears to hold for nimodipine as well. 14. 19 In our study the SID ratio in the umbilical artery wa~ significantly reduced after nimodipine administration. and there was also evidence of a reduction in fetal cerebrovascular resistance. The FHR did not change, and although there was a trend to an increase in the short-term and overall beat-to-beat variability these changes were not significant 1 hour after nimodipine administration. A similar lack of short-term effect has also been the experience of others investigating changes in FHR after maternal treatment with dihydropyridine calcium channel blockers. II 18 FHR analysis before and after nimodipine therapy was objective, and this method has previously been shown to be reliable in the detection of short-term alterations in fetal condition. It is therefore unlikely that there was any short-term detrimental fetal respiratory or metabolic effect that can be related to the administration of nimodipine in our study population. In conclusion, we have demonstrated that nimodipine appears to be a safe and effective antihypertensive agent for the management of patients with preeclampsia. Although the sample size is small. there is good evidence to suggest that the drug causes vasodilatation in small-diameter cerebral vessels in these women. For this reason nimodipine deserve~ further investigation as an anti seizure dgent for the prevention of eclampsia. The safety, ease of administration. and avoidance of the need for other antihypertensive medications make nimodipine an attractive alternative to intravenous magnesium sulfate. Further research into the use of this drug in preeclampsia appears warranted. We thank Dr. G.'V. Beck, PhD. and Dr. GJ. Krol, PhD, of the Clinical Pharmacology Department at Miles Inc. for analysis of the blood specimens.
423
REFERENCES 1. U'wis LK. Hmshaw DB. Wtll AD. Ha"o AN. Thompson JR. CT and angiographK correlatIon of ;,e\'ere neurologIcal disease in toxaemia of pregnanc\'. NeuroradlOlog\ 1988;30:59-64. 2. Bellort MA, MOIse KJ. The effect of magnc'>lllm sulfate on maternal bram blood flow in mild preeclamp'ld: .1 randonllzed placebo-(Ontrollcd study. A\I J OB"lrl (;\"HOl 1992;167: 1548-53. 3. Bellort MA. Effect of magne,lum su!filte on blond flow in the maternal retina in mIld ge,tational pruteinurK hypertcnsion: a prelimmary colour How Doppler sturly. Br J Ohstet Gynaecol 1992;99:641-5. 4. Redman CW, Roberts JM. :\Ianagement of pre-cclampsia. LanLet 1993;341:1451-4. 5. Altura BT, Altura BM. Interactions of Mg and K on cerebral ve;,seh-aspect~ in view of qrnke. ReVIew of pre~ent status and new finding'>. Magnesium 1981;:1: 195211. 6. Freedman DD, Wdters DD. "Sewnd generation" rlihydru. pvridme calcium antagonists. Greater \'a'cular ,electivltv and somc unique applications. Drugs 1987;3·1:0578-91'. 7. Belfort MA. Carpenter RJ. Moise I\J Jr. Saade (,R. The me of nimodipine in a patient with eclampSIa: color Doppler demomtration of retinal artery relaxation. A!,I.J O[l,rET GYKECOL 199:~; lfi9:204-G. 8. Arnolds B. von Reutern C;. TransClalllal Doppler sonography. ExaminatIOn techmqlles and normal reference \'.11ue,. Ultrasound Med BIOI 198fi;12:115-2:1. 9. Belfon MA. Doppler assessment of relmal blood flo\\,velocity dUting parenteral magnesium treatment in patients with preeclamp.,ia. MagneSIUm Res 199:1;6:239-46. 10. Da\\es GS. Visscr GIi. Goodman JD, Rcdman C\\'. Numerical analpi' ot the human fetal heart rate: thc qualit) of ultrasound record.,. A\tJ OBSTEI GY:--IElUI. 1981;141:-+352. 11. Krol GJ. Lettien JT, Yeh SC, Burkholder DE, BIrkett .II'. DIsposition and pharmacokmellcs of 14C-Iabelled llItrclldlpme in healthy volunteers. J CarcliO\ asc Phannacol 1987;suppl -+:5122-8. 12. Belton :\IA. Saade GR, :\lolse KJ Jr. The eflect uf magnesium ,ulfate on maternal retmal blood flow III preeclampSIa: a randomIzed placebo-controlled ,tud). A\I J OBsn I GV:--IE(()t. 1992:167:1348·53. 1:~. Bolton TB. Mcchanisms of actIon of transmitters and other substances on smooth muscle. Physinl Re\ 1979;59: 606-718. I -+. Lindow SW. Davies N, Davey DA. Smith JA. The cHect of ,ublingual 1lI1eclipine 011 ut~ruplacental bloud flow in hypertensive pregnancy. Br J Obstet Gvnaecol 1988;9:>: 1276-81. 15. BeHort MA, Kir;,hon B. l\"isoldlpine-a new orally administered calcium antagonist med in tht' tI edtment (If se\ ere pm,tpartum pregnancy-induLed h)pertemwn. S Afr !\led J 1992;81:267-70. 16. Uhmten LT. Anden"on KE. \\'ingelup L. Tredtment of premature labour with the calcnlln antagonist nifCdipinc. Arch Cvnecol 1980.229: 1-5. 17. Alborch E, 5alom .lB. Per ale;, AJ, et .11. Comparison of the antIComtnctor action of dihydlOpyridme;, (nimodipine and llIcardipinel and Mg2+ in isolated human cerebr,tl artenes. Eur.l PhdrmalOl 1992:229:8:1-9. 18. Allen J, Malgaard S, Forman A, et al. Acute effect;, of nitrendipme in pregn.lnn-induccd hvpeIlcmlon HI' r Ob,tet Gynaewl 1987,94:222-6. 19. Lunell NO. Caron L, Grunewald C, ct al. j,raciIpme .. tne\\ calcium ,llltagolllst: effeLt-. on materndl and fetdl hemOthnamlLs .J Canhova,c Pharm 199J;I1'buppl :\):S:\7--+0. 20. Belfort ,\1A. Anthony J Kir,hon B. RespIrator\, tunctlOn in severe ge'tatlOnal protclllUrIC h) pertcn,ion: the efTcc" of rapId volume expan,lon and 5nb5e'luent va,()(hldlatl
Phelan and Ahn
sure and heart rate durmg treatment with mmodipme In patients with ;,ubarachnoid hemorrhage. Neurochirurgia 1985;28:81-6. 22. Langley MS, Sorkin EM. Nimodipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential m cerebrovascular disease. Drugs 1989;37:669-99. 23. Gengo FM, Fagan SC, Krol G, Bernhard H. Nimodipine disposition and haemodynamic effects in patients with
August 1994 Am J Obstet Gynt'col
cirrhosIs and age-matched controls. Br J Clin Pharmacol 1987;23:47-53. 24. Kirch W. Ramsch KD, Duhrsen U, Ohnhaus EE. Clinical pharmacokinetics of nimodipme in normal and impaired renal function. IntJ Chn Pharm Res 1984;4:381-4. 25. Suwelack D. Weber H. Assessment of enterohepatic circulation of radioactivity following a single dose of [14C] mmodipme in the rat. Eur J Drug Metab Pharmacokinet 1985; 10:231-9.
Perinatal observations in forty-eight neurologically impaired term infants Jeffrey P. Phelan, MD, and Myoung Ock Ahn, MD, PhD, MPH Pomona, Ca lifo rnla , and Seoul, Korea OBJECTIVE: Our goal was to review the perinatal characteristics of 48 singleton term infants with central nervous system neurologic impairment. STUDY DESIGN: Medical records were retrospectively reviewed for maternal characteristics, prenatal and intrapartum care patterns, neonatal course, and long-term outcome. Those patients without evidence of an obvious acute asphyxial event, traumatic delivery, or preterm birth were excluded. The study population was then subclassified according to the admission fetal heart rate pattern. RESULTS: Of these 48 term infants the admission fetal heart rate pattern was nonreactive in 33 (69%) and reactive in 15 (31%). Maternal characteristics, prenatal care, and long-term outcome were statistically similar between the two groups. However, the nonreactive group exhibited significantly more characteristics consistent with a prior asphyxial event: thick "old" meconium, "fixed" nonreactive baseline fetal heart rate, meconium-stained skin, and meconium aspiration syndrome. In contrast, in the reactive group a fetal heart rate pattern developed that was consistent with Hon's theory for intrapartum asphyxia and manifested by a prolonged tachycardia in association with persistent nonreactivity, diminished fetal heart rate variability, and fetal heart rate decelerations. CONCLUSIONS: Among fetuses later found to be neurologically impaired, a persistent nonreactive fetal heart rate tracing obtained from admission to delivery appears to be evidence of prior neurologic injury. (AM J OaSTET GVNECOL 1994;171:424-31.)
Key words: Asphyxia, fetal heart rate, meconium, hypoxic ischemic encephalopathy, seizures Limited information is currently available on the fetal heart rate (FHR) patterns and the clinical characteristics of singleton term neurologically impaired infants. I·' However, those investigators I·' and others o.? have inferred that a relationship exists between persistent fetal
From the Department of Ob,tetncs and Gynecology, Pomona Valley Ho,pltal Medical Center, and the Department of ObstetnCl and Gynecology. Cha Women', Ho,pltal of Seou!. ReceIVed for publicatlOll October 15, 1993, rev/sed january 10, 1994; accepted january 28, 1994. Reprznt reque,ts: jeffrey P. Phelan, MD, SUIte 110, 1030 S. Arro.yo Parkwav, Pasadena, CA. 91105. Copynght © 1994 b\' Mosk-Year Book, Inc. 0002-9378/94 $3.00 + O' 6/1/54819
424
heart rate (FHR) nonreactivlty and subsequent longterm neurologic impairment. In fact, van der Moer et aF observed a "fixed" FHR pattern with a normal baseline heart rate after fetal decerebration. In many of these instances these same patients have had substantially higher rates of meconium-stained amniotic fluid and oligohydramnios. I. 3·9 These findings suggest a static condition rather than one that develops acutely during labor. On the basis of these observations, fetal neurologic impairment may well be manifested, in selected circumstances, by a persistent nonreactive FHR pattern with a stable baseline FHR in association with meconium-stained amniotic fluid. Thus the purpose of this report was to retrospectively
Key words: Nimodipine, cerebral blood flow, preeclampsia, antihypertensive
Preeclampsia is known to cause widespread vasoconstriction, and there is increasing evidence to suggest that eclampsia is associated with severe cerebral vasospasm. I The resultant cerebral ischemia could lower the threshold for seizure activity in affected regions of the brain. Magnesium sulfate, frequently given to patients with preeclampsia, reduces the pulsatility index in the middle cerebral and central retinal arteries ". " This may lead to improved cerebral perfusion with relief of cerebral ischemia, thereby preventing cell damage, cerebral edema, and convulsions. 4 Although the exact mechanism of action is unknown, there is evidence to suggest that magnesium sulfate acts by opposing calcium-dependent arterial vasoconstriction and by antagonizing the increase in the intracellular calcium concentration caused by ischemia.' Both of these mechanisms can reduce the potential for neuronal cell damage. h Given the significance of the calcium channel-blocking effect of magnesium sulfate, other drugs that have a similar From the DWlSlon oj Matnnal-Fetal MedlClne, Department of Obstet no and Gynecology, Baylor College oj Medlcme. Supported b~ a grant-m-md Ji'01l! the AII!erlcan HeUlt AssouatlOn. RerelVed for pllbltcatlOn Ortober 26, 1993; reCllled Feb1'llary 8, 199-1; accepted February 9, 1994. Reprint requests: Michael A. Be/jort, MD, DIViSIOn of Maternal-Fetal Medinne, Department oj ObstetriCS and Gynfcolog); One Baylor Plaza, HOllston. 1~,( 77030. Copynght © 199-1 by Mosby-Year Book. Inc 0002-9378/9-1 $3 00 + 0 6/1/55071
calcium antagonist action may be beneficial in preeclamptic patients. Of these, nimodipine, a dihydropyridine, appears to be the most selective cerebral vasodilator." In addition to its selective cerebral action, nimodipine has a less precipitate antihypertensive efl'ect than do the other dihydropyridine calcium antagonists. 6 The use of nimodipine in eclampsia ha5 resuILed in dramatic resolution of status eclampticus, a finding associated with retinal artery vasodilation. 7 We hypothesized that if calcium antagonism i~ an important mechanism in the cerebral vasodilator action of magnesium sulfate, then the use of a more specific, less toxic calcium channel blocker may simplify the management of preeclamptic patients. vVe therefore designed this study to investigate the maternal and tetal effects of nimodipine in patients with preeclampsia.
Material and methods The protocol for this study was approved by the Baylor College of Medicine Institutional Review Board for Human Investigation. All patients gave written informed consent. Patients with severe preeclampsia who were not in labor were entered into the study only after the decision to effect delivery had been made. The absence of fetal distress, as assessed by cardiotocography, was required for inclusion. Blood pressure was measured with an automated blood pressure monitor (Dinamap, Criticon, Tampa) with the patient at rest in 417
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Belfort et al.
Am
Table I. Demographic data (yr) Parity
A~e
Ge~tational age (wk) Systolic. blood pressure (mm Hg) DIastolic blood pressure (mm Hg) Proteinuna (semIquantitative analysis) Hemoglobin (gmfdl) Platelets (X IO"/f,d) Aspartate transamina5e (U/L) Alanine transaminase (U/L) Uric acid (mg/dl) Urea (mg/dl) Creatinine (mg/dl) Lactate dehydrogenase (U/L)
27 ± 4 o (3)
38 ± 2 166 ± 15 102 ± 9
4 (0)
12.9 240 24 15 5.6 10 0.7 214
(5.1) (174) (114) (99) (4.6) (7) (2) (321)
Normally distributed data are presented as mean ± SD, and non-normally di~tributed data are prc;ented as median and range.
IS-degree lateral recumbency. Hypertension was confirmed by two elevated blood pressures over a 30minute period. Preeclampsia was defined by at least two elevated diastolic blood pressures > 90 mm Hg after admission to the labor suite, associated with proteinuria of ;::: 3 + (diagnosed by both dipstick and sulfosalicylic acid examination ofa catheter specimen of urine). Nine of the 10 patients had diastolic blood pressures that remained > 90 mm Hg from admission until the beginning ot the study, and one patient had a diastolic blood pressure that dropped from lOS mm Hg on admission to 89 mm Hg at the baseline measurement. Only patients with normal blood pressure ( < 140/90 mm Hg) and absence of proteinuria at the 6-week postpartum visit were included in the final analysis of the data. Women who had been given magnesium sulfate or any long-term antihypertensive medication or who had received > 1 L of intravenous crystalloid solution before evaluation for the study were excluded. After inclusion, baseline maternal transcranial (middle cerebral artery), extracranial (internal carotid artery), and orbital (central retinal artery and ophthalmic artery) Doppler ultrasonography was performed by standard techniques.'" R 9 Baseline fetal ultrasonography (biometry, biophysical profile, and amniotic fluid index), fetal heart rate (FHR) monitoring, and Doppler studies of the middle cerebral artery and umbilical artery were also undertaken. Patients were positioned in a semirecumbent position with a IS-degree lett lateral tilt. A 2 MHz pulsed, range-gated transcranial Doppler probe (Medasanies Cerebrovascular Diagnostic System, Fremont, Calif.) with a 10 mm sample volume wa5 used to insonate the M I portion of the middle cerebral artery by the trans temporal approach." A Siemens-Quantum (Quantum Medical Systems, Issaquah, Wash.) angiodynagraph system was used for all color flow Doppler studies. A 7.S MHz linear transducer with a 2 mm sample volume was used to study blood velocity in the remaining mater-
J
AUf(mt 19'+1 Ob,tct (;ync(ol
nal vessels. A 3.S MHz curvilinear transducer with a 2 mm sample volume was used to study the umbilical and fetal middle cerebral arteries during a period of iCtal body and respiratory inactivity. At least IS successive waveforms, without visible pattern changes, were obtained at each examination. The maximum Doppler ultrasonic energy was 100 mW/cm", spatial peak temporal average. All calculations of mean velocity, pulsatility and systolic/diastolic (S/D) index values were performed by means of the software in the Medasonics and SiemensQuantum systems. A minimum of six waveforms were averaged for each parameter. The pulsatility index was used to present all data except for the fetal umbilical artery, where the conventional SID ratio was used. In those cases where both left and right vessels were insonated the average value was calculated. The FHR was recorded with a Sonicaid FM7 fetal monitor (Oxford/Sonicaid, Oxon, U.K.) and analyzed with an Oxford SOOO FHR computer (Oxford/Sonicaid). 10 This system was used to assess the baseline FHR in beats per minute, short-term beat-to-beat variability in milliseconds, and overall beat-to-beat variability in milliseconds and beats per minute. The Oxford SOOO fetal monitor did not have the capability for analyzing a signal from an internal scalp electrode, and all FHR data were acquired from an external Doppler transducer system. The advantage of such a computer analysis system is that an objective assessment of changes in FHR parameters is possible. A complete blood cell count, platelet count, coagulation profile, renal and liver function tests, and a nimodipine serum level were performed at baseline. The patient was then given a :~O mg nimodipine gelatin capsule orally with 10 ml of water. The FHR was continuously monitored for I hour, and then the maternal hemodynamic and the maternal and fetal Doppler examinations were repeated. The Doppler examinations were performed in the same order each time, with the transcranial measurements being obtained first. FHR analysis and maternal serum nimodipine level were repeated at the same time as the other I hour observations. Patients then underwent induction of labor or cesarean section as indicated and received one 30 mg nimodipine gelatin capsule orally every 4 hours from the time of the first dose until 24 hours after delivery. Maternal blood pressure, heart rate, and urine output were recorded hourly until 24 hours after delivery. Maternal venous blood and fetal umbilical cord blood (mixed arterial and venous specimen) were obtained at delivery for nimodipine levels. Umbilical cord blood was also taken for arterial and venous blood ga~ analysis. Patients were questioned hourly in a nondlrected fashion to determine the presence or absence of gastrointestinal, cardiovaslular, or other side effects. Blood specimem for nimodipine analysis were imme-
Belfort et al.
Volume 171, l\umber 2 Am J Obstet G) newl
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Table II. Maternal baseline and I-hour hemodynamic and Doppler data (mean ± SD) I'anable
Systolic blood pre,sure (mm Hg) Diastohc blood pressure (mm Hg) Heart rate (beats/min) Internal carotid artery systolic velocity (em/sec) Internal carotid artery dIastolic veloCIty (cm/sec) Internal carotid artery pulsatility index Middle cerebral arterv systohc velocity (em/sec) Middle cerebral artery diastolic velocity (em/sec) Middle cerebral artery pulsatility index Central retinal artery systolic velocitv (em/sec) Central retinal artery diastolic velocity (cm/sec) Central retinal artery pulsatility index Ophthalmic artery systolic veloeny (cm/sec) Ophthalmic artery diastolic velocity (cm/sec) Ophthalmic artery pulsatility index
*P
Baselme
166 102 81 41 17 1.16 99 50 0.77 13 5 1.09 42 13 1.4
± 15 ± 9 ± 14
± II
± 6 ± 0.29 ± 19 ± 15
± 0.13 ± ± ± ± ± ±
2
I 0.10 14 3 0.4
1 hI'
142 81 93 43 18 1.04
87
44 0.75 II 5 0.79 38 14 1.12
± 15* ± ± ± ± ± ±
± ± ± ± ±
±
8* 15* II 6 0.3 24 17 0.19 2* 2 0.19* J:)
± 3 ± 0.3*
< 0.05 compared with baseline value.
diately centrifuged at 5000 revolutions/min for 10 minutes and then frozen at - 70° C. The concentration of nimodipine in the serum was determined by the Clinical Pharmacology Department of Miles Inc. (Westhaven, Conn.). A capillary gas chromatograph (Varian 6000/6500) process similar to that used by the same laboratory for the analysis of nitrendipine was used. II All data sets were subjected to D'Agostino's test to confirm a normal distribution. Appropriate parametric and nonparametric tests for paired data were then used in the analysis. The maternal hemodynamic and Doppler data and FHR data were analyzed with a paired Student t test using the baseline and I hour values. The
signed-rank test was used for analysis of the fetal umbilical artery Doppler data. Regression analysis was used to examine the relationship between maternal and umbilical cord levels of nimodipine at birth. A probability value of < 0.05 was considered to indicate statistical significance. Results
Ten patients were enrolled in the study. Six were primiparous and four were multiparom. Nine of the 10 patients were Hispanic and one was of Asian-Indian origin. The demographic data of the study group IS presented in Table 1. Some of the patients were C'xpe-
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Augmt 1994 Am J Obstet Gynecol
Table III. Fetal Doppler and heart rate analysis data
Fetal middle cerebral artery systohc velocity (em/sec) Fetal mIddle cerebral artery dIastolic velocity (cm/sec) Fetal middle cerebral artery pulsatility index Umbilical artery SID ratio FHR (beats/mm) Short-term beat-to-beat variabihty (msec) Overall beat-to-beat variabIlity (msec) Overall beat-to-beat vanability (beats/min)
Bmelzne
1 hr
Significance
49 ± 14 13 ± 5 1.43 ± 0.5 2.67 (3.68) 136 ± 10 7.8 ± 4.0 42.4 ± 23.4 14.1 ± 7
46 ± 13 16 ± 6 1.20 ± 0.4 2.52 (3.57) 134 ± 12 9.03 ± 3.2 51.2 ± 18.5 16.8 ± 5.2
NS NS P = 0.01 P = 0.01 NS NS NS NS
Normally distributed data are presented as mean ± SD, and non-normally distributed data are presented as median and range. NS, Not sigmficant.
riencing symptoms of severe preeclampsia at the time of admission (headache [71 = 5]. scotomas [71 = 3], right-up per-quadrant pain [71 = 2], and nausea and emesis [n = 1]). In all cases these symptoms resolved within 20 to 30 minutes of receiving nimodipine. There was a significant reduction in systolic and diastolic blood pressure after nimodipine administration (Table II, Fig. 1). This effect was evident within 15 minutes in most cases and was well established by 1 hour. No additional antihypertensive agents were required during the study period, and both antepartum and postpartum blood pressure control was excellent (Fig. 1). The maternal heart rate was significantly increased at 1 hour (Table II) and remained elevated throughout the first 24 hours post partum (Fig. 1). There were no significant changes in velocity in the maternal internal carotid and middle cerebral arteries 1 hour after nimodipine administration (Table II). There was a small decrease in the internal carotid artery pulsatility index with a similar trend seen in the middle cerebral artery pulsatility index, but no statistically significant differences were noted (power to detect a difference of this magnitude was < 20o/c with this sample size), possibly representing a type II statistical error. There were significant reductions in the pulsatility index in the central retinal artery and ophthalmic artery 1 hour after oral administration of 30 mg of nimodipine. The change in central retinal artery pulsatility index was associated with a significant reduction in the central retinal artery systolic velocity (13 ± 2 cm/sec to 11 ± 2 cm/sec, p < 0.02). Fetal Doppler and heart rate data at the baseline and 1 hour after nimodipine administration are presented in Table III. There was no change in FHR, short-term beat-to-beat variability, or overall beat-to-beat variability I hour after nimodipine administration. There was, however, a significant reduction in the umbilical artery SID ratio and fetal middle cerebral artery pulsatility index over the first hour after nimodipine administration (Table III). All fetuses appeared to tolerate the reduction in maternal blood pressure without any evidence of distress.
All patients were delivered within 24 hours of administration of the first dose of nimodipine. In those cases where repeated nimodipine doses were given ante partum. there was no adverse effect noted on either mother or fetus. In particular, there were no instances of maternal hypotension with our scheduled dosage regimen. In all cases the drug appeared to be well tolerated by the fetus, and there were no episodes of fetal stress or distress noted. Anesthesia was well tolerated, and there were no problems with hypotension. Two patients had general anesthesia, two had spinal anesthesia, and the remaining six had an epidural anesthetic. Those patients who received regional anesthesia had prior volume expansion with a bolus infusion of 1000 ml of lactated Ringer's solution. Four women had a cesarean section performed immediately after the I-hour observations were completed. Indications for surgery included previous classic cesarean section, prior cesarean section (unknown scar) for a transverse lie, syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) (hematocrit 38.5%, platelets 101 ,OOO/mm', aspartate transaminase 131 U/L, alanine transaminase 107 U/L), and transverse lie with oligohydramnios. Six patients underwent induction of labor (median initial cervical dilatation 2 cm). Of these six women three were delivered vaginally (mean duration of the active phase of labor 10 ± 3 hours). The mean rate of oxytocin infusion at delivery was 6 mIU/min. No patient experienced uterine atony or postpartum hemorrhage. Three patients required a cesarean section, two for failure to progress and one for a ruptured uterus. In the case of the patient with rupture of the uterus there was no maternal hypotension or shock, and the diagnosis was made at the time of cesarean section for sudden fetal distress. The average blood loss was 400 ml at vaginal delivery and 800 ml at cesarean section. The mean hematocrit on admission was 37% ± 8% and decreased to a mean of 30% ± 6% 24 hours after delivery. No patient had convulsions at any time during this study, and none experienced symptomatic hypotension. One of the 10 patients had facial flushing within 15
Belfort et al
Volume 171. l\'umber 2 Am J Obstet G}necol
minutes of administration of nimodipine. Two patients experienced emesis approximately 20 minutes after administration. One of these women was experiencing nausea and emesis before entry in the study. In her case the drug had been given sublingually. After delivery all patients tolerated the nimodipine well. Blood pressure control remained good in the postpartum period (Fig. 1) without need for additional antihypertensive medication. No patient experienced symptomatic or asymptomatic hypotension. Because the patient who experienced a rupture of her uterus was excluded from the study at that time, her postpartum blood pressure data were not included in the analysis. This patient was started on magnesium sulfate post partum without any evidence of adverse interaction with the nimodipine. There was no difference in the pattern of blood pressure control between those patients delivered vaginally and those who underwent a cesarean section. All patients received a maintenance infusion of 125 ml of crystalloid per hour after the I-hour study measurements. Before delivery urine output remained above 40 ml/hr (except in one patient who required a intravenous crystalloid bolus with prompt response). Post partum all patients maintained a urine output > 30 ml/hr, and by 12 hours the mean urine output was > 100 ml/hr, which this was maintained for the remainder of the study period. The median maternal nimodipine level 1 hour after administration was 15.8 (range 79.0) ng/ml. There was a positive correlation between the maternal and fetal nimodipine blood levels at delivery (r = 0.96, P < 0.001), indicating good transfer of nimodipine across the placenta (Fig. 2). The median maternal serum nimodipine concentration at delivery was 7.32 (range 27.0) ng/ml and the umbilical cord serum concentration was 2.6 (13) ng/ml. The maternal/fetal ratio was 2.4: 1. In the four women who underwent cesarean section immediately after the I-hour observation (within 2 hours of the first dose), maternal and umbilical cord serum levels of nimodipine were analyzed separately. In these four patiems the median maternal serum nimodipine concentration at delivery was 9.68 (range 11.7) ng/ml, and the umbilical cord serum concentration was 3.46 (range 5.94) ng/ml. The maternal/fetal ratio was 2.6: 1. There was a positive correlation (r = 0.6) between the maternal ~erum nimodipine level and the change in the central retinal artery pulsatility index, suggesting that the higher the maternal nimodipine level the greater the reduction seen in the central retinal artery pulsatility index. The neonatal data are presented, excluding that of the infant of one patient (No.9) who had a ruptured uterus with severe fetal distress (data presented separately). Apgar scores (median) at 1 and 5 minutes after
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Maternal Serum Nimodipine Concentration (ng/ml) Fig. 2. Relationship hetween maternal and mixed (arterial dnd venous) umbilical cord serum nimodipine levels at delivery.
delivery were 8 (range 6 to 10) and 9 (range 8 to 10), respectively. The umbilical arterial blood gases were as follows: pH 7.25 ± 0.07, base excess -5.7 ± 4.6, Peo:! 47.4 ± 6.0 mm Hg, and bicarbonate 21.0 ± 4.3 m Eq/L. The umbilical venous blood gases were as follows: pH 7.30 ± 0.04, base excess -4.0 ± 3.2, Pco:! 42.9 ± 4.4 mm Hg, and bicarbonate 20.6 ± 5.7 mEq/L. None of the nine neonates included in the group analysis were delivered with evidence of rlistre~s or metabolic derangement. At the 6-week follow-up visit all nine infants were thriving. Infant No.9 was assigned Apgar scores at 1 and 5 minutes of 1 and 5, respectively. Cord blood gas analysis revealed an arterial pH of 6.81, Peo:! of 123 mm Hg, P0 2 of 14 mm Hg, and base excess of -18. The infant recovered rapidly and was extubated within 3 hours. There was no evidence of organ failure and a follow-up computed tomographic ~can on day of life 3 was normal. The baby was discharged in good condition on day of life 15 without any evidence of residual damage. Nimodipine levels in the maternal serum and fetal umbilical cord blood at delivery were 0.70 ng/ml and 0.94 ng/ml, respectively. Follow-up at 6 weeks ~howed the infant to be deVeloping normally. Comment
There is increasing evidence that cerebral vasospasm plays a role in the pathogenesis of eclampsia. I. 7 Cere-
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Bellort et al.
bral vasoconstriction has been demonstrated in angiographic and magnetic resonance imaging studies of eclamptic patients, and there are Doppler data to suggest that in preeclampsia vasospasm distal to the middle cerebral and central retinal arteries may be related to cerebral ischemia. I-e. 12 Whatever the mechanism involved in the initiation of cerebral vasospasm. the contraction of cerebral arteries is ultimately induced by an increase in free intracellular calcium. This depends on the influx of extracellular Ca e + combined with the release of Ca ~ + from intracellular stores. 13 Thus there is a theoretic basis for the use of calcium channel blockers in the management of preeclampsia. The dihydropyridine calcium antagonists have been used in pregnancy, primarily in research studies dealing with blood pressure control in patients with preeclampsia H . I ' and for the treatment of premature labor. lfi Nimodipine may be especially appropriate for preeclamptic patients, not only because it is an effective antihypertensive agent but also because it has a more potent vasodilator action on human cerebral vessels than does magnesium sulfate. '7 One of the major concerns when blood pressure is reduced in the mother is the effect of the drug on uteroplacental circulation. There is good evidence that dihydropyridine calcium channel blockers (nifedipine. 14 nitrendipine,18 and isradipine l9 ) do not reduce uteroplacental blood flow in spite of a significant reduction in maternal blood pressure. The maternal hemodynamic effects of nimodipine in our study were characterized by a 14% reduction in systolic blood pressure, a 22% reduction in diastolic blood pressure, and a 15% increase in maternal heart rate within the first hour of administration. These changes appeared to be well tolerated by both mother and fetus, and there was no evidence of the abrupt hypotension sometimes seen with intravenous vasodilators. The antihypertensive effect of the drug was maintained post partum without evidence of a rebound effect or tachyphylaxis. In addition, postpartum administration of nimodipine did not result in hypotensive episodes, even when it was given to normotensive patients. Our fmdings are consistent with the data of others regarding calcium channel blockers in normal pregnancy and preeclampsia and in nonpregnant patients. 1<>-21 The increase in heart rate that we observed was well tolerated without symptoms and probably reflects a baroreceptor-mediated compensation to a decrease in total peripheral resistance. There was no evidence that nimodipine prolonged labor or increased the occurrence of uterine atony and postpartum hemorrhage. We have studied the Doppler index values in the central retinal artery longitudinally in a group of normal pregnant patients (n = 9), and preliminary data indicate that the pulsatility index decreases from a peak
Augmt 19'H Am J Ob.(ci Gvnccol
of approximately 0.98 at 20 weeks to 0.85 at term (unpublished data). The preeclamptic patients in this study had a mean central retinal artery pulsatility index of 1.09 ± 0.1, supporting the theory that preeclampsia is associated with vasospasm in the cerebral microcirculation. The central retinal and ophthalmic artery pulsatility index values decreased significantly within 1 hour of administration of nimodipine. In the central retinal artery the effect of the drug was dose dependent. The vasodilator effect of nimodipine was, however, not seen to the same extent in the larger cerebral vessels (internal carotid. middle cerebral, and ophthalmic arteries). This finding is consistent with the literature for nonpregnant patients, where it has been demonstrated that the principal effect of nimodipine is directed at vessels with a diameter of < 100 f..Lm. 22 In addition, nimodipine acts primarily on constricted vessels,27 and the major vasospasm in preeclampsia is present in the small resistance vessels (central retinal arteries) but not in the larger conducting vessels (internal carotid and middle cerebral arteries). Although no patient in our population experienced seizure activity, the issue of the anticonvulsant action of nimodipine in preeclampsia cannot be addressed by this study. Power analysis calculations indicate that > 2000 severely preeclamptic patients, randomized to receive either magnesium sulfate or nimodipine, will be needed to detect a 50% reduction in the current number of patients who have convulsions in spite of antiseizure prophylaxis with magnesium sulfate. The fact that there was resolution of headache and scotomas in two of our patients within 15 minutes of receiving nimodipine is encouraging and suggests that there is a clinically evaluable increase in cerebral perfusion in severe cases of preeclampsia. This statement is supported by a case report in which nimodipine was used to control status eclampticus and where a decrease in cerebrovascular resistance was seen.7 Orally administered nimodipine is almost completely absorbed from the gastrointestinal tract with maximum serum concentrations occurring within 30 to 60 minutes in nonpregnant subjects."" Levels ofnimodipine similar to those noted in our patients were reported in healthy volunteers taking a 30 mg capsule sublingually (mean 19 ng/ml, range 4.6 to 53.6 ng/ml)."' The dosing schedule we used, which was based on that for nonpregnant su~jects, appeared to be effective. Dihydropyridine calcium antagonists may, however, be more rapidly metabolized in pregnancy, and experience with nisoldipine has demonstrated the need for larger doses and more frequent administration in the postpartum period than for nonpregnant patients. I, Further experience with nimodipine will be required to determine the optimum dose and dosing schedule in the postpartum preeclamptic patient.
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Volume 171, Number 2
Am J Ob,tet Gynewl
In our patients there was no relationship between serum level and vomiting, and the widely distributed data may possibly be the result of liver metabolism and a first-pass eHect. Nimodipine is preferentially metabolized in the liver."" and its use in patients with severely compromised hepatic function should be cautioned against. It has, however, been shown to be safe in young patients with renal compromise.""' In our study renal output remained satisfactory throughout, and in only one case was an additional crystalloid bolus infusion required. These data are consistent with the known natriuretic effect of dihydropyridine calcium channel blockers in nonpregnant and pregnant patients. Placental transfer of nimodipine has been shown to be limited in pregnant animals, with maternal levels being approximately eight to 15 times greater than those seen in the fetus."" A higher rate of transplacental transfer was noted in our study, with a maternal/fetal ratio of 2.4: 1. Dihydropyridine calcium channel blockers have not been demonstrated to reduce placental blood flow in either animal or human studies; this appears to hold for nimodipine as well. 14. 19 In our study the SID ratio in the umbilical artery wa~ significantly reduced after nimodipine administration. and there was also evidence of a reduction in fetal cerebrovascular resistance. The FHR did not change, and although there was a trend to an increase in the short-term and overall beat-to-beat variability these changes were not significant 1 hour after nimodipine administration. A similar lack of short-term effect has also been the experience of others investigating changes in FHR after maternal treatment with dihydropyridine calcium channel blockers. II 18 FHR analysis before and after nimodipine therapy was objective, and this method has previously been shown to be reliable in the detection of short-term alterations in fetal condition. It is therefore unlikely that there was any short-term detrimental fetal respiratory or metabolic effect that can be related to the administration of nimodipine in our study population. In conclusion, we have demonstrated that nimodipine appears to be a safe and effective antihypertensive agent for the management of patients with preeclampsia. Although the sample size is small. there is good evidence to suggest that the drug causes vasodilatation in small-diameter cerebral vessels in these women. For this reason nimodipine deserve~ further investigation as an anti seizure dgent for the prevention of eclampsia. The safety, ease of administration. and avoidance of the need for other antihypertensive medications make nimodipine an attractive alternative to intravenous magnesium sulfate. Further research into the use of this drug in preeclampsia appears warranted. We thank Dr. G.'V. Beck, PhD. and Dr. GJ. Krol, PhD, of the Clinical Pharmacology Department at Miles Inc. for analysis of the blood specimens.
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REFERENCES 1. U'wis LK. Hmshaw DB. Wtll AD. Ha"o AN. Thompson JR. CT and angiographK correlatIon of ;,e\'ere neurologIcal disease in toxaemia of pregnanc\'. NeuroradlOlog\ 1988;30:59-64. 2. Bellort MA, MOIse KJ. The effect of magnc'>lllm sulfate on maternal bram blood flow in mild preeclamp'ld: .1 randonllzed placebo-(Ontrollcd study. A\I J OB"lrl (;\"HOl 1992;167: 1548-53. 3. Bellort MA. Effect of magne,lum su!filte on blond flow in the maternal retina in mIld ge,tational pruteinurK hypertcnsion: a prelimmary colour How Doppler sturly. Br J Ohstet Gynaecol 1992;99:641-5. 4. Redman CW, Roberts JM. :\Ianagement of pre-cclampsia. LanLet 1993;341:1451-4. 5. Altura BT, Altura BM. Interactions of Mg and K on cerebral ve;,seh-aspect~ in view of qrnke. ReVIew of pre~ent status and new finding'>. Magnesium 1981;:1: 195211. 6. Freedman DD, Wdters DD. "Sewnd generation" rlihydru. pvridme calcium antagonists. Greater \'a'cular ,electivltv and somc unique applications. Drugs 1987;3·1:0578-91'. 7. Belfort MA. Carpenter RJ. Moise I\J Jr. Saade (,R. The me of nimodipine in a patient with eclampSIa: color Doppler demomtration of retinal artery relaxation. A!,I.J O[l,rET GYKECOL 199:~; lfi9:204-G. 8. Arnolds B. von Reutern C;. TransClalllal Doppler sonography. ExaminatIOn techmqlles and normal reference \'.11ue,. Ultrasound Med BIOI 198fi;12:115-2:1. 9. Belfon MA. Doppler assessment of relmal blood flo\\,velocity dUting parenteral magnesium treatment in patients with preeclamp.,ia. MagneSIUm Res 199:1;6:239-46. 10. Da\\es GS. Visscr GIi. Goodman JD, Rcdman C\\'. Numerical analpi' ot the human fetal heart rate: thc qualit) of ultrasound record.,. A\tJ OBSTEI GY:--IElUI. 1981;141:-+352. 11. Krol GJ. Lettien JT, Yeh SC, Burkholder DE, BIrkett .II'. DIsposition and pharmacokmellcs of 14C-Iabelled llItrclldlpme in healthy volunteers. J CarcliO\ asc Phannacol 1987;suppl -+:5122-8. 12. Belton :\IA. Saade GR, :\lolse KJ Jr. The eflect uf magnesium ,ulfate on maternal retmal blood flow III preeclampSIa: a randomIzed placebo-controlled ,tud). A\I J OBsn I GV:--IE(()t. 1992:167:1348·53. 1:~. Bolton TB. Mcchanisms of actIon of transmitters and other substances on smooth muscle. Physinl Re\ 1979;59: 606-718. I -+. Lindow SW. Davies N, Davey DA. Smith JA. The cHect of ,ublingual 1lI1eclipine 011 ut~ruplacental bloud flow in hypertensive pregnancy. Br J Obstet Gvnaecol 1988;9:>: 1276-81. 15. BeHort MA, Kir;,hon B. l\"isoldlpine-a new orally administered calcium antagonist med in tht' tI edtment (If se\ ere pm,tpartum pregnancy-induLed h)pertemwn. S Afr !\led J 1992;81:267-70. 16. Uhmten LT. Anden"on KE. \\'ingelup L. Tredtment of premature labour with the calcnlln antagonist nifCdipinc. Arch Cvnecol 1980.229: 1-5. 17. Alborch E, 5alom .lB. Per ale;, AJ, et .11. Comparison of the antIComtnctor action of dihydlOpyridme;, (nimodipine and llIcardipinel and Mg2+ in isolated human cerebr,tl artenes. Eur.l PhdrmalOl 1992:229:8:1-9. 18. Allen J, Malgaard S, Forman A, et al. Acute effect;, of nitrendipme in pregn.lnn-induccd hvpeIlcmlon HI' r Ob,tet Gynaewl 1987,94:222-6. 19. Lunell NO. Caron L, Grunewald C, ct al. j,raciIpme .. tne\\ calcium ,llltagolllst: effeLt-. on materndl and fetdl hemOthnamlLs .J Canhova,c Pharm 199J;I1'buppl :\):S:\7--+0. 20. Belfort ,\1A. Anthony J Kir,hon B. RespIrator\, tunctlOn in severe ge'tatlOnal protclllUrIC h) pertcn,ion: the efTcc" of rapId volume expan,lon and 5nb5e'luent va,()(hldlatl
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sure and heart rate durmg treatment with mmodipme In patients with ;,ubarachnoid hemorrhage. Neurochirurgia 1985;28:81-6. 22. Langley MS, Sorkin EM. Nimodipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential m cerebrovascular disease. Drugs 1989;37:669-99. 23. Gengo FM, Fagan SC, Krol G, Bernhard H. Nimodipine disposition and haemodynamic effects in patients with
August 1994 Am J Obstet Gynt'col
cirrhosIs and age-matched controls. Br J Clin Pharmacol 1987;23:47-53. 24. Kirch W. Ramsch KD, Duhrsen U, Ohnhaus EE. Clinical pharmacokinetics of nimodipme in normal and impaired renal function. IntJ Chn Pharm Res 1984;4:381-4. 25. Suwelack D. Weber H. Assessment of enterohepatic circulation of radioactivity following a single dose of [14C] mmodipme in the rat. Eur J Drug Metab Pharmacokinet 1985; 10:231-9.
Perinatal observations in forty-eight neurologically impaired term infants Jeffrey P. Phelan, MD, and Myoung Ock Ahn, MD, PhD, MPH Pomona, Ca lifo rnla , and Seoul, Korea OBJECTIVE: Our goal was to review the perinatal characteristics of 48 singleton term infants with central nervous system neurologic impairment. STUDY DESIGN: Medical records were retrospectively reviewed for maternal characteristics, prenatal and intrapartum care patterns, neonatal course, and long-term outcome. Those patients without evidence of an obvious acute asphyxial event, traumatic delivery, or preterm birth were excluded. The study population was then subclassified according to the admission fetal heart rate pattern. RESULTS: Of these 48 term infants the admission fetal heart rate pattern was nonreactive in 33 (69%) and reactive in 15 (31%). Maternal characteristics, prenatal care, and long-term outcome were statistically similar between the two groups. However, the nonreactive group exhibited significantly more characteristics consistent with a prior asphyxial event: thick "old" meconium, "fixed" nonreactive baseline fetal heart rate, meconium-stained skin, and meconium aspiration syndrome. In contrast, in the reactive group a fetal heart rate pattern developed that was consistent with Hon's theory for intrapartum asphyxia and manifested by a prolonged tachycardia in association with persistent nonreactivity, diminished fetal heart rate variability, and fetal heart rate decelerations. CONCLUSIONS: Among fetuses later found to be neurologically impaired, a persistent nonreactive fetal heart rate tracing obtained from admission to delivery appears to be evidence of prior neurologic injury. (AM J OaSTET GVNECOL 1994;171:424-31.)
Key words: Asphyxia, fetal heart rate, meconium, hypoxic ischemic encephalopathy, seizures Limited information is currently available on the fetal heart rate (FHR) patterns and the clinical characteristics of singleton term neurologically impaired infants. I·' However, those investigators I·' and others o.? have inferred that a relationship exists between persistent fetal
From the Department of Ob,tetncs and Gynecology, Pomona Valley Ho,pltal Medical Center, and the Department of ObstetnCl and Gynecology. Cha Women', Ho,pltal of Seou!. ReceIVed for publicatlOll October 15, 1993, rev/sed january 10, 1994; accepted january 28, 1994. Reprznt reque,ts: jeffrey P. Phelan, MD, SUIte 110, 1030 S. Arro.yo Parkwav, Pasadena, CA. 91105. Copynght © 1994 b\' Mosk-Year Book, Inc. 0002-9378/94 $3.00 + O' 6/1/54819
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heart rate (FHR) nonreactivlty and subsequent longterm neurologic impairment. In fact, van der Moer et aF observed a "fixed" FHR pattern with a normal baseline heart rate after fetal decerebration. In many of these instances these same patients have had substantially higher rates of meconium-stained amniotic fluid and oligohydramnios. I. 3·9 These findings suggest a static condition rather than one that develops acutely during labor. On the basis of these observations, fetal neurologic impairment may well be manifested, in selected circumstances, by a persistent nonreactive FHR pattern with a stable baseline FHR in association with meconium-stained amniotic fluid. Thus the purpose of this report was to retrospectively