Sympathetic innervation modulates ventricular impulse propagation and repolarisation in the immature rat heart.

OBJECTIVE: When cardiac sympathetic innervation in neonatal rats is retarded by antiserum to nerve growth factor, there is a corresponding increase in the QT interval on ECG. Since the propagation of the cardiac impulse and the repolarisation of cardiac cells both contribute to the QT interval, the aim of this study was to determine the role of sympathetic innervation in modulating ventricular impulse propagation and repolarisation. METHODS: Neonatal rats were treated for the first 10 days of life with nerve growth factor (NGF), its antiserum (As), or placebo. Standard microelectrode techniques were used to study the transmembrane action potential characteristics of subendocardial (ventricular septal) and subepicardial ventricular myocardium. Bipolar surface electrograms were used to record the velocity of impulse propagation and electron microscopy to examine the intercalated discs. RESULTS: In the subendocardium, the phase 0 upstroke velocity of the action potential (dV/dtmax) was lowest in the As treated rats. The latter group also showed the slowest conduction velocity. There were no differences in control action potential durations in the endocardium among the three groups, but in the epicardial tissues, action potential duration was longest in the As treated group. Thus the dispersion in action potential duration was smallest in the As treated animals. Electron microscopic studies of the intercalated discs of ventricular myocytes showed significant enhancement of nexal junction formation in NGF treated rats, whereas As treated animals showed a retarded pattern of both nexal and desmosomal junction formation. CONCLUSIONS: The differences in ultrastructure, conduction, and repolarisation seen in As and NGF treated animals may explain the prolonged QT interval seen in the As treated group.

Effects of prenatal methadone exposure on sex-dimorphic behavior in early school-age children.

Prenatal opiate exposure has been shown to alter the pattern of sex-dimorphic behavior in male and female rats. To conduct an exploratory study of opiate effects in humans, we compared the sex-dimorphic behavior of male and female offspring of women maintained on methadone during pregnancy to that of demographically matched control subjects. Standardized questionnaires completed by the primary caretakers served as assessment instruments. The six- to eight-year-old methadone-exposed boys showed more stereotypically feminine behavior than nonexposed male control subjects. There were no significant differences between methadone-exposed girls and their female control group. Based on these preliminary findings, we recommend that future follow-up studies of opiate-exposed children be broadened to include an assessment of their gender role behavior.

Effects of terbutaline on cardiac automaticity and contractility.

The effects of terbutaline, a sympathomimetic amine with predominantly beta 2-agonist properties, on cardiac automaticity and contractility were studied. For isolated rabbit right atria, terbutaline, 1 X 10(-9) to 1 X 10(-5)M, was significantly less potent than isoproterenol. The maximum increase in heart rate induced by terbutaline was 45 +/- 17 beats/min, that by isoproterenol, 120 +/- 9 beats/min. For canine Purkinje fibers, terbutaline had less effect on spontaneous rate than isoproterenol; maximum increases above control were 9.5 +/- 2.5 and 18.6 +/- 7.0 beats/min, respectively. For isolated feline ventricular muscle, terbutaline, 1 X 10(-9) to 1 X 10(-6)M, was significantly less potent than isoproterenol in increasing peak developed tension and the rate of tension development. Superfusion with Tyrode's solution containing terbutaline, 1 X 10(-7)M, plus graded concentrations of isoproterenol, 1 X 10(-9) to 1 X 10(-6)M, resulted in response which were less than those observed when isoproterenol alone was superfused. Maximal effects of isoproterenol plus terbutaline were equivalent to those of isoproterenol in its effect on cardiac contractility and automaticity and explain the clinical observation that terbutaline is less toxic than isoproterenol in its effects on cardiac rhythm and contraction when administered for the treatment of bronchial asthma.

Motion resistant pulse oximetry in neonates.

BACKGROUND: Pulse oximetry is widely used in neonates. However, its reliability is often affected by motion artefact. Clinicians confronted with questionable oxygen saturation (SpO(2)) values often estimate the reliability by correlating heart rate (HR) obtained with the oximeter with that obtained by electrocardiogram. OBJECTIVE: To compare the effects of motion on SpO(2) and HR measurements made with Masimo signal extraction technology and those made with a Nellcor N-200. DESIGN: Continuous pulse oximetry and HR monitoring were performed in 15 healthy, term infants (mean (SD) birth weight 3408 (458) g) undergoing circumcision, using Masimo and Nellcor pulse oximeters and a standard HR monitor (Hewlett-Packard). Simultaneous minute by minute behavioural activity codes were also assigned. Baseline data were collected for 10 minutes when the infant was quietly asleep and then continued during and after circumcision for a total duration of one hour. The oximeter HR and SpO(2) values were compared and related to HR values obtained by ECG during all three periods. The effect of behavioural activity on SpO(2) and HR was also evaluated. RESULTS: When compared with results obtained with the Nellcor, the mean SpO(2) and HR were higher and the incidence of artefact lower with the Masimo during all three periods. Masimo HR more accurately predicted HR obtained with a standard monitor, with lower residual error. SpO(2) and HR values obtained with the Nellcor were lower and more variable during all behavioural states, especially crying, when excessive motion artefact was most likely. CONCLUSIONS: The data suggest that Masimo signal extraction technology may offer improvement in pulse oximetry performance, particularly in clinical situations in which extreme motion artefacts are likely.

Intrauterine cocaine and crack exposure: neonatal outcome.

OBJECTIVE: Adverse health effects are associated with intrauterine cocaine exposure. The purpose of this study was to investigate the impact of fetal cocaine and crack exposure on neonatal outcome. STUDY DESIGN: We enrolled 386 mother-infant pairs, including 130 matched control pairs, in the study. The course of pregnancy and delivery was followed and neonatal outcome was assessed by physical and neurologic examination, as well as by the Brazelton Neonatal Behavioral Assessment Scale and the Neonatal Stress Scale. RESULTS: The cocaine-exposed neonates had significantly more adverse effects than the matched control infants. Birth weight, length, and head circumference were significantly lower in the cocaine- and crack-exposed infants (p < or = 0.001). There were significantly more premature infants (p < or = 0.007) in this group. They demonstrated significant abnormalities on the neurologic examination (p < or = 0.001), inferior performance on the Brazelton Neonatal Behavioral Assessment Scale (p < or = 0.001), and higher scores on the Neonatal Stress Scale (p < or = 0.001). Predictors of negative neonatal outcome were maternal age (p < or = 0.02), poor paternal relationship with the mother (p < or = 0.002), crack use (p < or = 0.004), cocaine use (p < or = 0.009), and marijuana use (p < or = 0.05). CONCLUSION: The single most important predictor of neonatal outcome is the frequency, quantity, and type of cocaine used.

Phenobarbital plasma levels in neonates.

This pilot study demonstrated marked variation in neonatal phenobarbital utilization. In order to rapidly achieve therapeutic levels, it is suggested that a loading dose of 8 to 10 mg per kg be administered for 2 days followed by reduction of dosage to a maintenance level of 5 to 6 mg per kg with frequent monitoring of plasma phenobarbital concentrations. The optimal plasma concentration of phenobarbital for control of neonatal seizures or withdrawal syndromes appeared to be between 15 to 30 mug per ml.

Mother-infant interaction in a multirisk population.

The relationship among maternal and observer ratings of infant temperament, observer ratings of maternal responsiveness, and maternal drug abuse habits, was studied in a population facing multiple risk factors. Intensity of maternal drug abuse was found to be negatively related to maternal ratings of infant temperament, and ratings of temperament were positively related to maternal responsiveness. Implications for research and practice are explored.

An ecological approach to development in children with prenatal drug exposure.

Knowledge about the effects of prenatal drug exposure on early development is reviewed within an ecological framework. The intersecting influences on maternal and child behavior in the early caregiving environment are considered, and similarities reported for drug-exposed children and other high-risk groups are noted. Data from a sample of 90 dyads are used to explore the impact of maternal stress, social support, and depression on children's behavior problems. Strategies for enhancing developmental outcomes in this population are discussed.

Resilient children: individual differences in developmental outcome of children born to drug abusers.

Since 1977, we have been following the neurobehavioral development of two groups of children: a group born to women on methadone maintenance and a drug-free comparison group. This study used the data on the children evaluated at 36 months of age to determine whether distinct patterns of developmental outcome can be identified, and which medical, familial, or environmental characteristics are associated with developmental differences. The children were clustered on four measures at 36 months: head circumference percentile, Merrill-Palmer Scale score, neurological evaluation, and referrals for developmental problems. Three distinct clusters emerged, with methadone children disproportionately frequent in Cluster 3, the group showing the poorest development. Comparisons of the clusters on a wide range of variables revealed consistent differences between Cluster 1 and Cluster 3 children in maternal responsiveness and incidence of neglect and family violence. These findings indicate that distinct developmental patterns do occur within this predominantly lower-class ghetto population; further, that children born to methadone-maintained women are more likely to show poor development. However, when the environment provides nurturance and stability, methadone children can show resilience and develop well.

Disposition of methadone and its relationship to severity of withdrawal in the newborn.

We studied the placental transfer of methadone, the relationship of neonatal plasma methadone concentrations to withdrawal symptomatology, and the relationship between maternal methadone dose and severity of neonatal withdrawal in 31 methadone-maintained mothers and their neonates. Methadone concentrations in maternal, cord and neonatal plasma were measured using a gas chromatographic micromethod. Neonatal plasma was assayed on days 0-5 of life. Urine methadone levels were measured for the first 3 days of neonatal life, using a similar assay. Twenty-five of the neonates experienced mild to severe withdrawal symptoms. There was no consistent relationship between the maternal methadone dose and the severity of neonatal symptoms. However, when neonatal withdrawal did occur, it began after plasma methadone levels fell below .06 mug/ml. The neonatal plasma methadone levels were consistently lower than those of the mother. Maternal methadone is transferred across the placenta and can induce significant withdrawal symptomatology in the newborn.

Children of methadone-maintained mothers: follow-up to 18 months of age.

Limited information is available on the long-term effects of in utero methadone exposure. This report describes the somatic and neurobehavioral findings of children in the first 18 months of life born to methadone-maintained mothers and to a matched drug-free comparison group of mothers. Findings during the neonatal period were (1) a 75% incidence of moderate-to-severe narcotic abstinence syndrome, (2) a significant incidence of head circumferences below the third percentile, and (3) elevated systolic blood pressure. In follow-up, the methadone children had (1) a significantly higher incidence of otitis media; (2) a significant incidence of head circumferences below the third percentile; (3) neurologic findings of tone discrepancies, developmental delays, and poor fine motor coordination; (4) a high incidence of abnormal eye findings; and (5) significantly lower scores on the Bayley mental and motor developmental indices. These neurobehavioral findings in children of methadone-treated mothers at 18 months of age may be predictors of later learning and behavioral problems.

Prenatal methadone exposure: effects on behavior in early infancy.

As part of an ongoing longitudinal study of the developmental effects of prenatal methadone exposure, 41 children born to methadone-maintained mothers and 23 children from matched backgrounds but with negative maternal history of drug abuse were evaluated at six months of age. Each child received physical and neurological examinations and a battery of behavioral assessments that included a visual habituation task, the Bayley Scales and the Object Permanence Scales. The groups did not differ significantly in frequency of suspect-abnormal neurological signs or in mean scores on the three behavioral measures. Despite the great within-group variances, performance on the behavioral measures was not related to maternal or neonatal characteristics. There were significantly more low PDI scores (predictors of developmental difficulties) among methadone subjects, particularly among methadone vs comparison males. These findings corroborate other studies that have shown 1) delayed motor development in methadone-exposed infants, 2) greater vulnerability of males to adverse environmental conditions, and 3) correlation between early methadone exposure and behavioral abnormalities in adult male rats. The significance of prenatal methadone exposure as a risk factor is discussed.

Pharmacologic observations on the neonatal withdrawal syndrome.

The relationship between a maternal dose of methadone and the incidence and severity of neonatal signs of withdrawal, placental transfer of drug, and the relationship between maternal and neonatal plasma levels of methadone were studied in 30 mothers and their infants. Plasma levels of methadone were analyzed using a gas chromatographic method. Our studies demonstrate that the relationship between maternal dose of methadone and the incidence of neonatal withrawal symptoms was closely related to the last maternal dose of methadone. The ratio of neonatal to maternal plasma concentrations of methadone was 2.2:1. Neonatal withdrawal symptoms appear to be related to individual variation in maternal metabolism of the drug, placental transfer of methadone, and most importantly, to the individual variations in the rate of excretion of methadone as reflected in the neonatal plasma t 1/2. At plasma levels of methadone greater than or equal to 0.06 mug/ml, the symptomatic patients appeared to be protected from withdrawal. When the plasma concentration fell below this level, withdrawal symptoms began within 24 hours.

Methadone-maintained mothers: 3-year follow-up of parental functioning.

A group of 57 methadone-maintained mothers and 31 matched drug-free controls were compared on their ability to provide adequate child care, capacity for satisfying interpersonal relationships, and motivation for self-improvement. Results indicate that, as a group, methadone mothers require more assistance in parenting, are more socially isolated, and are less likely to pursue vocational and educational activities. The interpersonal and environmental impact of poor parenting further compounds the effects of in utero exposure to methadone, placing these infants at high risk.

The response to overdrive pacing of triggered atrial and ventricular arrhythmias in the canine heart.

Although triggered activity has been identified in isolated atrial tissue with the use of cellular electrophysiologic techniques, there has been no identification of triggered atrial arrhythmias in situ. Moreover, it is unclear whether triggered rhythms of different causes and sites of origin in the heart exhibit uniform responses to pacing that might aid in their identification. We therefore studied arrhythmias induced by overdrive pacing in three canine preparations, and based the analysis of our results on guidelines derived from microelectrode studies. We studied ventricular tachycardias induced by ouabain or by anterior wall myocardial infarction and atrial (coronary sinus) arrhythmias induced by the infusion of epinephrine into the great cardiac vein. In the ouabain and postinfarction preparations, right ventricular epicardial pacing induced ventricular premature beats or tachycardias whose recovery intervals after cessation of pacing shortened and showed overdrive acceleration as pacing rate increased. The first postpacing beat displayed progressive fusion with the paced beats but transient entrainment could not be induced. In the coronary sinus, the recovery intervals of impulses induced by epinephrine and pacing decreased as the drive rate increased, and inducibility of the paced rhythms increased at faster drive rates. Thus, the recovery intervals of triggered activity induced in the coronary sinus are phenomenologically similar to those of infarct- and digitalis-induced triggered rhythms. This is the first demonstration of consistent behavior in response to pacing of diverse types of triggered activity. Considered in light of the failure to induce transient entrainment, the results emphasize the potential utility of pacing in clinical identification of triggered rhythms and their differentiation from reentry.

Prenatal cocaine exposure and the development of the human eye.

PURPOSE: The use of cocaine during pregnancy has been associated with congenital abnormalities of the developing eye. The authors report a prospective, controlled study of 40 cocaine-exposed and 40 nonexposed (control) preterm and full-term infants. METHODS: Detailed maternal and obstetric histories were obtained by chart review and interview. Infants with a positive urine toxicology screen for cocaine at birth or whose mothers tested positive for cocaine were recruited into the exposed group. Nonexposed infants were recruited at random from newborns admitted to the authors' nurseries. Mothers of these infants received routine prenatal care in the authors' clinics, and nonexposure was documented by maternal history and/or negative urine toxicologies that were available in 30% of these mother-infant pairs. General physical and ocular examinations, including measurement of axial length and intraocular pressure, were performed on all infants. RESULTS: Forty infants were recruited in each group, with gestational ages ranging from 25 to 42 weeks. Twenty-nine of the exposed infants and 26 of the control infants were full-term (gestational age, 37 weeks or older). A total of 160 eyes were examined. No differences were seen in the incidence of congenital anomalies, subconjunctival hemorrhages, retinal hemorrhages, or optic nerve abnormalities between the two groups. No differences in mean axial length (16.9 +/- 0.6 mm [exposed group] versus 17.1 +/- 0.7 mm [control group]) or intraocular pressure (15.4 +/- 3.8 mmHg [exposed group] versus 15.0 +/- 3.0 mmHg [control group]) were seen between full-term infants in both groups. Axial length correlated strongly with gestational age, birth weight, head circumference, and body length over the range of gestational ages evaluated in both groups. No effect of cocaine exposure on these correlations was demonstrated. The range of axial length was 12.1 to 18.0 mm in the exposed group and 12.4 to 18.6 mm in the control group. CONCLUSION: In this study group, no significant effect of prenatal cocaine exposure was seen on the infant eye. In both exposed and nonexposed groups, axial length measurements agreed closely with known statistical norms and correlated closely with other parameters of fetal growth.

Developmental changes in the effects of lidocaine and quinidine on the canine heart.

We studied the developmental changes that occur in the use-dependent effects of lidocaine and quinidine on the intact canine heart. At comparable intravenous dosages, adults showed higher total and free plasma lidocaine concentrations than young dogs, whereas for quinidine, the total and free levels were comparable. Lidocaine demonstrated a use-dependent depressant effect on intraventricular conduction in adults that was significantly greater than that in the young, and it significantly accelerated repolarization (QT interval) in the adult. In contrast, comparable effects of quinidine were seen on conduction in adult and young dogs, while repolarization was prolonged more in the young. These effects on conduction and repolarization in the adult and young hearts were explained by our earlier cellular electrophysiologic studies. Our findings indicate the following: (a) developmental changes in the cellular electrophysiologic effects of specific antiarrhythmic drugs are predictive of the effects in the in situ heart; (b) these effects are further modified by developmental differences in drug metabolism and protein binding; (c) developmental changes in the effects of one antiarrhythmic local anesthetic are not necessarily predictive of those for another; and (d) the effects of drugs on the adult heart may be, but are not necessarily, predictive of those in the young.

Beta adrenergic modulation of cardiac rhythm in a rat model of altered sympathetic neural development.

We previously have shown that treatment of neonatal rats (days 1-10) with Nerve Growth Factor (NGF) or its antibody (Ab) modifies alpha-adrenergic receptor-effector coupling, such that innervated hearts at day 10 show high levels of a 41 kDa GTP regulatory protein (G protein) that is a substrate for pertussis toxin and that links the alpha 1-receptor to the Na/K pump. This receptor-effector pathway results in alpha adrenergic-induced decreases in automaticity. In contrast, non-innervated hearts at day 10 show lower levels of the pertussis toxin sensitive G-protein and increases in automaticity induced by alpha-agonist. We now report the effects of administration of NGF, Ab or placebo on beta-adrenergic receptor-effector coupling in neonatal rats. Rats were administered NGF, Ab or placebo on days 1-10 of life. On day 10, the beta-receptor number and affinity and the stimulatory G-protein, Gs, were equivalent across groups. Moreover, the ventricular automatic response to beta-adrenergic receptor stimulation was equivalent across groups suggesting there was no change in receptor-effector coupling as a result of the difference in innervation. These results on beta-adrenergic receptor-effector coupling considered in light of our prior studies on alpha-adrenergic coupling suggest that the development of sympathetic innervation is more a determinant of alpha than beta adrenergic modulation of ventricular rhythm.