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.

CA125: a novel cardiac biomarker for infants with congenital diaphragmatic hernia.

BACKGROUND: The carbohydrate antigen 125 (CA125) was proven as a robust biomarker for risk stratification in adults with heart failure. This is the first study analyzing CA125 in a cohort of infants with congenital diaphragmatic hernia (CDH). METHODS: Sixty-eight infants with CDH, treated at the University Children's Hospital Bonn (Germany), between January 2018 and February 2021, were prospectively enrolled for analysis. CA125 values were measured at the following timepoints: 6,12, 24, 48 h, and during ECMO daily from day 1 to day 7. RESULTS: In infants not surviving to discharge, CA125 values were significantly higher at day 1 (6, 12, and 24 h). Infants with subsequent need for ECMO presented significantly higher CA125 values at 12 h of life. During ECMO, CA125 values measured at day 1 were significantly higher in infants not surviving to discharge. In the ROC analysis, a CA125 value of ≥10 U/ml was calculated as optimal cut-off for the prediction of ECMO and in-hospital mortality. CA125 values correlated significantly with the severity of PH and ventricular dysfunction. CONCLUSIONS: CA125 values correlate significantly with echocardiographic markers of PH and ventricular dysfunction and correlate significantly with parameters of disease severity (need for ECMO, mortality). IMPACT: CA125 was proven as robust cardiac biomarker in adult cohorts. Information about the utility as a biomarker in neonatal cohorts is lacking. This is the first study analyzing CA125 as a cardiac biomarker in a cohort of infants with congenital diaphragmatic hernia (CDH). CA125 correlates significantly with markers of echocardiographic assessment (PH and ventricular dysfunction) in infants with CDH and helps to identify infants at high risk for ECMO and in-hospital mortality. The results underline the need for the inclusion of cardiac biomarkers in the clinical routine in neonates at risk for cardiopulmonary failure.

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.

Crossed pulmonary arteries: An underestimated cardiovascular variant with a strong association with genetic syndromes-A report of 74 cases with systematic review of the literature.

Crossed pulmonary arteries (CPAs) represent an uncommon anatomic variant, usually associated with some specific syndromes and conotruncal defects. This finding has been described in 22q11.2 Deletion Syndrome (22q11.2DS). We evaluated the correlation between CPAs and genetic diseases, in order to better define the characteristics of this variant, considered a rare anatomic pattern. An in-depth analysis of CPAs genotype-phenotype correlations was performed via a literature review. We detected 74 CPAs patients through echocardiography. Of these 74 patients, 35.1% of patients showed additional intracardiac malformations, while 29.7% showed extracardiac vascular anomalies, of which 16.2% were associated with intracardiac defects and 13.5% were not. In all, 62.2% of patients were diagnosed with genetic diseases and 52.2% of them were 22q11.2DS patients. In conclusions, CPAs represent a cardiovascular variant, which is detectable in nonsyndromic individuals, but especially in various genetic syndromes and in particular in 22q11.2DS patients. Data on the real prevalence of this morphology is lacking in literature. Knowledge of this anatomic variant is useful to interpret the unusual course of the pulmonary branches and is helpful information before cardiovascular surgical correction. Moreover, due to the strong association of CPAs with some genetic syndromes, the identification of this anatomic pattern can indicate the utility of a genetic assessment of these patients.

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.

Smith-Magenis syndrome: Report of morphological and new functional cardiac findings with review of the literature.

Smith-Magenis syndrome (SMS) is a genetic disorder characterized by multiple congenital anomalies, sleep disturbance, behavioral impairment, and intellectual disability. Its genetic cause has been defined as an alteration in the Retinoic Acid-Induced 1 gene. Cardiac anomalies have been reported since the first description of this condition in patients with 17p11.2 deletion. Variable cardiac defects, including ventricular septal defects, atrial septal defects, tricuspid stenosis, mitral stenosis, tricuspid and mitral regurgitation, aortic stenosis, pulmonary stenosis, mitral valve prolapse, tetralogy of Fallot, and total anomalous pulmonary venous connection, have been anecdotally reported and systematic case series are still lacking. Herein, we define the spectrum of the cardiac phenotype and describe for the first time the cardiac function in a large cohort of pediatric patients with SMS. Revision of the literature and correlations between genotype and cardiac phenotype was performed.

Laterality, heterotaxy, and isolated congenital heart defects : The genetic basis of the segmental nature of the heart.

To date, the role of NODAL in normal and abnormal L-R asymmetry has been well established. In a recent paper, mutations of this gene have been reported in heterotaxy but also in transposition with D- or L-ventricular loop. The effects of NODAL and other laterality genes can be recognized separately in all three cardiac segments: for topology and septation of the atria, for ventricular looping, and for spiralization and alignment of the great arteries.

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.

Spontaneous breathing in selected neonates with very mild congenital diaphragmatic hernia.

AIMS: Current treatment guidelines recommend immediate postnatal intubation in all neonates with congenital diaphragmatic hernia (CDH). This study aimed to investigate the feasibility and outcomes of a spontaneous breathing approach (SBA) versus immediate intubation in neonates with prenatally diagnosed very mild CDH. METHODS: A retrospective study was conducted comparing neonates with very mild CDH (left-sided, liver-down, observed-to-expected lung-to-head ratio ≥45%) undergoing SBA and matched controls receiving standard treatment. Data on early echocardiographic findings, respiratory support, length of hospital stay, and clinical outcomes were analyzed. RESULTS: Of 151 CDH neonates, eight underwent SBA, while 31 received standard treatment. SBA was successful in six of eight patients. SBA patients had shorter length of stay (14 vs. 30 days, p = .005), mechanical ventilation (3.5 vs. 8.7 days, p = .011), and oxygen supplementation (3.2 vs. 9.3 days, p = .013) compared to matched controls. Echocardiographic evidence of pulmonary hypertension and cardiac dysfunction were significantly lower in SBA neonates after admission but similar before surgical repair. The SBA group tolerated enteral feeding earlier (day of life 7 vs. 16, p = .019). CONCLUSIONS: SBA appears feasible and beneficial for prenatally diagnosed very mild CDH. It was associated with a shortened hospital stay supportive therapies. However, larger trials are needed to confirm these findings and determine optimal respiratory support.

Use of N-Acetylcysteine in Preterm Neonates with Enteral Feeding Intolerance and Intestinal Obstruction: A Case Series and Review of the Literature.

(1) Background: The use of N-acetylcysteine (NAC) to relieve meconium obstruction of prematurity in the first days of life has been reported, with NAC reducing the viscosity of luminal contents by cleaving the disulfide bonds of mucoproteins. However, its use in this population should be further explored since it has been associated with hypernatremia and transient increase in transaminases and bilirubin. (2) Methods: In this retrospective study, we included neonates admitted because of enteral feeding intolerance and intestinal obstruction from 2019 to 2021 who received NAC as a rescue therapy before explorative laparotomy. (3) Results: We summarized the clinical presentation of six preterm neonates with enteral feeding intolerance and intestinal obstruction who received NAC as a rescue therapy. Four infants (66.7%) gradually improved without the need for explorative laparotomy, whereas two infants (33.3%) underwent the creation of an ileostomy. No cases of hypernatremia or hepatic derangement associated with NAC therapy were observed. (4) Conclusions: We described the use of NAC treatment by nasogastric tube and/or rectal enemas in preterm infants with enteral feeding intolerance and intestinal obstruction after a multidisciplinary assessment, but the limited sample size did not allow us to obtain definitive conclusions and further research is needed in this field, given the limited evidence about NAC treatment in preterm infants.

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.

Gender differences in congenital heart defects: a narrative review.

Background and Objective: Congenital heart defects (CHD) represent the most frequent human birth defects, occurring in almost 1% of all live newborns. Understanding the effects of gender in the prevalence of CHD has a key role in defining personalized prevention, disease identification, prognosis definition and individualized therapeutic strategies. Recently, the attempt to achieve a holistic approach to patients with CHD cannot be separated from accounting for existing gender differences. The main aim of this narrative review is to provide an overview of gender differences in the epidemiology of CHD. Methods: A standardized research through three electronic databases (PubMed/Scopus/Embase) was performed using a combination of keywords and Medical Subject Headings (MeSH) terms to include congenital heart diseases, gender difference(s), prevalence. Observational, prospective, population based and retrospective studies reporting gender differences in the prevalence of CHD were included. Conference abstracts were excluded as well as studies not written in English language and non-human studies. Further relevant papers were selected by hand-searching of the references list of selected articles. Key Content and Findings: Search results returned 1,904 papers. Screening articles by title and abstracts resulted in 17 articles for full text review. Of these, 10 were included for analysis and additional 11 articles were included after hand searching review of reference lists. A total of 21 articles were included. Conclusions: Our narrative review confirms that there is a significant gender variation in specific CHD subgroups. In particular, we summarized the evidence that there is a significantly greater risk for males to be born with severe CHD and for females with milder CHD subtypes. The etiology of the different distribution of CHD among genders is still under investigation and a deeper understanding of how gender influences the risk for CHD is warranted. In the future, a gender-based management of CHD should become an established medical approach.

Ductus arteriosus flow predicts outcome in neonates with congenital diaphragmatic hernia.

OBJECTIVE: To investigate whether the pattern of flow through the ductus arteriosus (DA) is associated with the need for extracorporeal membrane oxygenation support (ECMO) or death in neonates with congenital diaphragmatic hernia (CDH). DESIGN: Retrospective observational study. SETTING: German level III Neonatal Intensive Care Unit. PARTICIPANTS: 139 CDH neonates were born between March 2009 and May 2021. METHODS: DA flow pattern was assessed in echocardiograms obtained within 24 h of life by measuring flow time and velocity time integral (VTI) for both left-to-right (LR) and right-to-left (RL) components of the ductal shunt. A VTI ratio (VTILR/VTIRL) < 1.0 and an RL relative flow time (Flow timeRL/(Flow timeLR+Flow timeRL)) >33% were defined as markers of abnormal flow patterns. The primary outcome was the need for ECMO. The secondary outcome was death. RESULTS: 72 patients (51.8%) had a VTI ratio <1.0, 73 (52.5%) an RL relative flow time >33%. 59 patients (42.4%) had an alteration of both values. Need for ECMO was present in 37.4% (n = 52), while 19.4% (n = 27) died. A VTI ratio <1.0 had the highest diagnostic accuracy for the need for ECMO, (sensitivity 82.7%, specificity 66.7%, negative predictive value [NPV] 86.6%, and positive predictive value [PPV] 59.7%) as well as for death (sensitivity 77.8%, specificity 54.5%, NPV 91.0%, and PPV 29.2%). Patients with VTI ratio <1.0 were 4.7 times more likely to need ECMO and 3.3 times more likely to die. VTI ratio values correlated significantly with pulmonary hypertension (PH) severity (r = -0.516, p < 0.001). CONCLUSIONS: A VTI ratio <1.0 is a valuable threshold to identify high-risk CDH neonates. For improved risk stratification, other parameters-for example, left ventricular cardiac dysfunction-should be combined with DA flow assessment.

Staphylococcal Infections and Neonatal Skin: Data from Literature and Suggestions for the Clinical Management from Four Challenging Patients.

Staphylococcal infections in neonates might be associated with skin blistering since early antibiotic therapy has been shown to limit infection spread and positively influence outcomes; therefore, neonatologists should be aware of these conditions. This review examines the recent literature on the management of Staphylococcal infections that involve neonatal skin, discussing the most appropriate clinical approach to four cases of neonatal blistering diseases with Staphylococcal infections: a case of Staphylococcal bullous impetigo, a case of Staphylococcal scalded skin syndrome (SSSS), a case of epidermolysis bullosa with overlapping Staphylococcal infection, and a case of burns with overlapping Staphylococcal infection. In treating Staphylococcal infections involving skin in neonates, the presence or absence of systemic symptoms should be considered. In the lack of evidence-based guidelines in this age category, treatment should be individualized according to several factors including the extension of the disease or further skin comorbidities (such as skin fragility), with a multidisciplinary approach.

Insights into the Cardiac Phenotype in 9p Deletion Syndrome: A Multicenter Italian Experience and Literature Review.

Chromosome 9p deletion syndrome is a rare autosomal dominant disorder presenting with a broad spectrum of clinical features, including congenital heart defects (CHDs). To date, studies focused on a deep characterization of cardiac phenotype and function associated with this condition are lacking. We conducted a multicentric prospective observational study on a cohort of 10 patients with a molecular diagnosis of 9p deletion syndrome, providing a complete cardiological assessment through conventional echocardiography and tissue Doppler imaging echo modality. As a result, we were able to demonstrate that patients with 9p deletion syndrome without major CHDs may display subclinical cardiac structural changes and left-ventricle systolic and diastolic dysfunction. Albeit needing validation in a larger cohort, our findings support the idea that a complete cardiac assessment should be performed in patients with 9p deletion syndrome and should be integrated in the context of a long-term follow-up.

Use of levosimendan in hemodynamic management of heart failure in two neonates with intracranial arteriovenous shunts: a case series.

BACKGROUND: The hemodynamic status of newborns with intracranial arteriovenous shunts (AVSs) may be extremely complex. Mini-invasive hemodynamic monitoring through innovative techniques such as Near-Infrared Spectroscopy (NIRS) and Pressure Recording Analytical Method (PRAM) may help in understanding hemodynamics in newborns with AVSs. Levosimendan is a calcium sensitizer and inodilator, and it is known to improve ventricular function, but its use in newborns is limited. In our cases, we evaluated the effect of levosimendan on hemodynamics through NIRS and PRAM. CASE PRESENTATION: Herein, we report the cases of two neonates with intracranial arteriovenous shunts, in whom we used levosimendan to manage cardiac failure refractory to conventional treatment. Levosimendan was used at a dosage of 0.1 mcg/kg/min for 72 h. Combined use of NIRS and PRAM helped in real-time monitoring of hemodynamic effects; in particular, levosimendan determined significant improvement in myocardium contractility as well as a reduction of heart rate. CONCLUSION: In two neonatal cases of AVSs, levosimendan led to an overall hemodynamic stabilization, documented by the combination of NIRS and PRAM. Our results suggest introducing levosimendan as a second-line treatment in cases of severe cardiac dysfunction due to AVSs without improvement using standard treatment strategies. Future prospective and larger studies are highly warranted.

Are lung ultrasound features more severe in infants with bronchiolitis and coinfections?

Background: The lung ultrasound (LUS) score can be a useful tool to predict the need for respiratory support and the length of hospital stay in infants with bronchiolitis. Objective: To compare lung ultrasound features in neonates and infants up to three months of age with bronchiolitis to determine whether LUS scores (range 0-36) differ in infants with coinfections or not. Methods: Neonates and infants younger than three months admitted to neonatal units from October 2022 to March 2023, who underwent lung ultrasound evaluation on admission, were included in this retrospective study. Results: We included 60 patients who underwent LUS evaluation at admission. Forty-two infants (70.0%) had a single viral infection. Eighteen infants (30.0%) had a coinfection: fifteen infants (25.0%) had more than one virus at PCR; one infant (1.7%) had both a viral coinfection and a viral-bacteria coinfection; two infants (3.3%) had viral-bacteria coinfection. Infants with a single viral infection and those with coinfections had similar LUS scores globally and in different lung zones. An LUS score higher than 8 was identified to significantly predict the need for any respiratory support (p = 0.0035), whereas an LUS score higher than 13 was identified to significantly predict the need for mechanical ventilation (p = 0.024). Conclusion: In our small cohort of neonates and infants younger than three months hospitalized with bronchiolitis, we found no statistically significant differences in the LUS score on admission between patients with a single viral infection and those with multiple infections.