Blea C W, Barnard J M, Magness R R, Phernetton T M, Hendricks S K
Department of Obstetrics and Gynecology, University of Wisconsin-Madison, 53715, USA.
Am J Obstet Gynecol. 1997 Apr;176(4):922-30. doi: 10.1016/s0002-9378(97)70622-7.
Our purpose was to determine whether the fetal acidosis and hypoxia previously demonstrated in animal models with maternal nifedipine infusion is the result of a decrease in uteroplacental or fetoplacental blood flow and whether this effect is exacerbated by a higher drug concentration and duration of infusion.
Ten chronically instrumented pregnant ewes (gestational age 0.9 term, term = 145 days) received nifedipine infusions (n = 7) or vehicle (95% ethanol/water, 3:7) (n = 3). Three 90-minute periods were evaluated: 5 microg/kg/min infusion (low-dose nifedipine), no infusion, and 10 microg/kg/min (high-dose nifedipine). Paired maternal and fetal blood gases, glucose, lactate, and nifedipine levels were obtained every 30 minutes while hemodynamic parameters were monitored. We determined maternal and fetal blood flows using the radioactive microsphere technique.
Although maternal placental blood flows decreased by 25% during low-dose nifedipine (p < 0.05), this was only transient and there were no other decreases in uteroplacental or fetoplacental blood flow. Fetal blood flow increased to the adrenals and diaphragm with high-dose nifedipine (p < 0.05). Maternal and fetal lactate levels increased with both doses (p < 0.05). In addition, fetuses exhibited significant hypoxia (oxygen content fell 0.46 mmol/L) and acidosis (pH fell 0.06 units) throughout the nifedipine infusion and recovery period. Maternal heart rate increased transiently with both doses (p < 0.05); however, there were no changes in either fetal or maternal mean arterial pressure. Infusion of the vehicle alone did not alter maternal or fetal hemodynamics. Maternal and fetal plasma nifedipine levels reached steady-state by 30 minutes, and maternal/fetal ratios were 0.4 to 0.55. The maternal metabolic clearance rates for low- and high-dose nifedipine were 80.0 and 79.8 ml/min/kg, respectively. Maternal half-life calculation revealed a two-compartment model with a calculated half-life of 2.87 +/- 3.15 and 63.57 +/- 154.03 (+/-SD) minutes for the alpha and beta components, respectively.
Maternal nifedipine infusion is associated with hypoxia and acidosis in the sheep fetus, without persistent decreases in uteroplacental or fetoplacental blood flows or blood pressures. These fetal blood gas changes are more severe with high-dose nifedipine and longer duration of infusion and continue to deteriorate even when recovery is allowed. The deterioration of fetal blood gases is out of proportion to the transient decreases in uteroplacental blood flow and demonstrates that another mechanism for this fetal acidosis and hypoxia exists during nifedipine infusion.
我们的目的是确定先前在母体输注硝苯地平的动物模型中所证实的胎儿酸中毒和缺氧是否是子宫胎盘或胎儿胎盘血流减少的结果，以及这种效应是否会因更高的药物浓度和输注持续时间而加剧。
十只长期植入仪器的怀孕母羊（孕周0.9足月，足月=145天）接受硝苯地平输注（n=7）或赋形剂（95%乙醇/水，3:7）（n=3）。评估了三个90分钟时间段：5微克/千克/分钟输注（低剂量硝苯地平）、无输注和10微克/千克/分钟（高剂量硝苯地平）。每30分钟获取配对的母体和胎儿血气、葡萄糖、乳酸和硝苯地平水平，同时监测血流动力学参数。我们使用放射性微球技术测定母体和胎儿血流。
虽然在低剂量硝苯地平期间母体胎盘血流减少了25%（p<0.05），但这只是短暂的，子宫胎盘或胎儿胎盘血流没有其他减少。高剂量硝苯地平时胎儿流向肾上腺和膈肌的血流增加（p<0.05）。两种剂量下母体和胎儿乳酸水平均升高（p<0.05）。此外，在整个硝苯地平输注和恢复期胎儿表现出明显的缺氧（氧含量下降0.46毫摩尔/升）和酸中毒（pH下降0.06单位）。两种剂量下母体心率均短暂增加（p<0.05）；然而，胎儿或母体平均动脉压均无变化。单独输注赋形剂未改变母体或胎儿血流动力学。母体和胎儿血浆硝苯地平水平在3分钟时达到稳态，母体/胎儿比值为0.4至0.55。低剂量和高剂量硝苯地平的母体代谢清除率分别为80.0和79.8毫升/分钟/千克。母体半衰期计算显示为二室模型，α和β组分的计算半衰期分别为2.87±3.15和63.57±154.03（±标准差）分钟。
母体输注硝苯地平与绵羊胎儿的缺氧和酸中毒相关，而子宫胎盘或胎儿胎盘血流或血压无持续下降。高剂量硝苯地平和更长的输注持续时间时这些胎儿血气变化更严重，即使在允许恢复时仍继续恶化。胎儿血气的恶化与子宫胎盘血流的短暂减少不成比例，表明在硝苯地平输注期间存在另一种导致胎儿酸中毒和缺氧的机制。
