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Ovine fetal cardiorespiratory response to nicardipine
Ovine fetal cardiorespiratory response to nicardipine R. Harold Holbrook, Jr., MD,* Ellen M. Voss, BS, and Ronald N. Gibson, BS Stanford, California Nicardipine, a calcium antagonist associated with decreased uterine blood flow in near-term pregnant rabbits and fetal asphyxia after maternal administration in the rhesus monkey and sheep, was infused directly to the fetus in six chronically prepared pregnant ewes at 128 days' gestation. Changes in fetal mean arterial and diastolic blood pressure levels at 2 and 30 minutes after bolus injection of 50 IL9 were minimal; by 60 minutes these values had returned to preinfusion levels. No significant changes were observed after infusion of 100 ""g of nicardipine. Fetal heart rate, fetal arterial blood gas values, and maternal cardiovascular variables did not change at either dose. Fetal plasma concentrations of nicardipine were 78 ± 28 ng/ml and 114 ± 48 ng/ml at 30 minutes after infusion of 50 ""g and 100 ""g, respectively, well within the range previously reported to be associated with fetal asphyxia. These data suggest that the previously reported fetal acidosis from maternal infusion of nicardipine may be primarily due to a decrease in maternal uterine blood flow rather than a direct fetal effect of the drug. (AM J OBSTET GVNECOL 1989;161 :718-21.)
Key words: Premature labor, calcium channel blockers, nicardipine, fetus, sheep
Calcium antagonists are potential alternatives to ~ adrenergic agonists for preterm labor tocolysis. Nicardipine, a dihydropyridine derivative, has been found to inhibit uterine activity in the preterm pregnant rabbit,t-' the rhesus monkey,' and the postpartum rabbit. 5 Nicardipine also decreases contractility in isolated human myometrial strips 6 and delays delivery in pregnant rabbits. 5 Nifedipine, a similar dihydropyridine calcium antagonist, has been used as a tocolytic agent in human subjects, but maternal and fetal side effects have not been well studied. Maternally administered nicardipine, however, has been associated with fetal asphyxia in pregnant animals, and placental transfer has been documented. It is not clear whether fetal asphyxia is mediated through alteration in uteroplacental perfusion 0][' by a direct action on the fetus (e.g., alterations in umbilical or ductal blood flow). To determine the effect of nicardipine on the fetus independent of changes in uterine blood flow, we administered the drug directly to the fetus and measured the fetal cardiorespiratory response.
Material and methods Animal preparations and studies were performed in the Stanford Research Animal Facility. The study proFrom the Section of Maternal-Fetal MedICine, Department of Gynecology and Obstetncs, Stanford University School of Medicine. *Supported by National Institutes of Health Grants HD-19190 and HD-22727, Biomedical Research Support Grant S07 RR-05353, and the Mellon Foundation. Presented at the Ninth Annual Meeting of the Society of Pennatal Obstetricians, New Orleans, Louisiana, February 2-4, 1989. Reprint requests: R. Harold Holbrook, Jr., MD, Room A-342, Departm,mt of Gynecology and Obstetncs, Stanford Unzversity School of Medicine, Stanford, CA 94305.
6/6/13717
718
tocol was approved by the Stanford University Administrative Panel on Laboratory Animal Care. Six crossbred Western pregnant ewes at 128 days' gestation with single fetuses were fasted 24 hours before surgery and regional anesthesia was induced in the lower body with an epidural injection of 40 mg of tetracaine hydrochloride. Intravenous ketamine hydrochloride (8 mg/min) was administered to maintain sedation, and supplemental diazepam was given as needed up to a total dose of 2 mg/kg. Polyvinyl catheters (0.05 inch inner diameter, 0.09 inch outer diameter) were advanced into the ewe's descending aorta and inferior vena cava thro~gh the saphenous artery and vein. A midline abdominal incision was made to expose the uterus. Lidocaine 0.5% was used to induce local anesthesia in the fetus and polyvinyl catheters (0.03 inch inner diameter, 0.05 inch outer diameter) were placed in the fetal descending aorta and inferior vena cava through the saphenous artery and vein. A catheter was placed in the amniotic cavity for measurement of intrauterine pressure. All catheters were filled with sodium heparin, sealed with copper plugs, and tunneled to a pouch attached to the ewe's flank. The ewe received 40,000 U Ikg of penicillin postoperatively and was allowed to recover for 48 hours. With the ewe standing quietly in a study cage with free access to food and water, baseline measurements were made over a 10-minute period. Fetal arterial pressures and heart rate, maternal arterial pressures and heart rate, and amniotic pressure levels were measured on a Gould 28008 8-channel recorder. Fetal descending aortic oxygen saturation and hemoglobin levels were measured with a Radiometer OSM3 hem oximeter, and blood gases were measured with a Corning 170 blood gas analyzer at 39° C. After baseline measurements
Fetal effects of nicardipine infusion
Volume 161 Number 3
719
Table I. Fetal and maternal cardiorespiratory responses to fetal infusion of 50 ILg of nicardipine Preinfuswn
Fetal (n = 6) Heart rate Mean arterial pressure (mm Hg) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Hemoglobin (gm %) Hemoglobin saturation (%) Distal aortic pH Distal aortic P02 (mm Hg) Distal aortic Pco 2 (mm Hg) Maternal (n = 5) Heart rate Mean arterial pressure (mm Hg) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)
159 48 64 39 11.0 47.7 7.37 18.2 48.2 107 102 141 83
± 13
± 5 ± 7 ± 4 ± 1.4 ± 13.4 ± 0.03 ± 2.5 ± 3.5 ± ± ± ±
13 10 15 8
2 Mmutes
176 44 60 37 10.8 49.5 7.37 18.9 47.4 108 105 144 85
± ± ± ± ± ± ± ± ±
28 3* 4 3* 1.9 11.7 0.03 2.4 3.7
± 19
:±: 12
± 17 ± 10
30 Minutes
166 46 64 37 10.7 50.0 7.37 18.7 46.5 106 102 140 83
:±: 26
± ± ± ± ± ±
3* 3 4* 1.3 13.0 0.03 ± 3.0 ± 3.1 ± ± ± ±
15 11 14 9
60 Minutes
171 47 65 39 10.7 50.9 7.36 19.1 49.0 106 103 144 82
± ± ± ± ± ±
34 3 5 3 2.0 12.6 ± 0.04 ± 2.9 ± 3.1 ± 13
± 10
± 15 ± 9
All values represent the mean ± SD.
*P <0.05 versus preinfusion value. were obtained, a 50 ILg bolus of nicardipine hydrochloride (Syntex Pharmaceuticals, Palo Alto, Calif.), prepared as a fresh sterile solution of 2 mg/cc with 6 mg/cc sodium chloride added, was infused into the fetal inferior vena cava. The above measurements were then repeated at 2, 30, and 60 minutes. The animal was allowed to recover for at least 4 hours before baseline measurements were repeated. The study was repeated as above with 100 ILg bolus of nicardipine. At 30 minutes after each bolus injection of nicardipine, fetal blood was drawn from the inferior vena cava and centrifuged. The serum was stored frozen at - 80° C for later analysis by high-performance liquid chromatography. Nicardipine dosages were chosen on the basis of estimated fetoplacental blood volume to achieve a fetal plasma concentration of approximately 50 ng/ml at 60 minutes. This concentration is similar to that reported in studies in which fetal asphyxia developed after maternal administration. The ewe was killed by injection of pentobarbital and saturated potassium chloride before bilateral thoracotomy. The fetus was removed from the uterus and weighed. Fetal arterial pressure was corrected by subtraction of the amniotic fluid pressure. Fetal and maternal blood pressure levels and heart rates, and fetal descending aortic blood gas and pH levels were compared before and at each time period after each nicardipine infusion by one-way analysis of variance for repeated measures. When the repeated measures analysis of variance revealed differences between time periods, Fisher's nonparametric paired least significant difference test was used to determine between which measurements the differences were significant.
Results Fetal arterial pressure level and heart rate. descending aortic hemoglobin concentration, hemoglobin sat-
uration, and blood gas and pH levels were measured in six animals after infusion of 50 ILg of nicardipine. In five of these animals. maternal arterial pressure levels and heart rates were also obtained. Values of these variables at preinfusion and at 2,30, and 60 minutes are listed in Table I. A small (2 to 4 mm Hg) but significant decline in fetal mean and diastolic pressure was noted at 2 and 30 minutes after infusion, but these values returned to baseline by 60 minutes. Changes in all other maternal and fetal variables were not significantly different from preinfusion values at any of the time periods. Similar results were obtained after infusion of 100 ILg of nicardipine. Maternal and fetal variables were measured in five animals and are listed in Table II. No differences in any of the variables were noted at 2, 30, or 60 minutes after infusion. Fetal plasma concentrations of nicardipine after bolus administration of 50 /-Lg were 527 ± 345 ng/ml. 78 ± 28 ng/ml. and 41 ± 25 ng/ml at 2.30, and 60 minutes, respectively. With bolus administration of 100 ILg of nicardipine. the fetal plasma concentrations were 414 ± 17 ng/ml, 114 ± 48 ng/ml, and 61 ± 29 ng/ml at 2, 30, and 60 minutes, respectively. The calculated half-life for nicardipine in the fetal circulation was 25.6 ± 5.2 minutes and 22.3 ± 5.9 minutes for bolus administration of 50 ILg and 100 ILg of nicardipine, respectively.
Comment This study suggests that the previously reported fetal acidosis that occurs after maternal infusion of nicardipine4 may be primarily due to a decrease in maternal uterine blood flow rather than a direct fetal effect of the drug. The fall in uterine blood flow observed in near-term pregnant animals after maternal infusion of calcium antagonists has been considered to be mainly due to peripheral vasodilation. which results in mater-
720
Holbrook, Voss, and Gibson
September 1989 Am J Obstet Gynecol
Table II. Fetal and maternal cardiorespiratory responses to fetal infusion of 100 f.Lg of nicardipine Preinfuswn
Fetal (n = 5) Heart rate Mean arterial pressure (mm Hg) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Hemoglobin (gm %) Hemoglobin saturation (%) Distal aortic pH Distal aortic Po, (mm Hg) Distal aortic Peo, (mm Hg) Maternal (n = 5) Heart rate Mean arterial pressure (mm Hg) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)
161 44 60 36 11.1 43.2 7.32 17.7 55.2
± ± ± ± ± ± ± ± ±
34 10 13 9 2.9 20.0 0.10 3.0 8.2
98 105 149 84
± ± ± ±
12 10 13 9
2 Minutes
172 42 56 35 10.5 41.3 7.32 17.1 53.6
± ± ± ± ± ± ± ± ±
21 9 11 8 2.6 21.4 0.10 3.7 7.0
101 104 146 85
± ± ± ±
11 7 9 8
30 Minutes
166 42 58 34 10.4 45.4 7.31 18.1 52.6
± ± ± ± ± ± ± ± ±
19 8 10 7 2.0 19.6 0.11 2.7 7.3
120 104 146 83
± ± ± ±
38 11 12 12
60 Minutes
173 42 60 36 10.8 42.6 7.31 17.3 55.4 114 104 145 84
± ± ± ± ± ± ± ± ±
16 7 8 6 2.3 21.1 0.12 2.9 8.0
± 24 ± 9 ± 11 ± 9
All values represent the mean ± SD.
nal hypotension and a fall in perfusion pressure. The uterine vasculature is considered to be maximally dilated near term and a diversion of flow to other regions should be expected to occur. In the pregnant ewe, Golichowski et al. 7 and Harake et aLB observed that continuous maternal nifedipine infusion caused a significant fall in maternal arterial pressure levels and a (presumably reflex) rise in maternal heart rate. In Harake's study, a significant fall in uterine blood flow was observed at an infusion rate of 10 f.Lg/kg/min, and fetal pH, arterial oxygen content, and hemoglobin saturation declined significantly. Uterine vascular resistance did not change, however, and therefore the fall in uterine blood flow could be attributed to decreased maternal arterial pressure levels. There was no change in fetal heart rate or arterial blood pressure level. There was, however, an increase in total and regional fetal cerebral blood flow consistent with fetal adaptation to asphyxia. In the near-term pregnant rabbit, [·3 continuous maternal nicardipine infusion at dosages that caused significant reductions in prematurely induced uterine activity were found to cause a rise in maternal heart rate and fall in maternal arterial pressure level. A fall in total uterine and placental blood flow also occurred despite a significant increase in maternal cardiac output.' Ducsay et aI.' administered a bolus of 500 f.Lg of nicardipine to the pregnant rhesus monkey and then continuously infused 6 f.Lg/kg/min. A significant decline in maternal arterial pressure level and increase in maternal heart rate occurred. Despite fetal plasma concentrations of nicardipine, which averaged 6% of maternal serum levels, no changes occurred in fetal heart rate or arterial blood pressure level. There was however, a significant fall in fetal arterial pH and Po" and
an increase in fetal arterial Peo,. Uterine blood flow was not measured, but the lack of change in fetal blood pressure level suggests that the fetal asphyxia was more likely a result of a decrease in utero placental perfusion. In our study, bolus administration of nicardipine to the fetus resulted in fetal serum concentrations of 414 ± 17 ng I ml to 527 ± 345 ng I ml after 2 minutes, and 41 ± 25 ng/ml to 61 ± 29 ng/ml at 60 minutes after infusion. The observation that 2-minute serum levels were higher after injection of 50 f.Lg than they were after 100 f.Lg may be explained by an increased variability of serum levels measured soon after injection, before equilibrium is complete. The levels at 30 and 60 minutes, however, reflect the dosage injected, higher levels being associated with the injection of 100 f.Lg. In the rhesus monkey, Ducsay et aJ.< observed fetal asphyxia at peak fetal plasma nicardipine concentrations of 7 to 35 ng/ml. Harake et aLB described significant asphyxial changes at fetal plasma nifedipine levels of91 ± 8 ng/ml. Thus, it would appear that maternal administration of these agents, which results in maternal hypotension and decreased uterine blood flow, is required for these adverse fetal effects to occur. Because calcium antagonists apparently cross the primate placenta and are vasodilators, the chronically asphyxiated fetus may be adversely affected by these agents. Redistribution of blood flow to vital organs such as the brain, heart, and adrenals through a selective peripheral vasoconstriction may be reversed by vasodilators and result in worsening of fetal asphyxia. Whereas our study did not demonstrate a significant change in fetal peripheral resistance after nicardipine infusion in the normoxic fetus, the effect of this and similar agents on the compensated asphyxiated fetus is not known. When comparison is made of the side effects of ni-
Fetal effects of nicardipine infusion
Volume 161 Number 3
cardipine and nifedipine, it should be recognized that different calcium antagonists display different degrees of action on uterine, vascular, and cardiac tissue. 9 In addition, calcium antagonists affect fetal and adult cardiovascular systems differently and therefore the typical adult response should not necessarily be expected in the fetus. 10 Whereas our study confirms the tolerance of the normoxie ovine fetus to nicardipine, the reported adverse effects on uterine blood flow and limited experience with these agents in the treatment of human preterm labor limits enthusiasm for their unrestricted use. Ulmsten et al. 11 have reported that when nifedipine was used clinically to treat premature labor, maternal arterial pressure was not affected, but a transient increase in heart rate occurred. No change in fetal heart rate was observed, and there were no neonatal complications noted. However, Read and Wellb y l2 found that although neither maternal heart rate nor blood pressure levels were altered by maternal administration of nifedipine, fetal heart rate was significantly increased. We (Ferguson JE II, Holbrook RH Jr., Unpublished observations) noted decreased diastolic and mean blood pressure and reflex tachycardia in 12 preterm labor patients treated with sublingual and oral nifedipine. Whereas no adverse fetal effects have been reported in human beings, maternal hypotension does occur, and there exists the potential for adverse fetal effects at higher dosages or when fetal growth retardation or chronic asphyxia are present. Further studies of the response to the hypoxic fetus to calcium antagonists and changes in uterine blood flow in human beings are warranted.
721
REFERENCES 1. Lirette M, Holbrook RHJr., Katz M. Effect ofnicardipine HCI on prematurely induced uterine activity in the pregnant rabbit. Obstet Gynecol 1985;65:31-5. 2. Lirette M, Holbrook RH Jr., Katz M. Cardiovascular and uterine blood flow changes during nicardipine HCI tocolysis in the rabbit. Obstet Gynecol 1987;69:79-82. 3. Holbrook RHJr.. Lirette M, Katz M. Cardiovascular and tocolytic effects of nicardipine HCI in the pregnant rabbit: comparison with ritodrine HC!. Obstet Gynecol 1987; 69:83-7. 4. Ducsay CA, Thompson JS, Wu AT, Novy MJ. Effects of calcium entry blocker (nicardipine) tocolysis in rhesus macaques: fetal plasma concentrations and cardiorespiratory changes. AM J OBSTET GYNECOL 1987;157: 1482-6. 5. Csapo AI, Puri CP, Tarro S, Henzl MR. Deactivation of the uterus during normal and premature labor by the calcium antagonist nicardipine. AM J OBSTET GYNECOL 1982; 142:483-91. 6. Maigaard S, Forman A, Andersson K, Ulmsten U. Comparison of the effects of nicardipine and nifedipine on isolated human myometrium. Gynecol Obstet Invest 1983;16:354-66. 7. Golichowski AM, Hathaway DR, Fineberg N, Peleg D. Tocolytic and hemodynamic effects of nifedipine in the ewe. AMJ OBSTET GYNECOL 1985;151:1134-40. 8. Harake B, Gilbert R, Ashwal S. Power GG. Nifedipine: effects on fetal and maternal hemodynamics in pregnant sheep. AMJ OBSTET GYNECOL 1987;157:1003-8. 9. Granger SE. Hollingsworth M, Weston AH. A comparison of several calcium antagonists on uterine, vascular and cardiac muscles from the rat. Br J Pharmacol 1985; 85:255-62. 10. Boucek RJ Jr., Shelton M, Artman M, Mushlin PS, Starnes VA, Olson RD. Comparative effects of verapamil, nifedipine. and diltiazem on contractile function in the isolated immature and adult rabbit. Ped Res 1984; 18:948-52. 11. Ulmsten U, Andersson K, Wingerup L. Treatment of premature labor with the calcium antagonist nifedipine. Arch GynecoI1980;229:1-5. 12. Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br J Obstet Gynaecol 1986;93:933-7.
Key words: Premature labor, calcium channel blockers, nicardipine, fetus, sheep
Calcium antagonists are potential alternatives to ~ adrenergic agonists for preterm labor tocolysis. Nicardipine, a dihydropyridine derivative, has been found to inhibit uterine activity in the preterm pregnant rabbit,t-' the rhesus monkey,' and the postpartum rabbit. 5 Nicardipine also decreases contractility in isolated human myometrial strips 6 and delays delivery in pregnant rabbits. 5 Nifedipine, a similar dihydropyridine calcium antagonist, has been used as a tocolytic agent in human subjects, but maternal and fetal side effects have not been well studied. Maternally administered nicardipine, however, has been associated with fetal asphyxia in pregnant animals, and placental transfer has been documented. It is not clear whether fetal asphyxia is mediated through alteration in uteroplacental perfusion 0][' by a direct action on the fetus (e.g., alterations in umbilical or ductal blood flow). To determine the effect of nicardipine on the fetus independent of changes in uterine blood flow, we administered the drug directly to the fetus and measured the fetal cardiorespiratory response.
Material and methods Animal preparations and studies were performed in the Stanford Research Animal Facility. The study proFrom the Section of Maternal-Fetal MedICine, Department of Gynecology and Obstetncs, Stanford University School of Medicine. *Supported by National Institutes of Health Grants HD-19190 and HD-22727, Biomedical Research Support Grant S07 RR-05353, and the Mellon Foundation. Presented at the Ninth Annual Meeting of the Society of Pennatal Obstetricians, New Orleans, Louisiana, February 2-4, 1989. Reprint requests: R. Harold Holbrook, Jr., MD, Room A-342, Departm,mt of Gynecology and Obstetncs, Stanford Unzversity School of Medicine, Stanford, CA 94305.
6/6/13717
718
tocol was approved by the Stanford University Administrative Panel on Laboratory Animal Care. Six crossbred Western pregnant ewes at 128 days' gestation with single fetuses were fasted 24 hours before surgery and regional anesthesia was induced in the lower body with an epidural injection of 40 mg of tetracaine hydrochloride. Intravenous ketamine hydrochloride (8 mg/min) was administered to maintain sedation, and supplemental diazepam was given as needed up to a total dose of 2 mg/kg. Polyvinyl catheters (0.05 inch inner diameter, 0.09 inch outer diameter) were advanced into the ewe's descending aorta and inferior vena cava thro~gh the saphenous artery and vein. A midline abdominal incision was made to expose the uterus. Lidocaine 0.5% was used to induce local anesthesia in the fetus and polyvinyl catheters (0.03 inch inner diameter, 0.05 inch outer diameter) were placed in the fetal descending aorta and inferior vena cava through the saphenous artery and vein. A catheter was placed in the amniotic cavity for measurement of intrauterine pressure. All catheters were filled with sodium heparin, sealed with copper plugs, and tunneled to a pouch attached to the ewe's flank. The ewe received 40,000 U Ikg of penicillin postoperatively and was allowed to recover for 48 hours. With the ewe standing quietly in a study cage with free access to food and water, baseline measurements were made over a 10-minute period. Fetal arterial pressures and heart rate, maternal arterial pressures and heart rate, and amniotic pressure levels were measured on a Gould 28008 8-channel recorder. Fetal descending aortic oxygen saturation and hemoglobin levels were measured with a Radiometer OSM3 hem oximeter, and blood gases were measured with a Corning 170 blood gas analyzer at 39° C. After baseline measurements
Fetal effects of nicardipine infusion
Volume 161 Number 3
719
Table I. Fetal and maternal cardiorespiratory responses to fetal infusion of 50 ILg of nicardipine Preinfuswn
Fetal (n = 6) Heart rate Mean arterial pressure (mm Hg) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Hemoglobin (gm %) Hemoglobin saturation (%) Distal aortic pH Distal aortic P02 (mm Hg) Distal aortic Pco 2 (mm Hg) Maternal (n = 5) Heart rate Mean arterial pressure (mm Hg) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)
159 48 64 39 11.0 47.7 7.37 18.2 48.2 107 102 141 83
± 13
± 5 ± 7 ± 4 ± 1.4 ± 13.4 ± 0.03 ± 2.5 ± 3.5 ± ± ± ±
13 10 15 8
2 Mmutes
176 44 60 37 10.8 49.5 7.37 18.9 47.4 108 105 144 85
± ± ± ± ± ± ± ± ±
28 3* 4 3* 1.9 11.7 0.03 2.4 3.7
± 19
:±: 12
± 17 ± 10
30 Minutes
166 46 64 37 10.7 50.0 7.37 18.7 46.5 106 102 140 83
:±: 26
± ± ± ± ± ±
3* 3 4* 1.3 13.0 0.03 ± 3.0 ± 3.1 ± ± ± ±
15 11 14 9
60 Minutes
171 47 65 39 10.7 50.9 7.36 19.1 49.0 106 103 144 82
± ± ± ± ± ±
34 3 5 3 2.0 12.6 ± 0.04 ± 2.9 ± 3.1 ± 13
± 10
± 15 ± 9
All values represent the mean ± SD.
*P <0.05 versus preinfusion value. were obtained, a 50 ILg bolus of nicardipine hydrochloride (Syntex Pharmaceuticals, Palo Alto, Calif.), prepared as a fresh sterile solution of 2 mg/cc with 6 mg/cc sodium chloride added, was infused into the fetal inferior vena cava. The above measurements were then repeated at 2, 30, and 60 minutes. The animal was allowed to recover for at least 4 hours before baseline measurements were repeated. The study was repeated as above with 100 ILg bolus of nicardipine. At 30 minutes after each bolus injection of nicardipine, fetal blood was drawn from the inferior vena cava and centrifuged. The serum was stored frozen at - 80° C for later analysis by high-performance liquid chromatography. Nicardipine dosages were chosen on the basis of estimated fetoplacental blood volume to achieve a fetal plasma concentration of approximately 50 ng/ml at 60 minutes. This concentration is similar to that reported in studies in which fetal asphyxia developed after maternal administration. The ewe was killed by injection of pentobarbital and saturated potassium chloride before bilateral thoracotomy. The fetus was removed from the uterus and weighed. Fetal arterial pressure was corrected by subtraction of the amniotic fluid pressure. Fetal and maternal blood pressure levels and heart rates, and fetal descending aortic blood gas and pH levels were compared before and at each time period after each nicardipine infusion by one-way analysis of variance for repeated measures. When the repeated measures analysis of variance revealed differences between time periods, Fisher's nonparametric paired least significant difference test was used to determine between which measurements the differences were significant.
Results Fetal arterial pressure level and heart rate. descending aortic hemoglobin concentration, hemoglobin sat-
uration, and blood gas and pH levels were measured in six animals after infusion of 50 ILg of nicardipine. In five of these animals. maternal arterial pressure levels and heart rates were also obtained. Values of these variables at preinfusion and at 2,30, and 60 minutes are listed in Table I. A small (2 to 4 mm Hg) but significant decline in fetal mean and diastolic pressure was noted at 2 and 30 minutes after infusion, but these values returned to baseline by 60 minutes. Changes in all other maternal and fetal variables were not significantly different from preinfusion values at any of the time periods. Similar results were obtained after infusion of 100 ILg of nicardipine. Maternal and fetal variables were measured in five animals and are listed in Table II. No differences in any of the variables were noted at 2, 30, or 60 minutes after infusion. Fetal plasma concentrations of nicardipine after bolus administration of 50 /-Lg were 527 ± 345 ng/ml. 78 ± 28 ng/ml. and 41 ± 25 ng/ml at 2.30, and 60 minutes, respectively. With bolus administration of 100 ILg of nicardipine. the fetal plasma concentrations were 414 ± 17 ng/ml, 114 ± 48 ng/ml, and 61 ± 29 ng/ml at 2, 30, and 60 minutes, respectively. The calculated half-life for nicardipine in the fetal circulation was 25.6 ± 5.2 minutes and 22.3 ± 5.9 minutes for bolus administration of 50 ILg and 100 ILg of nicardipine, respectively.
Comment This study suggests that the previously reported fetal acidosis that occurs after maternal infusion of nicardipine4 may be primarily due to a decrease in maternal uterine blood flow rather than a direct fetal effect of the drug. The fall in uterine blood flow observed in near-term pregnant animals after maternal infusion of calcium antagonists has been considered to be mainly due to peripheral vasodilation. which results in mater-
720
Holbrook, Voss, and Gibson
September 1989 Am J Obstet Gynecol
Table II. Fetal and maternal cardiorespiratory responses to fetal infusion of 100 f.Lg of nicardipine Preinfuswn
Fetal (n = 5) Heart rate Mean arterial pressure (mm Hg) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Hemoglobin (gm %) Hemoglobin saturation (%) Distal aortic pH Distal aortic Po, (mm Hg) Distal aortic Peo, (mm Hg) Maternal (n = 5) Heart rate Mean arterial pressure (mm Hg) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)
161 44 60 36 11.1 43.2 7.32 17.7 55.2
± ± ± ± ± ± ± ± ±
34 10 13 9 2.9 20.0 0.10 3.0 8.2
98 105 149 84
± ± ± ±
12 10 13 9
2 Minutes
172 42 56 35 10.5 41.3 7.32 17.1 53.6
± ± ± ± ± ± ± ± ±
21 9 11 8 2.6 21.4 0.10 3.7 7.0
101 104 146 85
± ± ± ±
11 7 9 8
30 Minutes
166 42 58 34 10.4 45.4 7.31 18.1 52.6
± ± ± ± ± ± ± ± ±
19 8 10 7 2.0 19.6 0.11 2.7 7.3
120 104 146 83
± ± ± ±
38 11 12 12
60 Minutes
173 42 60 36 10.8 42.6 7.31 17.3 55.4 114 104 145 84
± ± ± ± ± ± ± ± ±
16 7 8 6 2.3 21.1 0.12 2.9 8.0
± 24 ± 9 ± 11 ± 9
All values represent the mean ± SD.
nal hypotension and a fall in perfusion pressure. The uterine vasculature is considered to be maximally dilated near term and a diversion of flow to other regions should be expected to occur. In the pregnant ewe, Golichowski et al. 7 and Harake et aLB observed that continuous maternal nifedipine infusion caused a significant fall in maternal arterial pressure levels and a (presumably reflex) rise in maternal heart rate. In Harake's study, a significant fall in uterine blood flow was observed at an infusion rate of 10 f.Lg/kg/min, and fetal pH, arterial oxygen content, and hemoglobin saturation declined significantly. Uterine vascular resistance did not change, however, and therefore the fall in uterine blood flow could be attributed to decreased maternal arterial pressure levels. There was no change in fetal heart rate or arterial blood pressure level. There was, however, an increase in total and regional fetal cerebral blood flow consistent with fetal adaptation to asphyxia. In the near-term pregnant rabbit, [·3 continuous maternal nicardipine infusion at dosages that caused significant reductions in prematurely induced uterine activity were found to cause a rise in maternal heart rate and fall in maternal arterial pressure level. A fall in total uterine and placental blood flow also occurred despite a significant increase in maternal cardiac output.' Ducsay et aI.' administered a bolus of 500 f.Lg of nicardipine to the pregnant rhesus monkey and then continuously infused 6 f.Lg/kg/min. A significant decline in maternal arterial pressure level and increase in maternal heart rate occurred. Despite fetal plasma concentrations of nicardipine, which averaged 6% of maternal serum levels, no changes occurred in fetal heart rate or arterial blood pressure level. There was however, a significant fall in fetal arterial pH and Po" and
an increase in fetal arterial Peo,. Uterine blood flow was not measured, but the lack of change in fetal blood pressure level suggests that the fetal asphyxia was more likely a result of a decrease in utero placental perfusion. In our study, bolus administration of nicardipine to the fetus resulted in fetal serum concentrations of 414 ± 17 ng I ml to 527 ± 345 ng I ml after 2 minutes, and 41 ± 25 ng/ml to 61 ± 29 ng/ml at 60 minutes after infusion. The observation that 2-minute serum levels were higher after injection of 50 f.Lg than they were after 100 f.Lg may be explained by an increased variability of serum levels measured soon after injection, before equilibrium is complete. The levels at 30 and 60 minutes, however, reflect the dosage injected, higher levels being associated with the injection of 100 f.Lg. In the rhesus monkey, Ducsay et aJ.< observed fetal asphyxia at peak fetal plasma nicardipine concentrations of 7 to 35 ng/ml. Harake et aLB described significant asphyxial changes at fetal plasma nifedipine levels of91 ± 8 ng/ml. Thus, it would appear that maternal administration of these agents, which results in maternal hypotension and decreased uterine blood flow, is required for these adverse fetal effects to occur. Because calcium antagonists apparently cross the primate placenta and are vasodilators, the chronically asphyxiated fetus may be adversely affected by these agents. Redistribution of blood flow to vital organs such as the brain, heart, and adrenals through a selective peripheral vasoconstriction may be reversed by vasodilators and result in worsening of fetal asphyxia. Whereas our study did not demonstrate a significant change in fetal peripheral resistance after nicardipine infusion in the normoxic fetus, the effect of this and similar agents on the compensated asphyxiated fetus is not known. When comparison is made of the side effects of ni-
Fetal effects of nicardipine infusion
Volume 161 Number 3
cardipine and nifedipine, it should be recognized that different calcium antagonists display different degrees of action on uterine, vascular, and cardiac tissue. 9 In addition, calcium antagonists affect fetal and adult cardiovascular systems differently and therefore the typical adult response should not necessarily be expected in the fetus. 10 Whereas our study confirms the tolerance of the normoxie ovine fetus to nicardipine, the reported adverse effects on uterine blood flow and limited experience with these agents in the treatment of human preterm labor limits enthusiasm for their unrestricted use. Ulmsten et al. 11 have reported that when nifedipine was used clinically to treat premature labor, maternal arterial pressure was not affected, but a transient increase in heart rate occurred. No change in fetal heart rate was observed, and there were no neonatal complications noted. However, Read and Wellb y l2 found that although neither maternal heart rate nor blood pressure levels were altered by maternal administration of nifedipine, fetal heart rate was significantly increased. We (Ferguson JE II, Holbrook RH Jr., Unpublished observations) noted decreased diastolic and mean blood pressure and reflex tachycardia in 12 preterm labor patients treated with sublingual and oral nifedipine. Whereas no adverse fetal effects have been reported in human beings, maternal hypotension does occur, and there exists the potential for adverse fetal effects at higher dosages or when fetal growth retardation or chronic asphyxia are present. Further studies of the response to the hypoxic fetus to calcium antagonists and changes in uterine blood flow in human beings are warranted.
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REFERENCES 1. Lirette M, Holbrook RHJr., Katz M. Effect ofnicardipine HCI on prematurely induced uterine activity in the pregnant rabbit. Obstet Gynecol 1985;65:31-5. 2. Lirette M, Holbrook RH Jr., Katz M. Cardiovascular and uterine blood flow changes during nicardipine HCI tocolysis in the rabbit. Obstet Gynecol 1987;69:79-82. 3. Holbrook RHJr.. Lirette M, Katz M. Cardiovascular and tocolytic effects of nicardipine HCI in the pregnant rabbit: comparison with ritodrine HC!. Obstet Gynecol 1987; 69:83-7. 4. Ducsay CA, Thompson JS, Wu AT, Novy MJ. Effects of calcium entry blocker (nicardipine) tocolysis in rhesus macaques: fetal plasma concentrations and cardiorespiratory changes. AM J OBSTET GYNECOL 1987;157: 1482-6. 5. Csapo AI, Puri CP, Tarro S, Henzl MR. Deactivation of the uterus during normal and premature labor by the calcium antagonist nicardipine. AM J OBSTET GYNECOL 1982; 142:483-91. 6. Maigaard S, Forman A, Andersson K, Ulmsten U. Comparison of the effects of nicardipine and nifedipine on isolated human myometrium. Gynecol Obstet Invest 1983;16:354-66. 7. Golichowski AM, Hathaway DR, Fineberg N, Peleg D. Tocolytic and hemodynamic effects of nifedipine in the ewe. AMJ OBSTET GYNECOL 1985;151:1134-40. 8. Harake B, Gilbert R, Ashwal S. Power GG. Nifedipine: effects on fetal and maternal hemodynamics in pregnant sheep. AMJ OBSTET GYNECOL 1987;157:1003-8. 9. Granger SE. Hollingsworth M, Weston AH. A comparison of several calcium antagonists on uterine, vascular and cardiac muscles from the rat. Br J Pharmacol 1985; 85:255-62. 10. Boucek RJ Jr., Shelton M, Artman M, Mushlin PS, Starnes VA, Olson RD. Comparative effects of verapamil, nifedipine. and diltiazem on contractile function in the isolated immature and adult rabbit. Ped Res 1984; 18:948-52. 11. Ulmsten U, Andersson K, Wingerup L. Treatment of premature labor with the calcium antagonist nifedipine. Arch GynecoI1980;229:1-5. 12. Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br J Obstet Gynaecol 1986;93:933-7.