Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression.

Despite the evident progress in neonatal medicine, retinopathy of prematurity (ROP) remains a serious threat to the vision of premature infants, due to a still partial understanding of the mechanisms underlying the development of this disease and the lack of drugs capable of arresting its progression. Although ROP is a multifactorial disease, retinal vascularization is strictly dependent on oxygen concentration. The exposition of the retina of a preterm newborn, still incompletely vascularized, to an atmosphere relatively hyperoxic, as the extrauterine environment, induces the downregulation of proangiogenic factors and therefore the interruption of vascularization (first ischemic phase of ROP). However, over the following weeks, the growing metabolic requirement of this ischemic retina produces a progressive hypoxia that specularly promotes the surge of proangiogenic factors, finally leading to proliferative retinopathy (second proliferative phase of ROP). The demonstration that the noradrenergic system is actively involved in the coupling between hypoxia and the induction of vasculogenesis paved the way for a pharmacologic intervention aimed at counteracting the interaction of noradrenaline with specific receptors and consequently the progression of ROP. A similar trend has been observed in infantile hemangiomas, the most common vascular lesion of childhood induced by pre-existing hypoxia, which shares similar characteristics with ROP. The fact that propranolol, an unselective antagonist of ß1/2 adrenoceptors, counteracts the growth of infantile hemangiomas, suggested the idea of testing the efficacy of propranolol in infants with ROP. From preclinical studies, ongoing clinical trials demonstrated that topical administration of propranolol likely represents the optimal approach to reconcile its efficacy and maximum safety. Given the strict relationship between vessels and neurons, recovering retinal vascularization with propranolol may add further efficacy to prevent retinal dysfunction. In conclusion, the strategy of contrasting precociously the progression of the disease appears to be more advantageous than the current wait-and-see therapeutic approach, which instead is mainly focused on avoiding retinal detachment.

Neonatal hypoxic-ischemic encephalopathy after acute carbon monoxide intoxication during pregnancy. A case report and brief review of the literature.

Carbon monoxide (CO) poisoning during pregnancy is a rare occurrence, associated with high maternal and fetal mortality rates. As CO can cross the placenta, leading to intrauterine hypoxia, CO intoxication can result in neurological sequelae and neurologic complications in fetuses who survive. We report a case of a preterm newborn acutely exposed to CO in-utero and delivered by emergent cesarean section at the 31st week of gestation due to the severe burns suffered by the mother following an indoor boiler explosion. As CO has serious adverse effects both on the mother and fetus, it is important to recognize and treat poisoning in a timely manner. Despite maternal blood CO levels, CO intoxication at critical stage of central nervous system development can lead to hypoxic-ischemic lesions, thus interdisciplinary care and follow up for these patients are mandatory.

Lung ultrasound supports clinical evaluation of feeding competence development in preterm neonates.

Introduction: The achievement of alimentary competencies is a milestone in the development of preterm neonates. Ten percent of neonates <37 weeks of gestational age and 25% of those VLBW experience swallowing disorders, with an increased risk of problems in the early phase of life (failure to thrive, growth retardation, inhalation, and consequent risk of pulmonary infection) and later in life due to delayed development of oromotor skills.The main diagnostic tools for swallowing disorders are endoscopic (fiber-optic endoscopic examination of swallowing, FEES) or radiographic (videofluoroscopic swallowing study, VFSS) exams. Given the invasiveness of these methods and the bias due to rheologic differences between bolus and contrast medium, FEES and VFSS are poorly reproducible. Moreover, neither of the technique is capable of detecting post-meal inhalations, especially microinhalations or those consequent to a whole meal rather than to a single swallowing.Lung ultrasound (LUS) is a widespread, repeatable, safe, fast point-of-care tool and we reported previous encouraging results in detecting silent and overt inhalation related to the meal in children with dysphagia/gastroesophageal reflux disease (GERD) risk factors. Methods: We report a pilot study, that investigated LUS approach (performing imaging before and after meals) to assess feeding competence development in a cohort of n. 19 newborns <32 weeks of age. Results: Meal monitoring by LUS did not show any significant difference in scoring before/after eating. The achievement of full enteral feeding correlates with GA at birth (p < 0.001) but not with LUS scoring. The introduction of the first meal by bottle correlates both with gestational age (p < 0.001) and ultrasound scores (p = 0.004). LUS score at 7 days of life resulted predictive for length of invasive/non-invasive respiratory support (p = 0.002) and length of oxygen supply (p = 0.001), while LUS score at 48 h of life did not (p n.s.). Discussion: Our study suggests that the development of oral feeding skills is not strictly dependent on gestational age. Moreover, our research suggests the predominant role of LUS in predicting the time of readiness to oral feeding, as the LUS score can be a marker of respiratory and lung wellness, and consequently a predictor of neonate stability during deglutitory apnea.

Fetal Oxygenation from the 23rd to the 36th Week of Gestation Evaluated through the Umbilical Cord Blood Gas Analysis.

The embryo and fetus grow in a hypoxic environment. Intrauterine oxygen levels fluctuate throughout the pregnancy, allowing the oxygen to modulate apparently contradictory functions, such as the expansion of stemness but also differentiation. We have recently demonstrated that in the last weeks of pregnancy, oxygenation progressively increases, but the trend of oxygen levels during the previous weeks remains to be clarified. In the present retrospective study, umbilical venous and arterial oxygen levels, fetal oxygen extraction, oxygen content, CO2, and lactate were evaluated in a cohort of healthy newborns with gestational age < 37 weeks. A progressive decrease in pO2 levels associated with a concomitant increase in pCO2 and reduction in pH has been observed starting from the 23rd week until approximately the 33-34th week of gestation. Over this period, despite the increased hypoxemia, oxygen content remains stable thanks to increasing hemoglobin concentration, which allows the fetus to become more hypoxemic but not more hypoxic. Starting from the 33-34th week, fetal oxygenation increases and ideally continues following the trend recently described in term fetuses. The present study confirms that oxygenation during intrauterine life continues to vary even after placenta development, showing a clear biphasic trend. Fetuses, in fact, from mid-gestation to near-term, become progressively more hypoxemic. However, starting from the 33-34th week, oxygenation progressively increases until birth. In this regard, our data suggest that the placenta is the hub that ensures this variable oxygen availability to the fetus, and we speculate that this biphasic trend is functional for the promotion, in specific tissues and at specific times, of stemness and intrauterine differentiation.

Fetal oxygenation in the last weeks of pregnancy evaluated through the umbilical cord blood gas analysis.

Introduction: Embryo and fetus grow and mature over the first trimester of pregnancy in a dynamic hypoxic environment, where placenta development assures an increased oxygen availability. However, it is unclear whether and how oxygenation changes in the later trimesters and, more specifically, in the last weeks of pregnancy. Methods: Observational study that evaluated the gas analysis of the umbilical cord blood collected from a cohort of healthy newborns with gestational age ≥37 weeks. Umbilical venous and arterial oxygen levels as well as fetal oxygen extraction were calculated to establish whether oxygenation level changes over the last weeks of pregnancy. In addition, fetal lactate, and carbon dioxide production were analyzed to establish whether oxygen oscillations may induce metabolic effects in utero. Results: This study demonstrates a progressive increase in fetal oxygenation levels from the 37th to the 41st weeks of gestation (mean venous PaO2 approximately from 20 to 25 mmHg; p < 0.001). This increase is largely attributable to growing umbilical venous PaO2, regardless of delivery modalities. In neonates born by vaginal delivery, the increased oxygen availability is associated with a modest increase in oxygen extraction, while in neonates born by cesarean section, it is associated with reduced lactate production. Independently from the type of delivery, carbon dioxide production moderately increased. These findings suggest a progressive shift from a prevalent anaerobic metabolism (Warburg effect) towards a growing aerobic metabolism. Conclusion: This study confirms that fetuses grow in a hypoxic environment that becomes progressively less hypoxic in the last weeks of gestation. The increased oxygen availability seems to favor aerobic metabolic shift during the last weeks of intrauterine life; we hypothesize that this environmental change may have implications for fetal maturation during intrauterine life.

Lung ultrasound in young children with neurological impairment: A proposed integrative clinical tool for deaeration-detection related to feeding.

Infants and children with neurological impairment, such as cerebral palsy (CP), often experience abnormal ingestion functions, including oropharyngeal dysphagia and gastroesophageal reflux disease, which led to aspiration-related respiratory complications, morbidity, hospitalization, or death. There is a lack of evidence-based, repeatable, infant-friendly instrumental procedures to assess aspiration-risk in infants with CP or other neurological disorders, with also a lack of clinical assessment measures to support the use of more invasive diagnostic techniques. To this purpose, in the current study we explore the feasibility of lung ultrasound (LUS), to assess lung deaeration possibly related to aspiration during meal, in a cohort of 35 subjects affected by CP or other encephalopathies, and 10 controls in the same age-range. We coupled LUS procedure with meal caregiver administration for each child. Our results support the feasibility of this innovative approach in the clinical setting. Exploratory findings revealed a number of lung abnormalities likely related to abnormal ingestion function in subjects. Subgroup analyses revealed possible differences in LUS abnormalities between CP and other encephalopathies, possibly related to different mechanism of disease or dysfunction. Also, some evidences arose about the possible relationship between such LUS abnormalities and feeding and swallowing abilities in CP or other encephalopathies. LUS showed preliminarily feasibility and effectiveness in detecting meal-related LUS abnormalities in a dynamic manner in the clinical setting. This approach demonstrated usefulness as a potential tool for improving assessment and management in complex care of infants and young children with severe neurological disorders.

Micro-extraction by packed sorbent combined with UHPLC-ESI-MS/MS for the determination of prostanoids and isoprostanoids in dried blood spots.

This work presents a reliable analytical procedure combining micro-extraction by packed sorbent (MEPS) and ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry to determine 8-iso prostaglandin F2α, 8-iso prostaglandin E2 and prostaglandin E2 in dried blood spots (DBSs). To reach this goal, we optimized a fast semi-automated MEPS procedure for the clean-up and pre-concentration of the analytes extracted from a single DBS (50 µL) by a 70:30 v/v methanol:water mixture. Limits of detection of about 20 pg mL-1, satisfactory recoveries (90-110%) and very good intra- and inter-day precisions (RSD ≤10%) were obtained for all the analytes. The innovative addition of internal standards on the filter paper before DBS sampling allowed to compensate changes in the amount of analyte during storage. Since prostanoids and isoprostanoids are biomarkers involved in the pathogenesis and progression of many diseases (e.g. ductal patency, diabetic nephropathy, and acute lung injury), our analytical method offers interesting diagnostic and prognostic opportunities in the medical field. The present method is currently used for the analysis of such biomarkers in DBSs from preterm newborns collected in the clinical setting.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study.

PURPOSE: To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE). MATERIALS AND METHODS: Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes. RESULTS: Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM. CONCLUSIONS: Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

An active one-lobe pulmonary simulator with compliance control for medical training in neonatal mechanical ventilation.

Mechanical ventilation is a current support therapy for newborns affected by respiratory diseases. However, several side effects have been observed after treatment, making it mandatory for physicians to determine more suitable approaches. High fidelity simulation is an efficient educational technique that recreates clinical experience. The aim of the present study is the design of an innovative and versatile neonatal respiratory simulator which could be useful in training courses for physicians and nurses as for mechanical ventilation. A single chamber prototype, reproducing a pulmonary lobe both in size and function, was designed and assembled. Volume and pressure within the chamber can be tuned by the operator through the device control system, in order to simulate both spontaneous and assisted breathing. An innovative software-based simulator for training neonatologists and nurses within the continuing medical education program on respiratory disease management was validated. Following the clinical needs, three friendly graphic user interfaces were implemented for simulating three different clinical scenarios (spontaneous breathing, controlled breathing and triggered/assisted ventilation modalities) thus providing physicians with an active experience. The proposed pulmonary simulator has the potential to be included in the range of computer-driven technologies used in medical training, adding novel functions and improving simulation results.

Ventral stream sensitivity in "healthy" preterm-born adolescents: psychophysical and neuropsychological evaluation.

BACKGROUND: Deficits of motion processing have been reported in premature and very low birth-weight subjects during infancy, childhood and adolescence. Less is known about ventral stream functioning in preterms. AIM: The aim of this study is to investigate ventral stream functioning in a sample of "healthy" adolescents born preterm with normal outcome and without brain damage. STUDY DESIGN: We enrolled thirty preterm-born adolescents (mean age: 14.2years, mean gestational age 28.9weeks, mean birth weight 1097g), and 34 age-matched term-born controls (mean age: 14.5years). All subjects were administered a psychophysical test known as "Form Coherence Task" and a comprehensive standardized battery of neuropsychological tests suitable for investigating ventral stream functioning including Street Completion Test, Poppelreuter-Ghent Test and the first part of the Visual Object and Space Perception (VOSP) battery. Dorsal stream visual functioning was investigated by the second part of the VOSP. RESULTS: Preterm (PT) subjects showed the same results in all "ventral" tasks with respect to full-term controls without any correlation to gestational age or birth weight. We found a significant negative correlation between Form Coherence Task and Letters Task (p=.014) and between Form Coherence and Silhouette Tasks (p=.017). No correlation was observed between Form Coherence Task and Street and Ghent Tests. A statistical difference was instead found between PTs and controls in two tasks of the VOSP battery that mostly involve the dorsal stream. CONCLUSIONS: Preterm birth per se (in absence of evident brain lesions) is not sufficient to compromise the development of ventral pathway.

Education in neonatology by simulation: between reality and declaration of intent.

An unexpected event is not rare in Neonatology and can be dramatic: the operators must act with the right skills and abilities in the shortest time. Often it is a team effort and each member must be trained adequately. According to the "Swiss cheese" model by J. Reason, an accident is never the consequence of a single error, but the very final result of a chain of misunderstandings, irregularities or negligence (cheese holes): several holes allow the final medical error. Therefore, we should avoid those holes in our work. The clinical risk is always around the corner. The legal issues are becoming more and more relevant and lead to a defensive medicine, which is definitely not the best practice. For this reason, raising the safety standards is mandatory. With this purpose, after a decade of experience in "traditional" training courses, we started testing a new strategy of continuous education in Neonatology by means of highfidelity simulation. Since 2008, we have arranged and managed a Center for Neonatal Simulation and Advanced Training in the Neonatology Unit of the University Hospital of Pisa. We have already delivered courses to pediatricians, neonatologists, anesthesiologists, gynecologists, emergency doctors, midwives and nurses, using an advanced Laerdal SimNewB simulator to teach diagnostic and therapeutic skills or communication strategies. The model has been proposed to the Italian Society of Neonatology and it has been decided to create a Task Force to discuss our model and encourage to use it in other Italian areas.