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.

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.

Optimizing fresh-frozen plasma transfusion in surgical neonates through thromboelastography: a quality improvement study.

Fresh frozen plasma (FFP) is largely misused in the neonatal setting. The aim of the study is to evaluate the impact of a Thromboelastography (TEG)-based Quality Improvement (QI) project on perioperative FFP use and neonatal outcomes. Retrospective pre-post implementation study in a level-III NICU including all neonates undergoing major non-cardiac surgery before (01-12/2017) and after (01-12/2019) the intervention. In 2018, the intervention included the following: (1) Training on TEG, (2) Implementation of TEG, and (3) Algorithm for TEG-directed FFP administration in surgical neonates. We compared pre- vs post-intervention patient characteristics, hemostasis, and clinical management. Linear and logistic regression models were used to evaluate the impact of the project on main outcomes. We analyzed 139 neonates (pre-intervention: 72/post-intervention: 67) with a mean (± SD) gestational age (GA) 34.9 (± 5) weeks and birthweight 2265 (± 980) grams which were exposed to 184 surgical procedures (pre-intervention: 91/post-intervention: 93). Baseline characteristics were similar between periods. In 2019, prothrombin time (PT) was longer (14.3 vs 13.2 s; p < 0.05) and fibrinogen was lower (229 vs 265 mg/dl; p < 0.05), if compared to 2017. In 2019, the intraoperative exposure to FFP decreased (31% vs 60%, p < 0.001), while the pre-operative FFP use did not change. The reduction of intraoperative FFP did not impact on mortality and morbidity. Intraoperative FFP use was lower in the post-intervention even after controlling for GA, American Society of Anesthesiologists score, PT, and fibrinogen (Odds ratio: 0.167; 95% CI: 0.070, 0.371).   Conclusion: The TEG-based QI project for the management of FFP during neonatal surgery reduced intraoperative FFP exposure. What is Known: • PT and aPTT are poor predictors of bleeding risk in acquired neonatal coagulopathy, leading to likely unnecessary fresh frozen plasma (FFP) transfusion in the Neonatal Intensive Care Setting.  • As neonatal hemostasis is a delicate balance between the concomitant reduction of pro- and anti-coagulants drivers, thromboelastography (TEG) is a promising alternative for coagulation monitoring. What is New: • The implementation of TEG, training, and shared protocols contributed to reduced intraoperative FFP use, which was not associated with increased mortality or bleeding events. • These findings inform future research showing that there is clinical equipoise to allow for larger studies to confirm the use of TEG in NICUs and to identify TEG cut-offs for transfusion practice.

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.

Is Fetal Endoscopic Tracheal Occlusion (FETO) a Predisposing Factor for Acid Gastro-Esophageal Reflux in Infants With Congenital Diaphragmatic Hernia?

Introduction: Various anatomical defects predispose patients with congenital diaphragmatic hernia (CDH) to develop gastroesophageal reflux disease (GERD). The fetal endoscopic tracheal occlusion (FETO) has increased the survival of patients with severe CDHs. The aim of this study was to study GERD in patients who underwent FETO. Materials and Methods: We included patients with CDH treated with or without FETO ("FETO" and "no-FETO" group, respectively) from 2013 to 2016. Data on gestational age (GA), birth weight (BW), initial observed/expected lung to head ratio (O/E LHR), final O/E LHR, duration of ventilation and hospitalization, maximal tracheal diameter, and pulmonary volume were collected. All patients underwent pH-metry after 1 year of life, and the results were compared between groups and correlated to risk factors. Results: Thirty-two patients were included in the study: 10 FETO and 22 no-FETO. No significant differences were observed in the pH-metric results of the two groups. No correlation was found between GA, BW, initial O/E LHR, maximal tracheal diameter, pulmonary volume, and pH-metric results. pH-metric results were correlated with the total duration of ventilation (R = 0.5, p = 0.003) and of hospitalization (R = 0.54, p = 0.001). Gastric herniation is associated with the worse pH-metric result. Conclusions: The FETO procedure does not seem to represent an independent risk factor for GERD. However, patients with the most severe CDH have the worst GERD.

The Thromboelastographic Profile at Birth in Very Preterm Newborns with Patent Ductus Arteriosus.

BACKGROUND: The role of hemostasis in the closure of patent ductus arteriosus (PDA) in preterm infants is controversial. OBJECTIVE: To assess thromboelastography (TEG) at birth in very-low-birth-weight (VLBW) infants affected by PDA. METHODS: This was an ancillary study of a prospective observational study aimed at defining the TEG profile in healthy VLBW infants in the first month of life. In this analysis, we included neonates of <33 weeks' gestational age (GA) with PDA and compared TEG traces based on (1) spontaneous closure versus the need for pharmacological treatment and (2) treatment response. We collected blood samples in the 1st day of life to perform recalcified native-blood TEG (reaction time, maximum amplitude, and lysis at 30 min [Ly30)]), standard coagulation tests, and a full blood count. RESULTS: We enrolled 151 infants with a PDA at the first echocardiogram; 111 experienced spontaneous PDA closure while 40 required treatment. Mean GA was 29.7 ± 1.7 and 27.6 ± 2.1 weeks, and birth weight was 1,158 ± 256 and 933 ± 263 g in the 2 groups, respectively (p < 0.001). The hemostatic profile was similar between groups. Median hematocrit (44.6 and 48.7%; p = 0.01) and platelet count (187 and 216 × 103/µL; p = 0.04) were lower in the treated group, although differences lost significance after controlling for GA and illness severity in the multivariate analysis. Responders to PDA treatment (n = 20) had a significantly lower median Ly30 than nonresponders (0 and 0.7%; p = 0.02). CONCLUSION: TEG at birth does not predict spontaneous PDA closure in preterm newborns. Fibrinolysis is enhanced in nonresponders to PDA treatment; this observation warrants further investigation.

Iron Homeostasis Disruption and Oxidative Stress in Preterm Newborns.

Iron is an essential micronutrient for early development, being involved in several cellular processes and playing a significant role in neurodevelopment. Prematurity may impact on iron homeostasis in different ways. On the one hand, more than half of preterm infants develop iron deficiency (ID)/ID anemia (IDA), due to the shorter duration of pregnancy, early postnatal growth, insufficient erythropoiesis, and phlebotomy losses. On the other hand, the sickest patients are exposed to erythrocytes transfusions, increasing the risk of iron overload under conditions of impaired antioxidant capacity. Prevention of iron shortage through placental transfusion, blood-sparing practices for laboratory assessments, and iron supplementation is the first frontier in the management of anemia in preterm infants. The American Academy of Pediatrics recommends the administration of 2 mg/kg/day of oral elemental iron to human milk-fed preterm infants from one month of age to prevent ID. To date, there is no consensus on the type of iron preparations, dosages, or starting time of administration to meet optimal cost-efficacy and safety measures. We will identify the main determinants of iron homeostasis in premature infants, elaborate on iron-mediated redox unbalance, and highlight areas for further research to tailor the management of iron metabolism.

Surgical Expertise in Neonatal Extracorporeal Membrane Oxygenation (ECMO): A Single Center Experience.

Introduction: The surgical technique for peripheral cannulation aimed at providing extracorporeal membrane oxygenation (ECMO) is well described. Training methods for surgeons still need proper standardization, especially in newborn patients. This study aims to evaluate the surgical training outcomes of a neonatal ECMO team. Materials and Methods: A 4 year training program (2014-2018) was developed to achieve the skills in the surgical technique for neonatal veno-arterial ECMO. Surgeons with experience in neonatal and vascular surgery were selected for the training. The training consisted of educational sessions, high-fidelity simulations, in vivo swine model procedures, international fellowship, and periodical simulations. The preliminary clinical experience in surgical neonatal ECMO management (2016-present) was analyzed by recording the following data: indications for ECMO and patients' data; effectiveness of cannulations (number; perioperative complications of cannulation; major surgical events during ECMO); efficacy of decannulation (number and perioperative complications). Results: 12 neonates (5 females) fitted the ELSO criteria for ECMO. Nine newborns were affected by CDH; 1 by H1N1 flu-related pneumonia; 1 by meconium aspiration syndrome and one by Respiratory Syncytial Virus related bronchiolitis. Mean weight at cannulation was 3,281 g (range 2,330-3,840 g); mean gestational age was 36 weeks. No procedure was aborted, and no intra-operatory mortality was recorded. Mean operative time was 86 ± 30 min. The caliber of the carotideal cannulas ranged from 8F (8 patients) to 10F (2 patients); the caliber of the jugular cannulas were: 8F cannula (2 patients), 10F (6 patients), and 12F (2 patients). Four complications occurred: a case of air in the circuit, two cases of azygous vein cannulation and a partial dislocation of the venous cannula during the daily care maneuvers. All of them were promptly recognized and successfully treated. The mean ECMO duration was 7.1 ± 4.2 days (range 2-16 days). Seven patients (78%) were decannulated effectively. Mean decannulation time was 53 min (range 45-80 min). No complications occurred during the decannulation process. No ECMO-related deaths were recorded. Conclusions: Neonatal respiratory ECMO still represents a challenge. Experienced neonatal surgeons can manage the neck vascular cannulation. The codified procedure must be adhered to after appropriate training and following a proper learning curve.

Drug Disposition and Pharmacotherapy in Neonatal ECMO: From Fragmented Data to Integrated Knowledge.

Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. As the survival and the overall outcome of patients rely on the treatment and reversal of the underlying disease, effective and preferentially evidence-based pharmacotherapy is crucial to target recovery. Currently limited data exist to support the clinicians in their every-day intensive care prescribing practice with the contemporary ECMO technology. Indeed, drug dosing to optimize pharmacotherapy during neonatal ECMO is a major challenge. The impact of the maturational changes of the organ function on both pharmacokinetics (PK) and pharmacodynamics (PD) has been widely established over the last decades. Next to the developmental pharmacology, additional non-maturational factors have been recognized as key-determinants of PK/PD variability. The dynamically changing state of critical illness during the ECMO course impairs the achievement of optimal drug exposure, as a result of single or multi-organ failure, capillary leak, altered protein binding, and sometimes a hyperdynamic state, with a variable effect on both the volume of distribution (Vd) and the clearance (Cl) of drugs. Extracorporeal membrane oxygenation introduces further PK/PD perturbation due to drug sequestration and hemodilution, thus increasing the Vd and clearance (sequestration). Drug disposition depends on the characteristics of the compounds (hydrophilic vs. lipophilic, protein binding), patients (age, comorbidities, surgery, co-medications, genetic variations), and circuits (roller vs. centrifugal-based systems; silicone vs. hollow-fiber oxygenators; renal replacement therapy). Based on the potential combination of the above-mentioned drug PK/PD determinants, an integrated approach in clinical drug prescription is pivotal to limit the risks of over- and under-dosing. The understanding of the dose-exposure-response relationship in critically-ill neonates on ECMO will enable the optimization of dosing strategies to ensure safety and efficacy for the individual patient. Next to in vitro and clinical PK data collection, physiologically-based pharmacokinetic modeling (PBPK) are emerging as alternative approaches to provide bedside dosing guidance. This article provides an overview of the available evidence in the field of neonatal pharmacology during ECMO. We will identify the main determinants of altered PK and PD, elaborate on evidence-based recommendations on pharmacotherapy and highlight areas for further research.

Abdominal cystic lymphangioma in a term newborn: A case report and update of new treatments.

INTRODUCTION: Lymphatic malformations are benign anomalies derived from the abnormal development of lymphatic channels. Usually asymptomatic, they can cause compression on adjacent structures or present acute complications (bleeding or infection). Small asymptomatic lesions can be conservatively managed since the possibility of spontaneous regressions is described, while symptomatic lesions require active management. Less invasive therapeutic options are now preferred instead of surgery (sclerotherapy, laser therapy). However, there are not uniform therapeutic protocols. CASE REPORT: We present the case of a term newborn with an abdominal cystic lymphangioma extending from the umbilical to the right inguinal area, reaching the medial surface of the right tight. Despite its large dimensions, which classically request surgical management, the patient was by chance asymptomatic, and the mass did not determine compression on the surrounding organs. Therefore, conservative management was tried, and a close clinical and radiological follow-up was started. This approach permitted a spontaneous regression of the mass and to avoid major surgical intervention. CONCLUSION: Our purpose is to underline the possibility of conservative management of the major multicystic masses and to focus on less invasive therapeutic options, like sclerotherapy, oral therapy, and laser therapy.

The use of sirolimus in the treatment of giant cystic lymphangioma: Four case reports and update of medical therapy.

RATIONALE: Lymphatic malformations (LMs) are rare and benign anomalies resulting from the defective embryological development of the primordial lymphatic structures. Due to their permeative growth throughout all tissue layers, treatment is often challenging. Small asymptomatic lesions can be conservatively managed, while symptomatic lesions require active management. Surgery has been historically considered the treatment of choice, but today less invasive therapeutic options are preferred (sclerotherapy, laser therapy, oral medications). However, there are not uniform therapeutic protocols. Sirolimus is an oral medication that has been reported to be effective in the recent literature. Here we present the case of 4 newborns with giant multicystic lymphangioma treated with oral sirolimus after surgical resection had failed. PATIENT CONCERNS: At birth the LMs were clinically appreciated as giant masses involving different organs and structures. DIAGNOSES: All patients had a prenatal diagnosis of giant multicystic lymphangioma confirmed at histological and cytological analysis. INTERVENTIONS: Patients were treated with oral sirolimus after unsuccessful surgical resection. OUTCOMES: In all patients, sirolimus determined an overall reduction of the mass and a global involution from the macro- to the microcystic composition. Sirolimus was safe and poor disadvantages had been observed. The main and isolated adverse effect at laboratory analysis was progressive dyslipidemia, with increasing levels of total cholesterol and triglycerides. LESSONS: To date, our experience with sirolimus in the management of LMs is favorable. We recommend the use of sirolimus after unsuccessful surgical excision have been tried or when the surgical approach is not feasible. A multidisciplinary follow-up is needed to monitor disease evolution.

The pathophysiology of retinopathy of prematurity: an update of previous and recent knowledge.

Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birthweight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new antivasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterized for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO2 regulate the normal or abnormal production of hypoxia-inducible factor 1 and vascular endothelial growth factors (VEGF), which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF-1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF-1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti-VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and ß-adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single-nucleotide polymorphisms within the ß-ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using ß-blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP.