Robert F. Covert

Special relationships between fetal inflammatory response syndrome and bronchopulmonary dysplasia in neonates

Abstract Objective: To confirm previous known relationships between Fetal Inflammatory Response Syndrome (FIRS) and neonatal bronchopulmonary dysplasia (BPD) and to present information on previously unknown special relationships between inflammatory variables and BPD. Study design: At delivery, we obtained biological specimens including umbilical cord venous blood for plasma interleukin-6 levels, as well as placental histology and bacteriology. Among other neonatal outcomes, we collected prospective information on BPD. Results: Of 141 newborns in the study, 16 had BPD; 79% of these had antecedent FIRS, 27% of those without FIRS had BPD. By multivariable regression, only very low birth weight (adjusted [adj] odds ratio [OR] 32.0, 95% Confidence Interval [CI] 5.0 to positive infinity) and FIRS (adj OR 5.7, 95% CI 1.1 to 42.3) remained significant risk factors. Escherichia coli, perhaps due to its pyogenic nature (strongly elicits inflammatory responses), may have had a special relationship with BPD. Conclusions: In our data, FIRS and neonatal BPD are highly associated. It is possible that certain pyogenic bacteria in the chorioamnion space may be implicated more often than others. Condensation: Neonates having Fetal Inflammatory Response Syndrome at delivery may later develop BPD. Pyogenic bacteria, such as Escherichia coli, may be implicated more frequently.

Umbilical cord serum ionized magnesium level and total pediatric mortality.

OBJECTIVE To estimate whether higher magnesium levels in umbilical cord blood at delivery are associated with increased total pediatric (fetal + neonatal + postneonatal) mortality. METHODS During the Magnesium and Neurologic Endpoints Trial, in addition to randomizing mothers having preterm labor into arms containing magnesium sulfate, other tocolytic agents, or saline controls, we obtained biologic specimens at delivery, including umbilical cord venous blood on which was determined the serum ionized magnesium level using the AVL 988–4 analyzer (Graz, Austria). Laboratory results were then matched with the pediatric mortalities. The study power was based on the anticipated reductions in neonatal intraventricular hemorrhage related to magnesium usage from 18.9% to 4.4%. For &agr; = .05, 1 − β (power) = 80%, two tailed, the total number of infants needed would be 140. RESULTS Of 149 mothers who gave permission for randomization, ionized magnesium levels were available for 82 children. Seven deaths occurred (one immediately before delivery, three as neonates, and three in the postneonatal period). The median level of ionized magnesium among the seven dead children was 0.76 mmol/L; among the 75 survivors, the median level of ionized magnesium was 0.55 mmol/L (Mann‐Whitney U test, P = .03). Using multivariable logistic regression analysis, the association remained statistically significant when controlling for possible confounding factors (adjusted odds ratio 7.7, 95% confidence interval 1.2, 47.6, P = .03). CONCLUSION These findings of a dose response between serum ionized magnesium and deaths in children increase our concern about the improper use of tocolytic magnesium.

Analysis of meconium for cocaine in neonates.

A solid-phase extraction method was developed for the extraction of first-day meconium samples from premature infants of cocaine-dependent mothers. Extracts were analysed by high-performance liquid chromatography and gas chromatography-mass spectrometry for cocaine and its metabolites. Control stools showed no drug. Meconium from cocaine-dependent mothers showed cocaine in the range 0.1-0.78 micrograms/g. Benzoylecgonine, ecgonine and ecognine methyl ester were not present in the samples, which suggests that the metabolism of cocaine in the premature neonate is limited.

Detection of Cocaine, Norcocaine, and Cocaethylene in the Meconium of Premature Neonates

Our objective was to investigate the methodologic detection of cocaine abuse during pregnancy by determining the viability of meconium analysis for cocaine and its metabolites using chromatographic procedures as an alternative to urine testing using enzyme multiplied immunoassay technique. Our design was as follows: meconium and urine were taken from 106 very low birthweight premature babies. Meconium analysis for cocaine and its metabolites using extraction and chromatographic analysis was compared with the criterion standard immunoassay testing for urine. The work was carried out at The University of Chicago Hospital, Department of Pediatrics and the University of Illinois at Chicago, Department of Pharmacodynamics. Our patients were very low birthweight, premature babies (mean birthweight 1109 g; mean gestational age 29.1 weeks). Gender was evenly divided between male and female. The outcome measures were as follows: two active metabolites, norcocaine and cocaethylene, were detected in the meconium, but not in the urine, of some of the neonates. Determination of cocaine exposure in the newborn influenced assignment of babies in research studies as well as psychosocial evaluation and subsequent treatment of the neonate. Our results were: of the 106 meconium samples analyzed, 21 (19.8%) were positive for cocaine (n = 19, 0.24-0.78 mg/kg), norcocaine (n = 7, 0.10-0.56 mg/kg), cocaethylene (n = 1, 0.12 mg/kg) or combinations thereof. Benzoylecgonine was not detected in any of the samples. Of the urine samples analyzed by immunoassay, only 8 (7.5%) were positive for cocaine metabolites. We conclude that meconium is a better sample than urine for determining cocaine exposure in utero.(ABSTRACT TRUNCATED AT 250 WORDS)

The association of coagulase-negative staphylococci isolated from the chorioamnion at delivery and subsequent development of cerebral palsy.

OBJECTIVE: To find out whether there is an association between cultures positive for coagulase negative staphylococci (CONS) taken from babies in the Neonatal Intensive Care Unit (NICU) and a subsequent outcome of cerebral palsy.STUDY DESIGN: At delivery, we obtained cultures from the chorioamnion space and, when medically indicated, we obtained bacterial cultures from children in the NICU. Surviving neonates underwent final examination for cerebral palsy at age 18 months.RESULTS: Of six children in the Magnesium and Neurologic Endpoints Trial who had cerebral palsy, chorioamnion cultures had been obtained for five of six. Four of these five children (80%) had CONS-positive cultures, whereas 26 of 102 (25%) children without cerebral palsy were CONS positive (p=0.02). In the NICU, of children with cerebral palsy, the prevalence of culture-proven CONS was 80% (4/5); for those without cerebral palsy, the prevalence was 17% (15/86) (p=0.01). Using multivariable logistic regression to control for confounding, CONS in the chorioamnion remained significant (adjusted odds ratio [OR] 37.7, 95% confidence interval [CI] 3.0 to +∞; p=0.003). However, when controlled for extremely low birth weight, nonvertex presentation, and being on a ventilator ≥20 days, the association between culture-proven CONS in the NICU and cerebral palsy became insignificant (adjusted OR 3.0, 95% CI 0.2 to +∞; p=0.42).CONCLUSION: CONS in the chorioamnion space are associated with cerebral palsy, but in these data, CONS in the NICU are not found to be associated with cerebral palsy.

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

Group B β-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 ± 109 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.

Association between Lenticulostriate Vasculopathy (LSV) and Neonatal Intraventricular Hemorrhage (IVH)

OBJECTIVES: To determine whether there is an unconfounded association between neonatal intraventricular hemorrhage (IVH) and lenticulostriate vasculopathy (LSV (also known as thalamostriate or mineralizing vasculopathy)).STUDY DESIGN: During the conduct of the Magnesium and Neurologic Endpoints Trial (MagNET), a randomized controlled trial involving maternal, hence fetal, exposure to antenatal magnesium sulfate in the context of preterm labor, head ultrasounds were obtained for each of the surviving neonates. Because of our previous experience in the diagnosis of LSV, when ascertaining the presence of IVH, as called for by the research protocol of our study, the presence or absence of LSV was also determined.RESULTS: We found LSV to be relatively prevalent (10% (14 of 140) among surviving babies). More importantly, it was significantly associated with the occurrence of neonatal IVH, even when controlled for possible confounding (adjusted OR 9.8, 95% confidence interval 1.3 to 73.1; p=0.03).CONCLUSION: Given the known relationships between IVH and neonatal morbidity and mortality, the finding of a statistically significant association between neonatal IVH and LSV may suggest more substantial implications for the latter than previously believed.

Three Different Strains of Heat-Killed Group B β-Hemolytic Streptococcus Cause Different Pulmonary and Systemic Hemodynamic Responses in Conscious Neonatal Lambs

ABSTRACT: Although group Bβ -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 × 109 colonyforming units, i.v.). All three GBS strains caused dosedependent 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 109 colonyforming 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.

Chloralose Alters Both Basal Hemodynamics and Cardiovascular Responses to Alveolar Hypoxia in Chronically Instrumented, Spontaneously Breathing Lambs'

ABSTRACT: 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<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% F1O2). 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

Thalamostriate Vasculopathy in Neonates in the MAGnet Trial: Association with Placental Funisitis and Intraventricular Hemmorrhage

Thalamostriate Vasculopathy in Neonates in the MAGnet Trial: Association with Placental Funisitis and Intraventricular Hemmorrhage