Salha S. Daniel

Transmission of Mepivacaine Hydrochloride (Carbocaine) Across the Human Placenta

Transmission of mepivacaine hydrochloride (Carbocaine) across the placenta was studied in 56 healthy women at term who received epidural analgesia during labor and delivery. All infants were delivered vaginally. Concentrations of mepivacaine were determined in maternal and umbilical cord blood by the methyl orange method. Mepivacaine administered into the maternal epidural space passed rapidly into the blood stream and crossed the placenta. Five mothers who received repeated injections, developed toxic symptoms; concentrations of the drug in blood were significantly higher than those in patients without complications. Twelve infants were depressed at birth; in 5, blood levels of the drug were significantly higher than those found in vigorous babies.

Mechanism of late deceleration of the fetal heart rate

Abstract An experimental model in the subhuman primate where the cardiovascular and acid-base state of the near-term fetus can be directly monitored during labor has been developed in our laboratory. The relationship between late deceleration of the fetal heart rate, acid-base state, and level of oxygenation was studied in a series of 30 experiments. In those fetuses which became acidotic, hypoxic, and hypotensive as labor advanced, there was an increase in base-line heart rate and late deceleration of the fetal heart rate following each uterine contraction. The late deceleration appeared as a marked transient bradycardia and was accompanied by a further decrease in fetal oxygen levels. In those fetuses which remained well oxygenated, there was no change in heart rate or in the level of oxygenation during uterine contractions of similar intensity. Late deceleration was abolished or suppressed when the level of fetal oxygenation was increased by administering a high concentration of oxygen to the mother. Since the fetal acidosis and hypotension remained, it is concluded that fetal hypoxia is the essential component producing late deceleration of the heart rate.

Vasopressin secretion induced by hypoxia in sheep: Developmental changes and relationship to β-endorphin release☆☆☆

To investigate the developmental changes in the secretion of vasopressin and the potential role of beta-endorphin as a stimulus to the release of vasopressin, the concentrations of these peptides were measured in fetal, newborn, and adult sheep after episodes of induced hypoxia. The studies confirm that hypoxia is a potent stimulus to the release of both vasopressin and beta-endorphin in the fetal animal. In both the newborn lamb and the ewe, more profound hypoxia is necessary for a similar release. In the fetus, the release of both vasopressin and beta-endorphin after hypoxia increased with gestational maturation. A comparison of control concentrations of both peptides, the discordance of release in the newborn lamb, and the absence of a change in concentrations of vasopressin with infusion of beta-endorphin implies that these hormones are released in parallel but independently during hypoxic stress.

The hemodynamic effects of intrauterine hypoxia: An experimental model in newborn lambs

An experimental animal model of intrauterine hypoxia and respiratory distress in newborn lambs was produced by inducing maternal hypotension. Serial hemodynamic data indicated that the oxygenation defect in the lambs was due to right-to-left shunting of blood through fetal channels rather than within the lungs. Shunting was mainly across the foramen ovale, but, in severely distressed animals, significant right-to-left shunt also occurred through the ductus arteriosus. Left-to-right shunts across the ductus arteriosus were found in lambs with milder respiratory distress. The implications of perinatal hypoxia as it affects the pulmonary vascular bed in human neonates with the respiratory distress syndrome (hyaline membrane disease) and persistence of the fetal circulation are discussed. It is speculated that the early pulmonary vascular esponses in the two diseases may be identical.

Umbilical vein occlusion and transient acceleration of the fetal heart rate. Experimental observations in subhuman primates.

Transient acceleration of the fetal heart rate is commonly seen in the cardiotachometer tracing of the human fetus during labor. A likely cause appeared to be partial occlusion of the umbilical cord. On the basis of this hypothesis, fetal cardiovascular responses to partial occlusion of the umbilical cord or isolated intra-abdominal portion of umbilical vein were studied in near-term pregnant baboons and rhesus monkeys prior to and following sympathetic blockade with dibenzyline and propranolol. The responses were of two types. In the well-oxygenated fetus, partial occlusion resulted in transient acceleration of heart rate and a decrease in pulse pressure. This response was abolished with dibenzyline or propranolol. In the hypoxic fetus, partial occlusion resulted in either bradycardia and hypotension or hypotension with no alteration in heart rate. Thus, transient acceleration of the fetal heart rate can be explained on the basis of a sympathetic response to diminished venous return. It would appear to be an early sign of a potential cord complication. This response will not be seen if the fetus becomes asphyxiated and hypoxic.

Adverse effects of maternal hypocapnea on the newborn guinea pig

Abstract 1. The influence of severe maternal respiratory alkalosis upon the acid-base status of the newborn guinea pig was investigated. 2. Maternal hyperventilation produced fetal acidosis and affected adversely the clinical status of the newborn, when maternal arterial pH exceeded 7.5.

Accidental intoxication of the fetus with local anesthetic drug during caudal anesthesia

Abstract Accidental intoxication with mepivacaine (a local anesthetic drug) occurred in 4 infants as a complication of attempted caudal anesthesia. All infants were depressed at birth and convulsed after artificial ventilation had been instituted. Two of the infants survived following respirator treatment, exchange transfusion, and gastric lavage.

Placental transfer and fetal metabolism of zidovudine in the baboon

Zidovudine (azidothymidine, AZT) is used in pregnancy to reduce mother to infant transmission of HIV. Understanding the disposition of AZT in the fetus is necessary to optimize therapeutic regimens directed toward the fetus. Recent studies in primates found similar steady-state levels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to those in the mother, raising the question of whether metabolite was of fetal or maternal origin. The objective of this study was to determine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compartment model at steady state. Steady-state concentrations were obtained after paired maternal and fetal infusions of AZT in chronically catheterized pregnant baboons. During maternal infusion, the mean (±SE) fetal to maternal ratio of AZT was <1 (0.84 ± 0.06, p < 0.02), suggesting clearance of AZT in the fetus. Mean total maternal clearance of AZT was 725 ± 49 mL/min and placental clearance was 36 ± 4 mL/min, or ∼5% of maternal clearance. Fetal clearance of AZT was estimated at ∼15% of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, but does not preclude the fetus from actively contributing to the metabolite in the fetal circulation. During infusion of AZT to the fetus, the concentration of AZT-glu in the fetus was 7.0 ± 0.8 times that in the mother. This is compelling evidence that glucuronide can be formed in the fetal compartment. Thus, fetal metabolism has an impact on the concentration of both AZT and AZT-glu in the fetal circulation.

Renal response of fetal lamb to complete occlusion of umbilical cord

The renal response of the fetal lamb to repeated complete occlusion of the umbilical cord was studied in nine chronically instrumented animals. Five episodes of occlusion of the umbilical cord, each lasting for two minutes, produced a twofold rise in fetal urine osmolality and sodium, chloride, and potassium concentrations. Output of urine and glomerular filtration rate remained essentially unchanged while free water clearance decreased from a control of +0.10 to -0.02 ml. per kilogram per minute at the end of the fifth episode. Electrolyte concentrations in urine remained elevated for at least two hours following the occlusions. In addition to changes in urine composition, there was a 50- to 200-fold increase in the fetal plasma concentration of vasopressin. These studies indicate that complete interruption of the umbilical circulation, even though of short duration, produces disturbances in fetal renal function that can lead to loss of electrolytes in the urine. They provide an explanation for the low sodium levels reported in asphyxiated newborn infants in renal failure.

FETAL MORPHINE METABOLISM AND CLEARANCE ARE CONSTANT DURING LATE GESTATION

Fetal metabolism significantly contributes to the clearance of drugs from the fetus. To understand how the changes in fetal metabolism expected in late gestation alter fetal drug clearance, serial measurements of morphine metabolism were made in the fetal baboon over the latter third of gestation. Clearance and metabolism were evaluated in the context of fetal growth, onset of labor, and the administration of classical enzyme induction agents. Morphine, a probe substrate for the enzyme uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7), was continuously infused to chronically catheterized fetal baboons while measuring morphine, morphine-3-β-glucuronide, and morphine-6-β-glucuronide concentrations. In some animals, intermittent infusions of the metabolites provided estimates of metabolite clearance and, hence, the rate of formation of metabolites and metabolic clearance. Overall, metabolic clearance of morphine from the fetus was 27 ± 9.0 ml · min–1 or 32% of total clearance. This is similar to the overall clearance in the adult baboon when standardized to weight. No change in any measure of metabolism or clearance of morphine or its glucuronide metabolites was found with gestational age, the presence of labor, or administration of UGT enzyme induction agents. Interpreting these findings using a physiologically based approach suggests that the intrinsic clearance of the fetal liver toward morphine is of sufficient magnitude that fetal hepatic clearance is flow-limited. The implication of a high intrinsic clearance is for significant placento-hepatic first-pass metabolism when drugs are administered to the mother. The previously held view of the “inadequacy of perinatal glucuronidation” needs to be reconsidered.