Effect of continuous infusion of fenoterol on maternal pelvic and fetal umbilical blood flow in pregnant sheep

The results from studies on the reactions of the uterine vascular bed upon intravenous administrations of beta-adrenergic drugs to the ewe are not all identical. This can be partly explained by different reactions of the pelvic vasculature on beta-adrenergic receptor stimulation. In order to assess whether any differences in flow reactions existed between the vascular beds of two maternal pelvic vessels upon beta-adrenergic receptor stimulation, we studied the effect of continuous maternal intravenous infusion with fenoterol on the blood flow in the maternal internal iliac and the median uterine artery in seven chronically instrumented pregnant sheep between 104 and 142 days gestation. Furthermore, the effects on umbilical venous blood flow, fetal heart rate, blood pressure and acid-base balance were analyzed. Maternal and fetal blood flows were measured with electromagnetic flow transducers. Fenoterol was administered to the ewe via a continuous intravenous infusion in two sequential periods of 30 minutes duration in a dose of 2 respectively 4 micrograms per minute. The blood flow in the internal iliac artery showed an increase of 10.5% (p less than 0.05) at the end of the infusion period and was still but not significantly elevated during the postinfusion period. No significant changes in median uterine artery blood flow were found during the fenoterol infusion, although an incremental trend was present. Fenoterol infusion to the mother had no effect on umbilical venous blood flow. Fetal pH and PO2 did not change, while fetal PCO2 was reduced (p less than 0.005) at the end of the infusion and recovery period, probably as a result of the concomitant maternal hyperventilation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of maternal hyperketonemia in hyperglycemic pregnant ewes and their fetuses

The fetus of the pregnant diabetic woman is exposed to hyperglycemia frequently accompanied by ketoacidosis. Previous studies have demonstrated that beta-hydroxybutyrate, a major ketone body, crosses the ovine placenta in significant amounts, leading to significant reductions in fetal PaO2 and increased fetal heart rate. In the present study the pregnant ewe was used to evaluate the maternal and fetal cardiovascular and metabolic responses to hyperketonemia in the presence of hyperglycemia and to determine if the combined diabetic insults were more detrimental to the fetus than hyperketonemia alone. A glucose priming dose of 25 gm was administered in the maternal femoral vein followed by a continuous glucose infusion of 200 mg/min to achieve steady maternal plasma glucose levels of 180 mg/dl. Once glucose levels were stable, beta-hydroxybutyrate was infused for 2 hours at a rate of 0.39 mmol/100 ml of uterine blood flow into both left and right uterine arteries. Infusion of glucose alone did not significantly alter fetal cardiovascular and blood gas parameters but did increase the fetal glucose level from 17 +/- 4 to 58 +/- 8 mg/dl. The simultaneous infusion of beta-hydroxybutyrate and glucose produced significant decreases in fetal PaO2 and oxygen content as were reported for hyperketonemia alone and significant time-related increases in fetal lactate levels and fetal heart rate. These data suggest that hyperketonemia in the pregnant ewe leads to quantitatively similar changes in oxygenation in both normoglycemic and hyperglycemic fetuses. These observations may in part help explain the increased perinatal mortality in the pregnant woman with uncontrolled diabetes.     

Pharmacokinetics and materno-fetal influence of ritodrine hydrochloride during the continuous treatment of threatened premature labor

The cardiovascular and metabolic effects of ritodrine hydrochloride on the mother and fetus were investigated during the 28-day and/or longer continuous treatment of threatened premature labor. Concentrations of ritodrine in maternal venous blood during the treatment, and placental transfer of the drug into the fetal circulation and amniotic fluid were also determined to ascertain the effectiveness and safety of the drug. Seventeen volunteer patients at 27-34 weeks of gestation were given a total dose of 2,850-7,350mg of ritodrine intravenously at a mean infusion rate of 72.9 micrograms/min for 28-66 days, when the maternal serum concentration of ritodrine was maintained at approximately 200ng/ml throughout the treatment period. A significant but slight increase in the maternal heart rate and serum glucose, and a slight fall in maternal blood pressure were observed during ritodrine infusion. The fetal heart rate did not change significantly. Although ritodrine also produced decreases in the red blood cell count, hemoglobin and hematocrit, these changes were transient and recovered to the control level thereafter. The ratios of umbilical venous blood and the amniotic fluid concentration of ritodrine to maternal venous concentrations determined at cesarean section were 0.68 and 1.64, respectively, suggesting that a gradual accumulation of placentally transferred ritodrine may occur when long-term continuous infusion is carried out. There were no noticeable drug-related findings in mothers and newborns during and after labor. These results indicate that threatened premature labor may be well effectively controlled by ritodrine without severe side-effects on the mother or fetus in treatment for along period.     

Effect of fenoterol (Th1165a) infusion on uterine and umbilical blood flow in pregnant sheep.

The effect of fenoterol (Th1165a) upon uterine artery blood flow (UtBF) and umbilical vein blood flow (UmBF) was investigated in near-term, nonlaboring chronic sheep preparations. During intravenous fenoterol infusions to the ewe in either incremental doses from 0.025 to 0.200 microng per kilogram per minute or constant infusions of 0.025 microng per kilogram per minute for 120 minutes. UtBF and UmBF did not change significantly. Dose-related maternal tachycardia, hyperglycemia, and relative acidemia occurred, but there were no significant changes in mean maternal and fetal arterial pressures or fetal heart rate. The simultaneous infusion of propranolol (2 microng per kilogram per minute) with fenoterol (0.200 microng per kilogram per minute) blocked the maternal tachycardia but resulted in a significant decrease in UmBF and a significant increase in UtBF. In all of the maternal infusions. UtBF significantly rose and plateaued up to 14 per cent above the control level during the 120 minute recovery period after infusion. A non-beta-adrenergic effect of fenoterol is suggested as the cause of this UtBF increase.     

Effects of ritodrine hydrochloride on uterine activity and the cardiovascular system in toxemic patients.

The effects of ritodrine hydrochloride were evaluated in 25 toxemic patients in active labor utilizing continuous electronic monitoring of fetal and maternal cardiovascular systems and uterine activity. Fetal scalp blood and free flowing maternal antecubital venous blood was obtained for pH, Po2, Pco2, base deficit and blood glucose determinations prior to and immediately following the study period. The initial ritodrine dose was 50 mug/min for 15 minutes. The dose was increased by 50 mug/min each 15 minutes until there was a clinically apparent reduction in uterine activity. Once this was accomplished, the infusion was maintained for 30 minutes. There was a consistent increase in the maternal heart rate (MHR) and a significant rise in fetal heart rate (FHR) late in the infusion and in the postinfusion period. There was a widening of the maternal pulse pressure mainly due to a reduction in diastolic pressure with little change in the mean blood pressure. Maternal and fetal pH decreased and base deficit increased during the study although the PO2 and PCO2 remained unchanged. Maternal and fetal blood glucose rose significantly following ritodrine infusion.     

Ovine fetal cardiorespiratory response to nicardipine

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 micrograms were minimal; by 60 minutes these values had returned to preinfusion levels. No significant changes were observed after infusion of 100 micrograms 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 micrograms and 100 micrograms, 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.     

Fetal vascular responses to maternal nicardipine administration in the hypertensive ewe

Calcium channel blockers such as nicardipine act as arterial vasodilators and are effective in the treatment of hypertension. Although they are also effective tocolytic agents, fetal effects have not been fully studied. Fifteen chronically catheterized near-term ewes were studied. Maternal and fetal cardiorespiratory parameters were measured in the control period and again 15 minutes after maternal venous infusion of angiotensin II. Nicardipine 20 micrograms/kg/min was given over 2 minutes and maternal and fetal cardiorespiratory parameters and fetal blood flow were measured 5.30 and 60 minutes later. Nicardipine reversed maternal hypertension and produced transient tachycardia. Fetuses responded initially with transient bradycardia and then developed hypercapnia and acidemia (p less than 0.03) by 60 minutes after nicardipine. Fetal placental blood flow decreased and vascular resistance increased by 5 minutes after nicardipine but returned toward control values after 30 minutes. Unexpectedly we observed the death of five fetuses by 65 minutes after nicardipine. We conclude that the administration of nicardipine in the hypertensive ewe results in significant alterations of fetal cardiorespiratory status and placental function that may lead to acidemia.     

Effect of antipyrine on prostaglandin levels and uterine and umbilical blood flow

Antipyrine and 4-aminoantipyrine have been used for approximately 20 years to measure uterine and umbilical blood flow. Fetal infusion of 4-aminoantipyrine has been shown to decrease myometrial activity and to significantly lower prostaglandin F2 alpha metabolite levels. Since prostaglandins are thought to be important in regulating uterine and umbilical blood flow, their decrease could cause significant changes in blood flow. The purpose of the present study was to evaluate the effects of antipyrine on uterine and umbilical blood flow as measured with electromagnetic flow probes and to determine whether antipyrine causes significant changes in levels of prostaglandin E2, prostaglandin F2 alpha metabolite, and prostaglandin I2 measured as 6-keto-prostaglandin F1 alpha. Antipyrine infusion produced significant reductions in the uterine venous levels of prostaglandin E2 and prostaglandin F2 alpha metabolite (p less than 0.05). These reductions in prostaglandin levels were not associated with any significant changes in maternal blood pressure, heart rate, uterine blood flow, or oxygen content. Although fetal prostaglandin levels tended to decrease during the antipyrine infusion, these changes were not significant. Fetal blood pressure, heart rate, umbilical blood flow, PaO2, and oxygen content were not significantly altered. These data suggest that the antipyrine method does not affect basal blood flow in the uterine or umbilical circulation even though uterine prostaglandin levels are significantly decreased.     

The oscillating 'vena cava syndrome' during quiet standing—an unexpected observation in late pregnancy

Summary. While studying the lung function of pregnant women at term in four different postures, we were surprised to note marked cyclic accelerations in the heart rate in two-thirds of the women when in a standing position. The mean cycle length was 105 s (range: 1–4 min) and the amplitude had a mean of 27 beats/min (range: 9–51). Blood flow velocity measurements with ultrasound Doppler over the femoral vein showed that there was an intermittent reduction of flow during quiet standing. When the venous return ceased, maternal heart rate increased, cardiac output decreased and blood pressure fell. After the venous blood flow was restored, maternal heart rate, cardiac output and blood pressure returned to normal until the cycle started again. Concomitant with these maternal heart rate changes, different patterns of fetal heart rate were observed. About 70% of the fetuses showed reduction in the long-term variability, increase in fetal heart rate or periodic accelerations. Although no woman fainted during quiet standing, the maternal circulatory changes were consistent with those seen in the classical vena cava syndrome.     

Effects of nitroglycerin and indomethacin on fetal-maternal circulation and on fetal cerebral blood flow and metabolism in sheep.

OBJECTIVE: Our purpose was to evaluate the effects of maternal administration of nitroglycerin and indomethacin on maternal and fetal hemodynamics and on fetal cerebral blood flow and metabolism in sheep. STUDY DESIGN: Invasive vascular and fetal carotid flow monitoring was established in 12 gravid ewes. Isotonic sodium chloride solution, nitroglycerin, and indomethacin were infused maternally, and maternal and fetal heart rate, blood pressure, blood gas values, fetal carotid blood flow, and flow variability were measured. Fetal cerebral uptake of oxygen, glucose, and lactate were calculated. RESULTS: Nitroglycerin infusion caused a significant increase in maternal and fetal heart rate and a significant decrease in maternal and fetal mean arterial pressure at a dosage of 10 microram/kg per minute, without a change in blood gas values. Neither drug had any effect on fetal carotid blood flow, flow variability, or cerebral substrate metabolism. CONCLUSION: Maternal administration of nitroglycerin and indomethacin caused no adverse maternal or fetal circulatory changes and did not alter fetal carotid blood flow or substrate metabolism.     

Effects of salbutamol and isoxsuprine on uterine and umbilical blood flow in pregnant sheep

The effects of salbutamol and isoxsuprine upon uterine artery blood flow (UtBF) and umbilical vein blood flow (UmBF) were investigated in near-term, nonlaboring chronic sheep preparations. During both intravenous salbutamol and isoxsuprine infusions to the ewe, UtBF and mean maternal arterial pressure decreased significantly. Also, dose-related maternal tachycardia, hyperglycemia, and relative acidemia occurred. There were no significant changes in UmBF, mean fetal arterial pressure, or fetal heart rate (FHR) during salbutamol infusions, but UmBF and FHR increased during isoxsuprine infusions. During the 120 minute postinfusion recovery period, UtBF rose significantly after the salbutamol infusions but not after the isoxsupine infusions. The effects and structure-activity relationship of these two drugs are comparable to those of ritodrine and fenoterol, two other beta-adrenergic agonists.     

Placental transfer of the thromboxane synthetase inhibitor ridogrel in the late-pregnant ewe.

OBJECTIVES: To assess the occurrence of placental transfer of the thromboxane synthetase inhibitor ridogrel in the pregnant ewe and to determine its effect on prostanoid levels in the ewe and fetal lamb, on uterine contractility and on maternal and fetal hemodynamics. STUDY DESIGN: Five chronically instrumented pregnant ewes at 122 days of gestation received intravenous infusions of 5 mg/kg/3 h ridogrel and solvent. Maternal and fetal arterial samples were obtained at predetermined intervals to determine concentrations of ridogrel and prostaglandin metabolites TXB2, 6-keto-PGF1alpha, PGF2alpha, and PGE2. Maternal and fetal responses of blood flow and pressures were determined. RESULTS: Fetal ridogrel levels were 25% of maternal concentrations. Ridogrel showed rapid and marked thromboxane synthetase inhibition and augmentation of levels of prostaglandin metabolites. There was no evidence of change in amniotic pressure, uterine blood flow, maternal and fetal blood pressure and heart rate. CONCLUSION: Ridogrel is a potent thromboxane synthetase inhibitor which passes the sheep placenta, does not influence maternal and fetal hemodynamics and uterine contractility, and shows similar antiplatelet activity in the ewe and the fetal lamb.     

The acute response of the umbilical artery pulsatility index to changes in blood volume in fetal sheep.

This experimental study was designed to test the effects of acute changes in fetal circulating blood volume on the umbilical artery pulsatility index (PI). Six fetal sheep were provided with an electromagnetic flow meter for measurement of umbilical venous blood flow, with catheters for determination of arterial blood pressure and umbilical venous pressure, and with a 5 MHz Doppler transducer around one umbilical artery for flow velocity waveform analysis. A catheter in the inferior vena cava was used to infuse 50 ml of maternal blood (hypervolemia) into the fetal circulation or to withdraw 50 ml of fetal blood (hypovolemia) after volume correction. Hypervolemia resulted in a rise in arterial pressure and umbilical venous pressure, without an effect on PI, umbilical blood flow or placental vascular resistance. Hypovolemia resulted in a decrease in fetal heart rate, arterial pressure, umbilical venous pressure and umbilical blood flow. Calculated placental vascular resistance was not changed, whereas the PI increased by 42%. We conclude that volume loading with 10-15% of fetal circulating volume does not affect the umbilical artery PI, whereas acute reduction of fetal blood volume with the same amount is associated with an increase in the umbilical artery PI, without changes in calculated placental vascular resistance.     

Maternal and fetal effects of low-dosage bupivacaine paracervical block

Vasoconstriction of the uterine arteries, hypertonus of the uterus, and the direct toxic effects of a local anesthetic on the fetus or a combination of the above have been presented as etiological factors of fetal bradycardia following paracervical block. The reduce fetal side-effects a superficial and lowdosage technique of PCB have been advocated. We have studied the effects of 25 mg of bupivacaine PCB using the above technique on fetal heart rate pattern (FHR), fetal acid-base balance, uterine activity, placental blood flow and maternal and fetal plasma levels of bupivacaine in 38 patients. The analgesic effect of a single 25 mg of bupivacaine PCB was good in 76%, moderate in 12% and poor in 12% of the cases. No changes in maternal heart rate or in blood pressure were noted. Fetal bradycardia defined as a decrease of mean fetal heart rate of at least 20 bpm or an absolute rate less than 100 bpm and a duration greater than two minutes occurred in 12% of the cases. The mean amplitude of the baseline fetal heart rate variability decreased significantly after PCB and a silent pattern (an amplitude less than 5 bpm) was observed in 20% of the cases. The most frequent (27%) pathological finding in our study was the disappearance of FHR accelerations after PCB. Similarly early and late decelerations of FHR occurred more often after PCB than during the control period before the block. The fetal pH from scalp blood samples did not, on average, decrease after PCB, but did so in cases with fetal bradycardia. Intervillous blood flow as measured by the 133Xe washout method did not change when measured before and after PCB. In addition in three cases with fetal bradycardia the changes in the intervillous blood flow were minimal. No significant changes in the mean uterine tone, amplitude and frequency of contractions were observed after PCB. However, an obvious uterine hypertonus was observed after PCB was observed in three cases of fetal bradycardia but not in two other cases of bradycardia or in the 8 cases of silent FHR pattern. Mean maternal bupivacaine concentration 20 minutes after PCB was 0.14 +/- 0.06 microgram/ml and 0.07 +/- 0.04 microgram/ml at birth. Simultaneous fetal and umbilical venous and arterial concentrations were correspondingly 0.04 +/- 0.02 microgram/ml, 0.03 +/- 0.01 microgram/ml and 0.03 +/- 0.01 microgram/ml, and they were significantly lower than respective maternal concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of propranolol infusion on the umbilical and uterine circulations of pregnant sheep.

Propranolol was infused intravenously for 60 minutes to five ewes (4 mug per kilogram per minute) or five fetal sheep (10 mug per kilogram per minute). The umbilical blood flow was significantly decreased by 18 per cent from control at 60 minutes with either maternal or fetal propranolol infusion. Uterine blood flow and maternal and fetal mean arterial pressure did not significantly change. Maternal and fetal heart rates decreased 18 and 9 per cent from control, respectively, during maternal propranolol infusion. With propranolol to the fetus, fetal heart rate decreased 15 per cent and maternal heart rate did not change. During all infusion, maternal and fetal arterial pH, PCO2 and PO2 remained within normal physiologic limits.     

Placental transport of alcohol and its effect on maternal and fetal acid-base balance.

The placental transport of alcohol and its effect on maternal and fetal acid-base balance studied in 10 sheep experiments by the maternal infusion of a 9.75 per cent solution of alcohol-dextrose at a rate of 15 c.c. per kilogram for 1 or 2 hours. Serial maternal and fetal blood sampling during and following the alcohol infusion revealed rapid placental diffusion of alcohol, a highly significant correlation between maternal and fetal blood alcohol concentrations, and a similar peak concentration of approximately 0.230 Gm. per 100 ml. in maternal and fetal blood that differed only in time of onset during the 1 and 2 hour infusion periods. Blood alcohol concentrations remained high for several hours during the postinfusion period. A significant maternal hyperlactacidemia and hyperglycemia were noted but did not result in significant alterations in maternal acid-base balance. An initial fetal metabolic acidosis and later mixed acidosis were observed during the alcohol infusion and worsened during the postinfusion period.     

Effect of long-term bromocriptine infusion on plasma prolactin and ovine chorionic somatomammotropin in the pregnant ewe and fetal sheep.

It has been shown in previous studies that the continuous infusion of bromocriptine (CB 154) into either the sheep fetus or pregnant ewe was followed by pronounced ultrastructural changes in the binucleate (BN) cells of the ovine chorionic epithelium, which are a likely source of ovine chorionic somatomammotropin (oCS). We have examined ovine fetal and maternal plasma prolactin (PRL) and oCS concentrations following intravascular CB 154 infusion separately into either the fetus (0.03 mg/hour) or ewe (0.2 mg/hour). The CB 154 infusions significantly depressed fetal and maternal plasma radioimmunoassayable PRL concentrations within 24 hours of the commencement of infusion. Maternal plasma radioimmunoassayable oCS concentration was significantly depressed during infusion of CB 154 to the ewe, but the infusion of CB 154 to the fetus did not lower fetal plasma radioimmunoassayable oCS concentration or affect the duration of gestation.     

Phasic blood flow patterns in the superior and inferior venae cavae and umbilical vein of fetal sheep

Measurements of phasic blood flow in the inferior and superior venae cavae and umbilical vein of fetal sheep (gestational age, 121 to 140 days) were made with chronically implanted electromagnetic flow transducers. In the venae cavae blood flow was inversely related to phasic changes in venous and/or intrathoracic pressure. During fetal apnea a forward surge of flow occurred during ventricular systole (systolic surge) and ventricular diastole (diastolic surge). Slower fetal heart rates were associated with a more prominent diastolic surge. Reductions in afterload caused by acetylcholine administration augmented the peak diastolic venous flow. In contrast, increased afterload caused by hypoxia and norepinephrine administration was associated with increased peak systolic flow. During regular fetal breathing movements the phasic flow pattern was determined largely by the respiratory cycle with the effect of the cardiac cycle superimposed. There was minimal venous pulsation in the intra-abdominal umbilical vein, compared with that of the intrathoracic venae cavae of the apneic fetus. Our findings demonstrate that fetal systemic vascular resistance profoundly influences right atrioventricular filling patterns.     

Lumbar epidural analgesia with bupivacaine in labor. Determination of drug concentration and pH in fetal scalp blood, and continuous fetal heart rate monitoring.

Lumbar epiduval analgesia with bupivacaine was given to 37 women for uncomplicated labor. After the blcokade serial determinations of pH and bupivacaine concentration were made in fetal scalp blood and maternal venous blood and there was continuous monitoring of the fetal heart rate. Fetal scalp blood pH was within normal limits and no pathologic FHR tracings were elicited by the blockade, although a temporary decrease of the baseline fetal heart rate irregularity was seen in about one-fifth of the cases. Fetal drug concentrations were low and about one-fourth of corresponding maternal values. After reinjection of bupivacaine the degree of drug accumulation was fairly similar in fetal and maternal blood.     

Hemodynamic effects of intravenous cocaine on the pregnant ewe and fetus

Cocaine is a potent vasoconstrictive agent that is currently the subject of widespread drug abuse. Because little is known of the physiologic responses to cocaine in pregnancy, the effects of intravenous cocaine on uterine blood flow and other maternal and fetal cardiovascular parameters were studied. Eight ewes in late pregnancy were equipped with electromagnetic flow probes around both uterine arteries and catheters were placed in the maternal and fetal inferior vena cavae and aortas. Bolus intravenous infusion of 0.5 and 1.0 mg/kg of maternal body weight achieved peak plasma cocaine levels similar to those observed in human subjects after abuse of the drug (mean level = 229 to 400 ng/ml, n = 8). After bolus infusion of 0.5 or 1.0 mg/kg of cocaine, mean maternal arterial pressure increased 32% and 37%, respectively (p less than 0.005). Fetal blood pressure rose 12.6% after a dosage of 0.5 mg/kg of cocaine. These cocaine infusions significantly decreased uterine blood flow by 36% and 42% for a duration of 15 minutes (p less than 0.005). Analysis of maternal catecholamine responses demonstrated a significant (210%) rise in plasma norepinephrine levels after cocaine infusion. These studies demonstrate that cocaine, when administered in doses that produce plasma levels observed in humans, significantly decreases uterine blood flow for a duration of greater than or equal to 15 minutes while inducing a hypertensive response in the pregnant ewe and fetus.