Magnesium and bupivacaine-induced convulsions in awake pregnant rats.

BACKGROUND: Magnesium sulfate (MgSO(4)) is widely used for the treatment and prevention of convulsions associated with preeclampsia. The aim of this study was to determine whether it alters the dose of bupivacaine required to produce convulsions in awake pregnant rats. METHOD: Twelve pregnant rats were pretreated with an intravenous infusion of either MgSO(4) or saline. Following 2 h of the pretreatment, bupivacaine was concomitantly infused in all animals until the onset of convulsions. Mean arterial pressure (MAP) and heart rate (HR) were monitored throughout. Serial arterial samples were obtained during the infusion. At the onset of convulsions, fetuses were delivered and maternal and fetal blood, as well as various tissue samples, were obtained. All samples were assayed for bupivacaine and magnesium concentrations. RESULTS: Maternal MAP and HR decreased significantly shortly after the initiation of MgSO(4), while saline did not affect these measurements. Baseline concentrations of magnesium in plasma were similar in both MgSO(4) and saline groups; magnesium increased significantly during the infusion of MgSO(4). The dose (mean+/-SD) of bupivacaine required to produce convulsions in the animals receiving MgSO(4) was significantly larger (10.2+/-1.9 mg/kg) than that in the saline group (5.9+/-1.0 mg/kg) (P<0.05). As a consequence, bupivacaine concentrations in the brain and liver at the onset of convulsions were greater in animals receiving MgSO(4) (16.0+/-8.4 and 18.2+/-4.3 microg/g wet weight, respectively) than in those given saline (12.1+/-2.2 and 9.9+/-2.0 microg/g wet weight, respectively). Fetal bupivacaine concentrations at the onset of convulsions in the MgSO(4) group were also higher than those in saline group. However, the rate of placental transfer of this drug was similar between MgSO(4) and saline animals. CONCLUSION: This study demonstrates that the clinically used concentration of magnesium sulfate increased the threshold of bupivacaine-induced convulsions in awake rats.

The effect of diazoxide on uterine blood flow in pregnant sheep.

Diazoxide, a labor inhibiting agent, was administered intravenously at various rates to seven pregnant, near-term sheep to evaluate its effect on cardiovascular and uterine hemodynamics. Uterine blood flow was measured with electromagnetic flow transducers. Rapid administration of diazoxide resulted in a profound maternal tachycardia with hypotension, an increase in uterine vascular resistance, and a significant decrease in uterine blood flow. With slow infusion of the drug, the changes in heart rate and blood pressure were minimized, uterine vascular resistance was decreased, and uterine blood flow was maintained. Therefore, slow infusion appears to be the preferred method for inhibiting labor with diazoxide.

Prolonged infusion of diazoxide in the management of premature labor in the baboon.

The management of premature labor by the prolonged infusion of diazoxide was evaluated in 33 pregnant baboons. The drug was administered intravenously to the mother with an average rate of 0.065 mg/kg/min for 4 hours. Mild to moderate spontaneous labors were significantly inhibited by diazoxide without jeopardizing the fetus. Diazoxide produced a significant increase in maternal heart rate, but its effect on fetal circulation was minimal. Fetal acid-base state and arterial oxygenation remained essentially unchanged throughout the period of observation. Intravenous administration of this drug to the fetuses caused only mild cardiovascular changes irrespective of its preexisting conditions. Thus, a slow intravenous infusion of diazoxide to the mother in a low dosage appears to be of value for inhibiting the uterine activity in early labor, without interfering with the fetal well-being.

Effect of terbutaline on cardiovascular state and uterine blood flow in pregnant ewes.

The cardiovascular and uterine hemodynamic effects of terbutaline, a beta-adrenergic receptor stimulant and labor inhibiting agent, were evaluated in the chronically instrumented, near-term pregnant ewe. The administration of terbutaline in the dose range required for labor inhibition in this species resulted in a mild maternal tachycardia and increase in pulse pressure without significant changes in uterine blood flow; uterine vascular resistance; or systolic, diastolic, or mean blood pressures. With infusion rates of terbutaline in excess of those required for labor inhibition, significant increases in maternal heart rate, pulse pressure, and systolic blood pressure were observed. Diastolic blood pressure decreased significantly during the higher infusion rates; however, uterine blood flow was unaffected. The minimal cardiovascular and uterine blood flow was unaffected. The minimal cardiovascular and uterine hemodynamic effects noted with the administration of terbutaline in the dose range necessary for labor inhibition indicate that this agent may possess advantages over several others currently in use for the treatment of premature labor.

Effects of terbutaline on the pregnant baboon and fetus.

The effects of terbutaline on the mother and fetus were evaluated in 8 near-term pregnant baboons. Significant suppression of postoperative spontaneous and oxytocin-augmented uterine activity was achieved with infusion rates of 0.36 and 0.56 microgram/kg/min, respectively. Maternal and fetal blood pressure and acid-base states as well as fetal heart rate were unaffected by the administration of terbutaline to the mother, but a mild maternal tachycardia was observed. Both maternal and fetal blood glucose increased during terbutaline infusion. Direct administration of terbutaline to the fetus did not alter the fetal cardiovascular or acid-base state. It is concluded that in the baboon, terbutaline is an effective tocolytic agent with minimal untoward effects on either mother or fetus.

Dexmedetomidine decreases extracellular dopamine concentrations in the rat nucleus accumbens.

The effects of dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, on extracellular dopamine (DA) concentrations in the nucleus accumbens of awake rats were collected via in vivo cerebral microdialysis and measured using HPLC with electrochemical detection. The administration of dexmedetomidine (DEX) at a low dose (2 microg/kg bolus i.v. over 2 min followed by a continuous infusion of 0.1 microg/kg per min) and a high dose (20 microg/kg bolus i.v. over 2 min followed by a continuous infusion of 1 microg/kg per min), significantly decreased extracellular dopamine concentrations in the nucleus accumbens. The observed decrease was dose-dependent, occurring sooner and to a greater magnitude in the rats receiving a high dose of DEX. This inhibitory modulation of accumbal dopamine was receptor-specific, as the decrease in extracellular DA produced by DEX was no longer evident following pre-treatment and co-infusion with the highly selective alpha(2)-adrenoceptor antagonist, atipamezole (ATZ). Thus, these data suggest that adrenoceptor agonists and antagonists may modulate dopaminergic neurotransmission via mechanisms that are specific to the alpha(2)-adrenoceptor.

Placental transfer of (3H)-GM1 and its distribution to maternal and fetal tissues of the rat.

The demonstration that ganglioside GM1 pretreatment reduced the ethanol induced neurobehavioral effects in adult pups exposed to ethanol in utero, prompted study to examine whether GM1 crosses the placenta and penetrates fetal tissues. The present results indicate that 3H-galactose labeled GM1 not only passes the placenta but also served as a substrate for the synthesis of polysialogangliosides, and remained in various tissues up to 48 h after maternal (3H)-GM1 administration.

Dose-related differences in the distribution of cocaine in the maternal-fetoplacental compartments in rats.

Our goals were to examine whether a high dose of cocaine to causing CNS toxic manifestations in the pregnant rats influences the delivery of cocaine to the fetus, and whether the non-placental compartments have a significant role in the distribution of cocaine to the fetal tissues. Either a low or high dose of cocaine was infused intravenously to near-term pregnant rats. Arterial blood pressure and heart rate were monitored. Cardiac output and uterine and placental blood flows were measured by using radiolabeled microspheres. Plasma and tissue samples were obtained from the mother, placenta, and fetus and analyzed for cocaine and its metabolites via capillary gas chromatography/mass spectrometry. A high dose of cocaine induced convulsions that were accompanied by increased arterial blood pressure and decreased uteroplacental blood flow. However, the distribution pattern of cocaine and metabolites in the mother and fetus were similar between the high and low dose groups. Considerable amounts of cocaine and its metabolites were in the placenta. Previously ignored non-placental tissues, such as the amnion and myometrium appear to be a significant source for cocaine accumulation in the fetus.

Long-term intravenous perinatal cocaine exposure on the mortality of rat offspring.

To examine the effects of chronic perinatal cocaine exposure, cocaine was administered intravenously throughout pregnancy and the postpartum period to the rat. Pregnant rats were divided into five groups: nontreated (naive); normal saline control (saline); cocaine first generation (cocaine); saline in the first generation and cocaine in the second generation (Sal-2G); and cocaine in both first and second generations (Coc-2G). The rats receiving cocaine in the second generation (Sal-2G and Coc-2G) were offspring of the saline and cocaine group, respectively. All cocaine-treated groups received cocaine 2 mg/kg/day intravenously (IV), and the saline group received normal saline 0.2 ml/day IV from GD 2 to the 21st day postpartum. Mean perinatal mortality was greater in all pups exposed to cocaine in utero during gestation; Cocaine (6.4%); Sal-2G (5.6%); Coc-2G (11.4%) groups than in the noncocaine groups (3.2%, 1.3%). Weight gain, physical, and neurological developments of the offspring were not affected. It was concluded that perinatal cocaine exposure had an increased perinatal mortality even at doses approximately 10 times lower than those previously reported, which were administered by extravascular routes. These findings indicate the importance of the route of drug administration in perinatal cocaine research.

The disposition of benzoylecgonine in maternal and fetal rats.

We tested our hypothesis that pregnancy alters the pharmacokinetic profile of benzoylecgonine, and that this metabolite accumulates in the fetus longer than in the mother. Chronically catheterized near-term pregnant and nonpregnant female Sprague-Dawley rats received an intravenous infusion of benzoylecgonine over a period of 30 min. Adult or fetal blood and tissue samples were obtained either at the end of the infusion or 6 h postinfusion for analysis of benzoylecgonine and other cocaine metabolite concentrations via gas chromatography/mass spectrometry (GC/MS). Pregnancy altered benzoylecgonine pharmacokinetics. At the end of the infusion, benzoylecgonine concentration in the fetal plasma was markedly lower than in the maternal plasma with a fetal/maternal ratio of 0.14+/-0.01. A significantly lower concentration of benzoylecgonine was found in both maternal and fetal brain at 0 h postinfusion, with tissue/plasma concentration ratios of 0.04 and 0.24, respectively, suggesting that benzoylecgonine does not readily penetrate into the brain. At 6 h, the fetal concentration of benzoylecgonine was significantly higher than in the corresponding maternal blood and tissues. Ecgonine methyl ester, a metabolite of benzoylecgonine was found in the maternal liver, but not in the fetus. In addition, the amniotic fluid concentration of benzoylecgonine became significantly higher in the 6-h postinfusion samples as compared to the end of infusion value, suggesting that repeated intrauterine exposure to cocaine may cause an accumulation of benzoylecgonine in the fetus.

Effect of standard diluted epinephrine infusion on epidural anesthesia in labor.

BACKGROUND AND OBJECTIVES: Epinephrine is used with local anesthetics to prolong the duration of epidural analgesia and decrease the peak plasma concentrations of local anesthetics. However, the duration of labor may be prolonged because epinephrine reduces uterine activity. We designed a prospective, randomized, and doubleblind study to examine the effects of epinephrine infusion on the quality of analgesia and plasma concentration of local anesthetic, as well as the effect on the uteroplacental circulation, duration of the first or second stage of labor, and fetal outcome. METHODS: Twenty-four parturients received continuous epidural bupivacaine 0.125% (8 mL/h) combined either with epinephrine (40 microg/h) (n = 12) or without epinephrine (n = 12) for analgesia during labor. If patients requested additional analgesia, a bolus of 1% or 1.5% lidocaine (6 to 10 mL) was given. RESULTS: Only the plain bupivacaine group required additional lidocaine. However, epinephrine infusion prolonged the median (range) duration of the second stages of labor: 69 (21 to 231) minutes with epinephrine group versus 31 (8 to 99) minutes without epinephrine group (P < .05), and decreased pH in umbilical artery at the time of delivery. Epinephrine infusion did not change the uterine and umbilical blood flow, which were determined as the resistance indices. Changes in the fetal heart rate and Apgar score were also comparable. Epinephrine significantly reduced the umbilical venous to maternal arterial bupivacaine concentration (P < .05). CONCLUSIONS: A standard diluted epinephrine infusion (40 microg/h) into epidural space decreased anesthetic requirements. The possibility of the prolonged duration of labor remains a problem.

The effects of single and fractionated doses of mepivacaine on the extent of thoracic epidural block.

BACKGROUND AND OBJECTIVES: The effects of single and fractionated doses of local anesthetic on the extent of thoracic epidural blockade has not yet been determined. This single blinded and randomized study was designed to examine the effects of the initial dose and timing of the additional dose of local anesthetic on the sensory block level of the thoracic epidural anesthesia. METHODS: Eighty-nine patients, who received thoracic epidural anesthesia followed by general anesthesia, were randomly divided into 4 groups: Group I received 5 mL of mepivacaine; Group II, 10 mL; Group III, 5 mL twice, with an interval of 5 minutes; and Group IV, 5 mL twice, with an interval of 10 minutes. After 15 minutes of either a single bolus or after the second bolus drug administration, the level of sensory block to coldness and pinprick were determined by an individual who was uninformed of the groups. RESULTS: The median (range) number of spinal segments with sensory block to coldness in Groups I, II, III, and IV were 8 (5 to 12), 12 (7 to 17)*, 11 (7 to 16)*, and 9 (6 to 17)# (*P < .05 v Group I, #P < .05 v Group II), respectively. The number of segments with sensory block to pinprick in the 4 groups were 7 (4 to 11), 11 (6 to 14)*, 10 (6 to 14)*, and 9 (4 to 16)*#, respectively. These differences were mainly due to the differences of the lower sensory block level. CONCLUSIONS: We concluded that the timing of the second administration of mepivacaine was one of the factors for the spread of the drug into thoracic epidural space. The more extensive sensory block level occurred by shorter time interval of the second drug administration.

Toxicity and distribution of lidocaine in nonasphyxiated and asphyxiated baboon fetuses.

The dosage and blood concentration of lidocaine required to produce central nervous and cardiovascular system toxicity in both nonasphyxiated and asphyxiated fetuses were determined in ten pregnant baboons with fetuses of average gestation of 158 days (term, 185 days). Lidocaine was infused into the fetal jugular vein until cardiac arrest occurred, following which fetal brain, heart, lungs liver and kidneys were obtained. Mean dosage and blood concentration of lidocaine associated with seizures were 9.4 mg/kg and 15.2 micrograms/ml, respectively, in the nonasphyxiated fetuses, and 3.9 mg/kg and 5.6 micrograms/ml, respectively, in the asphyxiated ones. The dosage and blood concentration of the drug required to produce cardiac arrest were significantly higher in the nonasphyxiated group (35 mg/kg and 269 micrograms/ml, respectively) compared to the sphyxiated group (9 mg/kg and 40 micrograms/ml, respectively). Tissue-plasma ratios of lidocaine were significantly higher (P less than 0.05) in the brain, heart, and liver of the asphyxiated fetuses as compared with the nonasphyxiated ones. The relative proportion of the injected dose found in the organs was also higher (P less than 0.05) in the asphyxiated group. These results indicate that the increased sensitivity of the asphyxiated fetus to lidocaine may be related in part to a greater uptake of local anesthetics by the fetal organs.

[The effect of cocaine on uterine contractions in the rat].

The abuse of cocaine during pregnancy has become a major problem in substance abuse in the U.S.A. Although cocaine often induces preterm labor, little is known about the effect of this drug on uterine contractions. In 23 pregnant (P) and 23 nonpregnant (NP) rats, a carotid artery and jugular vein were catheterized, and a balloon catheter was inserted into the uterine cavity 24 hrs prior to the study. Arterial blood pressure, heart rate, intrauterine pressure were recorded throughout the study. Uterine contractions were expressed in Montevideo Units (M.V.U.). Cocaine (1.25-20 mg/kg) or saline was administered intravenously to test its toxicity and the effect on uterine contractions. A 1.25 or 2.5 mg/kg dose of cocaine did not produce toxic symptoms, but 2.5 mg/kg resulted in a marked increase in M.V.U. in both P and NP. In P, the maximum change in M.V.U. was as high as 250% from the baseline value, twice as much as that observed in NP. Mean arterial blood pressure increased 15% on the average and heart rate decreased 10%. This study indicates that a non-toxic dosage of cocaine stimulates uterine contractions, and pregnancy enhances this effect.

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.

The influence of maternal psychological stress on the fetus.

The effects of maternal agitation, induced by exposure to bright light, upon fetal well-being were studied in pregnant rhesus monkeys at 139 to 148 days of gestation. Fetuses were classified as "healthy" or "asphyxiated" according to their initial acid-base state. Following variable periods of maternal excitement, a decrease in heart rate and arterial oxygenation was seen in all fetuses. Recovery occurred more rapidly in the healthy group, after maternal sedation was achieved, either by removing the stimulus or by additional administration of pentobarbital, 5 to 20 mg. intravenously. The beneficial effects of meternal sedation on the fetus have thus been demonstrated.

Effects of endotoxin on the pregnant baboon and fetus.

Effects of E. coli endotoxin upon uterine activity and maternal and fetal condition were studied in four pregnant baboons and their fetuses. Uterine activity increased significantly following administration of endotoxin to the mother. Endotoxin also produced maternal circulatory collapse, severe acidosis, and profound fetal asphyxia resulting in death. Death also occurred in three of the four mothers within 24 hours without amelioration of their conditions.

Etidocaine toxicity in the adult, newborn, and fetal sheep.

The systemic toxicity of etidocaine was compared in adult, newborn, and fetal sheep during continuous infusion of the drug into the jugular vein at the rate of 0.5 mg X kg-1 X min-1. All recipients exhibited symptoms of toxicity in the following order: convulsions, hypotension, respiratory arrest, and circulatory collapse. The dose of etidocaine required to produce CNS and cardiovascular toxicity was significantly different among the three age groups, being the highest in the fetus and the lowest in the adult. In contrast, no significant difference in etidocaine blood concentrations at the onset of each toxic symptom was observed among the groups except that convulsions and hypotension occurred at lower blood levels in the fetus as compared with the newborn and adult. Comparisons of etidocaine blood concentrations associated with the onset of convulsions and circulatory collapse (CC/CNS ratio) with those of lidocaine reported previously indicate that a narrower margin exists in adults and newborn following administration of etidocaine.

Pregnancy alters the hemodynamic responses to cocaine in the rat.

To test our hypotheses that the hemodynamic response to cocaine may be altered during pregnancy, cocaine (0.33 mg/kg/min) was infused intravenously to chronically catheterized pregnant and nonpregnant female rats. Cardiac output and regional blood flow were measured, and cocaine concentrations in plasma and tissues, as well as plasma cholinesterase activity were determined. Results were compared between pregnant and nonpregnant groups. Cocaine produced a significant decrease in heart rate, accompanied by a fall in cardiac output, and decreased cerebral, myocardial, and placental blood flow in pregnant rats. The plasma cocaine concentration in pregnant animals was lower than that of nonpregnant ones, but tissue concentrations were similar in both groups. These results indicate that pregnancy enhances cardiovascular responses to subtoxic doses of cocaine. There was little placental transfer of cocaine with a fetal to maternal plasma concentration ratio of 0.28.

Increased uterine activity and fetal deterioration during maternal hyperthermia.

The role of hyperthermia in the absence of infection has been investigated in the pregnant baboon. Twenty-three near term animals were used. Catheters were placed in maternal and fetal arteries and thermocouples implanted in maternal colon and fetal esophagus. Maternal temperature was raised to between 41 and 42 degrees Centigrade (C.), by applying external heat. The temperature gradient between fetus and mother (delta T F-M) was 0.47 degree C. under steady-state conditions with maternal temperature at 38 degrees C. and rose to 0.75 degree C. at 42 degrees C. Hyperthermia caused a twofold increase in uterine activity; a metabolic acidosis developed in the mother and a profound acidosis and hypoxia developed in the fetus. There was also a marked fall in blood pressure and an increase in heart rate in both mother and fetus; late deceleration of the fetal heart rate occurred at a higher oxygen level and pHa than has been observed under normothermic conditions.