Rita M. Ryan

Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation.

The optimal Fio2 during neonatal resuscitation is a subject of controversy. The effect of exposure to high levels of inspired oxygen on pulmonary arterial (PA) contractility is not known. We studied differences in PA vasoreactivity in term lambs initially ventilated with 21% or 100% oxygen, followed by continued ventilation using oxygen as needed for 24 h, or ventilated with 100% oxygen for 24 h and room air breathing 1-d-old lambs. Term lambs were delivered by cesarean section, intubated, and ventilated with 21% (21%Res) or 100% oxygen (100%Res) for the first 30 min of life. Subsequently, the ventilator Fio2 was adjusted to maintain a Pao2 between 45 and 65 mm Hg for 24 h. Five lambs were ventilated continuously with 100% oxygen (100%24h). Six spontaneously breathing newborn lambs (RA Spont) were studied for comparison. Lambs were killed at 24 h of life and PA rings were isolated and contracted with norepinephrine (NE) and KCl and some were relaxed with A23187 and SNAP in tissue baths. NE and KCl induced contractions were highest in PA isolated from 100%24h lambs, and were significantly higher in 100%Res lambs than PA from 21%Res lambs. Contraction responses in PA from RA Spont lambs were similar to 21%Res lambs. Relaxations to A23187 and SNAP were similar among all ventilated groups. PA contractility to NE and KCl is increased following both brief (30 min) and prolonged (24 h) exposure to 100% oxygen during mechanical ventilation. In contrast, normoxic resuscitation and ventilation do not increase PA contractility.

Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen.

The effect of resuscitation with varying levels of O2 on pulmonary hemodynamics at birth is not well known. We hypothesized that the decrease in pulmonary vascular resistance (PVR) and subsequent response to pulmonary vasoconstrictors and vasodilators will differ following resuscitation with 21%, 50%, or 100%O2 for 30 min at birth in normal term lambs. Lambs at 141 d gestation were delivered by cesarean section and ventilated with 21% (21% Res; n = 6), 50% (50% Res; n = 6), or 100% O2 (100% Res; n = 7) for 30 min followed by ventilation with 21% O2 in all three groups. A greater decrease in PVR was seen with 50% and 100% O2 ventilation than with 21% O2 (0.21 ± 0.02, 0.21 ± 0.02, and 0.34 ± 0.05 mm Hg/mL/min/kg, respectively). Subsequent pulmonary vasoconstriction to hypoxia (10% O2) and the thromboxane analog U46619 (0.5 and 1 μg/kg/min) was similar in all three groups. After inducing a stable elevation in PVR with U46619, impaired pulmonary vasodilation to inhaled NO (59 ± 4, 65 ± 4, and 74 ± 5% of baseline PVR with 21, 50, and 100%Res, respectively) and acetylcholine infusion (67 ± 8, 75 ± 6, and 87 ± 4% of baseline PVR with 21, 50, and 100%Res, respectively) and rebound pulmonary hypertension following their withdrawal were observed in the 100%Res group. We conclude that, while ventilation with 100% O2 at birth results in a greater initial decrease in PVR, subsequent pulmonary vasodilation to NO/acetylcholine is impaired.

Characteristics of pulmonary hypertension in preterm neonates

Objective:Characteristics of preterm infants who develop pulmonary hypertension (PHT) and their response to inhaled nitric oxide (iNO) are not well described. Our objective was to identify risk factors for PHT in infants <37 weeks gestational age (GA) and to evaluate their response to iNO.Study design:A retrospective chart review was conducted in infants <37 weeks GA born from July/2000 to October/2005 who had an echocardiographic diagnosis of PHT in the first 4 weeks of life. A comparison non-PHT group was generated matched for GA and birth date. Data on prenatal and postnatal characteristics, response to iNO and mortality were collected.Results:Low Apgar scores, preterm premature rupture of membranes, oligohydramnios, pulmonary hypoplasia and sepsis were independently predictive of PHT. Mortality was significantly higher in the PHT group (26.2% versus 4.1%; P<0.0001) compared to the control group. Low birth weight, severe intraventricular hemorrhage and male sex were significantly associated with death in infants with PHT. Thirty-seven percent (23/61) of infants with PHT were treated with inhaled NO. Infants <29-week GA had poor response to iNO and the response to iNO increased with GA (P<0.02).Conclusions:Low Apgar scores, oligohydramnios and pulmonary hypoplasia are associated with the development of PHT in premature infants. The percentage of infants responding to iNO increases with advancing GA.

Differential expression of VEGF mRNA splice variants in newborn and adult hyperoxic lung injury

Lung development and repair of hyperoxic injury require closely regulated growth and regeneration of alveolar capillaries. Vascular endothelial growth factor (VEGF), a mitogen for endothelial cells, is expressed by alveolar epithelial cells. Alternative splicing of VEGF mRNA results in isoforms of varying mitogenicity and solubility. We examined changes in the proportions of the VEGF splice variant mRNAs in rabbit lung development and in control, oxygen-injured, and recovering newborn and adult rabbit lungs. The proportion of the 189-amino acid VEGF mRNA, which codes for an isoform that binds to the extracellular matrix, increased fivefold during development (from 8% of total VEGF message at 22 days gestation to 40% in 10-day newborn lungs; P < 0.001). During neonatal oxygen injury, its expression declined from 38 to 8% of VEGF message (P < 0.002) and returned to the control value in recovery. A similar pattern was observed in adults. VEGF protein in lung lavage fluid increased slightly during hyperoxia, declined to barely detectable levels at the 50% lethal dose time point, and increased 10-fold (newborn) or up to 40-fold (adult) in recovering animals. We conclude that alternative splicing may have important roles in the regulation of VEGF activity in developing and injured lungs.Lung development and repair of hyperoxic injury require closely regulated growth and regeneration of alveolar capillaries. Vascular endothelial growth factor (VEGF), a mitogen for endothelial cells, is expressed by alveolar epithelial cells. Alternative splicing of VEGF mRNA results in isoforms of varying mitogenicity and solubility. We examined changes in the proportions of the VEGF splice variant mRNAs in rabbit lung development and in control, oxygen-injured, and recovering newborn and adult rabbit lungs. The proportion of the 189-amino acid VEGF mRNA, which codes for an isoform that binds to the extracellular matrix, increased fivefold during development (from 8% of total VEGF message at 22 days gestation to 40% in 10-day newborn lungs; P < 0.001). During neonatal oxygen injury, its expression declined from 38 to 8% of VEGF message ( P < 0.002) and returned to the control value in recovery. A similar pattern was observed in adults. VEGF protein in lung lavage fluid increased slightly during hyperoxia, declined to barely detectable levels at the 50% lethal dose time point, and increased 10-fold (newborn) or up to 40-fold (adult) in recovering animals. We conclude that alternative splicing may have important roles in the regulation of VEGF activity in developing and injured lungs.

Oxygen Concentration and Pulmonary Hemodynamics in Newborn Lambs with Pulmonary Hypertension

The effect of oxygen concentration on lowering pulmonary vascular resistance (PVR) during resuscitation in a model of persistent pulmonary hypertension of the newborn (PPHN) is not known. PPHN was induced in fetal lambs by ductal ligation 9 d before delivery. After delivery by cesarean section, resuscitation of PPHN lambs with 21%, 50%, or 100% O2 (n = 6 each) for 30 min produced similar decreases in PVR. Lambs were then ventilated with 50% O2 for 60 min and exposed to inhaled nitric oxide (iNO, 20 ppm). Initial resuscitation with 100% O2 significantly impaired the subsequent response to iNO compared with 21% O2 (42 ± 9% vs 22 ± 4% decrease from baseline PVR). Finally, each lamb was randomly and sequentially ventilated with 10%, 21%, 50%, or 100% O2. PVR decreased with increased concentrations of inhaled O2 up to 50%, there being no additional decrease in PVR with 100% O2. When PVR was correlated with Pao2, the maximal change in PVR was achieved at Pao2 values <60 mm Hg. We conclude that resuscitation with 100% O2 does not enhance pulmonary vasodilation compared with 21% and 50% O2, but impairs the subsequent response to iNO in PPHN lambs. Hypoxia increases PVR but hyperoxia does not confer significant additional pulmonary vasodilation in lambs with PPHN.

Inflammatory Mediators in the Immunobiology of Bronchopulmonary Dysplasia

Inflammation is important in the development of bronchopulmonary dysplasia (BPD). Polymorphonuclear cells and macrophages and proinflammatory cytokines/chemokines denote early inflammation in clinical scenarios such as in utero inflammation with chorioamnionitis or initial lung injury associated with respiratory distress syndrome or ventilator-induced lung injury. The persistence and non-resolution of lung inflammation contributes greatly to BPD, including altering the lung’s ability to repair, contributing to fibrosis, and inhibiting secondary septation, alveolarization, and normal vascular development. Further understanding of the role of inflammation in the pathogenesis of BPD, in particular, during the chronic inflammatory period, offers us the opportunity to develop inflammation-related prevention and treatment strategies of this disease that has long-standing consequences for very premature infants.

THE IMPACT OF PRENATAL DRUG EXPOSURE ON THE NEONATE

Several social or recreational drugs singly or together have demonstrated effects on the fetus and neonate, with those effects extending into adulthood. The use of recreational drugs during pregnancy remains a major health problem, with adverse effects including higher rates of fetal distress and demise, lower Apgar scores, growth retardation, and adverse neurodevelopmental outcome. Ethanol has the most profound effects, with physical stigmata of the drug seen in one third of exposed infants. In children without the affected physical appearance, profound neurodevelopmental sequelae have been demonstrated. Other drugs, such as cocaine, heroin, amphetamines, and nicotine, have been associated with impaired fetal growth and acute withdrawal during the neonatal period. Subsequently, these infants and children have an increased risk for altered neurodevelopment and long-term health status. Long-term follow-up and assessment are essential. The risk of neonatal withdrawal or abstinence syndrome is greatest with narcotic drugs but has been found to occur in neonates following exposure to cocaine, nicotine, and amphetamines. Early treatment with tincture of opium, paregoric, or phenobarbital is crucial. Assessment of the overall health status of the infant should include growth parameters, signs and symptoms of infection (especially hepatitis, syphilis, and immunodeficiency viruses), and neurobehavioral function. Such assessments should not be limited to the newborn period, as neurodevelopmental sequelae may not be manifest until later in infancy and childhood. In addition, evaluation of the social milieu is warranted because of the increased risk for neglect and abuse of drug-exposed infants and children. Early intervention, maternal drug rehabilitation treatment, and parenting classes are frequently prescribed, but their efficacy is variable. Further investigations should study the potential benefits of these recommendations.

Transient tachypnea of the newborn.

1. Lokesh Guglani, MD* 2. Satyan Lakshminrusimha, MD* 3. Rita M. Ryan, MD* 1. *Department of Pediatrics, University at Buffalo, Women and Childrens Hospital of Buffalo, Buffalo, NY The birth of a child is preceded by several changes to prepare for the transition from intrauterine to extrauterine life. The five major events that establish the lungs as the organ of gas exchange at birth include: clearance of fetal lung fluid, establishment of spontaneous breathing, decrease in pulmonary vascular resistance, release of surfactant, and cessation of the right-to-left shunting of venous blood returning to the heart. (1) During fetal life, fluid is secreted into the alveoli to maintain normal growth and function, (2) and fetal lung volume approximates the functional residual capacity that would be established once air breathing is initiated. (3) Clearance of lung fluid can be affected by several factors, and its impairment culminates in tachypnea and could necessitate transfer to an intensive care unit for monitoring and respiratory support. Transient tachypnea of the newborn (TTN), which is believed to result from incomplete resorption of fluid from the lungs of the newborn, presents an important diagnostic and therapeutic dilemma in the newborn nursery. This review focuses on TTN, with emphasis on fetal lung fluid mechanics and possible mechanisms of fetal lung fluid resorption as well as its pathophysiology, clinical and diagnostic features, and management. Some neonatologists refer to TTN as retained fetal lung liquid syndrome. The lungs are filled with liquid in utero, which increases from 4 to 6 mL/kg body weight at mid-gestation to about 30 to 50 mL/kg near term in fetal lambs. (4) Jost and Policard (5) first demonstrated that fluid within the fetal lung arises from the lung and contributes to the volume of amniotic fluid. The rate of production ranges from 2 mL/kg per hour in the initial part of pregnancy to 5 mL/kg per hour at term, thereby contributing one third to one half of the daily turnover of amniotic fluid. …

Meconium analysis for improved identification of infants exposed to cocaine in utero

We screened anonymously all mothers and infants born during a 3 1/2-month period to determine the prevalence of intrapartum cocaine use, test the maternal characteristics that are specific predictors of intrauterine cocaine exposure (IUCE), and compare the sensitivity of infant urine versus meconium samples for identification of IUCE. Of 1237 live births during the study period, a sample was obtained from 1201 mother-infant pairs. The overall prevalence of documented intrapartum cocaine exposure was 66 (5.5%) of 1201 pairs. Previously developed drug screening guidelines had a sensitivity of 89% for detecting IUCE in infants. Direct comparisons of samples from the same mother-infant pair revealed that there were no cases in which cocaine was found in infant urine but not in meconium; however, infant urine testing missed 25% of the infants who had positive findings in meconium. We conclude that (1) meconium testing was more likely than urine testing to identify an infant with IUCE, detecting an additional 33%; (2) there was significant maternal cocaine use (5.5%) in a teaching hospital with a mixed patient population; (3) maternal characteristics known to identify infants at risk of having IUCE were useful in our population; and (4) IUCE of neonates admitted to the neonatal intensive care unit was more common than that of infants admitted to the regular newborn nursery.

Growth factors in lung development.

Organized and coordinated lung development follows transcriptional regulation of a complex set of cell-cell and cell-matrix interactions resulting in a blood-gas interface ready for physiologic gas exchange at birth. Transcription factors, growth factors, and various other signaling molecules regulate epithelial-mesenchymal interactions by paracrine and autocrine mechanisms. Transcriptional control at the earliest stages of lung development results in cell differentiation and cell commitment in the primitive lung bud, in essence setting up a framework for pattern formation and branching morphogenesis. Branching morphogenesis results in the formation of the conductive airway system, which is critical for alveolization. Lung development is influenced at all stages by spatial and temporal distribution of various signaling molecules and their receptors and also by the positive and negative control of signaling by paracrine, autocrine, and endocrine mechanisms. Lung bud formation, cell differentiation, and its interaction with the splanchnic mesoderm are regulated by HNF-3beta, Shh, Nkx2.1, HNF-3/Forkhead homolog-8 (HFH-8), Gli, and GATA transcription factors. HNF-3beta regulates Nkx2.1, a transcription factor critical to the formation of distal pulmonary structures. Nkx2.1 regulates surfactant protein genes that are important for the development of alveolar stability at birth. Shh, produced by the foregut endoderm, regulates lung morphogenesis signaling through Gli genes expressed in the mesenchyme. FGF10, produced by the mesoderm, regulates branching morphogenesis via its receptors on the lung epithelium. Alveolization and formation of the capillary network are influenced by various factors that include PDGF, vascular endothelial growth factor (VEGF), and retinoic acid. Epithelial-endothelial interactions during lung development are important in establishing a functional blood-gas interface. The effects of various growth factors on lung development have been demonstrated by gain- or loss-of-function studies in null mutant and transgenic mice models. Understanding the role of growth factors and various other signaling molecules and their cellular interactions in lung development will provide us with new insights into the pathogenesis of bronchopulmonary dysplasia and disorders of lung morphogenesis.