Ototoxic and nephrotoxic drugs in neonatal intensive care units: results of a Spanish and Italian survey.

Neonates face heightened susceptibility to drug toxicity, often exposed to off-label medications with dosages extrapolated from adult or pediatric studies. Premature infants in Neonatal Intensive Care Units (NICUs) are particularly at risk due to underdeveloped pharmacokinetics and exposure to multiple drugs. The study aimed to survey commonly used medications with a higher risk of ototoxicity and nephrotoxicity in Spanish and Italian neonatal units. A prospective cross-sectional study was conducted in Italian and Spanish neonatal units using a web-based survey with 43 questions. A modified Delphi method involved experts refining the survey through online consensus. Ethical approval was obtained, and responses were collected from January to July 2023. The survey covered various aspects, including drug-related ototoxic and nephrotoxic management, hearing screening, and therapeutic drug monitoring. Responses from 131 participants (35.9% from Spain and 64.1% from Italy) revealed awareness of drug toxicity risks. Varied practices were observed in hearing screening protocols, and a high prevalence of ototoxic and nephrotoxic drug use, including aminoglycosides (100%), vancomycin (70.2%), loop diuretics (63.4%), and ibuprofen (62.6%). Discrepancies existed in guideline availability and adherence, with differences between Italy and Spain in therapeutic drug monitoring practices. CONCLUSIONS: The study underscores the need for clinical guidelines and uniform practices in managing ototoxic and nephrotoxic drugs in neonatal units. Awareness is high, but inconsistencies in practices indicate a necessity for standardization, including the implementation of therapeutic drug monitoring and the involvement of clinical pharmacologists. Addressing these issues is crucial for optimizing neonatal care in Southern Europe. WHAT IS KNOWN: • Neonates in intensive care face a high risk of nephrotoxicity and ototoxicity from drugs like aminoglycosides, vancomycin, loop diuretics, and ibuprofen. • Therapeutic drug monitoring is key for managing these risks, optimizing dosing for efficacy and minimizing side effects. WHAT IS NEW: • NICUs in Spain and Italy show high drug toxicity awareness but differ in ototoxic/nephrotoxic drug management. • Urgent need for standard guidelines and practices to address nephrotoxic risks from aminoglycosides, vancomycin, loop diuretics, and ibuprofen.

Congenital diaphragmatic hernia: automatic lung and liver MRI segmentation with nnU-Net, reproducibility of pyradiomics features, and a machine learning application for the classification of liver herniation.

Prenatal assessment of lung size and liver position is essential to stratify congenital diaphragmatic hernia (CDH) fetuses in risk categories, guiding counseling, and patient management. Manual segmentation on fetal MRI provides a quantitative estimation of total lung volume and liver herniation. However, it is time-consuming and operator-dependent. In this study, we utilized a publicly available deep learning (DL) segmentation system (nnU-Net) to automatically contour CDH-affected fetal lungs and liver on MRI sections. Concordance between automatic and manual segmentation was assessed by calculating the Jaccard coefficient. Pyradiomics standard features were then extracted from both manually and automatically segmented regions. The reproducibility of features between the two groups was evaluated through the Wilcoxon rank-sum test and intraclass correlation coefficients (ICCs). We finally tested the reliability of the automatic-segmentation approach by building a ML classifier system for the prediction of liver herniation based on support vector machines (SVM) and trained on shape features computed both in the manual and nnU-Net-segmented organs. We compared the area under the classifier receiver operating characteristic curve (AUC) in the two cases. Pyradiomics features calculated in the manual ROIs were partly reproducible by the same features calculated in nnU-Net segmented ROIs and, when used in the ML procedure, to predict liver herniation (both AUC around 0.85).          Conclusion: Our results suggest that automatic MRI segmentation is feasible, with good reproducibility of pyradiomics features, and that a ML system for liver herniation prediction offers good reliability.          Trial registration: https://clinicaltrials.gov/ct2/show/NCT04609163?term=NCT04609163&draw=2&rank=1 ; Clinical Trial Identification no. NCT04609163. What is Known: • Magnetic resonance imaging (MRI) is crucial for prenatal congenital diaphragmatic hernia (CDH) assessment. It enables the quantification of the total lung volume and the extent of liver herniation, which are essential for stratifying the severity of CDH, guiding counseling, and patient management. • The manual segmentation of MRI scans is a time-consuming process that is heavily reliant upon the skill set of the operator. What is New: • MRI lung and liver automatic segmentation using the deep learning nnU-Net system is feasible, with good Jaccard coefficient values and satisfactory reproducibility of pyradiomics features compared to manual results. • A feasible ML system for predicting liver herniation could improve prenatal assessments and CDH patient management.

Human Bone Marrow-Derived Mesenchymal Stromal Cells Reduce the Severity of Experimental Necrotizing Enterocolitis in a Concentration-Dependent Manner.

Necrotizing enterocolitis (NEC) is a devastating gut disease in preterm neonates. In NEC animal models, mesenchymal stromal cells (MSCs) administration has reduced the incidence and severity of NEC. We developed and characterized a novel mouse model of NEC to evaluate the effect of human bone marrow-derived MSCs (hBM-MSCs) in tissue regeneration and epithelial gut repair. NEC was induced in C57BL/6 mouse pups at postnatal days (PND) 3-6 by (A) gavage feeding term infant formula, (B) hypoxia/hypothermia, and (C) lipopolysaccharide. Intraperitoneal injections of PBS or two hBM-MSCs doses (0.5 × 106 or 1 × 106) were given on PND2. At PND 6, we harvested intestine samples from all groups. The NEC group showed an incidence of NEC of 50% compared with controls (p < 0.001). Severity of bowel damage was reduced by hBM-MSCs compared to the PBS-treated NEC group in a concentration-dependent manner, with hBM-MSCs (1 × 106) inducing a NEC incidence reduction of up to 0% (p < 0.001). We showed that hBM-MSCs enhanced intestinal cell survival, preserving intestinal barrier integrity and decreasing mucosal inflammation and apoptosis. In conclusion, we established a novel NEC animal model and demonstrated that hBM-MSCs administration reduced the NEC incidence and severity in a concentration-dependent manner, enhancing intestinal barrier integrity.

Viscoelastic coagulation testing in Neonatal Intensive Care Units: advantages and pitfalls in clinical practice.

The expression "developmental hemostasis" indicates the age-related physiological changes occurring during the maturational process of the hemostatic system. Despite the quantitative and qualitative alterations, the neonatal hemostatic system is competent and well-balanced. Conventional coagulation tests do not provide reliable information as they only explore the procoagulants during the neonatal period. In contrast, viscoelastic coagulation tests (VCTs), such as viscoelastic coagulation monitoring (VCM), thromboelastography (TEG or ClotPro), and rotational thromboelastometry (ROTEM), are point-of-care assays that provide a quick, dynamic and global view of the hemostatic process, allowing prompt and individualized therapeutic intervention when necessary. Their use in neonatal care is on the increase and they could help monitor patients at risk of hemostatic derangement. In addition, they are crucial for anticoagulation monitoring during extracorporeal membrane oxygenation. Moreover, implementing VCT-based monitoring could optimize blood product use.

Endothelial dysfunction in preterm infants: The hidden legacy of uteroplacental pathologies.

Millions of infants are born prematurely every year worldwide. Prematurity, particularly at lower gestational ages, is associated with high mortality and morbidity and is a significant global health burden. Pregnancy complications and preterm birth syndrome strongly impact neonatal clinical phenotypes and outcomes. The vascular endothelium is a pivotal regulator of fetal growth and development. In recent years, the key role of uteroplacental pathologies impairing endothelial homeostasis is emerging. Conditions leading to very and extremely preterm birth can be classified into two main pathophysiological patterns or endotypes: infection/inflammation and dysfunctional placentation. The first is frequently related to chorioamnionitis, whereas the second is commonly associated with hypertensive disorders of pregnancy and fetal growth restriction. The nature, timing, and extent of prenatal noxa may alter fetal and neonatal endothelial phenotype and functions. Changes in the luminal surface, oxidative stress, growth factors imbalance, and dysregulation of permeability and vascular tone are the leading causes of endothelial dysfunction in preterm infants. However, the available evidence regarding endothelial physiology and damage is limited in neonates compared to adults. Herein, we discuss the current knowledge on endothelial dysfunction in the infectious/inflammatory and dysfunctional placentation endotypes of prematurity, summarizing their molecular features, available biomarkers, and clinical impact. Furthermore, knowledge gaps, shadows, and future research perspectives are highlighted.

Veno-Arterial Extracorporeal Membrane Oxygenation (ECMO) Impairs Bradykinin-Induced Relaxation in Neonatal Porcine Coronary Arteries.

Extracorporeal membrane oxygenation (ECMO) is a lifesaving support for respiratory and cardiovascular failure. However, ECMO induces a systemic inflammatory response syndrome that can lead to various complications, including endothelial dysfunction in the cerebral circulation. We aimed to investigate whether ECMO-associated endothelial dysfunction also affected coronary circulation. Ten-day-old piglets were randomized to undergo either 8 h of veno-arterial ECMO (n = 5) or no treatment (Control, n = 5). Hearts were harvested and coronary arteries were dissected and mounted as 3 mm rings in organ baths for isometric force measurement. Following precontraction with the thromboxane prostanoid (TP) receptor agonist U46619, concentration−response curves to the endothelium-dependent vasodilator bradykinin (BK) and the nitric oxide (NO) donor (endothelium-independent vasodilator) sodium nitroprusside (SNP) were performed. Relaxation to BK was studied in the absence or presence of the NO synthase inhibitor Nω-nitro-L-arginine methyl ester HCl (L-NAME). U46619-induced contraction and SNP-induced relaxation were similar in control and ECMO coronary arteries. However, BK-induced relaxation was significantly impaired in the ECMO group (30.4 ± 2.2% vs. 59.2 ± 2.1%; p < 0.0001). When L-NAME was present, no differences in BK-mediated relaxation were observed between the control and ECMO groups. Taken together, our data suggest that ECMO exposure impairs endothelium-derived NO-mediated coronary relaxation. However, there is a NO-independent component in BK-induced relaxation that remains unaffected by ECMO. In addition, the smooth muscle cell response to exogenous NO is not altered by ECMO exposure.

Hemostasis in neonatal ECMO.

Extracorporeal membrane oxygenation (ECMO) is a life-saving support for cardio-respiratory function. Over the last 50 years, the extracorporeal field has faced huge technological progress. However, despite the improvements in technique and materials, coagulation problems are still the main contributor to morbidity and mortality of ECMO patients. Indeed, the incidence and survival rates of the main hemorrhagic and thrombotic complications in neonatal respiratory ECMO are relevant. The main culprit is related to the intrinsic nature of ECMO: the contact phase activation. The exposure of the human blood to the non-endothelial surface triggers a systemic inflammatory response syndrome, which chronically activates the thrombin generation and ultimately leads to coagulative derangements. Pre-existing illness-related hemostatic dysfunction and the peculiarity of the neonatal clotting balance further complicate the picture. Systemic anticoagulation is the management's mainstay, aiming to prevent thrombosis within the circuit and bleeding complications in the patient. Although other agents (i.e., direct thrombin inhibitors) have been recently introduced, unfractionated heparin (UFH) is the standard of care worldwide. Currently, there are multiple tests exploring ECMO-induced coagulopathy. A combination of the parameters mentioned above and the evaluation of the patient's underlying clinical context should be used to provide a goal-directed antithrombotic strategy. However, the ideal algorithm for monitoring anticoagulation is currently unknown, resulting in a large inter-institutional diagnostic variability. In this review, we face the features of the available monitoring tests and approaches, mainly focusing on the role of point-of-care (POC) viscoelastic assays in neonatal ECMO. Current gaps in knowledge and areas that warrant further study will also be addressed.

The role of magnetic resonance imaging in the diagnosis and prognostic evaluation of fetuses with congenital diaphragmatic hernia.

In recent years, magnetic resonance imaging (MRI) has largely increased our knowledge and predictive accuracy of congenital diaphragmatic hernia (CDH) in the fetus. Thanks to its technical advantages, better anatomical definition, and superiority in fetal lung volume estimation, fetal MRI has been demonstrated to be superior to 2D and 3D ultrasound alone in CDH diagnosis and outcome prediction. This is of crucial importance for prenatal counseling, risk stratification, and decision-making approach. Furthermore, several quantitative and qualitative parameters can be evaluated simultaneously, which have been associated with survival, postnatal course severity, and long-term morbidity. CONCLUSION: Fetal MRI will further strengthen its role in the near future, but it is necessary to reach a consensus on indications, methodology, and data interpretation. In addition, it is required data integration from different imaging modalities and clinical courses, especially for predicting postnatal pulmonary hypertension. This would lead to a comprehensive prognostic assessment. WHAT IS KNOWN: • MRI plays a key role in evaluating the fetal lung in patients with CDH. • Prognostic assessment of CDH is challenging, and advanced imaging is crucial for a complete prenatal assessment and counseling. WHAT IS NEW: • Fetal MRI has strengthened its role over ultrasound due to its technical advantages, better anatomical definition, superior fetal lung volume estimation, and outcome prediction. • Imaging and clinical data integration is the most desirable strategy and may provide new MRI applications and future research opportunities.

Proinflammatory Endothelial Phenotype in Very Preterm Infants: A Pilot Study.

Very preterm infants are exposed to prenatal inflammatory processes and early postnatal hemodynamic and respiratory complications, but limited data are available about the endothelial effect of these conditions. The present pilot study investigates the perinatal endothelial phenotype in very preterm infants (VPIs) and explores its predictive value on neonatal mortality and hemodynamic and respiratory complications. Angiopoietin 1 (Ang-1), Ang-2, E-selectin, vascular adhesion molecule 1 (VCAM-1), tissue factor (TF), and endothelin 1 (ET-1) concentrations were tested in first (T1), 3rd (T2), and 7-10th (T3) day of life in 20 VPIs using Luminex technology and compared with 14 healthy full-term infants (FTIs). Compared to FTIs, VPIs had lower Ang-1 at T1 and T2; higher Ang-2 at T1, T2, and T3; higher Ang-2/Ang-1 ratio at T1, T2, and T3; lower E-selectin at T1, T2, and T3; higher VCAM-1 at T1; higher TF at T2. No differences in concentrations were found in neonatal deaths. VPIs with hemodynamic or respiratory complications had higher Ang-2 at T3. Perinatal low Ang-1 and high Ang-2 associated with high VCAM-1 and TF in VPIs suggest a proinflammatory endothelial phenotype, resulting from the synergy of a pathological prenatal inheritance and a premature extrauterine transition.

Hemostatic Evaluation With Viscoelastic Coagulation Monitor: A Nicu Experience.

Background: Viscoelastic coagulation tests provide valuable information in neonatal intensive care units (NICUs), but the lack of reference intervals still limits their decision-making power according to gestational age. The aim of the present study is to evaluate the hemostasis of a cohort of full-term (FT) and late-preterm (LP) infants using the viscoelastic coagulation monitor (VCM®) system, a new portable device that uses untreated whole blood. Methods: An observational study was performed to identify non-coagulopathic FT and LP infants admitted to III° level NICU (January 2020 to December 2021) with a VCM test in the first 72 h of life. Results: Forty-five patients were enrolled, 26 FT and 19 LP. No statistical differences in hemostatic parameters were observed between FT and LP nor between stable and unstable neonates. Clotting time (CT) was positive correlated with PT (p = 0.032), not with aPTT (p = 0.185). From linear regression, platelet resulted associated with: clot formation time (CTF, p = 0.003), alpha angle (Alpha, p = 0.010), amplitude at 10 (A10, p = 0.001), amplitude at 20 min (A20, p < 0.001), maximum clot firmness (MCF, p < 0.001); and fibrinogen was associated with: A10 (p = 0.008), A20 (p = 0.015) and MCF (p = 0.024). Compared to the adult reference population, neonates showed shorter CT (mean (SD): 5.3 (1.4) vs. 7.0 (0.9) min, p < 0.001), CFT (2.4 (0.7) vs. 2.8 (0.6) minutes, p < 0.001) and higher Alpha (60.8 (6.3) vs. 55 (5)°, p < 0.001). In addition, the neonatal cohort showed an early transient difference in amplitude and fibrinolysis, as follows: A10 (28.0 (5.0) vs. 26 (4) VCM units, p =0.004), A20 (34.8 (5.0) vs. 33 (4) VCM units, p =0.012), and LI30 (99.8 (0.5) vs. 99 (1)%, p <0.001). Conclusions: The viscoelastic profile of FT and LP infants assessed with VCM showed a hemostatic competence characterized by accelerated coagulation and clot formation time, in line with other viscoelastic techniques. VCM system provides promising applications in the NICU setting.

Recurrence of Congenital Diaphragmatic Hernia: Risk Factors, Management, and Future Perspectives.

Recurrence is one of the most common surgical complications in Congenital Diaphragmatic Hernia (CDH). It could remain clinically silent for a long time or present as an acute complication week, months, or even years after the primary surgery. Several risk factors have been identified so far. An extended diaphragmatic defect represents one of the leading independent risk factors, together with indirect signs of large defect such as the liver position related to the diaphragm and the use of the prosthetic patch and with the use of a minimally invasive surgical (MIS) approach. However, the exact contribution of each factor and the overall risk of recurrence during the life span still need to be fully understood. This mini-review aims to give an overview of the current knowledge regarding CDH recurrence, focusing on predisposing factors, clinical presentation, management and follow-up of high-risk patients, and future perspectives.

Fetal MRI mediastinal shift angle and respiratory and cardiovascular pharmacological support in newborns with congenital diaphragmatic hernia.

In newborns with congenital diaphragmatic hernia (CDH), the mediastinal shift caused by the herniated organs negatively affects lung development. Assessment of the fetal magnetic resonance imaging (MRI) mediastinal shift angle (MSA) was shown to have an inverse correlation with the total fetal lung volume (TFLV), being associated with neonatal survival. However, a possible association with postnatal morbidity has never been investigated. We hypothesize that the degree of the mediastinal shift could be associated with higher respiratory and cardiocirculatory impairment, requiring intensive treatments and extended hospitalization in survivors. We retrospectively consider a cohort of isolated, left-sided CDH, for whom we calculated the MSA and the observed/expected (O/E) TFLV at fetal MRI. We performed a data collection regarding inotropic or vasoactive support, treatment with pulmonary vasodilators, mechanical ventilation, and length of stay. General linear models were performed. The MSA and O/E TFLV were inversely correlated (Pearson's coefficient - 0.65, p < 0.001), and deceased patients showed higher MSA values then survivors (p = 0.011). Among survivors, an increase in MSA was associated with longer pharmacological treatments (dobutamine: p = 0.016; dopamine: p = 0.049; hydrocortisone: p = 0.003; nitric oxide: p = 0.002; sildenafil: p = 0.039; milrinone: p = 0.039; oxygen: p = 0.066), and mechanical ventilation (p = 0.005), with an increasing trend in the length of hospitalization (p = 0.089).Conclusion: The MSA indirectly reflects lung hypoplasia and is associated with a higher neonatal intensity of cares. However, further studies are needed to consolidate the results.Trial registration: The study is an exploratory post hoc analysis of the registered NeoAPACHE protocol at ClinicalTrials.gov with the identifier NCT04396028. What is Known: • In congenital diaphragmatic hernia, the lung size, liver position, and defect side are the most common prenatal prognostic parameters used in clinical practice for morbidity and mortality prediction. • Lung hypoplasia, strictly associated with lung size, is estimated by observed/expected lung to head ratio and observed/expected total fetal lung volume with prenatal ultrasound and fetal magnetic resonance imaging, respectively. What is New: • A new, faster, more straightforward, and less operator-dependent tool to assess CDH severity could be the mediastinal shift angle calculation with fetal magnetic resonance imaging. • Postnatal clinical severity, considered as a postnatal cardiovascular and respiratory impairment that indirectly reflects lung hypoplasia, is associated with an increased mediastinal shift angle calculation.

Selective Bronchial Occlusion for Treatment of a Bronchopleural Fistula in an Extremely Preterm Infant.

Neonatal pulmonary air leak commonly occurs as a complication of mechanical ventilation in infants with underlying hyaline membrane disease. They can commonly be managed conservatively or with the application of a chest drain, but some severe cases pose a significant challenge in finding an alternative therapeutic solution. Selective bronchial occlusion represents an unconventional rescue therapy for treating bronchopleural fistula resistant to the standard therapy. A 27-week gestation preterm infant ventilated for respiratory distress syndrome developed tension right-sided pneumothorax. Conventional modalities of treatment were tried and were unsuccessful. Intermittent selective bronchial occlusion with a Fogarty's catheter and high-frequency oscillatory ventilation resulted in considerable improvement in the infant's clinical condition and radiographic findings.

A maChine and deep Learning Approach to predict pulmoNary hyperteNsIon in newbornS with congenital diaphragmatic Hernia (CLANNISH): Protocol for a retrospective study.

INTRODUCTION: Outcome predictions of patients with congenital diaphragmatic hernia (CDH) still have some limitations in the prenatal estimate of postnatal pulmonary hypertension (PH). We propose applying Machine Learning (ML), and Deep Learning (DL) approaches to fetuses and newborns with CDH to develop forecasting models in prenatal epoch, based on the integrated analysis of clinical data, to provide neonatal PH as the first outcome and, possibly: favorable response to fetal endoscopic tracheal occlusion (FETO), need for Extracorporeal Membrane Oxygenation (ECMO), survival to ECMO, and death. Moreover, we plan to produce a (semi)automatic fetus lung segmentation system in Magnetic Resonance Imaging (MRI), which will be useful during project implementation but will also be an important tool itself to standardize lung volume measures for CDH fetuses. METHODS AND ANALYTICS: Patients with isolated CDH from singleton pregnancies will be enrolled, whose prenatal checks were performed at the Fetal Surgery Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy) from the 30th week of gestation. A retrospective data collection of clinical and radiological variables from newborns' and mothers' clinical records will be performed for eligible patients born between 01/01/2012 and 31/12/2020. The native sequences from fetal magnetic resonance imaging (MRI) will be collected. Data from different sources will be integrated and analyzed using ML and DL, and forecasting algorithms will be developed for each outcome. Methods of data augmentation and dimensionality reduction (feature selection and extraction) will be employed to increase sample size and avoid overfitting. A software system for automatic fetal lung volume segmentation in MRI based on the DL 3D U-NET approach will also be developed. ETHICS AND DISSEMINATION: This retrospective study received approval from the local ethics committee (Milan Area 2, Italy). The development of predictive models in CDH outcomes will provide a key contribution in disease prediction, early targeted interventions, and personalized management, with an overall improvement in care quality, resource allocation, healthcare, and family savings. Our findings will be validated in a future prospective multicenter cohort study. REGISTRATION: The study was registered at ClinicalTrials.gov with the identifier NCT04609163.

Individualized Bleeding Risk Assessment through Thromboelastography: A Case Report of May-Hegglin Anomaly in Preterm Twin Neonates.

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder in the spectrum of myosin heavy chain-related disorders (MYH9-RD), characterized by congenital macrothrombocytopenia and white blood cell inclusions. MHA carries a potential risk of hemorrhagic complications. Bleeding diathesis is usually mild, but sporadic, life-threatening events have been reported. Data regarding the clinical course and outcomes of neonatal MYH9-RD are limited, and specific guidelines on platelet transfusion in asymptomatic patients are lacking. We present monochorionic twins born preterm at 32 weeks of gestation to an MHA mother; both presented with severe thrombocytopenia at birth. Peripheral blood smear demonstrated the presence of macrothrombocytes, and immunofluorescence confirmed the diagnosis of MHA. Close clinical monitoring excluded bleeding complications, and serial hemostatic assessments through a viscoelastic system demonstrated functionally normal primary hemostasis in both patients. Therefore, prophylactic platelet transfusions were avoided. Whole DNA sequencing confirmed the pathogenetic variant of MHA of maternal origin in both twins. Thromboelastography allowed real-time bedside bleeding risk assessment and supported individualized transfusion management in preterm newborns at risk of hemostatic impairment. This report suggests that dynamic and appropriate clotting monitoring may contribute to the more rational use of platelets' transfusions while preserving patients with hemorrhagic complications and potential transfusion-related side effects.

Severe Presentation of Congenital Hemolytic Anemias in the Neonatal Age: Diagnostic and Therapeutic Issues.

Congenital hemolytic anemias (CHAs) are a group of diseases characterized by premature destruction of erythrocytes as a consequence of intrinsic red blood cells abnormalities. Suggestive features of CHAs are anemia and hemolysis, with high reticulocyte count, unconjugated hyperbilirubinemia, increased lactate dehydrogenase (LDH), and reduced haptoglobin. The peripheral blood smear can help the differential diagnosis. In this review, we discuss the clinical management of severe CHAs presenting early on in the neonatal period. Appropriate knowledge and a high index of suspicion are crucial for a timely differential diagnosis and management. Here, we provide an overview of the most common conditions, such as glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and hereditary spherocytosis. Although rare, congenital dyserythropoietic anemias are included as they may be suspected in early life, while hemoglobinopathies will not be discussed, as they usually manifest at a later age, when fetal hemoglobin (HbF) is replaced by the adult form (HbA).

NeoAPACHE II. Relationship Between Radiographic Pulmonary Area and Pulmonary Hypertension, Mortality, and Hernia Recurrence in Newborns With CDH.

Congenital diaphragmatic hernia is a rare disease with high mortality and morbidity due to pulmonary hypoplasia and pulmonary hypertension. The aim of the study is to investigate the relationship between radiographic lung area and systolic pulmonary artery pressure (sPAP) on the first day of life, mortality, and hernia recurrence during the first year of life in infants with a congenital diaphragmatic hernia (CDH). A retrospective data collection was performed on 77 CDH newborns. Echocardiographic sPAP value, deaths, and recurrence cases were recorded. Lung area was calculated by tracing the lung's perimeter, excluding mediastinal structures, and herniated organs, on the preoperative chest X-ray performed within 24 h after birth. Logistic and linear regression analyses were performed. Deceased infants showed lower areas and higher sPAP values. One square centimeter of rising in the total, ipsilateral, and contralateral area was associated with a 22, 43, and 24% reduction in mortality risk. sPAP values showed a decreasing trend after birth, with a maximum of 1.84 mmHg reduction per unitary increment in the ipsilateral area at birth. Recurrence patients showed lower areas, with recurrence risk decreasing by 14 and 29% per unit increment of the total and ipsilateral area. In CDH patients, low lung area at birth reflects impaired lung development and defect size, being associated with increased sPAP values, mortality, and recurrence risk. Clinical Trial Registration: The manuscript is an exploratory secondary analysis of the trial registered at ClinicalTrials.gov with identifier NCT04396028.

Neonatal respiratory and cardiac ECMO in Europe.

Neonatal extracorporeal membrane oxygenation (ECMO) is a life-saving procedure for critically ill neonates suffering from a potentially reversible disease, causing severe cardiac and/or respiratory failure and refractory to maximal conventional management. Since the 1970s, technology, management, and clinical applications of neonatal ECMO have changed. Pulmonary diseases still represent the principal neonatal diagnosis, with an overall 74% survival rate, and up to one-third of cases are due to congenital diaphragmatic hernia. The overall survival rate in cardiac ECMO is lower, with congenital heart defect representing the main indication. This review provides an overview of the available evidence in the field of neonatal ECMO. We will address the changing epidemiology, basic principles, technologic advances in circuitry, and monitoring, and deliver a current multidisciplinary management framework, focusing on ECMO applications, complications, and long-term morbidities. Lastly, areas for further research will be highlighted.Conclusions: ECMO is a life support with a potential impact on long-term patients' outcomes. In the next years, advances in knowledge, technology, and expertise may push neonatal ECMO boundaries towards more premature and increasingly complex infants, with the final aim to reduce the burden of ECMO-related complications and improve overall patients' outcomes. What is Known: • ECMO is a life-saving option in newborns with refractory respiratory and/or cardiac failure. • The multidisciplinary ECMO management is challenging and may expose neonates to complications with an impact on long-term outcomes. What is New: • Advances in technology and biomaterials will improve neonatal ECMO management and, eventually, the long-term outcome of these complex patients. • Experimental models of artificial placenta and womb technology are under investigation and may provide clinical translation and future research opportunities.

The NeoAPACHE Study Protocol I: Assessment of the Radiographic Pulmonary Area and Long-Term Respiratory Function in Newborns With Congenital Diaphragmatic Hernia.

In newborns with congenital diaphragmatic hernia (CDH), the radiographic lung area is correlated with functional residual capacity (FRC) and represents an alternative method to estimate lung hypoplasia. In a cohort of newborn CDH survivors, we retrospectively evaluated the relationship between radiographic lung area measured on the 1st day of life and long-term respiratory function. As a secondary analysis, we compared radiographic lung areas and respiratory function between patients undergoing fetal endoscopic tracheal occlusion (FETO) and patients managed expectantly (non-FETO). Total, ipsilateral, and contralateral radiographic areas were obtained by tracing lung perimeter as delineated by the diaphragm and rib cage, excluding mediastinal structures and herniated organs. Tidal volume (VT), respiratory rate (RR), and their Z-Scores when compared to the norm were collected from pulmonary function tests (PFTs) performed at 12 ± 6 months of age. Linear regression analyses using the absolute Z-Score values for each parameter were performed. In CDH survivors, an increase in total and ipsilateral lung area measured at birth was related to a reduction in the absolute Z-Score for VT in PFTs (p = 0.046 and p = 0.023, respectively), indicating a trend toward an improvement in pulmonary volumes and VT normalization. Radiographic lung areas were not significantly different between FETO and non-FETO patients, suggesting a volumetric lung increase due to prenatal intervention. However, the mean Z-Score value for RR was significantly higher in the FETO group (p < 0.001), probably due to impaired diaphragmatic motility in the most severe cases. Further analyses are necessary to better characterize the role of the radiographic pulmonary area in the prognostic evaluation of respiratory function in patients with CDH. Clinical Trial Registration: This trial was registered at ClinicalTrials.gov with the identifier NCT04396028.