Assessment of hemodynamic dysfunction in septic newborns by functional echocardiography: a systematic review.

BACKGROUND: Neonatal sepsis remains a leading cause of mortality in neonatal units. Neonatologist-performed echocardiography (NPE) offers the potential for early detection of sepsis-associated cardiovascular dysfunction. This review examines available echocardiographic findings in septic neonates. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed prospective observational, cross-sectional, case control, and cohort studies on septic newborns with echocardiographic assessments from PubMed, Scopus and Embase. Quality assessment employed the Newcastle-Ottawa Scale, with results analyzed descriptively. RESULTS: From an initial pool of 1663 papers, 12 studies met inclusion criteria after relevance screening and eliminating duplicates/excluded studies. The review encompassed 438 septic newborns and 232 controls. Septic neonates exhibited either increased risk of pulmonary hypertension or left ventricular diastolic dysfunction, and a warm shock physiology characterized by higher cardiac outputs. DISCUSSION: The included studies exhibited heterogeneity in sepsis definitions, sepsis severity scores, echocardiographic evaluations, and demographic data of newborns. Limited sample sizes compromised analytical interpretability. Nonetheless, this work establishes a foundation for future high-quality echocardiographic studies. CONCLUSION: Our review confirms that septic neonates show significant hemodynamic changes that can be identified using NPE. These findings underscore the need for wider NPE use to tailor hemodynamics-based strategies within this population. IMPACT: 1. Our study emphasizes the value of neonatologist-performed echocardiography (NPE) as a feasible tool for identifying significant hemodynamic changes in septic neonates. 2. Our study underscores the importance of standardized echocardiographic protocols and frequent monitoring of cardiac function in septic neonates. 3. The impact of the study lies in its potential to increase researchers' awareness for the need for more high-quality echocardiographic data in future studies. By promoting wider use of NPE, neonatologists can more accurately assess the hemodynamic status of septic newborns and tailor treatment approaches, potentially improving patient outcomes.

The role of point-of-care ultrasound in the management of neonates with congenital diaphragmatic hernia.

In the last few years, current evidence has supported the use of point-of-care ultrasound (POCUS) for a number of diagnostic and procedural applications. Considering the valuable information that POCUS can give, we propose a standardized protocol for the management of neonates with a congenital diaphragmatic hernia (CDH-POCUS protocol) in the neonatal intensive care unit. Indeed, POCUS could be a valid tool for the neonatologist through the evaluation of 1) cardiac function and pulmonary hypertension; 2) lung volumes, postoperative pleural effusion or pneumothorax; 3) splanchnic and renal perfusion, malrotations, and/or signs of necrotizing enterocolitis; 4) cerebral perfusion and eventual brain lesions that could contribute to neurodevelopmental impairment. In this article, we discuss the state-of-the-art in neonatal POCUS for which concerns congenital diaphragmatic hernia (CDH), and we provide suggestions to improve its use. IMPACT: This review shows how point-of-care ultrasound (POCUS) could be a valid tool for managing neonates with congenital diaphragmatic hernia (CDH) after birth. Our manuscript underscores the importance of standardized protocols in neonates with CDH. Beyond the well-known role of echocardiography, ultrasound of lungs, splanchnic organs, and brain can be useful. The use of POCUS should be encouraged to improve ventilation strategies, systemic perfusion, and enteral feeding, and to intercept any early signs related to future neurodevelopmental impairment.

Current management of surgical neonates: is it optimal or do we need to improve? A national survey of the Italian Society of Neonatology.

PURPOSE: Few guidelines exist for the perioperative management (PM) of neonates with surgical conditions (SC). This study examined the current neonatal PM in Italy. METHODS: We invited 51 neonatal intensive care units with pediatric surgery in their institution to participate in a web-based survey. The themes included (1) the involvement of the neonatologist during the PM; (2) the spread of bedside surgery (BS); (3) the critical issues concerning the neonatal PM in operating rooms (OR) and the actions aimed at improving the PM. RESULTS: Response rate was 82.4%. The neonatologist is involved during the intraoperative management in 42.9% of the responding centers (RC) and only when the surgery is performed at the patient's bedside in 50.0% of RCs. BS is reserved for extremely preterm (62.5%) or clinically unstable (57.5%) infants, and the main barrier to its implementation is the surgical-anesthesiology team's preference to perform surgery in a standard OR (77.5%). Care protocols for specific SC are available only in 42.9% of RCs. CONCLUSION: Some critical issues emerged from this survey: the neonatologist involvement in PM, the spread of BS, and the availability of specific care protocols need to be implemented to optimize the care of this fragile category of patients.

Reply to the comment on "Fluid restriction in management of patent ductus arteriosus in Italy: a nationwide survey".

The Authors Chang Liu B.S and Yuan Shi commented our paper on Fluid restriction in management of patent ductus arteriosus (PDA) in Italy. With our study, we conducted a prospective cross-sectional survey among all Italian Neonatal Intensive Care Units (NICUs) to address conservative management of patent ductus arteriosus (PDA) in preterm infants below 29 weeks' gestational age (GA), with specific regard to fluid restriction (FR). The Authors wondered if the heterogeneity of use of fluid restriction both as a prophylactic tool and as a conservative tool when a hemodynamically significant PDA is diagnosed, was due to economic disparities among areas of the included centers. Conducting a secondary analysis of our data, we observed that if we separately consider the responses of two areas, northern and central-southern Italy, FR is slightly more frequently applied in Central and Southern regions (82%) as compared to Northern regions (78%), although this finding does not reach statistical significance. No correlation between the likelihood to adopt conservative measures and the amount of allowed fluid intake was found. The hypothesis that "less fluid intake resulted in milder clinical and echocardiographic presentations of PDA, and thus a lower rate of pharmacological treatment" cannot be supported by our current study design and might deserve future investigations.

Fluid restriction in management of patent ductus arteriosus in Italy: a nationwide survey.

We aimed at establishing the state of the art in fluid restriction practice in our national setting and providing a foundation for future research efforts. A prospective cross-sectional survey was conducted among all 114 Italian Neonatal Units in order to address conservative management of patent ductus arteriosus (PDA) in preterm infants below 29 weeks' gestational age (GA), with specific regard to fluid restriction. Response rate was 80%. Conservative measures for PDA management are provided in the majority of NICUs and 80% of centers reduce fluid intake in neonates with PDA. No relationship can be found among pharmacologically or surgically treated patients per year and the approach to fluid restriction. The minimum intake administered at regimen when fluid restriction is applied is associated to the ratio between the maximum number of neonates managed pharmacologically and number of admitted < 29 weeks' GA newborns. CONCLUSION: Our survey shows an extreme variability among centers in terms of use of fluid restriction as a prophylactic tool but also in terms of its use (both opportunity and modality) when a hemodynamically significant PDA is diagnosed. This variability, that can be also found in randomized trials and observational studies, suggests that further evidence is needed to better understand its potential beneficial effects and its potential harms such as dehydration, hypotension, decreased end-organ perfusion, and reduced caloric intake. WHAT IS KNOWN: • The lack of demonstrable improvement following the treatment of patent ductus arteriosus has recently paved the way to a more conservative approach. • Fluid restriction is the most commonly applied conservative treatment of PDA. WHAT IS NEW: • Among Italian NICUs an extreme variability in terms of indications, timing and modalities of application of Fluid restriction can be found. • This variability reflects the lack of standardization of this practice and the contrasting evidence on its efficacy.

Brain cortical assessment by MRI in fetuses with left congenital diaphragmatic hernia.

OBJECTIVE: To evaluate fetal brain development using MRI (magnetic resonance imaging) in CDH (congenital diaphragmatic hernia). METHODS: 52 isolated left CDH and 104 control fetuses were imaged using MRI. Brain morphometry (Biparietal diameter-BPD, brain fronto-occipital diameter-BFOD, third ventricle, posterior ventricles, transcerebellar diameter-TCD, anteroposterior and craniocaudal cerebellar vermis diameter-AP and CC) and cortical structures (bilateral cingulate fissure-CF, insular fissure-IF, insular depth - ID) were compared with controls using Mann-Whitney test. RESULTS: Median gestational age at MRI (p = 0.95)and the median biparietal diameter (p = 0.737) were comparable. Among morphometric parameters, only the brain fronto-occipital diameter was significantly smaller in CDH (p = 0.001) and the third ventricle was significantly greater in CDH (<0.0001). Among cortical structures, the cingulate and insular fissures were significantly deeper in CDH fetuses (p < 0.0001) as the insular depth ID was smaller in CDH (p < 0.03). CONCLUSIONS: CDH fetuses have a smaller fronto-occipital diameter, reduced insular depth, deeper cingulate and insular fissure, and greater third ventricle width as compared to controls. These findings suggest that left CDH may have an impact on fetal brain development with an overall reduction in brain volume.

Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension.

Epigenetic regulators such as microRNAs (miRNAs) have a key role in modulating several gene expression pathways and have a role both in lung development and function. One of the main pathogenetic determinants in patients with congenital diaphragmatic hernia (CDH) is pulmonary hypertension (PH), which is directly related to smaller lung size and pulmonary microarchitecture alterations. The aim of this review is to highlight the importance of miRNAs in CDH-related PH and to summarize the results covering this topic in animal and human CDH studies. The focus on epigenetic modulators of CDH-PH offers the opportunity to develop innovative diagnostic tools and novel treatment modalities, and provides a great potential to increase researchers' understanding of the pathophysiology of CDH.

Hemodynamic Assessment of a Large Pulmonary Arteriovenous Malformation in a Neonate: Case Report and Review of Literature.

Herein we report the case of a neonate with a prenatally diagnosed large pulmonary arteriovenous malformation, managed with minimally invasive hemodynamic monitoring in our Neonatal Intensive Care Unit. The combination of Near-Infrared Spectroscopy and Pressure Recording Analytical Method could guide neonatal management of critical cases of vascular anomalies: immediate data are offered to clinicians, from which therapeutic decisions such as timing of surgical resection are made to achieve a positive outcome. We also systemically collected and summarized information on patients' characteristics of previous cases reported in literature to data, and we compared them to our case.

Severe herpes virus 6 interstitial pneumonia in an infant with three variants in genes predisposing to lung disease.

Infections due to human herpesvirus 6 (HHV-6) are frequent during early childhood. Usually, they have a favorable clinical course. Conversely, HHV-6 congenital infections occur in about 1% of neonates and may present with more severe clinical pictures. HHV-6 can be found in lung tissues and bronchoalveolar lavage (BAL) samples from patients with pneumonia and in immunocompromised patients can cause mild to severe pneumonia. In neonates, the role of HHV-6 in the genesis of severe pneumonia is poorly defined still now. We describe a healthy infant with a late-onset (15 days of life) severe interstitial pneumonia and heavy HHV-6 genome load, persistently detected in its BAL fluid. The baby underwent high-frequency oscillatory ventilation, hydroxychloroquine, steroids, and ganciclovir for 6 weeks and at 9 months she died. Next-generation sequencing of genes known to cause neonatal respiratory insufficiency revealed the presence of a "probably pathogenetic" heterozygous variant in the autosomal recessive DRC1 gene, a heterozygous variant of unknown significance (VUS) in the autosomal recessive RSPH9 gene, and a heterozygous VUS in the autosomal recessive MUC5B gene. HHV-6 infection should be considered in the differential diagnosis of late-onset severe respiratory distress in neonates and the co-occurrence of genetic predisposing factors or modifiers should be tested by specific molecular techniques. The intensity of HHV-6 genome load in BAL fluid could be an indicator of the response to antiviral therapy.

Propofol Formulation Affects Myocardial Function in Newborn Infants.

This study aimed to evaluate the effects of propofol in diluted and undiluted formulations on cardiac function in infants. Infants > 30 days received propofol sedation for central line insertion. Cases were divided into two groups: those who received undiluted 1% propofol (P1%); and those who received a diluted formulation (Pd) of equal volumes propofol 1% and 0.9% NaCl. Echocardiograms were performed pre (t0)-, immediately post (t1)-, and 1-h post (t2) propofol administration. Myocardial deformation was assessed with tissue Doppler imaging (TDI) analysis and peak longitudinal strain (LS). 18 cases were included: nine (50%) P1% and nine (50%) Pd. In the P1% group, TDI velocities and LS were significantly reduced at t1 and t2. In the Pd Group, only TDI velocities in the left ventricle were reduced at t1, but not at t2. Dilution of propofol may minimize myocardial dysfunction while maintaining adequate sedation in infants. Further comparative studies are needed to investigate the safety and efficacy of this approach.

Defining outcomes following congenital diaphragmatic hernia using standardised clinical assessment and management plan (SCAMP) methodology within the CDH EURO consortium.

Treatment modalities for neonates born with congenital diaphragmatic hernia (CDH) have greatly improved in recent times with a concomitant increase in survival. In 2008, CDH EURO consortium, a collaboration of a large volume of CDH centers in Western Europe, was established with a goal to standardize management and facilitate multicenter research. However, limited knowledge on long-term outcomes restricts the identification of optimal care pathways for CDH survivors in adolescence and adulthood. This review aimed to evaluate the current practice of long-term follow-up within the CDH EURO consortium centers, and to review the literature on long-term outcomes published from 2000 onward. Apart from having disease-specific morbidities, children with CDH are at risk for impaired neurodevelopmental problems and failure of educational attainments which may affect participation in society and the quality of life in later years. Thus, there is every reason to offer them long-term multidisciplinary follow-up programs. We discuss a proposed collaborative project using standardized clinical assessment and management plan (SCAMP) methodology to obtain uniform and standardized follow-up of CDH patients at an international level.

Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial).

OBJECTIVES: To determine the optimal initial ventilation mode in congenital diaphragmatic hernia. BACKGROUND: Congenital diaphragmatic hernia is a life-threatening anomaly with significant mortality and morbidity. The maldeveloped lungs have a high susceptibility for oxygen and ventilation damage resulting in a high incidence of bronchopulmonary dysplasia (BPD) and chronic respiratory morbidity. METHODS: An international, multicenter study (NTR 1310), the VICI-trial was performed in prenatally diagnosed congenital diaphragmatic hernia infants (n = 171) born between November 2008 and December 2013, who were randomized for initial ventilation strategy. RESULTS: Ninety-one (53.2%) patients initially received conventional mechanical ventilation and 80 (46.8%) high-frequency oscillation. Forty-one patients (45.1%) randomized to conventional mechanical ventilation died/ had BPD compared with 43 patients (53.8%) in the high-frequency oscillation group. An odds ratio of 0.62 [95% confidence interval (95% CI) 0.25-1.55] (P = 0.31) for death/BPD for conventional mechanical ventilation vs high-frequency oscillation was demonstrated, after adjustment for center, head-lung ratio, side of the defect, and liver position. Patients initially ventilated by conventional mechanical ventilation were ventilated for fewer days (P = 0.03), less often needed extracorporeal membrane oxygenation support (P = 0.007), inhaled nitric oxide (P = 0.045), sildenafil (P = 0.004), had a shorter duration of vasoactive drugs (P = 0.02), and less often failed treatment (P = 0.01) as compared with infants initially ventilated by high-frequency oscillation. CONCLUSIONS: Our results show no statistically significant difference in the combined outcome of mortality or BPD between the 2 ventilation groups in prenatally diagnosed congenital diaphragmatic hernia infants. Other outcomes, including shorter ventilation time and lesser need of extracorporeal membrane oxygenation, favored conventional ventilation.

High-Sensitivity Troponin T and N-Terminal Pro-Brain Natriuretic Peptide in Prediction of Outcome in Congenital Diaphragmatic Hernia: Results from a Multicenter, Randomized Controlled Trial.

UNLABELLED: Biomarkers may be helpful in prediction of outcomes of infants with congenital diaphragmatic hernia. The predictive value of high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide was investigated in 128 infants with congenital diaphragmatic hernia. After correction for multiple testing, those biomarkers did not predict severe pulmonary hypertension, death, need of extracorporeal membrane oxygenation, or bronchopulmonary dysplasia. TRIAL REGISTRATION: Netherlands Trial Registry: 1310.

Score for Neonatal Acute Physiology-II Predicts Outcome in Congenital Diaphragmatic Hernia Patients.

OBJECTIVE: Accurate and validated predictors of outcome for infants with congenital diaphragmatic hernia are needed. Score for Neonatal Acute Physiology-II has been validated to predict mortality in newborns. We investigated whether Score for Neonatal Acute Physiology-II scores in congenital diaphragmatic hernia could predict mortality, need for extracorporeal membrane oxygenation (in patients born in a center with extracorporeal membrane oxygenation availability), and development of bronchopulmonary dysplasia (oxygen dependency beyond 28 d after birth) in survivors. DESIGN: Data were obtained from a prospective, multicenter randomized controlled trial of initial ventilation strategy carried out by the Congenital Diaphragmatic Hernia EURO Consortium (NTR 1310). SETTING: ICUs of level III university children's hospitals. PATIENTS: Congenital diaphragmatic hernia infants without severe chromosomal anomalies or severe cardiac anomalies born between November 2008 and December 2013. INTERVENTIONS: Randomization for initial ventilation strategy (high-frequency oscillation/ conventional mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Logistic regression analyses were used to evaluate associations between Score for Neonatal Acute Physiology-II and outcome parameters. Of the 171 included patients, 46 died (26.9%), 40 of 108 (37.0%) underwent extracorporeal membrane oxygenation, and 39 of 125 survivors (31.2%) developed bronchopulmonary dysplasia. In nonsurvivors, the median Score for Neonatal Acute Physiology-II was 42.5 (interquartile range, 33.5-53.8) and 16.5 (interquartile range, 9.0-27.5) in survivors (p < 0.001). Score for Neonatal Acute Physiology-II also significantly differed between extracorporeal membrane oxygenation and non-extracorporeal membrane oxygenation-treated patients (p < 0.001), and survivors with and without bronchopulmonary dysplasia (p < 0.001). Multivariable logistic regression analyses adjusted for hernia side, liver position, ventilation mode, gestational age, center and observed-to-expected lung-to-head-ratio showed that Score for Neonatal Acute Physiology-II was associated with mortality (odds ratio, 1.16 [1.09-1.23]; p < 0.001) and need for extracorporeal membrane oxygenation support (odds ratio, 1.07 [1.02-1.13]; p = 0.01), but not for the development of bronchopulmonary dysplasia (odds ratio, 1.04 [0.99-1.09]; p = 0.14). CONCLUSIONS: The Score for Neonatal Acute Physiology-II predicts not only mortality but also need for extracorporeal membrane oxygenation in congenital diaphragmatic hernia patients. We, therefore, recommend to implement this simple and rapid scoring system in the evaluation of severity of illness in patients with congenital diaphragmatic hernia and thereby have insight into the prognosis within 1 day after birth.

Ductus Arteriosus in Fetal and Perinatal Life.

The ductus arteriosus represents an essential vascular structure connecting the pulmonary artery and the aorta. Over the past decades, there has been substantial advancement in our understanding of both the fundamental and clinical aspects of the ductus arteriosus. In particular, the clarification of the regulatory mechanisms governing ductal patency in critical stages such as the fetal and the perinatal period has enabled optimal management of both physiological and pathological conditions in which the ductus arteriosus plays a crucial role. Furthermore, a more in-depth understanding of the regulatory mechanisms controlling this fundamental structure has facilitated the development of advanced therapeutic strategies and personalized interventions. In the present review, we provide a comprehensive overview of the ductus arteriosus during fetal and perinatal life, encompassing its physiological functions, pathological conditions, and clinical implications. Through this examination, we aim to contribute to a broader understanding of the ductus arteriosus' role in these critical developmental stages and its significance in clinical practice.

Nutritional Strategies for Preterm Neonates and Preterm Neonates Undergoing Surgery: New Insights for Practice and Wrong Beliefs to Uproot.

The nutrition of preterm infants remains contaminated by wrong beliefs that reflect inexactitudes and perpetuate old practices. In this narrative review, we report current evidence in preterm neonates and in preterm neonates undergoing surgery. Convictions that necrotizing enterocolitis is reduced by the delay in introducing enteral feeding, a slow advancement in enteral feeds, and the systematic control of residual gastric volumes, should be abandoned. On the contrary, these practices prolong the time to reach full enteral feeding. The length of parenteral nutrition should be as short as possible to reduce the infectious risk. Intrauterine growth restriction, hemodynamic and respiratory instability, and patent ductus arteriosus should be considered in advancing enteral feeds, but they must not translate into prolonged fasting, which can be equally dangerous. Clinicians should also keep in mind the risk of refeeding syndrome in case of high amino acid intake and inadequate electrolyte supply, closely monitoring them. Conversely, when preterm infants undergo surgery, nutritional strategies are still based on retrospective studies and opinions rather than on randomized controlled trials. Finally, this review also highlights how the use of adequately fortified human milk is strongly recommended, as it offers unique benefits for immune and gastrointestinal health and neurodevelopmental outcomes.

A new variant in the GATA6 gene associated with tracheoesophageal fistula, pulmonary vein stenosis and neonatal diabetes.

INTRODUCTION: GATA6 is a gene that encodes a transcription factor with a key role in the development of several organ systems, including the development of the pancreas. It is associated with neonatal diabetes but also with other extra-pancreatic anomalies. CASE PRESENTATION: This report describes the association of tracheoesophageal fistula (TEF), pulmonary vein stenosis (PVS), and neonatal diabetes caused by a novel mutation of the GATA6 gene in a small-for-gestational-age male neonate born at 32 weeks of gestation. Next-Generation Sequencing revealed the novel heterozygous variant c.1502C>G in the GATA6 gene, which determines the introduction of the premature stop codon p.Ser501Ter at the protein level. This de novo nonsense variant was not detected in the analyzed parental DNA samples and has not been previously described in the literature. At about two months of life, a PVS was suspected. The PVS progressively increased with the development of an intramural component, resulting in severe postcapillary pulmonary hypertension. The child died at about 4 months of life. CONCLUSION: TEF can be associated with GATA6 variants. In the case of neonatal diabetes and TEF, neonatologists should be aware of this association and should also investigate the child for complex congenital heart disorders, such as in our case, with a cardiac computed tomography.

Multicentre, randomised controlled trial of physiological-based cord clamping versus immediate cord clamping in infants with a congenital diaphragmatic hernia (PinC): statistical analysis plan.

BACKGROUND: Infants born with congenital diaphragmatic hernia (CDH) are at high risk of respiratory insufficiency and pulmonary hypertension. Routine practice includes immediate clamping of the umbilical cord and endotracheal intubation. Experimental animal studies suggest that clamping the umbilical cord guided by physiological changes and after the lungs have been aerated, named physiological-based cord clamping (PBCC), could enhance the fetal-to-neonatal transition in CDH. We describe the statistical analysis plan for the clinical trial evaluating the effects of PBCC versus immediate cord clamping on pulmonary hypertension in infants with CDH (PinC trial). DESIGN: The PinC trial is a multicentre, randomised controlled trial in infants with isolated left-sided CDH, born ≥ 35.0 weeks of gestation. The primary outcome is the incidence of pulmonary hypertension in the first 24 h after birth. Maternal outcomes include estimated maternal blood loss. Neonatal secondary outcomes include mortality before discharge, extracorporeal membrane oxygenation therapy, and number of days of mechanical ventilation. Infants are 1:1 randomised to either PBCC or immediate cord clamping using variable random permutated block sizes (4-8), stratified by treatment centre and estimated severity of pulmonary hypoplasia (i.e. mild/moderate/severe). At least 140 infants are needed to detect a relative reduction in pulmonary hypertension by one third, with 80% power and 0.05 significance level. A chi-square test will be used to evaluate the hypothesis that PBCC decreases the occurrence of pulmonary hypertension. This plan is written and submitted without knowledge of the collected data. The trial has been ethically approved. TRIAL REGISTRATION: ClinicalTrials.gov NCT04373902 (registered April 2020).