International Online Survey on the Management of Patent Ductus Arteriosus.

INTRODUCTION: There is uncertainty and lack of consensus regarding optimal management of patent ductus arteriosus (PDA). We aimed to determine current clinical practice in PDA management across a range of different regions internationally. MATERIALS AND METHODS: We surveyed PDA management practices in neonatal intensive care units using a pre-piloted web-based survey, which was distributed to perinatal societies in 31 countries. The survey was available online from March 2018 to March 2019. RESULTS: There were 812 responses. The majority of clinicians (54%) did not have institutional protocols for PDA treatment, and 42% reported variable management within their own unit. Among infants <28 weeks (or <1,000 g), most clinicians (60%) treat symptomatically. Respondents in Australasia were more likely to treat PDA pre-symptomatically (44% vs. 18% all countries [OR 4.1; 95% CI 2.6-6.5; p < 0.001]), and respondents from North America were more likely to treat symptomatic PDA (67% vs. 60% all countries [OR 2.0; 95% CI 1.5-2.6; p < 0.001]). In infants ≥28 weeks (or ≥1,000 g), most clinicians (54%) treat symptomatically. Respondents in North America were more likely to treat PDAs in this group of infants conservatively (47% vs. 38% all countries [OR 2.3; 95% CI 1.7-3.2; p < 0.001]), and respondents from Asia were more likely to treat the PDA pre-symptomatically (21% vs. 7% all countries [OR 5.5; 95% CI 3.2-9.8; p < 0.001]). DISCUSSION/CONCLUSION: There were marked international differences in clinical practice, highlighting ongoing uncertainty and a lack of consensus regarding PDA management. An international conglomeration to coordinate research that prioritises and addresses these areas of contention is indicated.

Effective ventilation and chest compressions during neonatal resuscitation - the role of the respiratory device.

BACKGROUND: The success of cardiopulmonary resuscitation (CPR) in newborns largely depends on effective lung ventilation; however, a direct randomized comparison using different available devices has not yet been performed. METHODS: Thirty-six professionals were exposed to a realistic newborn CPR scenario. Ventilation with either a bag-valve mask (BVM), T-piece, or ventilator was applied in a randomized manner during CPR using a Laerdal manikin. The primary outcome was the number of unimpaired inflations, defined as the peak of the inflation occurring after chest compression and lasting at least 0.35 s before the following chest compression takes place. The secondary outcomes were tidal volume delivered and heart compression rate. To simulate potential distractions, the entire scenario was performed with or without a quiz. Statistically, a mixed model assessing fixed effects for experience, profession, device, and distraction was used to analyze the data. For direct comparison, one-way ANOVA with Bonferroni's correction was applied. RESULTS: The number of unimpaired inflations was highest in health care professionals using the BVM with a mean ± standard deviation of 12.8 ± 2.8 (target: 15 within 30 s). However, the tidal volumes were too large in this group with a tidal volume of 42.5 ± 10.9 ml (target: 25-30 ml). The number of unimpaired breaths with the mechanical ventilator and the T-piece system were 11.6 (±3.6) and 10.1 (±3.7), respectively. Distraction did not change these outcomes, except for the significantly lower tidal volumes with the T-piece during the quiz. CONCLUSIONS: In summary, for our health care professionals, ventilation using the mechanical ventilator seemed to provide the best approach during CPR, especially in a population of preterm infants prone to volutrauma.

MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway.

Melanoma-associated antigen D2 (MAGED2) plays an essential role in activating the cAMP/PKA pathway under hypoxic conditions, which is crucial for stimulating renal salt reabsorption and thus explaining the transient variant of Bartter's syndrome. The cAMP/PKA pathway is also known to regulate autophagy, a lysosomal degradation process induced by cellular stress. Previous studies showed that two members of the melanoma-associated antigens MAGE-family inhibit autophagy. To explore the potential role of MAGED2 in stress-induced autophagy, specific MAGED2-siRNA were used in HEK293 cells under physical hypoxia and oxidative stress (cobalt chloride, hypoxia mimetic). Depletion of MAGED2 resulted in reduced p62 levels and upregulation of both the autophagy-related genes (ATG5 and ATG12) as well as the autophagosome marker LC3II compared to control siRNA. The increase in the autophagy markers in MAGED2-depleted cells was further confirmed by leupeptin-based assay which concurred with the highest LC3II accumulation. Likewise, under hypoxia, immunofluorescence in HEK293, HeLa and U2OS cell lines demonstrated a pronounced accumulation of LC3B puncta upon MAGED2 depletion. Moreover, LC3B puncta were absent in human fetal control kidneys but markedly expressed in a fetal kidney from a MAGED2-deficient subject. Induction of autophagy with both physical hypoxia and oxidative stress suggests a potentially general role of MAGED2 under stress conditions. Various other cellular stressors (brefeldin A, tunicamycin, 2-deoxy-D-glucose, and camptothecin) were analyzed, which all induced autophagy in the absence of MAGED2. Forskolin (FSK) inhibited, whereas GNAS Knockdown induced autophagy under hypoxia. In contrast to other MAGE proteins, MAGED2 has an inhibitory role on autophagy only under stress conditions. Hence, a prominent role of MAGED2 in the regulation of autophagy under stress conditions is evident, which may also contribute to impaired fetal renal salt reabsorption by promoting autophagy of salt-transporters in patients with MAGED2 mutation.

Implementation and Assessment of a Laparotomy-Assisted Three-Port Fetoscopic Spina Bifida Repair Program.

Open spina bifida (OSB) is a congenital, non-lethal malformation with multifactorial etiology. Fetal therapy can be offered under certain conditions to parents after accurate prenatal diagnostic and interdisciplinary counseling. Since the advent of prenatal OSB surgery, various modifications of the original surgical techniques have evolved, including laparotomy-assisted fetoscopic repair. After a two-year preparation time, the team at the University of Giessen and Marburg (UKGM) became the first center to provide a three-port, three-layer fetoscopic repair of OSB via a laparotomy-assisted approach in the German-speaking area. We point out that under the guidance of experienced centers and by intensive multidisciplinary preparation and training, a previously described and applied technique could be transferred to a different setting.

Success rate and duration of orotracheal intubation of premature infants by healthcare providers with different levels of experience using a video laryngoscope as compared to direct laryngoscopy in a simulation-based setting.

Background: Endotracheal intubation of very low birth weight infants (VLBWI) is an essential procedure in NICUs, but intubation experience is often limited. Video laryngoscopy (VL) has been described as a tool to improve intubation skills, but studies in high-risk neonatal populations are limited. Objective: The aim of this study was to investigate whether VL is a useful tool to support airway management in high-risk premature infants with inexperienced operators. Methods: In this crossover study predominantly inexperienced participants were exposed in random sequence to VL and conventional direct laryngoscopy (DL) for endotracheal intubation of a VLBWI simulation manikin to measure total time, number of attempts, success rate on first attempt, view of the vocal cords and perceived subjective safety until successful intubation. Results: In our study group of 94 participants there was no significant difference in the total time (mean VL: 34 s (±24 s); DL: 37 s (±28 s), p = 0.246), while the number of intubation attempts using VL was significantly lower (mean VL: 1.22 (±0.53); DL: 1.37 (±0.60), p = 0.023). Success rate of VL during the first attempt was significantly higher (VL: 84%; DL 69%, p = 0.016), view of the vocal cords was significantly better and perceived subjective safety was increased using VL. Conclusions: Our study results suggest that with rather inexperienced operators, VL can be a useful tool to increase rate of successful endotracheal intubation of VLBWI and to improve their perceived safety during the procedure, which may have an impact on mortality and/or morbidity.

Effects of inhaled nitric oxide (iNO) in pulmonary hypertension secondary to arteriovenous malformations: a retrospective cohort study from the European iNO registry.

This study aims to assess the effects of inhaled nitric oxide (iNO) on oxygenation in the management of pulmonary hypertension (PH) secondary to arteriovenous malformations (AVMs) in neonates. This is a matched retrospective cohort study from January 1, 2013, to December 31, 2017. The European inhaled nitric oxide registry from 43 neonatal and pediatric ICUs in 13 countries across Europe was used to extract data. The target population was neonates treated with iNO for the management of PH. The cases (PH secondary to AVMs treated with iNO) were matched (1:4 ratio) to controls (PH without AVMs treated with iNO). The main outcome measure was the absolute change of oxygenation index (OI) from baseline to 60 min after starting iNO in cases and controls. The primary outcome of our study was that the mean absolute change in OI from baseline to after 60 min was higher among cases 10.7 (14), than in controls 6 (22.5), and was not statistically different between the groups. The secondary outcome variable - death before discharge - was found to be significantly higher in cases (55%) than in controls (8%). All the other variables for secondary outcome measures remained statistically insignificant.   Conclusion: Infants with PH secondary to AVMs treated with iNO did not respond differently compared to those presented with PH without AVMs treated with iNO. Right ventricular dysfunction on echocardiography was higher in cases than controls (cases: 66.7% and controls: 28.6%) but was not statistically significant. What is Known: • Arterioenous malformation (AVM) is a well-known cause of persistent pulmonary hypertension in newborns. Inhaled nitric oxide (iNO) is most commonly used as first-line therapy for pulmonary hypertension in newborns. • Around 40-50% of vein of Galen malformations (VOGMs) are found to have congestive heart failure in the neonatal period. What is New: • Neonates may present with an isolated PH of the newborn as the main feature of the VOGMs. A large proportion of cases with AVMs have been associated with right ventricular cardiac dysfunction.  • Results from one of the largest database registries in the world for iNO have been used to answer our research question.

Interventions for Promoting Meconium Passage in Very Preterm Infants-A Survey of Current Practice at Tertiary Neonatal Centers in Germany.

Meconium passage is often delayed in preterm infants. Faster meconium passage appears to shorten the time to full enteral feeds, while severely delayed meconium passage may indicate meconium obstruction. Neonatologists often intervene to promote meconium passage, assuming that benefits outweigh potential risks such as necrotizing enterocolitis (NEC). We performed an anonymous online survey on different approaches to facilitate meconium passage among tertiary neonatal intensive care units (NICUs) in Germany between February 2022 and April 2022. We collected information on enteral nutrition, gastrointestinal complications, and interventions to promote meconium passage. We received 102 completed questionnaires (response rate 64.6%). All responders used interventions to promote meconium passage, including enemas (92.0%), orally applied contrast agents (61.8%), polyethylene glycol (PEG) (46.1%), acetylcysteine (19.6%), glycerin suppositories (11.0%), and maltodextrin (8.8%). There was substantial heterogeneity among NICUs regarding frequency, composition, and mode of administration. We found no differences in NEC incidence between users and nonusers of glycerin enemas, high or low osmolar contrast agents, or PEG. There is wide variability in interventions used to promote meconium passage in German NICUs, with little or no evidence for their efficacy and safety. Within this study design, we could not identify an increased risk of NEC with any intervention reported.

Frequency and duration of extreme hypoxemic and hyperoxemic episodes during manual and automatic oxygen control in preterm infants: a retrospective cohort analysis from randomized studies.

OBJECTIVE: Neonatal exposure to episodic hypoxemia and hyperoxemia is highly relevant to outcomes. Our goal was to investigate the differences in the frequency and duration of extreme low and high SpO2 episodes between automated and manual inspired oxygen control. DESIGN: Post-hoc analysis of a cohort from prospective randomized cross-over studies. SETTING: Seven tertiary care neonatal intensive care units. PATIENTS: Fifty-eight very preterm neonates (32 or less weeks PMA) receiving respiratory support and supplemental oxygen participating in an automated versus manual oxygen control cross-over trial. MAIN MEASURES: Extreme hypoxemia was defined as a SpO2 < 80%, extreme hyperoxemia as a SpO2 > 98%. Episode duration was categorized as < 5 seconds, between 5 to < 30 seconds, 30 to < 60 seconds, 60 to < 120 seconds, and 120 seconds or longer. RESULTS: The infants were of a median postmenstrual age of 29 (28-31) weeks, receiving a median FiO2 of 0.28 (0.25-0.32) with mostly receiving non-invasive respiratory support (83%). While most of the episodes were less than 30 seconds, longer episodes had a marked effect on total time exposure to extremes. The time differences in each of the three longest durations episodes (30, 60, and 120 seconds) were significantly less during automated than during manual control (p < 0.001). Nearly two-third of the reduction of total time spent at the extremes between automated and manual control (3.8 to 2.1% for < 80% SpO2 and 3.0 to 1.6% for > 98% SpO2) was seen in the episodes of at least 60 seconds. CONCLUSIONS: This study shows that the majority of episodes preterm infants spent in SpO2 extremes are of short duration regardless of manual or automated control. However, the infrequent longer episodes not only contribute the most to the total exposure, but also their reduction in frequency to the improvement associated with automated control.

Cerebral Oxygenation in Preterm Infants Developing Cerebral Lesions.

Background: We investigated the association between cerebral tissue oxygen saturation (cStO2) measured by near-infrared spectroscopy (NIRS) and cerebral lesions including intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL). Methods: Preterm infants <1,500 g received continuous cStO2 monitoring, initiated at the earliest time possible and recorded until 72 h of life. Mean cStO2 over periods of 5, 15, 30 min and 1 h were calculated. To calculate the burden of cerebral hypoxia, we defined a moving threshold based on the 10th percentile of cStO2 of healthy study participants and calculated the area under the threshold (AUT). cStO2 <60% for >5 min was regarded a critical event. The study was registered on clinicaltrials.gov (ID NCT01430728, URL: https://clinicaltrials.gov/ct2/show/NCT01430728?id=NCT01430728&draw=2&rank=1). Results: Of 162 infants (gestational age: mean 27.2 weeks, standard deviation 20 days; birth weight: mean 852 g, standard deviation 312 g) recorded, 24/12 (14.8%/7.4) developed any/severe IVH/PVL. Mean cStO2 was significantly lower in infants with IVH/PVL as well as severe IVH/PVL. In addition, we observed critical events defined by mean cStO2 over 5 min <60% in four infants with severe IVH/PVL during NIRS monitoring. AUT showed no statistically significant difference between outcome groups. Conclusion: These findings suggest that cStO2 is lower in infants developing IVH/PVL. This may be related to lower oxygenation and/or perfusion and implies that cStO2 could potentially serve as an indicator of imminent cerebral lesions.

Prevalence and Infant Mortality of Major Congenital Malformations Stratified by Birthweight.

BACKGROUND: Low birthweight and major congenital malformations (MCMs) are key causes of infant mortality. OBJECTIVES: The aim of this study was to explore the prevalence of MCMs in infants with low and very low birthweight and analyze the impact of MCMs and birthweight on infant mortality. METHODS: We determined prevalence and infant mortality of 28 life-threatening MCMs in very-low-birthweight (<1,500 g, VLBW), low-birthweight (1,500-2,499 g, LBW), or normal-birthweight (≥2,500 g, NBW) infants in a cohort of 2,727,002 infants born in Germany in 2006-2017, using de-identified administrative data of the largest statutory public health insurance system in Germany. RESULTS: The rates of VLBW, LBW, and NBW infants studied were 1.3% (34,401), 4.0% (109,558), and 94.7% (2,583,043). MCMs affected 0.5% (13,563) infants, of whom >75% (10,316) had severe congenital heart disease. The prevalence (per 10,000) of any/cardiac MCM was increased in VLBW (286/176) and LBW (244/143), as compared to NBW infants (38/32). Infant mortality rates were significantly higher in infants with an MCM, as opposed to infants without an MCM, in each birthweight group (VLBW 28.5% vs. 11.5%, LBW 16.7% vs. 0.9%, and NBW 8.6% vs. 0.1%). For most MCMs, observed survival rates in VLBW and LBW infants were lower than expected, as calculated from survival rates of VLBW or LBW infants without an MCM, and NBW infants with an MCM. CONCLUSIONS: Infants with an MCM are more often born with LBW or VLBW, as opposed to infants without an MCM. Many MCMs carry significant excess mortality when occurring in VLBW or LBW infants.

Comparison of Cardiac Output Measurement by Electrical Velocimetry with Echocardiography in Extremely Low Birth Weight Neonates.

INTRODUCTION: Electrical velocimetry (EV) offers a noninvasive tool for continuous cardiac output (CO) measurements which might facilitate hemodynamic monitoring and targeted therapy in low birth neonates, in whom other methods of CO measurement are not practicably feasible. METHODS: This prospective observational study compared simultaneous cardiac output measurements by electrical velocimetry (COEV) with transthoracic echocardiography (COTTE) in extremely low birth weight (ELBW) neonates in the neonatal intensive care unit (NICU). Echocardiography was performed by 1 single examiner. Data were analyzed by Bland-Altman analysis and independent-samples analysis of variance. A mean percentage error (MPE) of <30% and limits of agreement (LOA) up to ±30% were considered clinically acceptable. RESULTS: Thirty-eight ELBW neonates were studied and yielded 85 pairs of COEV and COTTE measurements. Bland-Altman analysis showed an overall bias (the mean difference) and LOA of -126 and -305 to +52 mL min-1, respectively, and an MPE of 66%. Patients with patent ductus arteriosus had a higher bias with LOA and MPE of -166.8, -370.7 to +37 mL min-1, and 69%, respectively. The overall true precision was 58%. CONCLUSION: This study showed high bias and lack of agreement between EV and TTE for measurement of CO in ELBW infants in NICU, limiting applicability of EV to monitor absolute values.

Sustained Inflation Versus Intermittent Positive Pressure Ventilation for Preterm Infants at Birth: Respiratory Function and Vital Sign Measurements.

OBJECTIVE: To characterize respiratory function monitor (RFM) measurements of sustained inflations and intermittent positive pressure ventilation (IPPV) delivered noninvasively to infants in the Sustained Aeration of Infant Lungs (SAIL) trial and to compare vital sign measurements between treatment arms. STUDY DESIGN: We analyzed RFM data from SAIL participants at 5 trial sites. We assessed tidal volumes, rates of airway obstruction, and mask leak among infants allocated to sustained inflations and IPPV, and we compared pulse rate and oxygen saturation measurements between treatment groups. RESULTS: Among 70 SAIL participants (36 sustained inflations, 34 IPPV) with RFM measurements, 40 (57%) were spontaneously breathing prior to the randomized intervention. The median expiratory tidal volume of sustained inflations administered was 5.3 mL/kg (IQR 1.1-9.2). Significant mask leak occurred in 15% and airway obstruction occurred during 17% of sustained inflations. Among 34 control infants, the median expiratory tidal volume of IPPV inflations was 4.3 mL/kg (IQR 1.3-6.6). Mask leak was present in 3%, and airway obstruction was present in 17% of IPPV inflations. There were no significant differences in pulse rate or oxygen saturation measurements between groups at any point during resuscitation. CONCLUSION: Expiratory tidal volumes of sustained inflations and IPPV inflations administered in the SAIL trial were highly variable in both treatment arms. Vital sign values were similar between groups throughout resuscitation. Sustained inflation as operationalized in the SAIL trial was not superior to IPPV to promote lung aeration after birth in this study subgroup. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02139800.

T Lymphocytes, Multi-Omic Interactions and Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) remains a significant clinical challenge in neonatal medicine. BPD is clearly a multifactorial disease with numerous antenatal and postnatal components influencing lung development. Extremely immature infants are born in the late canalicular or early saccular stage and usually receive intensive care until the early alveolar stage of lung development, resulting in varying magnitudes of impairment of alveolar septation, lung fibrosis, and abnormal vascular development. The interactions between T lymphocytes, the genome and the epigenome, the microbiome and the metabolome, as well as nutrition and therapeutic interventions such as the exposure to oxygen, volutrauma, antibiotics, corticosteroids, caffeine and omeprazole, play an important role in pathogenesis and disease progression. While our general understanding of these interactions thanks to basic research is improving, this knowledge is yet to be translated into comprehensive prevention and clinical management strategies for the benefit of preterm infants developing BPD and later during infancy and childhood suffering from the disease itself and its sequelae. In this review, we summarise existing evidence on the interplay between T lymphocytes, lung multi-omics and currently used therapeutic interventions in BPD, and highlight avenues for potential future immunology related research in the field.

"Current concepts in assisted mechanical ventilation in the neonate" - Part 2: Understanding various modes of mechanical ventilation and recommendations for individualized disease-based approach in neonates.

Mechanical ventilation is a lifesaving intervention in critically ill preterm and term neonates. However, it has the potential to cause significant damage to the lungs resulting in long-term complications. Understanding the pathophysiological process and having a good grasp of the basic concepts of conventional and high-frequency ventilation is essential for any medical or allied healthcare practitioner involved in the neonates' respiratory management. This review aims to describe the various types and modes of ventilation usually available in neonatal units. It also describes recommendations of an individualized disease-based approach to mechanical ventilation strategies implemented in the authors' institutions.

Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial.

OBJECTIVES: Most studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO. METHODS: A 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life. RESULTS: A total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes. CONCLUSIONS: iNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants.

Near-Infrared spectroscopy for perfusion assessment and neonatal management.

Term and preterm infants often present with adverse conditions after birth resulting in abnormal vital functions and severe organ failure, which are associated or sometimes caused by low oxygen and/or blood supply. Brain injury may lead to substantial mortality and morbidity often affecting long-term outcome. Standard monitoring techniques in the NICU focus on arterial oxygen supply and hemodynamics and include respiratory rate, heart rate, blood pressure and arterial oxygen saturation as measured by pulse oximetry but provide only limited information on end organ oxygen delivery. Near-Infrared Spectroscopy can bridge this gap by displaying continuous measurements of tissue oxygen saturation, providing information on the balance of oxygen delivery and consumption in organs of interest. Future techniques using multi-wavelength devices may provide additional information on oxidative metabolism in real time adding important information.