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Biomedical subjects

A M Rudolph

Publications and source records attributed to A M Rudolph.

At least 91 records · Page 5Linked to original sources
PubMed1986

Pharmacokinetic studies of the disposition of acetaminophen in the sheep maternal-placental-fetal unit.

Pharmacokinetic studies of the disposition of acetaminophen were carried out in 12 chronically catheterized pregnant sheep. Acetaminophen was infused separately into the mother and the fetus on two occasions to steady state. The transplacental clearances from both sides of the placental membrane and the nontransplacental clearances in both the mother and the fetus were then determined using an indirect method, a two-compartment open pharmacokinetic body model. The placental clearance and the nontransplacental clearances were also determined independently by direct methods by measuring the extraction ratio and urinary clearances in both the mother and fetus. Model dependent (indirect) and model independent (direct) methods yielded similar results. Neither acetaminophen glucuronide nor acetaminophen sulfate was transferred across the placenta. However, acetaminophen was transferred in both directions exclusively via a passive diffusion mechanism with an extraction ratio of 0.12 across the placenta. Neither glucuronidation nor sulfation capacity was found in the sheep placenta. However, the conjugation pathways accounted for nearly all the nontransplacental elimination of acetaminophen in the mother. Both transplacental clearance and nontransplacental clearance of acetaminophen in the fetus increased with gestational age. The glucuronidation and sulfation activities were determined in the fetus in utero and found to be 16 and 74% of the respective activities in the pregnant ewe on a body weight basis. The two conjugation clearances did not increase significantly with the gestational age of the fetus during the third trimester.

Acetaminophen↗
PubMed1985

The cardiovascular and metabolic effects of halothane in normoxic and hypoxic newborn lambs.

Oxygen consumption, cardiac output, and tissue oxygen delivery were measured in normoxic and hypoxic 1-3-day-old lambs during the following six conditions: 1) (control) paralysis with pancuronium and controlled ventilation with room air; 2) paralysis, controlled ventilation and hypoxia (PaO2 = 30 +/- 3 mmHg, [SD]); 3) paralysis, controlled ventilation with room air and 0.5 MAC halothane; 4) paralysis, controlled ventilation, hypoxia, and 0.5 MAC halothane; 5) paralysis, controlled ventilation with room air, and 1 MAC halothane; and 6) paralysis, controlled ventilation, hypoxia, and 1 MAC halothane. During normoxia, 0.5 and 1 MAC halothane decreased total body oxygen consumption, cardiac output, and arterial blood pressure. One-half MAC halothane had no effect on blood flow to any organ except muscle, whose flow decreased 64%. One MAC halothane decreased blood flow to the brain, heart, kidney, muscle, and gut. Both concentrations of halothane decreased serum catecholamine levels below control values and prevented hypoxia from increasing catecholamine levels. Hypoxia decreased the oxygen consumption about 40% from the immediately previous normoxic value, whether the animals were anesthetized or not. Tissue oxygen delivery followed changes in blood flow. The cardiac output, arterial blood pressure, and heart rate of anesthetized, hypoxic animals were not different from those in the previous normoxic condition. Halothane did not prevent redistribution of blood flow to the heart and brain of hypoxic animals, nor did halothane prevent hypoxic pulmonary vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Metabolic responses of the kidney in fetal sheep: effect of acute and spontaneous hypoxemia.

To examine the effects of hypoxemia on carbohydrate and O2 consumption by the fetal kidney, we inserted catheters into the descending aorta, inferior vena cava, and left renal vein of 14 fetal sheep at 120-130 days gestation. Three to nine days after surgery, nine fetuses had an arterial PO2 of 22 +/- 2 mmHg and O2 content of 2.68 +/- 0.65 mM. In these fetuses, the kidneys consumed O2 (107 +/- 21 mumol X min-1 X 100 g-1, mean +/- SD) and lactate (14 +/- 9.6 mumol X min-1 X 100 g-1) but produced glucose (5.6 +/- 6.5 mumol X min-1 X 100 g-1; 95% confidence limits, 0.62 and 10.5). When acute hypoxemia was induced by decreasing maternal fractional inspired O2 (FIO2) to 0.09, renal O2 consumption fell slightly (to 82 +/- 21 mumol X min-1 X 100 g-1), and there was net glucose uptake and net lactate release. A group of five fetuses was spontaneously hypoxemic 3-5 days after surgery and had an arterial PO2 of 14 +/- 2 mmHg and O2 content of 1.99 +/- 0.51 mM. Renal blood flow and O2 consumption were greater in these fetuses than in the normoxemic fetuses. There was net lactate uptake and no net flux of glucose across the renal circulation. These results demonstrate that renal metabolism of carbohydrate is altered by changes in fetal oxygenation.

Animals↗
PubMed1985

Fetal atrioventricular valve insufficiency associated with nonimmune hydrops: a two-dimensional echocardiographic and pulsed Doppler ultrasound study.

Of 466 fetuses who underwent cardiac ultrasound examination with cross-sectional and M mode echocardiography and pulsed Doppler ultrasound and in whom we were able to follow the natural history, 12 were found to have atrioventricular valve insufficiency and nonimmune hydrops. Eleven fetuses (all of whom had structural heart disease) died either in utero or during the early postnatal period. In the one surviving hydropic fetus with supraventricular tachyarrhythmia and atrioventricular valve regurgitation but without structural heart disease, all the abnormalities disappeared on treatment with digoxin and verapamil. Seven fetuses who had atrioventricular valve insufficiency but did not develop nonimmune hydrops all survived pregnancy and the early neonatal period. The syndrome of atrioventricular valve insufficiency, nonimmune hydrops, and structural heart disease has a poor prognosis. The hydrops in this instance reflects fetal cardiac failure related to venous hypertension and low colloid oncotic pressure.

Echocardiography↗
PubMed1985

Autoregulation of cerebral blood flow in the preterm fetal lamb.

The purpose of the present study was to determine if autoregulation of cerebral blood flow (CBF) is present in the preterm fetal lamb and, if present, to measure the range of mean arterial blood pressure over which autoregulation exists. Thirty-seven measurements of CBF were made in seven preterm fetal lambs (118-122 days gestation) over a mean carotid arterial blood pressure (CBP) range of 18-90 mm Hg. CBF was measured by the radionuclide-labeled microsphere technique. CBP was altered by graduated inflation of balloons placed around the brachiocephalic trunk and the aortic isthmus. To eliminate the effects of reflex changes in heart rate, the carotid sinus and aortic nerve were ablated bilaterally. CBF was linearly related to mean CBP from 18-45 mm Hg, constant over a mean CBP of 45-80 mm Hg, and again linear from 80-90 mm Hg. Resting mean CBP (normotension) was 53.8 +/- 1.9 mm Hg during the control period and 51.7 +/- 0.8 mm Hg during the equilibration periods. This study demonstrates that although autoregulation of CBF is intact in the preterm fetal lamb, the range is narrowed compared to the term lamb and resting mean CBP lies close to the lower limit of autoregulation.

Animals↗
PubMed1985

Renal metabolism in fetal and newborn sheep.

The substrate and oxygen uptake by some organs in intact developing animals has been described, however, the kidney has not been studied. To examine substrate and oxygen uptake by the kidney, we implanted polyvinyl catheters into the renal vein, descending aorta, inferior vena cava, and urinary bladder of 11 fetal sheep (120-125 days gestation) and eight newborn lambs (1 day postnatal). Four days after surgery, blood samples were obtained simultaneously from the renal vein, aorta, and inferior vena cava for determination of oxygen content and saturation, and glucose and lactate concentrations. Renal blood flow was determined by the radionuclide-labeled microsphere method in the fetal lambs and by measuring 14C-inulin clearance in the newborn lambs. The fetal and newborn kidneys consumed oxygen at rates of 123 +/- 16 and 785 +/- 79 mumol/min/100 g kidney weight (mean +/- SEM), respectively. The increase in oxygen consumption from the fetal to the newborn period was accompanied by an increase in oxygen extraction from 25-35%, a large increase in oxygen delivery from 418 +/- 38 to 2231 +/- 127 mumol/min/100 g, and marked increases in glomerular filtration rate and sodium reabsorption (measured in six additional fetal sheep and the eight newborn lambs). This suggests that the postnatal increase in renal tubular activity is associated with an increase in oxygen consumption. Lactate was taken up by both fetal and newborn kidneys, and in nine of the 11 fetuses and in four of the eight newborns, there was net glucose release from the kidney.

Animals↗
PubMed1985

Developmental changes in myocardial contractile reserve in the lamb.

We have assessed serial changes in myocardial contractility and reserve in the normal lamb over the first month of life using an in vivo adaptation of the endsystolic pressure-volume relationship. Via a left thoracotomy, we insert a catheter tip pressure transducer into the left ventricle, affix an echo transducer onto the left ventricular epicardium, place an electromagnetic flow transducer around the pulmonary artery, and insert catheters for monitoring and infusions. We measure contractility by generating left ventricular wall stress-volume index (the cube of dimension) curves, at the same time increasing afterload by infusing phenylephrine. The slope of the endsystolic wall stress-volume index relationship is our index of contractility. Weekly studies were performed at rest and during isoproterenol infusion in 12 animals, and after propranolol administration in four. The data showed a progressive decrease in resting contractility but no change in maximal contractility during isoproterenol infusion over the 4 wk. Taking each week separately, the average increase in contractility during isoproterenol infusion was small at 1 wk (13%), moderate at 2 and 3 wk (24 and 26%, respectively), and large at 4 wk (79%). beta-Adrenergic blockade with propranolol caused a significant decrease in contractility in three of four animals studied at 1 wk, in only one of four animals at 2 wk, and in none of four animals at 3 or 4 wk. Thus, the newborn lamb shows a limited reserve in contractility that increases progressively with age; the limited reserve appears secondary to a high resting beta-adrenergic state.

Animals↗
PubMed1985

Chronic hypoxemia in the newborn lamb: cardiovascular, hematopoietic, and growth adaptations.

We have created a model of chronic hypoxemia in the newborn lamb by decreasing pulmonary blood flow in the presence of an atrial septal defect. Via a left lateral thoracotomy, we place an inflatable balloon around the pulmonary artery and perform an atrial septostomy under direct vision. We also insert several vascular catheters and place an electromagnetic flow transducer around the ascending aorta. Three days after surgery, we inflated the balloon in 11 lambs such that arterial oxygen saturation decreased to 60 to 75%. Studies were performed on these lambs twice weekly and weekly on 12 normoxemic lambs. Growth decreased sharply (47 +/- 123 versus 221 +/- 82 g/day) at the onset of hypoxemia and remained low, although oxygen consumption followed the normal gradual decline. Heart rate remained elevated throughout the study. Arterial PCO2 levels decreased from 40 +/- 5 to 35 +/- 7 torr and remained low. Systemic blood flow decreased at balloon inflation but quickly returned to normal. Mixed venous saturation was low, but could decrease further with shivering. Systemic oxygen delivery decreased initially but returned to normal as Hb concentration rose (from 9.4 +/- 1.5 to 12.5 +/- 2.2 g/dl). P50 increased normally over the study period. Four of the 11 hypoxemic lambs died during the study. These data show that, in the chronically hypoxemic newborn, systemic oxygen delivery is maintained primarily by a rising Hb. Total body oxygen consumption is maintained at rest but is redistributed away from anabolic requirements and toward cardiorespiratory work. This signal to decrease growth occurs despite less than maximal oxygen extraction at rest.

Animals↗
PubMed1985

Hepatic oxygen consumption, lactate uptake, and glucose production in neonatal lambs.

Previous studies have evaluated neonatal hepatic metabolism in vitro, and neonatal hepatic oxygen consumption has been measured in vivo, but direct measurements of neonatal hepatic metabolism have not been reported. We studied seven neonatal lambs at age 7-10 days after placing catheters chronically in the hepatic vein, portal vein, descending aorta, left ventricle, and inferior vena cava. Hepatic blood flow was measured by the radioactive microsphere technique. Oxygen consumption and glucose and lactate fluxes were measured using the Fick principle. 14C-lactate was infused intravenously and lactate and glucose specific activities were measured and used to calculate hepatic gluconeogenesis from lactate. Neonatal hepatic blood flow was 254.5 +/- 50.3 ml/min/100 g (mean +/- SD) with 5.4 +/- 4.6% from the hepatic artery and 94.6 +/- 4.6% from the portal vein. Hepatic oxygen consumption was 7.2 +/- 2.4 ml/min/100 g and oxygen extraction was 44.9 +/- 15.4%. Oxygen extraction correlated inversely with oxygen delivery. In the seven lambs, there was net hepatic lactate uptake of 10.2 +/- 5.0 mg/min/100 g (1.13 +/- 0.56 mM) and hepatic glucose production of 30.8 +/- 11.3 mg/min/100 g (1.71 +/- 0.62 mM). In the five lambs in which hepatic gluconeogenesis was measured, 12.4 +/- 5 mg (1.37 +/- 0.56 mM) of lactate was converted to glucose per 100 g liver, accounting for 38.4% of the hepatic glucose production in these lambs. Blood flow and oxygen and substrate delivery to the neonatal liver are lower than those to the fetal liver but the neonatal liver extracts more oxygen and substrates and is able to produce glucose by gluconeogenesis from lactate.

Animals↗
PubMed1985

Perinatal oxygen delivery and cardiac function.

In this review, we have considered interrelationships between blood flow and oxygen requirements of the body during fetal and neonatal development. During fetal life, blood is oxygenated in the placenta and returns to the fetus through the umbilical vein. The ductus venosus serves as a bypass of umbilical venous blood from the hepatic microcirculation. Preferential streaming of blood in the inferior vena cava facilitates delivery of well-oxygenated ductus venosus blood to the brain and heart. During fetal stress of hypoxia or umbilical cord compression, flow through the liver and ductus venosus is modified to facilitate oxygen delivery to the fetal body and local organ vascular responses, and to maintain blood flow and oxygen delivery to vital organs, such as the brain, heart, and adrenal gland. During fetal life, immaturity of the fetal myocardium accounts for limited ability for cardiac output to be augmented when ventricular filling pressure is increased above the resting level; yet immediately after birth, cardiac output increases dramatically. Experimental evidence points to an important role of prenatal thyroid hormone in maturation of the myocardium for postnatal requirements. In association with the increase in oxygen requirements after birth, cardiac output increases, but because resting requirements for blood flow are high, there is a limited ability for cardiac output to be increased further. With postnatal development, cardiac output requirements in relation to body weight decrease, partly in parallel with reduced oxygen requirements related to body weight, but also as a result of rightward shift of the oxygen dissociation curve as fetal hemoglobin is replaced by adult hemoglobin. Understanding the circulatory and metabolic changes that occur in the perinatal period and the mechanisms of response to stress is important in management of the newborn infant with cardiorespiratory distress.

Animals↗
PubMed1985

Lactate uptake by the fetal sheep liver.

Lactate is produced by the sheep placenta and is an important metabolic substrate for fetal sheep. However, lactate uptake and release by the fetal liver have not been assessed directly. We measured lactate flux across the liver in 16 fetal sheep at 129 (120-138) days gestation that had catheters chronically maintained in the fetal descending aorta, inferior vena cava, right or left hepatic vein, and umbilical vein. Lactate and hemoglobin concentrations and oxygen saturation were measured in blood drawn from all vessels. Umbilical venous, portal venous, and hepatic blood flow were measured by injecting radionuclide-labeled microspheres into the umbilical vein while obtaining a reference sample from the descending aorta. We found net hepatic uptake of lactate (5.0 +/- 4.4 mg/min per 100 g liver). A large quantity of lactate was delivered to the liver (94.2 +/- 78.1 mg/min per 100 g), so that the hepatic extraction of lactate was only 7.7 +/- 6.5%. Hepatic oxygen consumption was 3.18 +/- 3.3 ml/min per 100 g, and the hepatic lactate/oxygen quotient was 2.07 +/- 1.54. There was no significant correlation between hepatic lactate uptake and hepatic lactate or glucose delivery, hepatic oxygen consumption, hepatic blood flow, hepatic glucose flux, total body oxygen consumption, arterial pH, oxygen content, or oxygen saturation. There was, however, a significant correlation between hepatic lactate uptake and umbilical lactate uptake (r = 0.74, P less than 0.005) such that net hepatic lactate uptake was nearly equivalent to that produced across the umbilical-placental circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Gluconeogenesis by the fetal sheep liver in vivo.

Hepatic gluconeogenesis is an important source of glucose postnatally. Whether hepatic gluconeogenesis contributes to fetal glucose supply has not been studied directly in vivo. Previous studies of gluconeogenesis in fetal sheep have assessed total fetal glucose production, and the results have been controversial. To assess the specific role of the liver in gluconeogenesis in fetal sheep, we placed catheters in the right or left hepatic vein, umbilical vein and the inferior vena cava of six fetal sheep (mean gestational age 134 days) and infused a radioactive gluconeogenic substrate (14C-lactate or 14C-alanine) into the fetal inferior vena cava. We measured 14C-glucose radioactivity (dpm/ml) in the right or left hepatic vein and calculated the arteriovenous difference in 14C-glucose radioactivity (dpm/ml) across the right or left liver lobe. We found that only 0.35% of the 14C substrates perfusing either the right or the left hepatic lobe of the fetal liver were converted to 14C-glucose. Even when considerable glucose was released by the liver, the percentage of substrates converted to glucose remained very low (maximum 1.7%), indicating that gluconeogenesis did not contribute significantly to the glucose released. We conclude that gluconeogenesis by the fetal liver contributes negligibly to the glucose supply in fetal sheep.

Alanine↗
PubMed1985

Distribution and fate of acetaminophen conjugates in fetal lambs in utero.

The disposition of the two major metabolites of acetaminophen, acetaminophen glucuronide (A-G) and acetaminophen sulfate (A-S), was studied in nine chronically catheterized fetal lambs during the third trimester. After a bolus i.v. injection, both conjugates exhibited biphasic log plasma concentration vs. time curves with terminal half-lives of 3.36 to 7.60 hr for A-G and 4.61 to 8.20 hr for A-S. The steady-state volumes of distribution and the total clearances of both conjugates increased with the gestational age of the fetus. The ratios of renal clearance to total clearance were 1.00 +/- 0.06 and 0.95 +/- 0.07, respectively, for A-G and A-S. Neither placental transfer nor systemic hydrolysis of either conjugate was detectable in our experiments. The ratios of renal clearance to glomerular filtration rate, as determined by [14C] inulin renal clearance, were 0.96 +/- 0.06 and 0.67 +/- 0.10 for A-G and A-S, respectively. These ratios corresponded to the free fractions of the two conjugates in the plasma, which were 0.96 +/- 0.03 and 0.64 +/- 0.09, respectively, for A-G and A-S. Our data indicate that transplacental transfer of acetaminophen conjugates is not detectable and both conjugates are predominantly eliminated from the fetal plasma through renal excretion by glomerular filtration in the fetal kidney. As the conjugates are apparently not hydrolyzed in the fetus, they remain in the fetus and the surrounding amniotic fluid until birth.

Acetaminophen↗
PubMed1984

Surgical treatment of truncus arteriosus in the first 6 months of life.

One hundred six infants were seen at the University of California Medical Center between 1974 and 1981 with the diagnosis of truncus arteriosus. One hundred of these underwent physiologic correction prior to 6 months of age. Six infants died prior to operation while undergoing intense medical therapy to improve their basic condition. There were 11 operative deaths with a mortality rate of 11%. Of the 86 long-term survivors, 55 have returned for conduit change because of either body growth or pseudointima proliferation of the conduit. There had been no mortalities at the time of conduit change, and 29 of these were repaired using a straight tube between the ventricle and pulmonary trunk, while 26 had valve conduits placed. Physiologic correction in the first 6 months of life has been accomplished with a low mortality rate and apparent good long-term results with none of the survivors having evidence of elevated pulmonary vascular resistance.

Blood Vessel Prosthesis↗