Accelerated fetal lung maturity profiles and maternal cocaine exposure.

OBJECTIVE: To determine the effect of maternal cocaine exposure on fetal lung maturity as measured by surfactant-albumin ratios determined by the TDx-FLM test. METHODS: A case-control study design was used to compare fetal lung maturity as assessed by a surfactant-albumin ratio assay (TDx-FLM) in amniotic fluid (AF) obtained from women who were known to use cocaine and those who were not known to use cocaine during the study pregnancy. Multiple logistic regression procedures were used to control for gestational age and possible confounders, such as obstetric and nonobstetric complications, other substance abuse, race, infant sex, and payer status. RESULTS: Maternal cocaine use during pregnancy was associated with an accelerated fetal lung maturity profile (adjusted odds ratio [OR] 2.04, 95% confidence interval [CI] 1.04-4.00) as determined by the TDx-FLM test. Other variables found to be statistically significant predictors of a mature fetal lung profile were cigarette smoking during the current pregnancy (OR 1.61, 95% CI 1.02-2.56). Preterm labor, preterm rupture of membranes, nonobstetric illness during pregnancy, and exposure to other abused substances were not associated with accelerated fetal lung maturity. CONCLUSION: Maternal cocaine use during pregnancy is associated with a doubling of the probability of a mature fetal lung profile as determined by TDx-FLM analysis of AF. Tobacco use is also a predictor of accelerated fetal lung maturity profiles.

Prediction of cerebral blood flow in fetal lambs by carotid artery ultrasonic flow transducer.

To determine whether common carotid artery blood flow measured with an ultrasonic flow transducer would predict brain blood flow in fetal sheep, we measured unilateral common carotid artery blood flow and compared this to simultaneous measurements of total brain blood flows made by radioisotope-labelled microsphere techniques. We studied anaesthetized, exteriorized fetal sheep with intact umbilical circulation after ligation of extracranial, extracerebral arteries and placement of a common carotid artery flow transducer; five fetuses at 120 d gestation had 19 total comparison measurements. As measured by microsphere technique, mean basal blood flow during undisturbed conditions to regional brain areas were similar to normal values reported for the exteriorized ovine fetus; these flows were highly correlated to fetal PaCO2 and successfully varied over a wide range (total brain 9.1-200.4 ml/min/100g and total cortex 6.1-153.1 ml/min/100g) in subsequent experimental conditions of hypercapnia or occluded blood flow. Blood flow as measured by flow transducer significantly correlated (P < or = 0.01) with microsphere measurements of blood flow to total brain (r = 0.56) and total cortex (r = 0.62); regional flow to cerebellum (r = 0.70) and thalamus (r = 0.60) also correlated to transducer measurements. Stronger correlations were observed at low-flow conditions to total brain (r = 0.83) and to total cortex (r = 0.90). As measured by microsphere technique, right and left cortical blood flows were highly correlated (P = 0.0001, r = 0.97), indicating that the flow transducer or surgical manipulation did not disturb the distribution of cerebral blood flow. The mean values for zero flow reference of the transducer were < 1.5% of mean basal flow values. It is concluded that the common carotid artery flow transducer technique developed in this study provides an accurate prediction of blood flow to total brain and total cortex over a wide range of values in fetal sheep. This technique provides a methodologic advantage to sequential experimental interventions and may prove advantageous to studies of fetal sheep cerebral circulation.

Fetal death in a population of black women.

To describe the clinical causes of fetal death in black women, we performed a record review of the primary causes of fetal deaths (n = 315, > or = 500 g or > or = 24 weeks' gestation) occurring over an 11-year period in a population of 26,852 black women who delivered at the Chicago Lying-in Hospital, University of Chicago Hospitals, Chicago, IL. The over-all fetal death rate (FDR) per 1,000 total births was 11.7, consistent with U.S. vital statistics data for blacks. The FDR per 10,000 births attributed to hypertension was nine times greater in our population than in a historical comparison population of Canadian white women: 19.5 (95% CI = 13.7, 25.4) versus 2.2 (P < .0001), respectively, although the prevalence of hypertension was only 1.2 times greater in the population of black women. Furthermore, hypertension in pregnancy accounted for 15% of the excess fetal mortality in our population of urban black women as compared to the population of Canadian white women. Health care providers should be aware of the risk of fetal death in hypertensive, innercity, U.S. black women.

Concentration-dependent effects of cocaine on monoamine-induced constriction of cannulated, pressurized cerebral arteries from fetal sheep.

Drugs, such as cocaine, which may alter monoamine neurotransmitter responsiveness, could adversely affect the regulation of cerebral vasculature. Cocaine exhibits at least two mechanisms that may alter vascular responsiveness: synaptic uptake inhibition, which may augment response to stimulation, and Na+ channel inhibition, which may attenuate response. To help elicit the concentration-dependent effects of cocaine, the effects of cocaine on monoamine neurotransmitter responsiveness were studied in vitro on fetal sheep cerebral arteries (120 days gestation). The changes in diameter of segments of cannulated, pressurized fetal sheep cerebral artery were measured with a videomicroscaler system. Cumulative concentration-response curves (10(-10) to 10(-4)M) were generated for two monoamines, norepinephrine and serotonin, alone and in the presence of cocaine (10(-5) or 10(-4)M). Cocaine caused concentration-dependent alteration of response. At 10(-4)M, cocaine attenuated mean maximal norepinephrine-induced vasoconstriction 46.2% (P < 0.05). At 10(-5)M, cocaine increased sensitivity to norepinephrine (log EC50 decreased -6.63 +/- 0.09 to -7.11 +/- 0.03) and to serotonin (log EC50 decreased -7.24 +/- 0.04 to -7.81 +/- 0.09) (P < 0.05). The higher concentration of cocaine (10(-4)M) did not significantly decrease log EC50 norepinephrine. Cocaine (10(-4)M) also attenuated the response to single doses of norepinephrine (10(-6)M) and serotonin (10(-6)M) by 26.5% and 40.0%, respectively (P < or = 0.05). It is concluded that cocaine has concentration-dependent effects on vasoconstriction of the fetal sheep cerebral artery in vitro. This cocaine-induced alteration of cerebral vascular responsiveness to monoamines may be important in the regulation of fetal cerebral blood flow.

Effects of cocaine, benzoylecgonine, and cocaine metabolites in cannulated pressurized fetal sheep cerebral arteries.

Prenatal cocaine exposure has been reported to cause neurovascular complications in the developing fetus. To determine the effect of cocaine on the fetal neurovasculature, we studied the in vitro response of fetal sheep cerebral arteries to cocaine and cocaine metabolites. The change in diameter of cannulated pressurized cerebral artery segments from fetal sheep was measured using a video microscaler system. Cumulative dose-response curves (10(-12)-10(-4) M) were generated for cocaine and the major cocaine metabolites in fetal sheep cerebral artery segments. Benzoylecgonine (> 10(-10) M) also caused concentration-dependent constriction, and cerebral artery segments were significantly more sensitive to benzoylecgonine than to cocaine and the other cocaine metabolites. Benzoylecgonine-induced vasoconstriction appeared to be mediated through alpha-adrenergic stimulation, predominantly through stimulation of alpha 1-adrenergic receptor subtypes. We conclude that cocaine and benzoylecgonine cause significant fetal cerebral artery vasoconstriction in vitro. Cocaine and benzoylecgonine-induced cerebral vasoconstriction may contribute to the perinatal neurovascular complications associated with prenatal cocaine exposure.

Hemodynamic and cerebral blood flow effects of cocaine, cocaethylene and benzoylecgonine in conscious and anesthetized fetal lambs.

We studied hemodynamic responses to cocaine and two metabolites, cocaethylene (CE) and benzoylecgonine (BE), in five conscious ewes and fetuses, which were chronically instrumented to measure maternal and fetal aortic pressures, uterine artery blood flow (Qutr) and fetal common carotid artery blood flow (Qcar) to estimate cerebral blood flow. Conscious ewes of 121 to 128 days' (mean, 124 days) gestation received 1.0 mg/kg i.v. of cocaine (n = 12 doses), CE (n = 14) or BE (n = 12) and responses were compared to seven additional ewes and fetuses at 115 to 127 days' (mean, 122 days) gestation each given one 1.0 mg/kg i.v. of cocaine dose while anesthetized with halothane. In conscious ewes, cocaine, CE and BE all caused maternal and fetal hypertension. Qutr decreased 31% after cocaine, increased 37% after CE and was unaffected by BE. Cocaine induced fetal hypoxemia; fetal arterial blood gas tensions were unaffected by CE or BE. Fetal Qcar was reduced 51% at peak effect by cocaine (57 +/- 8 to 28 +/- 6 ml/min) and 46% by CE (65 +/- 7 to 33 +/- 6 ml/min), and was unaffected by BE because of variable subject response, although all three drugs increased calculated fetal cerebral vascular resistance. The cocaine-induced changes were attenuated or abolished in anesthetized sheep. Fetal/maternal peak serum concentrations were 100% for CE and only 2% for BE; amniotic fluid concentrations of CE were 10-fold higher than both fetal and maternal serum concentrations. Cocaine and cocaine metabolites have important effects on maternal and fetal hemodynamics and fetal cerebral blood flow which, for CE and BE, are not dependent on decreased uterine blood flow or fetal hypoxemia.

Response to prostaglandin E1 in neonates with intracranial arteriovenous malformation treated for suspected congenital heart disease.

Two neonates with cardiovascular symptoms associated with intracranial AVM were initially considered to have ductal-dependent congenital heart disease. Prostaglandin E1 (PGE1) infusion, initiated to achieve patency of the ductus arteriosus, produced improved oxygenation and cardiovascular status in both infants. Other vascular effects of PGE1, including pulmonary and extracranial systemic vasodilation, likely accounted for these unique observations in the infants with intracranial AVM. Not only may the signs and symptoms of congenital heart disease be imitated by intracranial AVM, but improved oxygenation and cardiovascular status with PGE1 infusion used for suspected congenital heart disease may be observed as well.

Hemodynamic interaction of chloralose pretreatment with subsequent beta-adrenergic receptor antagonism in lambs.

alpha-Chloralose is a commonly used anesthetic agent in cardiovascular research despite a paucity of information whether it may have important pharmacologic interaction with subsequently given adrenergic drugs. To assess any potential pharmacologic interaction, we studied the cardiovascular response to beta-adrenergic receptor antagonism (propranolol, 1 mg/kg i.v.) after either chloralose (30 mg/kg i.v.) or saline control in paired studies in 10 chronically instrumented neonatal lambs. Chloralose increased heart rate by 46% as compared to control (283 +/- 37 vs. 194 +/- 48 beats/min, p = 0.0002) and had no significant effect on cardiac output; chloralose also increased mean pulmonary arterial pressure by 45% (27 +/- 13 vs. 19 +/- 6 mm Hg, p = 0.050) and pulmonary vascular resistance by 79% (0.211 +/- 0.13 vs. 0.118 +/- 0.04 mm Hg/ml/kg/min, p = 0.050). The group pretreated with chloralose had significantly elevated heart rate (186 +/- 23 vs. 157 +/- 31 beats/min, p = 0.03), mean pulmonary arterial pressure (29 +/- 9 vs. 22 +/- 6 mm Hg, p = 0.03) and pulmonary vascular resistance (0.228 +/- 0.13 vs. 0.130 +/- 0.05 mm Hg/ml/kg/min, p = 0.05) after propranolol as compared to the conscious saline-treated group. We conclude that pretreatment with chloralose as an anesthetic agent may produce important pharmacologic interaction with subsequent adrenergic drugs in neonatal lambs. While anesthesia may be necessary in animal research, investigators should be aware that the anesthetic agent may also qualitatively and quantitatively influence measured outcome variables.

Three different strains of heat-killed group B beta-hemolytic streptococcus cause different pulmonary and systemic hemodynamic responses in conscious neonatal lambs.

Although group B beta-hemolytic streptococcus (GBS) causes pathologic hemodynamic alterations in both human neonates and neonatal animal models of sepsis, little is known about strain-dependent differences in hemodynamic responses to GBS. This study compared pulmonary and systemic hemodynamic dose-response profiles in conscious neonatal lambs with three different strains of heat-killed GBS originally isolated from infected human neonates (group 1: serotype Ib, early-onset sepsis; group 2: serotype Ib, necrotizing enterocolitis; and group 3: serotype III, meningitis). Regression models of hemodynamic responses were characterized after lambs were injected with heat-killed GBS (dose range 0.1-6.0 x 10(9) colony-forming units, i.v.). All three GBS strains caused dose-dependent increases in mean pulmonary arterial pressure and pulmonary and systemic vascular resistances and decreases in cardiac output and heart rate. The GBS strain used in group 1 caused a greater effect on mean pulmonary arterial pressure and systemic vascular resistance than those used in groups 2 and 3 and was the only strain to cause an increase in mean systemic arterial pressure. The GBS strains used in groups 1 and 2 had a greater effect on pulmonary vascular resistance than that used in group 3. No group differences were observed in cardiac output and heart rate responses, which were, however, influenced by age, gender, and duration of postoperative recovery of the lambs. No attenuation or augmentation of hemodynamic effect was observed after sequential doses of 10(9) colony-forming units of GBS given in a single day. This study demonstrates strain-dependent quantitative differences in pulmonary vascular response and qualitative differences in systemic vascular response to heat-killed GBS.

Risk of intracranial hemorrhage and other adverse outcomes after cocaine exposure in a cohort of 323 very low birth weight infants.

We conducted a prospective cohort study of 323 consecutively born very low birth weight infants (< or = 1499 gm) to determine any association between prenatal cocaine exposure and (1) intracranial ultrasonographic abnormalities and (2) other adverse perinatal outcomes. The infants were assigned to either a cocaine-exposed group (n = 86) or a cocaine-nonexposed group (n = 146) on the basis of combined detection methods for prenatal maternal cocaine abuse including maternal history, maternal and infant urine immunoassay (Emit), and meconium analysis (high-performance liquid chromatography and gas chromatography-mass spectrometry). Ninety-one infants were not assigned because of early death before complete testing (n = 80) or missed tests (n = 11). The detected incidence of cocaine exposure in the assigned population was 37% (86/232). Meconium testing with high-performance liquid chromatography and gas chromatography-mass spectrometry was the sole means of detection in 30% (26/86) of cases. The cocaine-nonexposed infants did not differ from the cocaine-exposed infants in the incidence of intraventricular hemorrhage (36% vs 35%), grades III and IV intraventricular hemorrhage (14% vs 14%), or periventricular leukomalacia (4% vs 2%). Adverse outcomes increased by cocaine exposure were abruptio placentae (8% vs 18%; p = 0.046), surgical ligation of a patent ductus arteriosus (1% vs 7%; p = 0.02), and seizures (5% vs 17%; p = 0.004). We conclude that prenatal cocaine exposure does not increase the incidence or severity of intracranial hemorrhage or periventricular leukomalacia but does increase the risk of abruptio placentae, surgical ligation of a patent ductus arteriosus and seizures in very low birth weight infants.

Effect of beta-adrenergic receptor antagonism on chloralose-induced hemodynamic changes in newborn lambs.

alpha-Chloralose is an anesthetic commonly used in cardiovascular research. Using a chronically instrumented neonatal lamb model, we previously determined that chloralose has important effects on basal hemodynamics and arterial oxygen tension as compared with those of paired conscious control lambs. We wished to determine whether beta-adrenergic receptor stimulation accounted for chloralose-induced hemodynamic effects and to investigate the influence of chloralose and beta-adrenergic receptor antagonism on oxygen metabolism. In paired studies, five lambs were given chloralose intravenously (30 mg/kg i.v.) after propranolol (1 mg/kg i.v.) or saline control. The group pretreated with propranolol had reduced heart rate (HR 206 +/- 12 vs. 244 +/- 10 beats/min, p = 0.04) and cardiac output (CO 253 +/- 29 vs. 302 +/- 40 ml/min/kg, p = 0.005) 30 min after chloralose as compared with control; pretreatment with propranolol also attenuated the systemic hypertensive response to chloralose (77 +/- 8 vs. 89 +/- 5 mm Hg, p = 0.055). No difference in the response of stroke volume (SV), atrial or pulmonary arterial pressures, or pulmonary and systemic vascular resistances (PVR, SVR) were observed between treatment groups. No differences between propranolol and saline treatment groups were observed in arterial and mixed venous oxygen contents, arteriovenous (A-V) oxygen difference, oxygen extraction, or oxygen consumption; a reduction in oxygen delivery observed after propranolol as compared with saline was not altered by chloralose. We conclude that tachycardia and increase in CO induced by chloralose in lambs probably are mediated by beta-adrenergic receptor stimulation, which may be direct or indirect.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of aminophylline on the pulmonary and systemic hemodynamic response to group B beta-hemolytic Streptococcus and leukotriene D4 in newborn lambs.

Aminophylline, a methyl xanthine, has been used for many years in the treatment of apnea of prematurity and bronchospasm. Aminophylline relaxes smooth muscle through several proposed mechanisms. We hypothesized that aminophylline might be effective in relaxing preconstricted pulmonary vascular smooth muscle and would be ideally suited for clinical trial in babies with pulmonary hypertension. To test this hypothesis, the haemodynamic response of chronically instrumented newborn lambs to injections of heat-killed Group B beta-hemolytic Streptococcus (GBS) and leukotriene (LT) D4, potent pulmonary vasoconstrictors was compared before and after pretreatment with a clinically therapeutic dose of intravenous aminophylline. GBS (10(9)cfu) significantly increased pulmonary arterial pressure 130%. LTD4 (1.0 microgram/kg) significantly increased pulmonary arterial pressure 142% and systemic arterial pressure 23% and decreased cardiac output 47%. Aminophylline did not significantly affect the baseline variables or alter the pulmonary or systemic haemodynamic response to either stimuli. Therefore, it is unlikely that aminophylline will be clinically useful in the treatment of babies with persistent pulmonary hypertension whose etiology is infectious or leukotriene-mediated.

Oxygen metabolism and catecholamine secretion during chloralose anesthesia in lambs.

Anesthetic agents are required when restraining animals in most forms of animal research. In particular, alpha-chloralose is a widely used anesthetic for respiratory and cardiovascular research despite limited controlled studies investigating whether chloralose could represent a variable influencing cardiorespiratory reflexes in acute animal studies. We previously used a chronically-instrumented neonatal lamb model to determine that chloralose had important effects on oxygen delivery and on basal hemodynamics. To investigate the influence of chloralose on oxygen metabolism and catecholamine secretion in relation to these hemodynamic changes, we studied 12 lambs before and after infusion of chloralose (30 mg/kg, i.v.) or control saline vehicle. Chloralose caused no differences in arterial or mixed venous oxygen contents, arterio-venous oxygen difference, or oxygen delivery, consumption, or extraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of heat-killed group B beta-hemolytic streptococcus in newborn lambs: role of leukotriene D4.

Group B beta-hemolytic streptococcus (GBS) infection is an important cause of neonatal pneumonia and sepsis. GBS infection is frequently associated with persistent pulmonary hypertension of the newborn. To better understand the early pulmonary hypertension phase of GBS-induced acute lung injury in a conscious animal, we characterized the pulmonary and systemic hemodynamic response of spontaneously breathing, chronically instrumented newborn lambs to injections of heat-killed type Ib GBS, 0.1-9.0 x 10(9) colony forming units. Heat-killed GBS caused marked dose-dependent increases in mean pulmonary arterial pressure and calculated pulmonary vascular resistance, 190 and 370% at the maximum dose, respectively. Similarly, GBS caused dose-dependent increases in mean systemic arterial pressure and systemic vascular resistance (28.5 and 108% at the maximum dose, respectively) and a decrease in cardiac output (33.5%). Arterial oxygen tension worsened at the higher doses. GBS-induced pulmonary hypertension was decreased by two structurally unrelated, putative leukotriene D4 receptor antagonists. Pretreatment with LY171883 blocked GBS-induced pulmonary hypertension by 95%, and WY48,252 attenuated this effect by 27%. Both drugs completely blocked the hemodynamic effects of exogenous leukotriene D4. For comparison, several lambs received bolus injections of live GBS, either alone or after pretreatment with LY171883. The hemodynamic response to live GBS and attenuation of that response by LY171883 were similar to those caused by similar doses of heat-killed GBS. Thus, bolus injections of heat-killed GBS provide a reproducible model of pulmonary hypertension in conscious newborn lambs. In addition, the sulfidopeptide leukotrienes appear to be important mediators of GBS-induced pulmonary hypertension in newborn lambs.

Factors associated with age of onset of necrotizing enterocolitis.

To investigate factors associated with risk and age of onset for necrotizing enterocolitis (NEC), a retrospective case-control review was performed of patients with NEC and control infants matched for birthweight and date of admission. NEC cases were defined by Bell staging criteria and were included if pneumatosis intestinalis, histologic confirmation, or a recognized complication of NEC was identified in association with clinical signs and symptoms. NEC was significantly related to birthweight and premature post-conceptional age. In contrast to control infants, patients with NEC had higher 5 minute Apgar scores, less significant respiratory disease, and more rapid feeding practices. Two distinct subgroups of patients with NEC based on postnatal age of onset were apparent. Patients with early onset NEC (21 days or less postnatal age) had less significant respiratory disease and were fed more rapidly than late onset patients. Late onset NEC (more than 21 days postnatal age) occurred frequently in convalescing, relatively well premature infants who were still, however, of preterm postconceptional age. Relatively well premature infants with minimal respiratory disease are still at risk for NEC. Advances in neonatal care and survival of very low birthweight infants may account for a shift in prevalence to older infants who are yet of preterm postconceptional age.

Chloralose alters both basal hemodynamics and cardiovascular responses to alveolar hypoxia in chronically instrumented, spontaneously breathing lambs.

We studied the effects of chloralose anesthesia on the basal hemodynamic state and on the cardiovascular response to alveolar hypoxia in chronically instrumented, spontaneously breathing lambs, compared with responses to the saline vehicle. Chloralose significantly increased heart rate (23%), mean systemic arterial pressure (11%), systemic vascular resistance (21%), mean pulmonary arterial pressure (23%), and pulmonary vascular resistance (46%) (n = 30, p less than 0.05, ANOVA). These changes were unrelated to baseline tone of the circulation, cardiac output, mean left atrial pressure, or physiologically important changes in arterial blood gas tensions. In addition, chloralose-treated lambs had increased heart rate, systemic vascular resistance, and pulmonary vascular resistance compared to controls during alveolar hypoxia (13-15% FiO2). Importantly, chloralose-treated lambs did not increase their cardiac output during alveolar hypoxia as did control lambs. During hypoxia, systemic vascular resistance remained elevated in chloralose-treated lambs, but declined in control lambs. Chloralose has been recommended as an ideal anesthetic agent for cardiovascular experimentation. Our data suggest that chloralose-induced alterations in basal hemodynamics and in cardiovascular responses to alveolar hypoxia represent an uncontrolled variable in acute experimental studies. Complex cardiovascular alterations caused by anesthesia should be considered in experimental design.

Chloralose alters circulatory response to alpha-receptor stimulation and blockade.

Chloralose anesthesia is commonly used in animals for cardiovascular research despite limited data on possible receptor-drug interactions. To investigate potential interactions with alpha-adrenergic receptors, we studied the response of chronically instrumented, spontaneously breathing young lambs to alpha-receptor stimulation (by methoxamine) and blockade (by phentolamine) after infusion of 30 mg/kg of chloralose or an equal volume of vehicle. Both experiments were performed in each animal on different days and in alternate order. Chloralose altered the systemic arterial pressure and heart rate response to both alpha-agonist challenge and to alpha-blockade when compared with control. Despite potentiating the systemic arterial pressor response to methoxamine, chloralose attenuated the reflex decrease in heart rate after alpha-agonist-induced hypertension. This observation suggests that the baroreceptor reflex was blunted. Chloralose, commonly considered an ideal anesthetic for cardiovascular studies, may have important effects on the cardiovascular response to alpha-adrenergic test agents. The potential for interactive effects should be considered in experimental designs that couple the use of chloralose and alpha-adrenergic agents.