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Objective: To examine the use and perceived safety of stylets for neonatal intubation in a cohort of providers in the United States., Study Design: A cross-sectional survey was sent to members of the American Academy of Pediatrics Section on Neonatal-Perinatal Medicine., Result: A total of 640 responses were received. 57% reported using a stylet 'every time' or 'almost every time' they intubated. The preferred stylet bend was a smooth bend of <30 degrees. 71% of respondents believed that stylets were safe. Reported complications from stylet use included tube dislodgement during stylet removal (32%), airway injury with bleeding (9%), and tracheal perforation (2%)., Conclusion: Stylet use was common. There was fair consistency on preference for stylet bend and position. Stylet use was believed to be safe, but complications were observed by many respondents. Additional studies are needed to examine the risks and benefits of stylet use during neonatal intubation.

Objective: Nasal-tragus length (NTL) estimates of endotracheal tube (ETT) depth are replacing weight-based estimates for endotracheal tube depth in neonates requiring endotracheal intubation. Existing neonatal simulators were designed before interest in using the NTL, and may lack fidelity in this measurement. The objective of this study is to evaluate the accuracy of the adjusted NTL formula and the Neonatal Resuscitation Program (NRP) gestational age/weight-based ETT depth chart in predicting proper endotracheal tube insertion depth in a cohort of neonatal simulators., Study Design: The NTL and appropriate intubation depth to the mid-trachea were measured for 11 commonly used neonatal intubation simulators., Results: The NTL+1 cm formula incorrectly estimates the mid-tracheal depth in 82% of simulators, and the weight-based chart incorrectly estimates depth in 75% of test simulators. Only one simulator experienced a mainstem intubation with ETT insertion to the depth predicted by the NTL+1 cm formula., Conclusions: The majority of neonatal resuscitation simulations lacked physical fidelity with regard to mid-tracheal ETT insertion depth. The NRP gestational age/weight-based chart outperformed the NTL+1 cm formula but still resulted in endotracheal tube misplacement in the majority of neonatal simulators. The majority of simulators had adequate functional fidelity using either method for ETT depth estimation.

Intraventricular hemorrhage (IVH) is a common and potentially devastating adverse outcome affecting up to 30% of preterm infants. β-Lactam antibiotics affect platelet activation through interaction with platelet surface receptors. The objective of this study was to evaluate an association between ampicillin use and the development of IVH in preterm infants. This was a single-center and a retrospective case-control study of preterm low-birth-weight infants diagnosed with IVH and matched controls without IVH. Conditional logistic regression was performed on 10 clinical features from the first week of life to evaluate the association with IVH. Data were obtained for 174 subjects with no significant differences between groups in demographic factors and level of illness indicators. Earlier administration of the first dose of ampicillin was associated with increased odds of developing IVH (odds ratio [OR]: 0.95, p = 0.028) when controlling for other common associations. Longer courses of ampicillin were not significantly associated with the development of IVH (OR: 1.13, p = 0.089). The odds of developing IVH in our population increased with earlier, but not longer initial courses of ampicillin. Further research into the associations with IVH should include the assessment of ampicillin dose, timing, and duration., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Proficiency in airway management is critical for neonatal health-care professionals. Simulation is a proven method to improve airway management skills. Skills transfer from simulation to the real life requires simulators with appropriate physical and functional fidelity., Study Design: A cohort of neonatal health-care professionals evaluated eight different neonatal airway simulators for physical and functional fidelity., Result: Twenty-seven subjects completed 151 simulator evaluations. Significant differences were found between the simulators evaluated (P<0.001). The manikins with the highest fidelity scores were the SimNewB, Newborn Anne and Premature Anne (Laerdal Medical). The task trainers with the highest fidelity scores were the Neonatal Intubation Trainer (Laerdal Medical) and the Newborn Airway Trainer (Syndaver Labs)., Conclusion: Simulator fidelity is an important aspect of simulation training, but is rarely evaluated. The results of this study can aid in choosing the best simulators for training and research, and provide feedback to the industry to guide future simulator development.

Objective: The purpose of this study was to assess the Adverse Outcome Index perinatal quality indicator system that was derived from administrative data., Study Design: Adverse events were identified for 10 component measures; the Adverse Outcome Index was calculated by the National Perinatal Information Center from 42 months of administrative data. After retrospective chart review, we estimated positive predictive value for 10 measures that were obtained by corrected calculations of Adverse Outcome Index., Results: Positive predictive values were 86-100% in 7 indicators, with lower values in 3 indicators: neonatal death, 0/2 fetuses; inborn birth trauma, 22/33 infants (67%); and maternal return to the operating room, 16/33 women (48.5%). In term admission to the neonatal intensive care unit, 107 false negatives were identified, with a negative predictive value of 45%., Conclusion: Indicator positive predictive value was variable. Performance can be strengthened by methods to identify both false-positive and false-negative adverse events that would include chart review and some measure specification revisions to improve alignment with original indicator intent. Interhospital comparison application requires further study., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Objectives: To determine the risks and benefits associated with the transfusion of packed red blood cells (PRBCs) in extremely low birth weight (ELBW) infants. We hypothesized that when ELBW infants underwent transfusion with the University of Washington Neonatal Intensive Care Unit (NICU) 2006 guidelines, no clinical benefit would be discernible., Study Design: We conducted a retrospective chart review of all ELBW infants admitted to the NICU in 2006. Information on weight gain, apnea, heart rate, and respiratory support was collected for 2 days preceding, the day of, and 3 days after PRBC transfusion. The incidence, timing, and severity of complications of prematurity were documented., Results: Of the 60 ELBW infants admitted to the NICU in 2006, 78% received PRBC transfusions. Transfusions were not associated with improved weight gain, apnea, or ventilatory/oxygen needs. However, they were associated with increased risk of bronchopulmonary dysplasia, necrotizing enterocolitis, and diuretic use (P < .05). Transfusions correlated with phlebotomy losses, gestational age, and birth weight. No association was found between transfusions and sepsis, retinopathy of prematurity, or erythropoietin use., Conclusions: When our 2006 PRBC transfusion guidelines were used, no identifiable clinical benefits were identified, but increased complications of prematurity were noted. New, more restrictive guidelines were developed as a result of this study.

Objective: To compare reports of medical errors in hospitalized children submitted using an electronic, anonymous reporting system with those submitted via traditional incident reports., Study Design: During the 3-month study period in 2003, reports of medical errors from 2 units at a large children's hospital were made using an electronic, anonymous system. Three reviewers independently evaluated each report and determined whether the events described constituted a medical error. An identical procedure was used to categorize medical error data collected via incident reports from the 2 study units from 1999 to 2002., Results: A total of 146 reports were made using the anonymous system, 131 of which documented medical errors. The rate of reporting medical errors with the anonymous system was 2.41/100 patient-days. The rate of reporting medical errors via incident reports in 1999-2002 was 2.40/100 patient-days. However, 33.8% of all incident reports dealt with mislabeled laboratory specimens; after excluding these reports, the rate of medical errors documented via incident reports was 1.56/100 patient-days. The rate of reporting was significantly higher with the anonymous system (rate ratio 1.54, 95% confidence interval 1.26, 1.90). With the anonymous system, 25.2% of reported medical errors were near-misses compared with 12.6% of the errors reported with the incident report system (P = .001)., Conclusions: Implementation of the anonymous reporting system with training was associated with a statistically significant increase in the rate of reported medical errors. The reporting of near-miss events was significantly increased, suggesting this may be a useful format for gathering data on this type of medical error., ((c) 2007 Society of Hospital Medicine.)

Objective: Zinc protoporphyrin/heme ratio (ZnPP/H) has been well established as an indicator of functional iron deficiency in subjects 6 months of age to adult. The primary objective of this study was to establish normative values for ZnPP/H in NICU patients and secondarily to explore the utility of this test as an indicator of iron deficiency in neonates. Study design ZnPP/H and complete blood counts were obtained weekly on consecutive NICU patients. Gestational age, growth variables, iron supplementation, erythropoietin treatment, and blood transfusions were documented. Results are reported as mean +/- SD. A value of P <.05 was considered significant., Results: ZnPP/H ratios (n = 639) were evaluated from 143 infants. During the first week of life, ZnPP/H was inversely correlated with gestational age (n = 78, P <.001, r = -0.72). Maternal diabetes, growth retardation, and exposure to chorioamnionitis were independent risk factors for high ZnPP/H. Both iron supplementation and blood transfusion decreased ZnPP/H (P <.001). Erythropoietin treatment was associated with an increase in reticulocyte count and ZnPP/H (P <.001)., Conclusions: ZnPP/H is inversely correlated with gestational age, and the range in all newborn infants is higher than in adults. ZnPP/H is elevated in certain infant subpopulations, which suggests that they may require additional iron supplementation.

Objective: To study traditional risk factors and the intergenerational risk factor maternal low birth weight (LBW) for respiratory distress syndrome (RDS) in infants in multiple ethnic groups., Methods: The population-based database consists of hospital records linked to Washington state maternal and infant vital records. Four racial-ethnic groups were studied, whites, blacks, Native Americans, and Hispanics. Poisson regression models were used to estimate relative risks of various factors for RDS., Results: Rates for RDS were whites 1.2%, blacks 1.9%, Native Americans 1.3%, and Hispanics 1.0%. Maternal LBW was associated with increased relative risk (RR) for RDS in whites (2.6, 95% confidence interval [CI] 1.6, 4.2) and blacks (3.3, 95% CI 1.9, 5.6) for infants born vaginally. Compared with mothers of normal infants, birth weights of mothers of infants with RDS and delivered vaginally were significantly lower in whites, blacks, and Native Americans. The association of maternal LBW with RDS persisted in blacks even when multiple risk factors were added to the model (RR 2.4; 95% CI 1.1, 5.1)., Conclusion: The association of maternal LBW with RDS is probably due in part to the association of maternal LBW with infant LBW and preterm birth. The strong persistent association of maternal LBW with RDS in blacks suggests that improvement of perinatal outcomes in that group will require improvement of long-term birth weight distribution.

Unlabelled: Induction of TGF-beta1 by the matricellular protein SPARC in a rat model of glomerulonephritis., Background: SPARC has been implicated as a counteradhesive and antiproliferative protein associated with deposits of extracellular matrix in renal disease., Method: We have examined the effect of recombinant SPARC containing a C-terminal His tag (rSPARC) in an acute model of mesangial cell injury that is induced in the rat by an antibody against the Thy1 antigen on the mesangial cell membrane. The recombinant protein was administered 24 hours after the induction of nephritis and was infused through day 4., Results: rSPARC was localized to the renal glomeruli of rats treated with anti-Thy1 antibody. Type I collagen and fibronectin, as well as transforming growth factor-beta1 (TGF-beta1), were increased at day 5 in rats treated with rSPARC (N = 4, P < 0.05 vs. delivery buffer), but only minimal effects were seen on mesangial cell and endothelial cell proliferation. In primary cultures of rat mesangial cells, infusion of rSPARC was associated with increases in TGF-beta1 mRNA and in total, secreted TGF-beta1 protein., Conclusions: rSPARC stimulates expression of TGF-beta1 both in vitro and in vivo. Given the closely regulated expression of SPARC, TGF-beta1, and type I collagen in several animal models of glomerulonephritis, we propose that SPARC could be one of the major mediators of the induction of TGF-beta1 in renal disease.

Perfluorochemical (PFC) liquids have both low surface tension and a high capacity to dissolve O2 and CO2, and have been shown to improve gas exchange and lung compliance in animal models of lung injury. We have previously demonstrated that perflubron and other PFC liquids enhance transgene expression in lungs of spontaneously breathing normal rodents after intratracheal instillation of either adenoviral or liposomal vectors followed by a single instillation of PFC liquid. We reasoned that PFC liquids may also be useful for enhancing transgene expression in abnormal lungs. GM-CSF knockout mice develop chronic accumulation of surfactant lipids and proteinaceous material in alveolar spaces and serve as a useful model of chronic alveolar filling. Intratracheal instillation of the adenoviral vector Adlac-Z resulted in patchy in situ distribution of beta-Gal activity, predominantly in larger proximal airways. In contrast, in mice instilled with Adlac-Z followed by instillation of a single dose of perflubron (10 ml/kg body weight), increased expression was observed in distal airway and alveolar epithelial cells. In particular, expression was observed in epithelial cells of debris-filled alveoli. Spectrophotometric measure of quantitative beta-Gal activity in lung homogenates demonstrated increased activity in lungs of mice receiving Adlac-Z plus perflubron compared with lungs of animals receiving Adlac-Z alone. These studies demonstrate that use of perflubron enhances transgene expression in lungs of animals with a chronic alveolar filling process. This approach may be applicable for gene delivery in diseases marked by chronic airway or alveolar filling such as cystic fibrosis.

Secreted protein acidic and rich in cysteine (SPARC) has been shown to be coexpressed with type I collagen in tissues undergoing remodeling and wound repair. We speculated that SPARC is required for the accumulation of collagen in lung injury and that its absence would attenuate collagen accumulation. Accordingly, we have assessed levels of collagen in SPARC-null mice in an intratracheal bleomycin-injury model of pulmonary fibrosis. Eight- to ten-week-old SPARC-null and wild-type (WT) mice received bleomycin (0.0035 U/g) or saline intratracheally and were subsequently killed after 14 days. Relative levels of SPARC mRNA were increased 2.7-fold (P < 0.001) in bleomycin-treated WT lungs in comparison with saline-treated lungs. Protein from bleomycin-treated WT lung contained significantly more hydroxyproline (191.9 microg/lung) than protein from either bleomycin-treated SPARC-null lungs or saline-treated WT and SPARC-null lungs (147.4 microg/lung, 125.4 microg/lung, and 113. 0 microg/lung, respectively; P < 0.03). These results indicate that SPARC is increased in response to lung injury and that accumulation of collagen, as indicated by hydroxyproline content, is attenuated in the absence of SPARC. The properties of SPARC as a matricellular protein associated with cell proliferation and matrix turnover are consistent with its participation in the development of pulmonary fibrosis.

Experiments designed to examine the role of the first intron in regulation of the Col1a1 gene by transfection and in transgenic mice have led to conflicting conclusions. Recently, Hormuzdi et al. [Hormuzdi, S.G., Penttinen, R., Jaenisch, R., Bornstein, P., 1998. A gene-targeting approach identifies a function for the first intron in expression of the alpha1(I) collagen. Mol. Cell. Biol. 18, 3368-3375.] created a targeted deletion in this intron in mice and demonstrated an age-dependent reduction in expression of the mutated allele in lung and skeletal muscle. In this study, intratracheal instillation of bleomycin in mice was used to induce pulmonary fibrosis in control and intron-deleted animals. This stimulus for collagen synthesis was associated with a marked upregulation of the intron-deleted allele in mutant mice. Our results establish that the inhibition of expression of the mutant Col1a1 gene is not fixed, since the gene can still respond to physiological signals. We propose that cis-acting elements, elsewhere in the gene, can compensate for the lack of intronic sequences in the mutated Col1a1 allele and account for the conditional nature of the inhibition. This model has the potential to resolve the conflicting results of previous transfection and transgenic experiments in which different fragments of the Col1a1 gene were used.

Perfluorochemical (PFC) liquids have been shown to improve gas exchange and lung compliance in models of lung injury. We reasoned they may also be useful as a vehicle for gene transfer by improving transgene distribution throughout the lung as well as increasing total transgene expression. We have developed a model for PFC liquid use in spontaneously breathing rodents that obviates the need for intubation and ventilation. Intratracheal instillation of the adenoviral vector Adlac-Z resulted in patchy distribution of beta-galactosidase (beta-gal) activity as demonstrated using X-gal histochemistry. In contrast, in rats instilled with Adlac-Z followed by instillation of PFC liquid, more uniformly distributed and increased beta-gal activity was observed. Activity in distal airway and alveolar epithelium was particularly increased. Quantitative measure of beta-gal activity in lung homogenates demonstrated a 3- to 6-fold increase in total activity in lungs of rats receiving Adlac-Z and PFC liquid compared to animals receiving Adlac-Z alone. These studies show that PFC liquids can enhance both the distribution and the total amount of transgene expressed following adenoviral-mediated vector transfer to lungs during spontaneous breathing. Use of PFC liquids may increase the efficacy of gene transfer strategies for treatment of cystic fibrosis and other lung diseases.

The family of growth factors that includes epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are thought to play a role in the regulation of fetal lung development and epithelial repair after injury. To further elucidate the potential role of these growth factors and their receptor in normal human lung development and in response to injury, their distribution was determined by immunohistochemistry in normal fetal lung, as well as both normal and injured postnatal human lung. We studied 14 specimens of human lung tissue: from three fetuses, four normal infants, two preterm infants with hyaline membrane disease, and five infants with late bronchopulmonary dysplasia (BPD). EGF, TGF-alpha, and EGF receptor (EGF-R) colocalized in airway epithelium in normal fetal and in postnatal human lung. They were also colocalized in scattered alveolar epithelial cells in postnatal lung. Large numbers of alveolar macrophages immunostained for EGF, TGF-alpha, and EGF-R in lungs with late stages of BPD. The colocalization of these growth factors suggests parallel expression of EGF family members. Moreover, the colocalization of these growth factors with their receptor in developing lung suggests that they may act through an autocrine mechanism. The prominent expression of these growth factors in alveolar macrophages in BPD suggests they may be involved with the pathogenesis of this disease.

Adhesion of cells to components of the extracellular matrix has been shown to be critical in normal lung development, particularly during the pseudoglandular stage, when conducting airways are forming through a process of branching morphogenesis. Expression of factors that inhibit cellular adhesion might also modulate branching morphogenesis. SPARC is a secreted glycoprotein that exhibits antiadhesive effects on cultured cells and is widely expressed in embryonic tissues. In this report, we examine the distribution of SPARC in fetal rat lung during development and its effect on the process of branching morphogenesis. Immunohistochemistry and in situ hybridization studies revealed that SPARC was present in the airway epithelial cells during the pseudoglandular stage of lung development, and in blood vessels and smooth muscle cells associated with airways during the canalicular and saccular stages of development. We used an in vitro model of rat lung branching morphogenesis to examine airway branching in the presence of: a) a neutralizing anti-SPARC antibody; or b) a synthetic peptide from a region of SPARC that, like the native protein, perturbs cell adhesion and diminishes the synthesis of fibronectin and thrombospondin 1. Lungs cultured in the presence of either reagent exhibited diminished branching and an abnormal morphology that was characterized in part by dilated airways. These findings implicate SPARC in the development of the airways.

To investigate the potential role of transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGF-R) in the fibroproliferative response to acute lung injury, we determined lung steady-state TGF-alpha and EGF-R mRNA levels, TGF-alpha protein levels, and the distribution of TGF-alpha and EGF-R immunoreactive protein of bleomycin-injured and control rat lungs. At 2 and 4 days after a single intratracheal injection of bleomycin, TGF-alpha mRNA levels increased to 159% and 184% of control values, respectively. EGF-R mRNA levels increased to 163%, 314%, and 170% of control values at 1, 7, and 14 days after bleomycin instillation. TGF-alpha protein levels in whole lung extracts increased to 230% of control values at 4 days after bleomycin administration. TGF-alpha and EGF-R immunoreactivity was detected in macrophages, alveolar septal cells, and airway epithelium of control and bleomycin-injured animals with an apparent increase in the intensity and number of specifically immunostained cells following lung injury. TGF-alpha and EGF-R immunoreactive proteins were detected in foci of cellular proliferation and in areas of intraalveolar fibrosis. We conclude that TGF-alpha and the EGF-R are present in normal and bleomycin-injured rat lung and that the expression of this growth factor and its receptor are up-regulated following lung injury. These results suggest that increased expression of TGF-alpha and the EGF-R may be an important mechanism that modulates the fibroproliferative response to acute lung injury.

To define the distribution of transforming growth factor-alpha (TGF-alpha) and its relationship to epidermal growth factor (EGF) and EGF receptor in lung development and to determine whether epithelial cells produce TGF-alpha, we studied the expression of TGF-alpha, EGF, and their receptor in late-gestation fetal rat lung and in cultured fetal rat lung cells. TGF-alpha, EGF, and EGF receptor were colocalized in epithelial and smooth muscle cells of bronchioles and bronchi and in epithelial cells of saccules. Epithelial cells cultured from late-gestation fetal rat lung transcribe TGF-alpha and EGF receptor mRNA and produce TGF-alpha and EGF receptor proteins. Cultured fibroblasts contained EGF receptor mRNA, but no detectable TGF-alpha mRNA. These results demonstrate fetal lung epithelial cells are a source for TGF-alpha and suggest that TGF-alpha might act through an autocrine or paracrine mechanism with epithelial and mesenchymal cells. The colocalization of TGF-alpha and EGF suggests that these growth factors might act in parallel in lung development.

Transforming growth factor-alpha (TGF-alpha), a member of the epidermal growth factor (EGF) family, is a potent mitogen for several cell types. To investigate the possible role of TGF-alpha in the development of midgestation human fetal lung, we studied its distribution with immunohistochemistry and determined levels of steady-state TGF-alpha mRNA by Northern analysis of cellular RNA isolates from lung. Lung was obtained from fetuses at 10 to 22 wk of gestation (n = 14) and immunostained for TGF-alpha. TGF-alpha was localized in epithelial cells at all gestational ages examined. Immunostaining was particularly prominent in bronchiolar epithelial cells. TGF-alpha immunoreactivity was also associated with arterial smooth muscle cells, as well as with nerves. Occasional chondrocytes were also associated with TGF-alpha immunoreactivity. Total cellular RNA was isolated from lung tissue obtained from additional fetuses at gestational ages 10 to 24 wk (n = 22). TGF-alpha mRNA was present in RNA extracts of all fetal lungs studied. We conclude that TGF-alpha is probably produced in human fetal lung during mid-gestation. The prominent immunostaining of bronchiolar epithelial cells for TGF-alpha is consistent with its playing a role in distal airway formation.

Two newborns, 1 male and 1 female, had both Ondine curse, also known as congenital, central hypoventilation syndrome, and Hirschsprung disease. Both infants demonstrated insufficient respiration while asleep and normal respiration when awake. The lesser affected child had an otherwise normal neurologic examination, but suffered from seizures. He died at 18 months of age; neuropathologic examination of the brain was unremarkable. The girl had a severe and ultimately fatal form of this disorder and manifested a variety of neurologic abnormalities indicative of developmental failure of the neural crest-derived tissues. These abnormalities included unreactive pupils and deafness. She died at 40 days of age; autopsy permission was denied. The etiology of sleep apnea is not known. Mechanisms of central integration may be abnormal but the association with neural crest maldevelopment implicates the peripheral nervous system.