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Chronically prepared fetal sheep were subjected to 48 h infusions of theophylline, an adenosine antagonist, enprofylline, a xanthine without adenosine antagonism, or saline. Theophylline increased mean (+/- SD) incidence of REM sleep from 49.3 +/- 8.3% to 57.3 +/- 6.7% (p < 0.02) and wakefulness from 1.3 +/- 1.4% to 8.1 +/- 7.1% (p < 0.01). On the first day of theophylline infusion incidence of fetal breathing (FB) increased from 37.9 +/- 8.1% to 53.7 +/- 11.6% of total time (p < 0.002) and from 76.4 +/- 10.2% to 87.6 +/- 10.3% of REM sleep (p < 0.02). Diaphragmatic EMG/min increased from 6.9 +/- 4.0 to 17.3 +/- 13 arbitrary units (p < 0.02). By the second day of infusion, FB had returned to baseline value. Enprofylline and saline had no effect. 125 micrograms phenyl isopropyl adenosine (PIA) i.v. caused fetal apnea that was reduced from 143 +/- 45.5 min on the control day to 39.8 +/- 34.7 min (p < 0.001) during theophylline infusion. Enprofylline and saline had no effect, suggesting that the observed theophylline effect was due to its adenosine antagonism rather than to non-specific xanthine action. We conclude that endogenous adenosine suppresses FB, but since theophylline did not alter the basic relationship between FB and REM sleep it is not primarily responsible for apnea during NREM sleep.

The disposition and cardiovascular effects of ethanol were studied in near-term pregnant sheep and their fetuses after intravenous infusions either to the mother or the fetus. Placental transfer of ethanol from mother to fetus was rapid, but transfer from the fetal to maternal circulation was impaired when ethanol was administered directly to the fetus. Plasma clearance of ethanol was similar from the mother and fetus in utero. In the maternal infusion experiments, both maternal and fetal heart rate increased with plasma ethanol concentration. However, in the fetal infusion experiments, both maternal and fetal heart rate increased with plasma ethanol concentration. However, in the fetal infusion experiments, fetal heart rate was inversely related to plasma ethanol concentrations while maternal mean arterial blood pressure increased with maternal plasma ethanol concentration. Further studies in neonatal lambs are needed to determine if ethanol has adverse effects on hemodynamics when the neonate is separated from its protective intrauterine environment.

To define the dose response of apnea and breathing to morphine we studied 12 fetuses at 116-141 days of gestation using our window technique. We instrumented the fetus to record electrocortical activity (ECoG), eye movements (EOG), diaphragmatic activity (integral of EMGdi), heart rate, carotid blood pressure, and amniotic pressure. Saline and morphine in doses of 0.03, 0.1, 0.5, 1, and 3 mg/kg were injected in random order in the jugular vein of the fetus during low-voltage ECoG. Fetuses were videotaped for evaluation of fetal behavior. We found 1) that saline did not elicit a response; 2) apnea, associated with a change from low- to high-voltage ECoG, increased from 2.2 +/- 1.5 (SE) min in two fetuses at a dose of 0.03 mg to 20 +/- 6.3 min in seven fetuses at 3 mg/kg (P less than 0.005); 3) the length of the breathing responses, associated with a change from high- to low-voltage ECoG, were 15 +/- 1.8 and 135.9 +/- 18.1 min (P less than 0.0005); 4) integral of EMGdi X frequency, an index equivalent to minute ventilation, increased from 1,763 +/- 317 arbitrary units to 10,658 +/- 1,843 at 1.0 mg/kg and then decreased to 7,997 +/- 1,335 at 3.0 mg/kg. These changes were related to a steady increase in integral of EMGdi, whereas frequency decreased at 3 mg/kg. There was an increase in breathing response to morphine plasma concentrations or morphine doses.(ABSTRACT TRUNCATED AT 250 WORDS)

We asked whether the anesthetic requirement (MAC) of fetal lambs is lower than that of pregnant ewes. In five pregnant ewes anesthetized with a subarachnoid block, a fetal foot was withdrawn through a hysterotomy. The ewe then breathed 1.5% halothane and a clamp was applied to the fetal foot at 2-min intervals. We concomitantly obtained arterial blood from previously implanted catheters. When fetal movement in response to clamping the foot ceased, halothane was discontinued and the stimulus and sampling continued until the fetus began to move. Anesthesia was again resumed and continued until movement stopped. Anesthesia was then deepened and MAC was determined in the mother (stimulus--ear clamp). The fetal blood concentrations of halothane at MAC were 48 +/- 28 mg/L; they were 133 +/- 5 mg/L in the mother. This difference was highly significant (P less than 0.001). Calculated end-tidal concentrations were 0.33% and 0.69%, respectively. In two animals delivered by cesarean section, MAC increased progressively over the first 12 h of life. Progesterone levels concomitantly decreased.

The effect of halothane anaesthesia on the foetal responses to acute haemorrhage was studied in chronically prepared ewes. An average of 27.9 ml X kg-1 of foetal blood was withdrawn resulting in an acute 20 per cent decrease in mean arterial pressure which returned toward the control value after 186 seconds. After the blood loss, cardiac output was reduced by 26.1 per cent and heart rate decreased by 26 per cent. Blood flows to the kidneys, placenta and musculoskeletal structures were reduced by 24.7, 38.2 and 35.3 per cent respectively but flow to the brain increased by 30 per cent. Reinfusion of lost blood, corrected flow reductions and the supply to the gastrointestinal organs increased above control values. This study showed that foetal lambs were able to tolerate an acute blood loss under halothane anaesthesia. An adequate perfusion pressure and blood flow to critical organs, such as the brain was maintained by increasing systemic vascular resistance. The compensation, however, was incomplete. Placental blood flow, maternal-foetal gas exchanges, and redistribution of cardiac output away from gastrointestinal tract and skin were impaired.

The kinetic disposition of ethanol was studied in neonatal lambs. The mean plasma clearance rate was 36 mg/l/h, 17% of that in near-term pregnant sheep. Activity increased slowly during the first 5 days of life. Hepatic alcohol dehydrogenase activity in the neonatal lamb was only 7% of that in adult sheep, but was similar to activity in the near-term fetus. Placental enzyme activity was even lower than that in the fetus and neonate, suggesting only a minor role for it in the metabolic disposition of ethanol during pregnancy. The pH optimum for alcohol dehydrogenase was higher in the fetus and neonate (9.6) than in maternal liver or placenta (9.0). The pharmacodynamic consequences of prolonged neonatal exposure to ethanol due to impaired metabolism remain to be explored.