Julius Neumark

Does Ritodrine Worsen Maternal Hypotension During Epidural Anesthesia in Gravid Ewes

The purpose of this study was to determine whether prior administration ritodrine worsens maternal hypotension during epidural anesthesia in gravid ewes. Twenty-four experiments were performed in nine chronically instrumented animals between 0.8 and 0.9 of timed gestation. The experimental sequence included the following: 1) at time-zero, intravenous (iv) administration of ritodrine, 0.004 mg.kg-1.min-1, or normal saline (NS) for 2 h; 2) at 120 min discontinuation of ritodrine, and administration of a 500 ml iv bolus of NS over 15 min; and 3) at 135 min epidural injection of 2% lidocaine or NS. There were three groups of experiments: 1) iv ritodrine-epidural lidocaine (n = 9); 2) iv NS-epidural lidocaine (n = 8); and 3) iv ritodrine-epidural NS (n =7). Epidural injection of lidocaine resulted in a median sensory level of T9 in both the ritodrine-lidocaine and NS-lidocaine groups. At 165 min (i.e., 30 min after the epidural injection of lidocaine), maternal mean arterial pressure was 19 +/- 3% below baseline (P = 0.0001) in the ritodrine-lidocaine group and 22 +/- 7% below baseline (P = 0.0001) in the NS-lidocaine group (NS between groups). At 120 min ritodrine had increased maternal cardiac output 45 +/- 6% above baseline (P = 0.0001) in the ritodrine-lidocaine group and 39 +/- 6% above baseline (P = 0.0001) in the ritodrine-NS group. Cardiac output remained above baseline (P less than 0.01) after epidural injection of lidocaine in the ritodrine-lidocaine group. In contrast, in the NS-lidocaine group cardiac output was 13 +/- 5% below baseline (P = 0.005) at 150 min. Fetal arterial pH did not change significantly in either the ritodrine-lidocaine or ritodrine-NS group.(ABSTRACT TRUNCATED AT 250 WORDS)

Uptake and Distribution of Lidocaine in Fetal Lambs

The fetal uptake of lidocaine was measured continually and quantitatively during and after a constant rate intravenous (iv) maternal infusion into five chronically prepared pregnant ewes. Lidocaine, 6 mg/kg (base), was infused at a constant rate for 1 h and measurements continued to 5 h. Rate of fetal uptake was determined from the product of the umbilical venous (UV) and fetal aortic (FA) concentration difference and umbilical blood flow (Qu). Total fetal uptake was determined by integrating fetal uptake rate with respect to time. Maternal and fetal protein binding was determined, and its effect on fetal blood concentrations was evaluated. Mean total fetal uptake as it related to time and infused dose increased linearly (r = 0.998, P less than 0.001) with a constant, weight-normalized fetal-maternal dose fraction of 0.45 during the infusion. Despite rapidly declining blood concentrations after the infusion, uptake increased an additional 17%. The sevenfold variation in uptake appeared to be inversely related to the biodegradation rate of lidocaine. Fetal-maternal concentration ratios (F/M) increased during declining blood concentrations. Protein binding determinations for maternal and fetal blood were 43.6 +/- 2.48% and 26.9 +/- 1.59%, respectively. These values were used to calculate the F/M in conjunction with the maternal and fetal pH. At maternal-fetal equilibrium the calculated F/M, 1.0 +/- 0.05, closely approximated the observed, 1.0 +/- 0.03. Variations in lidocaine concentrations among the vital organs 4 h after the infusion were small, but high concentrations of metabolites were found in the lungs and kidneys. The results challenge the validity of placental transfer estimates commonly based on the F/M and umbilical cord blood concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Incidence of Venous Air Embolism During Cesarean Section is Unchanged by the Use of a 5 to 10° Head-Up Tilt

One hundred healthy parturients were divided at random into two demographically similar groups and were positioned for cesarean section either horizontally or flexed 5 to 10° head up, with a 15° lateral tilt. A Doppler ultrasound transducer was positioned over the fourth intercostal space parasternally. Initially, two patients received spinal, three general, and 95 epidural anesthesia. Two patients subsequently needed general for failed epidural anesthesia. Changes in Doppler heart tones (>15 sec duration) indicative of venous air embolism (VAE) were identified 15 times in 11 patients—seven in supine and four in head-up patients (no statistically significant diference). Six awake patients (three horizontal, three head-up) developed chest tightness or pain during surgery, but only one episode correlated with VAE. No patient developed breathlessness. Moderate hypotension (>lo% decrease in systolic arterial pressure [SAP]) occurred in seven of 11 (63.6%) patients with, and in 26 (29.2′%) of 89 patients without, VAE (P < 0.001). More severe hypotension (SAP <90 mm Hg) due to bleeding occurred once. We conclude that a modest (5–10°) head-up position does not influence the occurrence of VAE in patients having cesarean section. An 21% incidence of clinically insignificant VAE, although low, is still worrisome, as even small air bubbles in the circulation are potentially harmful, especially if the foramen ovule is patent. VAE during cesarean section should be anticipated and the anesthetic management planned accordingly.

Disposition of Intrapartum Narcotic Analgesics in Monkeys

Maternal-fetal disposition and neonatal respiratory depressant effect of narcotic analgesics were studied by administration of meperidine (2 mg/kg, IV) or alfentanil (IV infusion, 0.1 mg/kg total dose) during labor in rhesus monkeys. Fetal/maternal plasma ratios were lower for alfentanil, the more highly protein-bound drug (fetal/maternal ratio 0.20 at birth versus 0.46 for meperidine). However, elimination of alfentanil was delayed in the neonate. Indeed, plasma concentrations of alfentanil increased during the first 2 postnatal hours, indicating a compartmental shift from tissues to circulation in the eonate. As regards respiratory depression, six of ten narcotic-treated monkeys had suboptimal (<60 breath/mm) respiratory rates at birth. Respiratory rate was negatively correlated with cord vein normeperidine and meperidine levels; the strongest correlation was with normeperidine (r = −0.84, P < 0.01). Neonatal normeperidine elimination in the postnatal period was prolonged, as has also been observed in humans. These studies serve as a basis for comparing the neonatal neurobehavioral effects of the two analgesics and support the use of the rhesus monkey as an animal model to further understanding of the effects of narcotic analgesics on neonatal respiration.

Does Gestational Age Affect the Pharmacokinetics and Pharmacodynamics of Lidocaine in Mother and Fetus

The pharmacokinetics and pharmacodynamics of lidocaine were studied in nine chronically prepared pregnant ewes and their fetuses at a mean (±SE) gestation of 119 ± 1.0 days, and the results were compared to the data previously published for ten animals at 138 ± 1.2 days of gestation (term 148 days). Lidocaine was infused intravenously to the mother at a constant rate of 0.1 mg·kg−1·min−1 over a period of 180 min, in order to reach a steady-state maternal plasma lidocaine concentration of approximately 2 μg/ml. Maternal and fetal blood samples and maternal urine were collected at intervals throughout the infusion for determination of pH, blood gases, and lidocaine concentrations. Maternal and fetal heart rate, blood pressure, and intraamniotic pressure were continuously recorded. Fetal cardiac output and organ blood flow were determined before and at the end of lidocaine infusion using radionuclide-labeled microspheres. Lidocaine tissue concentrations were determined in several maternal and fetal organs excised at the end of infusion. In both groups, the steady-state plasma concentrations of lidocaine were similar; namely, 2.3 ± 0.17 and 2.1 ± 0.21 μg/ml in preterm and term ewes, respectively. There were also no significant differences in steady-state plasma drug concentrations in preterm and term fetuses (1.3 ± 0.11 and 1.2 ± 0.15 μg/ml). The mean fetal maternal concentration ratios (F/M) were the same; namely, 0.6. Maternal urinary excretion of lidocaine correlated with urine pH, being greater in the more acid urine. Tissue uptake of drug tended to be higher in the preterm than term mothers, but only significantly so in the brain and adrenals. In the fetuses, tissue uptake was similar in both groups except in the lungs and liver, where it was higher at term. Liver uptake was significantly higher in the fetuses than in the corresponding ewes. Maternal and fetal vital signs and blood gases, as well as the fetal cardiac output and organ blood flow, were not altered by lidocaine infusion. It is concluded that the pharmacokinetics and dynamics of lidocaine in the mother and fetus are not affected by maturation between 80% and 95% of gestation.

Fetal Lung Maturation: Amniotic Fluid Catecholamines, Phospholipids, and Cortisol

The identification of beta-adrenergic receptors in the fetal lung led us to investigate amniotic fluid catecholamine levels in relation to other indices of fetal pulmonary maturity in late pregnancies (n = 62). Significant correlations were found between the percentage of phosphatidylglycerol and concentrations of norepinephrine (r = 0.44, p less than 0.001), its intraneuronal deaminated metabolite 3,4-dihydroxyphenylglycerol (DOPEG; r = 0.74, p less than 0.0001), epinephrine (4 = 0.43, p less than 0.001), and cortisol (r = 0.78, p less than 0.001). Highly significant elevations of these substances were noted with accelerated pulmonary maturation. Lecithin/sphingomyelin (L/S) ratios showed a significant correlation with cortisol levels (r = 0.50, p less than 0.001); however, significant associations between L/S ratios and catecholamine levels were found only when complicated pregnancies were excluded. These findings support the contention that fetal contention that fetal adrenergic activity participates in the process of pulmonary maturation.

Hemodynamic Effects of Alpha-Adrenergic Blockade During Hypoxia in Fetal Sheep

During hypoxemia there is a redistribution of cardiac output in the sheep fetus associated with increased vascular resistance in some fetal organs. The role of the alpha-adrenergic blocking drug to eight chronically instrumented hypoxemic sheep fetuses. We measured arterial blood pressure and heart rate, determined cardiac output and organ blood flows by means of radionuclide-labeled microspheres, and calculated vascular resistances in fetuses before and during hypoxia, and after injection of phenoxybenzamine 15 mg into the inferior vena cava of the hypoxemic fetus. Hypoxemia resulted in an increased vascular resistance in certain vascular beds. Alpha-adrenergic blockade during hypoxia abolished the increase in vascular resistance of the fetal body and caused an increase in the blood flow to some tissues which had a hypoxia-induced vasoconstriction. After alpha-adrenergic blockade during hypoxia, mean arterial blood pressure decreased from 48 +/- 6 to 42 +/- 6 mm Hg (p less than 0.05) and heart rate increased from 128 +/- 19 to 235 +/- 51 beats per minute (p less than 0.001). Cardiac output increased 23% and blood flow to the brain was maintained. We conclude that the alpha-adrenergic system is important in maintaining the redistribution of cardiac output that occurs in hypoxic fetal sheep.