Elevated plasma glycoproteins in fetal sheep do not bind basic lipophilic drugs.

We have evaluated the contribution of nonprecipitable N-acetylneuraminic acid (NANA)-containing plasma glycoproteins found in fetal sheep plasma to the binding of three basic lipophilic drugs: propranolol, lidocaine, and methadone. In adult plasma, the measurement of NANA correlates linearly with the bound fraction of these drugs since the NANA concentration almost exclusively represents the alpha 1-acid glycoprotein (AGP) present, and AGP is the predominant binding protein for these drugs. We found that NANA concentrations in fetal sheep are nearly 20 times those of the mother which, if due to AGP, would suggest an equivalent elevation in binding. Our results opposed this hypothesis since the ratios of bound-to-free drug concentrations in fetal plasma were only 20-36% of the maternal values. From this we conclude that NANA-containing glycoprotein concentrations do not appropriately predict the binding of basic lipophilic drugs in fetal plasma, in contrast to what has been found in adult plasma.

Anaesthetic considerations in caesarean section for quadruplets.

A case of a caesarean delivery with epidural analgesia of a term parturient with quadruplets is presented. Maternal considerations of hypotension, respiratory embarrassment and aspiration of gastric content and foetal considerations of prematurity and impaired placental function are discussed relative to the use of general anaesthesia or epidural analgesia.

A comparison of T4 and T7 dermatomal levels of analgesia for caesarean section using the lumbar epidural technique.

We compared analgesia to the T4 dermatomal level with analgesia to the T7 level with and without prophylactic intramuscular administration of ephedrine 25 mg to determine the adequacy and side effects of such analgesia for caesarean section. Unmedicated patients were prehydrated (727 +/- 303 ml of saline solution) and kept in a left lateral tilt position. Sufficient three per cent chloroprocaine was given to obtain analgesia to the T7 (T6-T8) dermatomal level (455 +/- 128 mg) or to the T4 (T3-T5) dermatomal level (758 +/- 168 mg). Patients who received analgesia to the higher level required less narcotic than those who received analgesia to the lower level (21 per cent versus 48 per cent) (p less than 0.05). The incidence of hypotension in patients with analgesia at the T4 level was 21 per cent for those receiving ephedrine and 64 per cent for those who did not receive ephedrine (p less than 0.05). Intramuscular administration of ephedrine 25 mg was not associated with increased plasma levels of norepinephrine, epinephrine or dopamine. There was no difference in Apgar score, behavioural test scores, neonatal acid-base status or oxygenation in children of mothers in the different groups. We conclude that a T4 dermatomal level of analgesia combined with intramuscular administration of ephedrine 25 mg, provides more maternal comfort than a T7 level of analgesia does, with or without ephedrine, and is without significant maternal or foetal side effects.

Nitroglycerin therapy for phenylephrine-induced hypertension in pregnant ewes.

Obstetrical situations in which endogenous or exogenous vasoactive amines precipitously increase maternal blood pressure and decrease uterine blood flow may be associated with increased maternal morbidity and mortality and with development of fetal acidosis and distress. We examined the effectiveness of nitroglycerin in lowering maternal blood pressure and increasing uterine blood flow during the infusion of the alpha-adrenergic agent phenylephrine. During the phenylephrine infusion maternal blood pressure increased 20%, cardiac output decreased 25%, total peripheral vascular resistance increased 60%, pulmonary arterial pressure increased 40%, uterine blood flow decreased 50%, and fetal arterial pH decreased from 7.37 to 7.30 (p less than 0.05). While maintaining the phenylephrine infusion at a constant rate, the infusion of nitroglycerin rapidly returned maternal systemic pressure and pulmonary arterial pressure to control values, decreased total peripheral resistance to 18% above control, increased cardiac output to 12% below control, increased uterine artery blood flow to 30% below control, and increased the fetal arterial pH from 7.30 to 7.35 (p less than 0.05). It is concluded that maternal hypertension resulting from intense alpha-adrenergic stimulation may be treated rapidly and effectively by the intravenous infusion of nitroglycerin with a partial restoration (20%) of uterine artery blood flow toward control.

Pharmacokinetics of magnesium sulfate in the sheep model.

The pharmacokinetic parameters of MgSO4 were followed in the pregnant sheep model following intravenous dosages of MgSO4 comparable to those used in the therapy of the preeclamptic woman. Hemodynamic parameters, including maternal arterial pressure, central venous pressure, systemic vascular resistance, pulmonary artery pressure, heart rate, cardiac output, cardiac index, rate pressure product, stroke volume, stroke index, blood gases, fetal arterial pressure, heart rate, and blood gases, all remain stable during the infusion of MgSO4. Biochemical changes accompanying MgSO4 infusion in these doses were evaluated. It was found that the fetal serum levels of MgSO4 were approximately 70% of those in the mother. The MgSO4 was rapidly excreted into the maternal urine and 8.9% of the MgSO4 infused was cleared by 2 hr after the termination of the infusion. MgSO4 was also excreted by the fetus into amniotic fluid. It was found that a minimum dosage of 1 mg/kg/hr of magnesium was required to achieve a magnesium level in maternal serum at the lower limit of the therapeutic range of 4 mEq/L.

Placental passage and uterine effects of fentanyl.

Using the chronic maternal-fetal sheep preparation, 27 pregnant ewes were studied to determine the effects of intravenous fentanyl on maternal and fetal physiology, with particular reference to its placental passage, and its effects on uterine blood flow and uterine tone. Three doses of fentanyl were studied--50, 75, and 100 micrograms. Maternal and fetal arterial blood was collected for determination of fentanyl levels. All blood levels, both maternal and fetal, were normalized to the 50-micrograms dose. The maternal normalized blood levels were found to fit a biexponential equation describing a two-compartment open model. The half-life of the maternal elimination phase was 42 +/- 7.0 min with an overall elimination constant (K) of 0.21 min-1. Maternal plasma fentanyl levels decreased very rapidly in the first 10 min after injection, at which time only 9% of the peak value remained. Fentanyl was detectable in fetal blood as early as 1 min and levels peaked at 5 min. Once equilibrium was established between maternal and fetal blood, the maternal levels remained 2.5 times those of the fetal level from 5 min to 60 min after drug injection. Both maternal and fetal drug levels declined in an approximately parallel fashion. No significant deleterious changes were seen in any maternal or fetal cardiovascular or acid-base parameters, and uterine blood flow and uterine tone were also unaffected (P greater than 0.05).

The maternal and fetal cardiovascular effects of epidural fentanyl in the sheep model.

Since the demonstration of opiate receptors in the spinal cord in the mid-1970s, investigators have been looking for the most effective epidural narcotic. With the use of the chronically catheterized maternal sheep model, we injected two different doses of preservative-free fentanyl (50 and 100 micrograms) into the epidural space. No statistically significant changes were observed, either in maternal or fetal arterial pressure and acid-base status or in maternal central venous pressure, systemic and pulmonary vascular resistance, cardiac output, and intrauterine pressure (p greater than 0.05). With a dose of 50 micrograms of fentanyl, maternal levels of fentanyl peaked at 60 minutes (50 pg/ml) and the fetal levels of fentanyl peaked at 45 minutes (20 pg/ml). With the 100 micrograms dose of fentanyl, maternal levels of fentanyl peaked at 45 minutes (230 pg/ml) and the fetal levels peaked at 15 minutes (110 pg/ml). We conclude that the injection of 50 and 100 micrograms of fentanyl into the maternal epidural space has no adverse effects on mother or fetus in the sheep model.

Cardiovascular effects and placental passage of dantrolene in the maternal-fetal sheep model.

Using the chronic maternal-fetal sheep preparation, nine pregnant ewes were studied to determine the effects of intravenous dantrolene sodium on maternal and fetal physiology, with particular reference to its placental passage, and its effects on uterine blood flow and uterine tone. Two doses of dantrolene sodium were studied: 1.2 mg/kg and 2.4 mg/kg. After 2.4 mg/kg, maternal cardiac output increased 29% (P less than 0.05) after 1 min and returned to normal after 30 min. Maternal mean arterial pressure increased 13% after 1 min and remained significantly elevated (P less than 0.01) for 3 h. No significant changes (P greater than 0.05) were observed in maternal heart rate, uterine artery blood flow, or central venous pressure. Maternal arterial pH declined from 7.42 to 7.39 (P less than 0.01) after 1 min and returned to baseline values after 10 min. Fetal heart rate decreased 24% (P less than 0.01) after 3 min and returned to normal after 10 min; the mean fetal arterial pressure remained unchanged (P greater than 0.05). Fetal arterial pH declined from 7.29 to 7.27 (P less than 0.05) after 1 min and remained significantly decreased for 120 min. Similar changes of lesser magnitude and shorter duration were seen following the 1.2 mg/kg dose. Maternal levels of dantrolene were less than 3 micrograms/ml. Although an equilibrium between maternal and fetal plasma dantrolene concentrations was apparent at 5 min, the fetal levels of dantrolene were approximately 10% of the mother's. The results indicate that the administration of intravenous dantrolene at 1.2 mg/kg or 2.4 mg/kg has no clinically significant adverse effect on mother or fetus in the sheep model.

Uterine blood flow and plasma norepinephrine changes during maternal stress in the pregnant ewe.

Because maternal stress may adversely affect the fetus, the authors tested the effects of brief episodes (15-60 sec) of maternal stress in 18 awake pregnant ewes. Maternal agitation and stuggling occurred either following non-painful stimuli such as loud noises or sudden movements of personnel (ten animals) or following the brief application of the ewe's skin of a uniform electrical stimulus of 30 volts with a frequency of 167 Hz for 30-60 sec (eight animals). Stimulation of either type produced a 45-50 per cent increase in mean maternal arterial blood pressure and a concomitant 32-52 per cent decrease in uterine blood flow (P less than 0.05). The decreases in uterine blood flow were brief, lasting less than 3 min, and were not associated with fetal asphyxia. Maternal plasma norepinephrine levels were measured following electrically induced maternal stress and were increased 25 per cent. The authors conclude that maternal stress may decrease uterine blood flow secondary to release of endogenous norepinephrine.

The maternal and fetal cardiovascular effects of epidural morphine in the sheep model.

Interest in the use of epidural narcotics for analgesia has been widespread since the demonstration of opiate receptors in the spinal cord in the mid nineteen-seventies. Recently, several studies have attempted to evaluate the effectiveness of epidural narcotics for the relief of pain in labor and after cesarean section. Using the chronically catheterized maternal-fetal sheep model, we injected 5 mg of preservative-free morphine into the epidural space. No statistically significant changes were observed, neither in maternal or fetal arterial pressure and acid-base status, nor in maternal central venous pressure, systemic and pulmonary vascular resistance, cardiac output, or intrauterine pressure (p greater than 0.05). There was a significant, although small, decrease in maternal heart rate (8%) and uterine blood flow (9%) at 120 minutes (p less than 0.05), and then a return to control values. The maternal levels of morphine peaked at 15 minutes (29 ng/ml) and the fetal levels of morphine peaked at 90 minutes (3 to 4 ng/ml). We conclude that the injection of 5 mg of morphine into the maternal epidural space has no adverse effect on mother or fetus in the sheep model.

Ketamine, catecholamines, and uterine tone in pregnant ewes.

Blood levels of ketamine, measured in both mother (1,230 ng/ml at 1 minute) and fetus (470 ng/ml at 1 minute) illustrate not only rapidly decreasing levels of the drug after its intravenous administration but also its transplacental passage. Concentrations of norepinephrine, epinephrine, and dopamine did not change in the mother or fetus after ketamine, with the exception of maternal levels of epinephrine, which were significantly higher at 45 minutes than control values (p less than 0.05). Maternal effects of ketamine consisted of increases in mean arterial pressure (7% p less than 0.05), cardiac output (16% p less than 0.01), and respiratory acidosis, all of which were slight and transitory. Although resting uterine tone increased (39% p less than 0.01), the uterine blood flow remained constant. None of the physiologic alterations could be correlated with changes in catecholamine levels. Therefore, the cardiovascular and uterine stimulating properties of ketamine at a dose of 0.7 mg/kg are small and are not the result of increased catecholamine levels in plasma. Further studies are necessary to elucidate the mechanism.

Enflurane analgesia in obstetrics.

The effects of enflurane analgesia (approximately 0.5%) were studied in 55 patients during the second stage of normal vaginal delivery and were compared with effects of nitrous oxide (approximately 40%) in 50 similar patients. The enflurane and oxygen mixture was rated satisfactory by 89% of the mothers and 80% of the anesthesiologists. These ratings did not differ significantly from those for nitrous oxide. Obstetricians, however, rated the enflurane and oxygen mixture superior. The newborns of mothers receiving both agents wee vigorous and comparable when assessed by Apgar scores and cord blood gas tensions. The estimate of blood loss was similar in both groups. Serum inorganic fluoride concentrations in the mother after anesthesia were not significantly increased from preanesthetic levels with either agent. There was no biochemical evidence of renal toxicity. In neonates of mothers given enflurane, the mean umbilical cord concentration of serum inorganic fluoride ions was 2.4 +/- 0.2 micromoles/L, a value well below that associated with nephrotoxicity.