H. O. Morishima

Toxicity of Lidocaine in Adult, Newborn, and Fetal Sheep

The relative central nervous system and cardiovascular toxicity of lidocaine was compared in adult, newborn, and fetal sheep during continuous infusion of lidocaine into the jugular vein at the rate of 2 mg.kg−1.min−1. An identical sequence of toxic manifestations occurred in the adult, newborn, and fetus: convulsions, hypotension, respiratory arrest, and circulatory collapse. Doses necessary to produce these manifestations were highest in fetuses and lowest in adults. For example, in order to elicit convulsions, 5.8 ± 1.8 mg/kg of lidocaine was required in the adults, 18.4 ± 2.2 in the newborns, and 41.9 ± 6.0 in the fetuses. Measurements of lidocaine concentrations in blood demonstrated that these toxic symptoms occurred at levels which were not significantly different among the three groups. The results indicate that fetal and newborn lambs are no more sensitive to lidocaine toxicity than are adult sheep. The fact that the highest doses were required in the fetuses is probably related to the placental clearance of the drug into mothers and better fetal maintenance of arterial PO2 despite convulsions and respiratory arrest (cessation of breathing-like movements).

Pharmacologic effects of nicotine upon the fetus and mother in the rhesus monkey.

Abstract The short-term pharmacologic effects of nicotine upon the cardiovascular performance, acid-base status, and oxygenation of the mother and fetus were investigated in 43 rhesus monkeys in the second half of gestation. Nicotine given intravenously to the mother in either a single dose of 1.0 mg. per kilogram or a constant infusion at a rate of 100 μg per kilogram per minute elicited bradycardia and hypertension which was followed by persistent hypotension. The fetus responded with hypotension and bradycardia (single injection) or tachycardia (constant infusion). Direct intravenous injection of nicotine into the fetus in a single dose of 0.9 to 2.5 mg. per kilogram produced changes similar to those seen in the mother but quite different from those which occurred in the fetus when nicotine was given to the mother. The cardiovascular responses were more pronounced in the mature fetuses than in the less mature ones, indicating that sensitivity to nicotine is related to the development of the autonomic nervous system. Hypoxia and acidosis of the metabolic and respiratory type developed in the more mature fetus following administration of nicotine to the mother while the less mature fetus showed no significant changes in its acid-base status. The adverse effects of nicotine on the fetus following its administration to the mother seem to be due to the combined effects of impaired placental perfusion and a direct action of the transmitted nicotine upon the cardiovascular system of the fetus.

Temperature gradient between fetus and mother as an index for assessing intrauterine fetal condition.

Temperature gradient between fetus and mother (deltaTF-M) was measured in 29 pregnant baboons. Thermocouples were implanted in the fetal esophagus and the maternal colon, and, in some instances, thermistor probes were also placed in the fetal esophagus, scalp, and shoulder muscle. Under steady-state conditions, the fetal temperature was found to be higher than that of the mother. Temperatures in the fetal esophagus, scalp, and shoulder were 0.47, 0.28, and 0.19 degrees C. respectively, higher than those in the maternal colon. There was an increase in deltaTF-M during acute fetal stress induced by asphyxia, secondary to occlusion of the umbilical cord, maternal aorta, or inferior vena cava, or to acutely increased uterine activity. This increase in deltaTF-M most likely reflects impairment of heat dissipation from the fetus to the maternal compartment. A decreased deltaTF-M was observed when the stress on the fetus was subacute and prolonged. This is probably the result of a diminution of heat production by the fetus as the metabolic rate is lowered during prolonged hypoxia. Ten to 30 minutes after the cessation of vital signs of the fetus, the deltaTF-M became zero.

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.

Reduced uterine blood flow and fetal hypoxemia with acute maternal stress: Experimental observation in the pregnant baboon

The effects of maternal hyperexcitability on the fetus were studied in 17 baboons. In the period of agitation, induced by stressful stimulus such as exposure to bright light or by clamping of the toe, the mother exhibited an increase in arterial blood pressure and, in some instances, arrhythmia. These changes were accompanied by an increased uterine activity and reduced uterine blood flow, and resulted in a decrease in heart rate and arterial oxygenation in all fetuses. Fetal recovery was prompt after maternal agitation was terminated, either by removal of the stimulus or by sedation with pentobarbital or nitrous oxide. This sedation also prevented a decrease in uterine blood flow when stress was repeated.

Effect of ethanol upon uterine activity and fetal acid-base state of the rhesus monkey

Abstract Thirteen pregnant monkeys during the third trimester of their gestation were infused intravenously with ethanol (2 to 4 Gm. per kilogram) after a spontaneous onset of labor or following its induction by infusion of oxytocin. In the animals near term administration of ethanol did not alter appreciably either the intensity or frequency of uterine contractions. This pertained both to the animals in spontaneous labor and those stimulated by oxytocin. Ethanol was ineffective even in cases in which the dose was increased to a level which produced depression of maternal respiration. Only in animals before term and in which uterine contractions were irregular, partial suppression of labor was observed. This was associated with fetal hypotension, tachycardia, and acidosis, while only minimal changes were observed in the acid-base state of the mother.

Comparison of the effects of sevoflurane and isoflurane anesthesia on the maternal-fetal unit in sheep

PurposeThe aim of this study was to determine the hemodynamic and blood gas effects of inhalational anesthetics on the maternal-fetal sheep unit. The principal hypothesis, tested in chronically instrumented near-term pregnant ewes, was that sevoflurane anesthesia may be safe and useful for the mother and fetus during pregnancy, compared with isoflurane.MethodsSix chronically instrumented pregnant and 3 nonpregnant ewes were tested repeatedly to establish the minimum alveolar concentration (MAC) for sevoflurane and isoflurane to be used in the hemodynamic and blood gas studies. Progressively increasing concentrations of sevoflurane or isoflurane in oxygen were administered to 12 pregnant ewes. Uterine blood flow, maternal and fetal heart rates, blood pressure, arterial blood gases, and intra-amniotic pressure were subsequently measured.ResultsThe MAC of sevoflurane was 1.52 ± 0.1 15% and 1.92 ± 0.17% in pregnant and nonpregnant ewes, respectively; while the MAC of isoflurane in the pregnant and nonpregnant sheep was 1.02 ± 0.12% and 1.42 ± 0.19%, respectively. In both the sevoflurane and isoflurane groups, changes in maternal and fetal blood gases were minimal during exposure to low-dose (0.5–1.0 MAC) inhaled concentrations. Although uterine blood flow was maintained and the fetus remained well oxygenated at higher concentrations of both agents (2.0 MAC of either agent), the agents produced decreases in maternal and fetal arterial pressure.ConclusionA “low-dose” concentration (0.5–1.0 MAC) of sevoflurane may be safe and useful for both mother and fetus during near-term pregnancy. However, a high concentration (1.5–2.0 MAC) of sevoflurane or isoflurane may induce hemodynamic instability in the mother and fetus when administered.

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.

Systemic toxicity of ropivacaine during ovine pregnancy.

Ropivacaine is a new amide local anesthetic structurally related to bupivacaine and mepivacaine. Its potency and duration of action are similar to those of bupivacaine but its therapeutic index may be greater. Since pregnancy enhances the cardiotoxicity of bupivacaine, the current study was devised to compare the toxicity of ropivacaine in chronically instrumented nonpregnant and pregnant ewes during continuous intravenous infusion of the drug at the rate of 0.5 mg.kg-1.min-1. In all animals, symptoms of local anesthetic toxicity occurred in the usual order--convulsions, hypotension, apnea, and circulatory collapse. There were no significant differences between the two groups of animals in the doses and plasma concentrations of ropivacaine associated with each toxic manifestations. For example, circulatory collapse occurred at a mean dose of 11.3 +/- 1.1 mg.kg-1 in nonpregnant and 12.4 +/- 0.9 mg.kg-1 in pregnant animals, with corresponding plasma concentrations of 7.3 +/- 0.3 and 9.6 +/- 2.1 micrograms.ml-1 (P = not significant). Protein binding of ropivacaine in the concentration range associated with toxic manifestations was similar in sera obtained from nonpregnant and pregnant ewes. In conclusion, ovine pregnancy does not enhance the systemic toxicity of ropivacaine, possibly because of an absence of gestation-related increase in the availability of free drug.

Effect of ropivacaine and bupivacaine on uterine blood flow in pregnant ewes.

The effects of ropivacaine, a new amide local anesthetic, on uterine blood flow and fetal well-being were compared with those of bupivacaine in 10 chronically instrumented pregnant ewes. In random sequence, animals received two intravenous infusions of each drug. The low infusion rate regimens were chosen to result in clinically relevant maternal plasma concentrations of local anesthetics, whereas the more rapid rates of infusions were given to assess the safety of higher maternal drug concentrations. An epinephrine infusion was given to demonstrate the appropriateness of the animal model for the measurement of uterine blood flow. Maternal and fetal heart rates, arterial blood pressure, and the ewes central venous pressure, intraamniotic pressure, and uterine blood flow were recorded continuously. Arterial blood samples were taken from mother and fetus at frequent intervals to determine acid-base status and local anesthetic concentrations. A total of 39 studies were performed. None of the infusions of either local anesthetic resulted in a significant decrease in uterine blood flow or deterioration in fetal condition. The mean maternal plasma concentrations at the end of infusions were as follows: ropivacaine low dose, 1.60 +/- 0.35 micrograms/mL; bupivacaine low dose, 1.55 +/- 0.15 micrograms/mL; ropivacaine high dose, 2.50 +/- 0.37 micrograms/mL; and bupivacaine high dose, 1.83 +/- 0.19 micrograms/mL. Epinephrine infusion resulted in a 25% decrease in uterine blood flow without adverse fetal effects. We conclude that neither ropivacaine nor bupivacaine, as administered in this study, led to any ill effects on uterine artery blood flow or fetal well-being.