The Intertemporal Role of Respiratory Support in Improving Neonatal Outcomes: A Narrative Review.

Defining improvements in healthcare can be challenging due to the need to assess multiple outcomes and measures. In neonates, although progress in respiratory support has been a key factor in improving survival, the same degree of improvement has not been documented in certain outcomes, such as bronchopulmonary dysplasia. By exploring the evolution of neonatal respiratory care over the last 60 years, this review highlights not only the scientific advances that occurred with the application of invasive mechanical ventilation but also the weakness of the existing knowledge. The contributing role of non-invasive ventilation and less-invasive surfactant administration methods as well as of certain pharmacological therapies is also discussed. Moreover, we analyze the cost-benefit of neonatal care-respiratory support and present future challenges and perspectives.

Minimal invasive surfactant therapy in preterm infants with respiratory distress syndrome: a single center experience.

BACKGROUND: Minimal invasive surfactant therapy (MIST) includes the tracheal instillation of surfactant via a thin catheter for the treatment of preterm infants with respiratory distress syndrome (RDS). We aimed to evaluate the impact of MIST compared to intubation, surfactant, extubation (INSURE) technique on respiratory outcomes. METHODS: A prospectively recruited cohort of preterm infants ≤32 weeks with RDS was compared against a historical cohort of infants treated with INSURE. The primary outcome was the need for mechanical ventilation within 72 hours of age and secondary outcomes the overall need and duration of mechanical ventilation, the development of bronchopulmonary dysplasia, common morbidities, and survival. RESULTS: Thirty-six infants treated with MIST of 29.1±2.2 weeks' gestation and 1219±238 grams' birthweight compared against 37 infants of 28.8±2.3 weeks' gestation and 1195±336 grams' birthweight treated with INSURE. A lower proportion of infants treated with MIST required mechanical ventilation within 72 hours of age compared to those treated with INSURE (11% compared 32%, p=0.042). However, no significant differences were noted regarding the overall intubation incidence, bronchopulmonary dysplasia, other morbidities, or survival. CONCLUSIONS: In spontaneously breathing infants ≤32 weeks with RDS, the MIST technique was associated with a lower need for intubation within 72 hours of age, but otherwise with no significant differences regarding BPD or other neonatal morbidities.

A New ABCA3 Gene Mutation c.3445G>A (p.Asp1149Asn) as a Causative Agent of Newborn Lethal Respiratory Distress Syndrome.

Mutations in adenosine triphosphate-binding cassette transporter A3 (ABCA3) (OMIM: 601615) gene constitute the most frequent genetic cause of severe neonatal respiratory distress syndrome (RDS) and interstitial lung disease (ILD) in children. Interstitial lung disease in children and especially in infants, in contrast to adults, is more likely to appear as a result of developmental deficits or is characterized by genetic aberrations of pulmonary surfactant homeostasis not responding to exogenous surfactant administration. The underlying ABCA3 gene mutations are commonly thought, regarding null mutations, to determine the clinical course of the disease while there exist mutation types, especially missense variants, whose effects on surfactant proteins are difficult to predict. In addition, clinical and radiological signs overlap with those of surfactant proteins B and C mutations making diagnosis challenging. We demonstrate a case of a one-term newborn male with lethal respiratory failure caused by homozygous missense ABCA3 gene mutation c.3445G>A (p.Asp1149Asn), which, to our knowledge, was not previously reported as a causative agent of newborn lethal RDS. Therapeutic strategies for patients with ABCA3 gene mutations are not sufficiently evidence-based. Therefore, the description of the clinical course and treatment of the disease in terms of a likely correlation between genotype and phenotype is crucial for the development of the optimal clinical approach for affected individuals.

Early caloric deprivation in preterm infants affects Bayley-III scales performance at 18-24 months of corrected age.

BACKGROUND: Adequate nutrition is essential for optimal neurodevelopment to preterm infants. Our aim was to evaluate the impact of caloric deprivation on Bayley-III scales performance at 18-24 months of corrected age, in a cohort of preterm infants. METHODS: We prospectively enrolled infants with gestational age <30 weeks and birth weight <1500 g. Apart from a whole cohort analysis, we performed a subgroup analysis between infants received inadequate calories (<85 Kcal/kg/day) during the first two weeks of age, compared to a standard nutrition group. All infants underwent a Bayley-III assessment at 18-24 months of corrected age. RESULTS: From the 63 preterm infants analysed, 25% had caloric deprivation compared to 75% with adequate nutrition. Caloric deprived infants were of lower gestational age and birth weight, and received a lower amount of enteral feeding during the first 14 days of age. There were no differences between the two groups regarding the common neonatal co-morbidities. Caloric deprived infants had significantly lower composite index scores at 18-24 months of corrected age. Caloric deprivation, late onset sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia were significant risk factors of neurodevelopmental impairment. CONCLUSIONS: Several neonatal factors affect the neurodevelopmental outcome of preterm infants, and nutrition may pose an important role.

Intraventricular Hemorrhage and Platelet Indices in Extremely Premature Neonates.

Intraventricular hemorrhage (IVH) is a multifactorial disorder, the most important risk factors of which are prematurity and low birth weight. Disturbances in cerebral blood flow, inherent fragility of the germinal matrix vasculature, and platelet/coagulation disturbances are the 3 major pathogenic mechanisms. In this context, we investigated the role of platelet indices and several maternal and neonatal characteristics in the development of IVH through a retrospective cohort analysis of 130 extremely premature neonates, 24% of whom presented with severe IVH. There was a significant difference in platelet counts between the IVH and the control group on the first day of life (P=0.046). Presence of IVH was linked with lower birth weight (P=0.006) and lower gestational age (P=0.001). Platelet count on the first day of life was positively correlated with survival (P=0.001) and, along with platelet mass, was indicative of the worst IVH grade recorded for each neonate (P=0.002 and 0.007, respectively). Prolonged prothrombin time was also correlated with IVH (P<0.001), but factor analysis supported no prominent role. Maternal medications seem to play a minor role as well. In conclusion, IVH in extremely premature infants cannot be solely explained by platelet parameters, and further studies are required to determine the relationships between IVH, platelet indices, and outcomes.

Intraventricular Hemorrhage and Platelet Indices in Extremely Premature Neonates.

Intraventricular hemorrhage (IVH) is a multifactorial disorder, the most important risk factors of which are prematurity and low birth weight. Disturbances in cerebral blood flow, inherent fragility of the germinal matrix vasculature, and platelet/coagulation disturbances are the 3 major pathogenic mechanisms. In this context, we investigated the role of platelet indices and several maternal and neonatal characteristics in the development of IVH through a retrospective cohort analysis of 130 extremely premature neonates, 24% of whom presented with severe IVH. There was a significant difference in platelet counts between the IVH and the control group on the first day of life (P=0.046). Presence of IVH was linked with lower birth weight (P=0.006) and lower gestational age (P=0.001). Platelet count on the first day of life was positively correlated with survival (P=0.001) and, along with platelet mass, was indicative of the worst IVH grade recorded for each neonate (P=0.002 and 0.007, respectively). Prolonged prothrombin time was also correlated with IVH (P<0.001), but factor analysis supported no prominent role. Maternal medications seem to play a minor role as well. In conclusion, IVH in extremely premature infants cannot be solely explained by platelet parameters, and further studies are required to determine the relationships between IVH, platelet indices, and outcomes.

Recurrent giant cell fibroblastoma: Malignancy predisposition in Kabuki syndrome revisited.

Kabuki syndrome is a genetic condition characterized by distinctive facial phenotype, mental retardation, and internal organ malformations. Mutations of the epigenetic genes KMT2D and KDM6A cause dysregulation of certain developmental genes and account for the multiple congenital anomalies of the syndrome. Eight cases of malignancies have been reported in young patients with Kabuki syndrome although a causative association to the syndrome has not been established. We report a case of a 12-year-old girl with Kabuki syndrome who developed a tumor on the right side of her neck. A relapsing tumor 19 months after initial excision, proved to be giant cell fibroblastoma. Τhis is the first report of giant cell fibroblastoma -a rare tumor of childhood- in a patient with Kabuki syndrome.

Correlation of brain ultrasonography scans to the neuromotor outcome of very-low-birth-weight infants during the first year of life.

To evaluate the consistency of the Hammersmith Infant Neurological Examination scores of very-low-birth-weight infants at 6 and 12 months of age and its correlation to cranial ultrasonography findings, we designed a prospective study between January 2005 and January 2008, in the tertiary Neonatal Unit of Aristotle University of Thessaloniki, Greece. All infants enrolled had a cranial ultrasonography performed at term. Preterm infants born at <32 weeks gestation with a birth weight <1500 g were eligible for the study. One hundred seventy-four infants were finally enrolled; out of those, 46 (26%) had an optimal score at 6 and 76 (44%) at 12 months of age. Mean global scores were 61 and 69 at 6 and 12 months, respectively. The Hammersmith Infant Neurological Examination score significantly increased between 6 and 12 months, equally in all ultrasonography groups. The presence of cystic periventricular leukomalacia was associated to lower scores and neurologic impairment.

Sizeable acquired subglottic cyst in a baby with Williams-Beuren syndrome: association or coincidence?

We describe a case of an acquired subglottic cyst presented with persistent stridor and voice hoarsening in a baby diagnosed with Williams-Beuren syndrome that was born premature and required intubation during neonatal period. We also comment on whether this is a coincidence or there can be an association between impaired elastogenesis, a feature of patients with the syndrome and the formation of a subglottic cyst.

Neuromotor outcomes in infants with bronchopulmonary dysplasia.

We examine the neuromotor outcomes of preterm infants with bronchopulmonary dysplasia. Two hundred and nineteen infants (gestational age, ≤ 32 weeks; birth weight, ≤ 1500 g) were studied. Neuromotor development was assessed using the Hammersmith Infant Neurological Examination. All potential risk factors associated with neuromotor scores (P < 0.015) were included in the generalized linear model (multiple linear regression) to determine if bronchopulmonary dysplasia had an independent relationship with neuromotor scores. Infants with severe bronchopulmonary dysplasia had lower global scores at ages 6 and 12 months. After adjustment for confounding factors, scores of infants with severe bronchopulmonary dysplasia were reduced by 13.2 units, whereas scores for those with periventricular leukomalacia were reduced by 11.1 units, at age 6 months. At age 12 months, scores for those with periventricular leukomalacia were reduced by 11.9 units. Duration of hospital stay reduced scores by 0.1 for each additional day increase in hospital. Bronchopulmonary dysplasia constitutes a major cause of poor neuromotor outcomes at age 6 months, but improvements in motor outcomes occur over time.

Influence of smoking during pregnancy on haemostasis in healthy full term neonates.

BACKGROUND: Clinical and experimental researches have linked smoking to disturbances of coagulation and fibrinolysis. Several potential mechanisms are incriminated involving inflammation, fibrinogen synthesis and clotting factors. Based on the fact that the majority of tobacco components cross the placental barrier, the objective of our current study is to investigate the influence of smoking during pregnancy on neonatal haemostasis. STUDY DESIGN: The study was based on a comparative evaluation of coagulation and fibronolysis between healthy full term infants of women who smoked during pregnancy and a control group. Subjects consisted of 39 newborns of smoking and 43 newborns of nonsmoking mothers. Blood samples were obtained shortly after birth and before the administration of vitamin K. Investigation included: PT, INR, aPTT, fibrinogen, coagulation factors II, V, VII, VIII, IX, X, XI, XII, vWillebrand (vWF), protein C and S, APCr, anti-thrombin (AT), t-PA and PAI-1. The independent t- test was used to compare the differences between the values of coagulation and fibrinolytic parameters at the p<0.05 level. RESULTS: We discovered a statistically significant decrease in factor II and protein S levels and an elevation in t-PA and factor VIII concentrations in newborns of smoking mothers, without clinical manifestations of altered haemostasis. There were no significant differentiations in other coagulation or fibrinolytic parameters. CONCLUSION: The alteration in factor II, protein S, t-PA and factor VIII in neonates exposed in utero to tobacco smoke is not accompanied by loss in the balance between coagulation and fibrinolytic pathways.

Is the use of rFVIIa safe and effective in bleeding neonates? A retrospective series of 8 cases.

BACKGROUND: Recombinant activated factor VII (rFVIIa), originally developed for the treatment of life-threatening bleeding in hemophilic patients with inhibitors to factors VIII or IX, has been increasingly used to control hemorrhage unresponsive to conventional treatment, in the absence of a defined coagulopathy or thrombocytopathy. To date, clinical experience of rFVIIa administration in neonates, especially preterms, is rather limited, because of the lack of controlled studies and based solely on some published case reports and 1 prospective pilot study. The objective of this study was to retrospectively evaluate the clinical outcome of newborns treated with recombinant activated factor VII for intractable bleeding or severe coagulation disturbances, resistant to conventional hemostatic therapy. METHODS: The medical records of 8 neonates treated with rFVIIa (100 micro g/kg) were retrospectively reviewed for the course of hemorrhage and the hemostatic interventions performed before and up to 24 hours after the administration rFVIIa. Coagulation parameters of 3 different time-points were assessed and compared: before administration of any blood product (time-point 1), before administration of the first dose of rFVIIa (time-point 2), and 4 hours after the administration of the last dose of rFVIIa (time-point 3). The safety and tolerability profile of rFVIIa in bleeding neonates was also evaluated. RESULTS: Six preterm and 2 term patients were included in the study. Seven patients presented with refractory bleeding and 1 was diagnosed with severe coagulopathy unresponsive to the conventional treatment. Prompt hemostasis was achieved in half of the patients with their coagulation profile being restored within 4 hours after the administration of the first dose of rFVIIa. Improvement in prothrombin time, activated partial thromboplastin time, and fibrinogen after rFVIIa administration was statistically significant, as compared with that observed after conventional treatment. No major safety issues were observed during the study. All 8 patients survived and had their hemorrhage or coagulopathy controlled within 4 hours after transfusion of the last dose of rFVIIa. CONCLUSIONS: In this study, the hemostatic agent rFVIIa was well-tolerated and behaved in a safe and efficacious manner in all infants treated for life-threatening bleeding and coagulation disorders. Future prospective controlled trials are needed to determine the efficacy, safety, tolerability, and possibly the optimal dose and timing of rFVIIa administration.

Loss of FEV1 in cystic fibrosis: correlation with HRCT features.

The purpose of this study was to determine which high-resolution computed tomography (HRCT) features in patients with cystic fibrosis are most strongly associated with functional impairment as expressed by forced expiratory volume in one second (FEV1). Forty-seven patients with cystic fibrosis underwent chest HRCT and had pulmonary function tests. The HRCT examinations were evaluated for 11 features scored using a modification of Bhalla system and FEV1 was recorded as percentage of the predicted value. Univariate and multivariate correlations between HRCT scores and FEV1 were performed. The most common HRCT feature was bronchiectasis (98%) followed by atelectasis-consolidation (81%), bronchial wall thickening (77%), tree-in-bud sign (74%), mucous plugging (72%) and mosaic perfusion pattern (47%). On univariate analysis the following features correlated strongly with FEV1: bronchial wall thickening ( p<0.0000001), tree-in-bud sign ( p<0.0000001), mucous plugging ( p<0.0000001), atelectasis-consolidation (p<0.0000001), thickening of interlobular septa ( p<0.0002), severity ( p<0.0002) and extent of bronchiectasis ( p<0.0002). On multivariate analysis bronchial wall thickening and atelectasis-consolidation were the strongest independent determinants of the FEV1. We found a regression equation between FEV1 and the two HRCT features: FEV1=constant variable+a multiplied by bronchial wall thickening+b multiplied by atelectasis-consolidation (a and b=regression coefficients, R(2)=0.48). The major morphological determinants of functional abnormality in cystic fibrosis, as expressed by the loss of FEV1, are bronchial wall thickening and atelectasis-consolidation.