Microbial cell-free DNA-sequencing as an addition to conventional diagnostics in neonatal sepsis.

BACKGROUND: Bloodstream infections remain a challenge for neonatologists, as traditional culture-based methods are time-consuming and rely on adequate blood volume. Next-generation sequencing (NGS) offers an alternative, as it can identify microbial cell-free DNA (mcfDNA) in a small blood sample, providing rapid pathogen detection. This study aimed to assess the diagnostic performance of DISQVER®-NGS compared to blood cultures in neonatal patients with suspected sepsis. METHODS: In neonates with suspected sepsis, blood cultures and samples for NGS were prospectively collected. Patients were divided into four categories: 1) sepsis, blood culture positive, 2) clinical sepsis, culture negative, 3) suspected sepsis, 4) validation cohort. RESULTS: NGS detected bacterial, viral or fungal mcfDNA in 24 of 82 samples. Blood cultures were collected in 46 of 84 patients (15/46 positive). DISQVER® correctly identified pathogens in 9/15 patients with a positive blood culture, two with intrinsic resistance to their antibiotic regimen. In seven samples NGS reported the mcfDNA of bacteria that could have theoretically grown in culture but did not. CONCLUSIONS: NGS may enhance sensitivity in sepsis diagnostics by detecting mcfDNA in neonates with suspected sepsis. Interpreting NGS results requires correlation with clinical data, laboratory values, and routine microbiological tests for a comprehensive understanding of the patient's condition. IMPACT: Conventional blood culture methods have limitations in accuracy and turnaround time. The study aimed to investigate the diagnostic performance of the Next-Generation Sequencing method DISQVER® compared to traditional blood cultures in neonatal patients with suspected sepsis. Our findings suggest that NGS has the potential to augment the precision of conventional diagnostic techniques, can lead to improved detection of pathogens and targeted treatment approaches in neonatal sepsis. It is emphasized that further validation and integration with clinical and microbiological data are required to ensure optimal clinical utility.

Parents-reported nutrition and feeding difficulties in infants with congenital diaphragmatic hernia after hospital discharge.

PURPOSE: Congenital diaphragmatic hernia (CDH) affects 1 in 3000-5000 newborns. In survivors, long-term complications include gastroesophageal reflux (GER), feeding difficulties, and failure to thrive. Data from the parents' perspective remain scarce. This study aims to report the prevalence and impact of feeding difficulties on CDH families after discharge. METHODS: National web-based survey amongst families with CDH infants in 2021. RESULTS: Caregivers of 112 CDH survivors participated. The baseline characteristics were representative with 54 % male, 83 % left-sided CDH, prenatal diagnosis in 83 %, and 34 % requiring extracorporeal membrane oxygenation. Most infants (81 %) were discharged within three months, with 62 % feeding by mouth, and 30 % requiring a feeding tube. Persisting feeding difficulties were experienced by 73 %, GER being the most common (66 %), followed by insufficient weight gain (64 %). After discharge, 41 % received medical support for failure to thrive. The primary-care pediatrician was consulted most frequently for information (61 %) and treatment of feeding difficulties (74 %). Therapeutic success was reported in 64 %. A cessation of symptoms was achieved in 89 % within three years. CONCLUSION: The majority of CDH infants had persistent feeding difficulties. This survey highlights the impact surrounding feeding problems on CDH families. Further studies and support systems are needed to raise the quality of life in CDH infants and their families.

Cardiac function in congenital diaphragmatic hernia.

Cardiac function is known to play critical role in the pathophysiological progression and ultimate clinical outcome of patients with congenital diaphragmatic hernia (CDH). While often anatomically normal, the fetal and neonatal heart in CDH can suffer from both right and left ventricular dysfunction. Here we explore the abnormal fetal heart, early postnatal right and left ventricular dysfunction, the interplay between cardiac dysfunction and pulmonary hypertension, evaluation and echocardiographic assessment of the heart, and therapeutic strategies for managing and supporting the pathophysiologic heart and CDH. Further, we take a common clinical scenario and provide clinically relevant guidance for the diagnosis and management of this complex process.

Applications of Point-of-Care-Ultrasound in Neonatology: A Systematic Review of the Literature.

Point-of-care ultrasound (POCUS) integration into neonatology offers transformative potential for diagnostics and treatment, enhancing immediacy and precision of clinical decision-making in this vulnerable patient population. This systematic review aims to synthesize evidence on POCUS applications, benefits, challenges, and educational strategies in neonatology. Literature search was conducted using SPIDER scheme keywords and MeSH terms related to POCUS and neonatology. Studies focusing on POCUS applications, its impact on clinical outcomes, and educational interventions for skill acquisition were included and analyzed using standardized tools, followed by a narrative synthesis of the findings. The search yielded 68 relevant publications, encompassing original research, reviews, and guidelines. POCUS applications varied across cardiovascular, pulmonary, neurological, and abdominal assessments. Key benefits included a reduced need for invasive procedures and rapid bedside diagnosis. Challenges included steep learning curves for clinicians and the need for standardized training and guidelines. Educational strategies highlighted the effectiveness of simulation-based training in enhancing ultrasound proficiency among neonatal care providers. POCUS represents a significant advancement in neonatal medicine, offering benefits for patient care. Addressing identified challenges through comprehensive training programs and developing standardized guidelines is crucial for optimized use. Future research should focus on evaluating educational outcomes and long-term impacts of POCUS integration into neonatal care.

Vasoactive Management of Pulmonary Hypertension and Ventricular Dysfunction in Neonates Following Complicated Monochorionic Twin Pregnancies: A Single-Center Experience.

OBJECTIVES: Twins resulting from a complicated monochorionic (MC) twin pregnancy are at risk for postnatal evolution of pulmonary hypertension (PH) and cardiac dysfunction (CD). Both pathologies are important contributors to short- and long-term morbidity in these infants. The aim of the present retrospective single-center cohort study was to evaluate the need for vasoactive treatment for PH and CD in these neonates. METHODOLOGY: In-born neonates following a complicated MC twin pregnancy admitted to the department of neonatology of the University Children's Hospital Bonn (UKB) between October 2019 and December 2023 were screened for study inclusion. Finally, 70 neonates were included in the final analysis, with 37 neonates subclassified as recipient twins (group A) and 33 neonates as donor twins (group B). RESULTS: The overall PH incidence at day of life (DOL) 1 was 17% and decreased to 6% at DOL 7 (p = 0.013), with no PH findings at DOL 28. The overall incidence of CD was 56% at DOL 1 and decreased strongly until DOL 7 (10%, p = 0.015), with no diagnosis of CD at DOL 28. The use of dobutamine, norepinephrine, and vasopressin at DOL 1 until DOL 7 did not differ between the subgroups, whereas the dosing of milrinone was significantly higher in Group B at DOL 1 (p = 0.043). Inhaled nitric oxide (iNO) was used in 16% of the cohort, and a levosimendan therapy was administered in 34% of the neonates. One-third of the cohort was treated with oral beta blockers, and in 10%, an intravenous beta blockade (landiolol) was administered. The maximum levosimendan vasoactive-inotropic score (LVISmax) increased from DOL 1 (12.4 [3/27]) to DOL 2 (14.6 [1/68], p = 0.777), with a significant decrease thereafter as measured at DOL 7 (9.5 [2/30], p = 0.011). CONCLUSION: Early PH and CD are frequent diagnoses in neonates following a complicated MC twin pregnancy, and an individualized vasoactive treatment strategy is required in the management of these infants.

Arterial hypertension in infants with congenital diaphragmatic hernia following surgical repair.

Pulmonary hypertension (PH) and cardiac dysfunction are established comorbidities of congenital diaphragmatic hernia (CDH). However, there is very little data focusing on arterial hypertension in CDH. This study aims to investigate the incidence of arterial hypertension in neonates with CDH at hospital discharge. Archived clinical data of 167 CDH infants who received surgical repair of the diaphragmatic defect and survived for > 60 days were retrospectively analyzed. Blood pressure (BP) values were averaged for the last 7 days before discharge and compared to standard BP values for sex, age, and height provided by the AHA in 2004. BP values reaching or extending the 95th percentile were defined as arterial hypertension. The use of antihypertensive medication was analyzed at discharge and during hospitalization. Arterial hypertension at discharge was observed in 19 of 167 infants (11.3%) of which 12 (63%) were not receiving antihypertensive medication. Eighty patients (47.9%) received antihypertensive medication at any point during hospitalization and 28.9% of 152 survivors (n = 44) received antihypertensive medication at discharge, although in 45.5% (n = 20) of patients receiving antihypertensive medication, the indication for antihypertensive medication was myocardial hypertrophy or frequency control. BP was significantly higher in ECMO compared to non-ECMO patients, despite a similar incidence of arterial hypertension in both groups (13.8% vs. 10.1%, p = 0.473). Non-isolated CDH, formula feeding, and minimal creatinine in the first week of life were significantly associated with arterial hypertension on univariate analysis. Following multivariate analysis, only minimal creatinine remained independently associated with arterial hypertension.   Conclusion: This study demonstrates a moderately high incidence of arterial hypertension in CDH infants at discharge and an independent association of creatinine values with arterial hypertension. Physicians should be aware of this risk and include regular BP measurements and test of renal function in CDH care and follow-up. What is Known: • Due to decreasing mortality, morbidity is increasing in surviving CDH patients. • Pulmonary hypertension and cardiac dysfunction are well-known cardiovascular comorbidities of CDH. What is New: • There is a moderately high incidence of arterial hypertension in CDH infants at discharge even in a population with frequent treatment with antihypertensive medication. • A more complicated hospital course (ECMO, higher degree of PH, larger defect size) was associated with a higher risk for arterial hypertension.

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).

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.

A comparative analysis of the Vasoactive-Inotropic Score, the Vasoactive-Ventilation-Renal Score, and the Oxygenation Index as outcome predictors in infants with a congenital diaphragmatic hernia.

OBJECTIVES: To date, different severity scores and indices are available to predict outcome in infants with a congenital diaphragmatic hernia (CDH). The Oxygenation Index (OI) and the Vasoactive-Inotropic Score (VIS) has already been evaluated in the CDH population. The Vasoactive-Ventilation-Renal (VVR) Score was recently evaluated as new severity score in several studies on infants with need for cardiac surgery. The score was shown to outperform the VIS and OI as outcome predictors in these infants, but no data are available regarding the evaluation of the VVR Score in CDH infants. PATIENTS AND METHODS: This was a retrospective single-center analysis at the University Children's Hospital, Bonn, Germany, during the study period from January 2019 until December 2022. Of 108 CDH infants treated at our institution, a final cohort of 100 neonates met the inclusion criteria. INCLUSION CRITERIA: diagnosis of CDH (right-sided, left-sided, or bilateral). EXCLUSION CRITERIA: early mortality (before surgical correction of the diaphragm), palliative care after birth, no available data for OI, VIS, and VVR Score calculation. The OI, the VIS, and the VVR Score were calculated at three selected timepoints: at 48-72 h after birth (T1), before surgery (T2), and after surgery (T3). MAIN RESULTS: The primary clinical endpoint (in-hospital mortality) was reached in 21% of the infants. Infants surviving to discharge were allocated to group A, infants with fatal outcome to group B. In the univariate analysis, the OI was significantly higher in infants allocated to group B at T2 (p < .001), and T3 (p < .001). The VIS was significantly higher only at T1 in infants allocated to group B (p = .001). The VVR Score was significantly higher at T1 (p = .017), and at T3 (p = .002) in infants not surviving to discharge. In the multivariate analysis, the OI at T2 + T3 (p < .001), the VIS at T1 (p = .048), and the VVR Score at T1 + T3 (p = .023, and p = .048, respectively) remained significantly associated with in-hospital mortality. The OI presented the highest area under the curve (AUC) at T2 and T3 (T2:0.867, p = .001; T3:0.833, p = .000) regarding the primary endpoint in the overall cohort. In the subgroup of infants without need for extracorporeal membrane oxygenation (ECMO) therapy (n = 60) the VVR Sore presented the best performance with an AUC of 0.942 (p = .000) at T3. CONCLUSION: The severity scores OI, VIS, and VVR-Score are independent predictors of in-hospital mortality in CDH infants. The OI seems to outperform the VIS and VVR-Score as outcome predictor immediately before and after CDH surgery, whereas the VVR Score presented the best performance in the subgroup of CDH infants without need for ECMO and mild-to-moderate CDH defects.

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.

[Characteristics and Outcome of Neonates With Postnatally Diagnosed Congenital Diaphragmatic Hernia]. / Charakteristika und Outcomedaten von Neugeborenen mit pränatal nicht diagnostizierter angeborener Zwerchfellhernie.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is one of the most severe neonatal malformations with a mortality of 20-35%. Currently, the rate of prenatally recognized CDHs is 60-80%. This study investigated the characteristics and outcome data of children with prenatally unrecognized CDH. METHODS: Postnatally diagnosed CDH newborns treated at the University Hospital Bonn between 2012 and 2021 were included. Treatment and outcome data were compared according to type of maternity hospital, Apgar values, and between prenatally and postnatally diagnosed CDH. RESULTS: Of 244 CDH newborns, 22 were included. Comparison for birth in a facility with vs. without pediatric care showed for mortality: 9% vs. 27%, p=0.478; ECMO rate: 9% vs. 36%, p=0.300; age at diagnosis: 84 vs. 129 min, p=0.049; time between intubation and diagnosis: 20 vs. 86 min, p=0.019. Newborns in the second group showed significantly worse values for pH and pCO2. Furthermore, there was a tendency for higher mortality and ECMO rates in children with an Apgar score<7 vs.≥7. Children diagnosed postnatally were significantly more likely to have moderate or severe PH and tended to have cardiac dysfunction more often than those diagnosed prenatally. DISCUSSION: In our cohort, ca. one in 10 newborns received a postnatal CDH diagnosis. Birth in a facility without pediatric care is associated with later diagnosis, which may favor hypercapnia/acidosis and more severe pulm.

Unique Cardiopulmonary Interactions in Congenital Diaphragmatic Hernia: Physiology and Therapeutic Implications.

Congenital diaphragmatic hernia (CDH) results in abdominal contents entering the thoracic cavity, affecting both cardiac and pulmonary development. Maldevelopment of the pulmonary vasculature occurs within both the ipsilateral lung and the contralateral lung. The resultant bilateral pulmonary hypoplasia and associated pulmonary hypertension are important components of the pathophysiology of this disease that affect outcomes. Despite prenatal referral to specialized high-volume centers, advanced ventilation strategies, pulmonary hypertension management, and the option of extracorporeal membrane oxygenation, overall CDH mortality remains between 25% and 30%. With increasing recognition that cardiac dysfunction plays a large role in morbidity and mortality in patients with CDH, it becomes imperative to understand the different clinical phenotypes, thus allowing for individual patient-directed therapies. Further research into therapeutic interventions that address the cardiopulmonary interactions in patients with CDH may lead to improved morbidity and mortality outcomes.

Hemolysis during Venovenous Extracorporeal Membrane Oxygenation in Neonates with Congenital Diaphragmatic Hernia: A Prospective Observational Study.

OBJECTIVE: To investigate the incidence of hemolysis and its association with outcome in neonates with congenital diaphragmatic hernia (CDH) requiring venovenous extracorporeal membrane oxygenation (ECMO) treatment using a Medos Deltastream circuit with a DP3 pump, a hilite 800 LT oxygenator system, and a »' tubing. STUDY DESIGN: Plasma free hemoglobin (PFH) was prospectively measured once daily during ECMO using spectrophotometric testing. Patients (n = 62) were allocated into two groups according to presence or absence of hemolysis. Hemolysis was defined as PFH ≥ 50 mg/dL on at least 2 consecutive days during ECMO treatment. Hemolysis was classified as either moderate with a maximum PFH of 50-100 mg/dL or severe with a maximum PFH >100 mg/dL. RESULTS: Hemolysis was detected in 14 patients (22.6%). Mortality was 100% in neonates with hemolysis compared with 31.1% in neonates without hemolysis (P < .001). In 21.4% hemolysis was moderate and in 78.6% severe. Using multivariable analysis, hemolysis (hazard ratio: 6.8; 95%CI: 1.86-24.86) and suprasystemic pulmonary hypertension (PH) (hazard ratio: 3.07; 95%CI: 1.01-9.32) were independently associated with mortality. Hemolysis occurred significantly more often using 8 French (Fr) cannulae than 13 Fr cannulae (43% vs 17%; P = .039). Cutoff for relative ECMO flow to predict hemolysis were 115 ml/kg/ minute for patients with 8 Fr cannulae (Area under the curve [AUC] 0.786, P = .042) and 100 ml/kg/ minute for patients with 13 Fr cannulae (AUC 0.840, P < .001). CONCLUSIONS: Hemolysis in CDH neonates receiving venovenous ECMO is independently associated with mortality.

Percutaneous, ultrasound-guided single- and multisite cannulation for veno-venous extracorporeal membrane oxygenation in neonates.

AIMS: Extracorporeal membrane oxygenation (ECMO) is a widely used technique to support neonates with severe respiratory failure. Data on percutaneous, ultrasound-guided veno-venous (VV) ECMO cannulation in neonates is still scarce. Aim of this study was to describe our institutional experience with ultrasound-guided percutaneous, VV ECMO cannulation in neonates with severe respiratory failure. METHODS: Neonates receiving ECMO support at our department between January 2017 and January 2021 were retrospectively identified. Patients receiving VV ECMO cannulation performed by the percutaneous Seldinger technique by single- or multisite cannulation were analyzed. RESULTS: A total of 54 neonates received ECMO cannulation performed by the percutaneous Seldinger technique. In 39 patients (72%) a 13 French bicaval dual-lumen cannula was inserted and in 15 patients (28%) two single-lumen cannulae were used. Cannulae positioning using the multisite approach was in all cases as desired. The tip of the 13 French cannula was located in the IVC in 35/39 patients, in four patients position was too proximal but did not dislocate during the ECMO run. One (2%) preterm neonate (weight 1.75 kg) developed a cardiac tamponade which was successfully managed with drainage. Median duration of ECMO was 7 days (interquartile range: 5-16 days). Forty-four patients (82%) were successfully weaned from ECMO and in 31/44 (71%) the ECMO cannulae were removed with a delay of 0.9-7.2 days (median 2.8 days) after weaning without noticing complications. CONCLUSIONS: A correct cannula placement using the ultrasound-guided percutaneous Seldinger technique, for both single- and multisite cannulation, seems feasible in most neonatal patients receiving VV ECMO.

Dynamics of pulmonary hypertension severity in the first 48†h in neonates with prenatally diagnosed congenital diaphragmatic hernia.

Introduction: Pulmonary hypertension (PH) is one of the major contributing factors to the high morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH). The severity and duration of postnatal PH are an established risk factor for patient outcome; however, the early postnatal dynamics of PH have not been investigated. This study aims to describe the early course of PH in CDH infants, and its relation to established prognostic markers and outcome measures. Methods: We performed a monocentric retrospective review of neonates with prenatally diagnosed CDH, who received three standardized echocardiographic examinations at 2-6 h, 24, and 48 h of life. The degree of PH was graded as one of three categories: mild/no, moderate, or severe PH. The characteristics of the three groups and their course of PH over 48 h were compared using univariate and correlational analyses. Results: Of 165 eligible CDH cases, initial PH classification was mild/no in 28%, moderate in 35%, and severe PH in 37%. The course of PH varied markedly based on the initial staging. No patient with initial no/mild PH developed severe PH, required extracorporeal membrane oxygenation (ECMO)-therapy, or died. Of cases with initial severe PH, 63% had persistent PH at 48 h, 69% required ECMO, and 54% died. Risk factors for any PH included younger gestational age, intrathoracic liver herniation, prenatal fetoscopic endoluminal tracheal occlusion (FETO)-intervention, lower lung to head ratio (LHR), and total fetal lung volume (TFLV). Patients with moderate and severe PH showed similar characteristics, except liver position at 24- (p = 0.042) and 48 h (p = 0.001), mortality (p = 0.001), and ECMO-rate (p = 0.035). Discussion: To our knowledge, this is the first study to systematically assess the dynamics of PH in the first postnatal 48 h at three defined time points. CDH infants with initial moderate and severe PH have a high variation in postnatal PH severity over the first 48 h of life. Patients with mild/no PH have less change in PH severity, and an excellent prognosis. Patients with severe PH at any point have a significantly higher risk for ECMO and mortality. Assessing PH within 2-6 h should be a primary goal in the care for CDH neonates.

Intravenous sildenafil for treatment of early pulmonary hypertension in preterm infants.

Data is lacking on the effect of continuous intravenous sildenafil treatment in preterm infants with early pulmonary hypertension (PH), especially in very low birth weight (VLBW) infants. Preterm infants (< 37 weeks of gestational age) with intravenous sildenafil treatment and diagnosis of PH between 01/12 and 12/21 were retrospectively screened for analysis. The primary clinical endpoint was defined as response to sildenafil according to the improvement of the oxygenation index (OI), the saturation oxygenation pressure index (SOPI) and PaO2/FiO2-ratio. Early-PH was defined as diagnosis < 28 day of life (DOL). 58 infants were finally included, with 47% classified as very low birth weight (VLBW) infants. The primary endpoint was reached in 57%. The likelihood to die during in-hospital treatment was more than three times higher (72 vs 21%, p < 0.001) in infants without response to sildenafil. The echocardiographic severity of PH and right-ventricular dysfunction (RVD) decreased significantly from baseline to 24 h (p = 0.045, and p = 0.008, respectively). Sildenafil treatment leads to significant improvement of the oxygenation impairment in 57% of the preterm infants, with similar response rates in VLBW infants. Intravenous sildenafil treatment is associated with a significant decrease of the PH-severity and RVD.

Evaluation of levosimendan as treatment option in a large case-series of preterm infants with cardiac dysfunction and pulmonary hypertension.

Levosimendan as a calcium-sensitizer is a promising innovative therapeutical option for the treatment of severe cardiac dysfunction (CD) and pulmonary hypertension (PH) in preterm infants, but no data are available analyzing levosimendan in cohorts of preterm infants. The design/setting of the evaluation is in a large case-series of preterm infants with CD and PH. Data of all preterm infants (gestational age (GA) < 37 weeks) with levosimendan treatment and CD and/or PH in the echocardiographic assessment between 01/2018 and 06/2021 were screened for analysis. The primary clinical endpoint was defined as echocardiographic response to levosimendan. Preterm infants (105) were finally enrolled for further analysis. The preterm infants (48%) were classified as extremely low GA newborns (ELGANs, < 28 weeks of GA) and 73% as very low birth weight infants (< 1500 g, VLBW). The primary endpoint was reached in 71%, without difference regarding GA or BW. The incidence of moderate or severe PH decreased from baseline to follow-up (24 h) in about 30%, with a significant decrease in the responder group (p < 0.001). The incidence of left ventricular dysfunction and bi-ventricular dysfunction decreased significantly from baseline to follow-up (24 h) in the responder-group (p = 0.007, and p < 0.001, respectively). The arterial lactate level decreased significantly from baseline (4.7 mmol/l) to 12 h (3.6 mmol/l, p < 0.05), and 24 h (3.1 mmol/l, p < 0.01).  Conclusion: Levosimendan treatment is associated with an improvement of both CD and PH in preterm infants, with a stabilization of the mean arterial pressure during the treatment and a significant decrease of arterial lactate levels. Future prospective trials are highly warranted. What is Known: • Levosimendan as a calcium-sensitizer and inodilator is known to improve the low cardiac output syndrome (LCOS), and improves ventricular dysfunction, and PH, both in pediatric as well as in adult populations. Data related to critically ill neonates without major cardiac surgery and preterm infants are not available. What is New: • This study evaluated the effect of levosimendan on hemodynamics, clinical scores, echocardiographic severity parameters, and arterial lactate levels in a case-series of 105 preterm infants for the first time. Levosimendan treatment in preterm infants is associated with a rapid improvement of CD and PH, an increase of the mean arterial pressure, and a significant decrease in arterial lactate levels, as surrogate marker for a LCOS. • How this study might affect research, practice, or policy. As no data are available regarding the use of levosimendan in this population, our results hopefully animate the research community to conduct future prospective trails analyzing levosimendan in randomized controlled trials (RCT) and observational control studies. Additionally, our results potentially motivate clinicians to introduce levosimendan as second second-line therapy in cases of severe CD and PH in preterm infants without improvement using standard treatment strategies.

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.