Higher awakening threshold of preterm infants in prone position may be a risk factor for SIDS.

AIM: The supine sleeping position in the prevention of sudden infant death syndrome in preterm infants is poorly understood. We aimed to investigate the effect of sleep posture on cardiorespiratory parameters and movement patterns in preterm infants close to discharge. METHODS: This observational study included neonates born in 2022 at the University Hospital Schleswig-Holstein, Lübeck, Germany. Motion sensor data, heart rate, respiratory rate and oxygen saturation were recorded for infants with postconceptional age 35-37 weeks during sleep in the prone and supine positions. RESULTS: We recorded data from 50 infants, born at 31 (24-35) weeks of gestation (mean(range)), aged 5.2 ± 3.7 weeks (mean ± SD), of whom 48% were female. Five typical movement patterns were identified. In the prone position, the percentage of calm, regular breathing was higher and active movement was less frequent when compared to the supine position. The percentage of calm irregular breathing, number of apnoeas, bradycardias, desaturations and vital sign changes were not influenced by position. CONCLUSION: The prone position seems to be associated with a higher arousal threshold. The supine position appears advantageous for escape from life-threatening situations such as sudden infant death syndrome.

LAMP3 deficiency affects surfactant homeostasis in mice.

Lysosome-associated membrane glycoprotein 3 (LAMP3) is a type I transmembrane protein of the LAMP protein family with a cell-type-specific expression in alveolar type II cells in mice and hitherto unknown function. In type II pneumocytes, LAMP3 is localized in lamellar bodies, secretory organelles releasing pulmonary surfactant into the extracellular space to lower surface tension at the air/liquid interface. The physiological function of LAMP3, however, remains enigmatic. We generated Lamp3 knockout mice by CRISPR/Cas9. LAMP3 deficient mice are viable with an average life span and display regular lung function under basal conditions. The levels of a major hydrophobic protein component of pulmonary surfactant, SP-C, are strongly increased in the lung of Lamp3 knockout mice, and the lipid composition of the bronchoalveolar lavage shows mild but significant changes, resulting in alterations in surfactant functionality. In ovalbumin-induced experimental allergic asthma, the changes in lipid composition are aggravated, and LAMP3-deficient mice exert an increased airway resistance. Our data suggest a critical role of LAMP3 in the regulation of pulmonary surfactant homeostasis and normal lung function.

The Derivation of Epigastric Motion to Assess Neonatal Breathing and Sleep: An Exploratory Study.

INTRODUCTION: New non-medical monitors are offered for respiration monitoring of neonates. Epigastric motion during sleep was investigated by means of a wearable tracker in parallel to clinical monitoring. COHORT: 23 hospitalised neonates ready for discharge. METHODS: A 3-axes-accelerometer and -gyroscope was placed in a standard epigastric position. Between two routine care rounds signals were recorded in parallel to monitoring of impedance pneumography (IP), ECG and pulse oximetry. Motion signals vs. time charts were evaluated using 10-min episodes and semiquantitatively assigned to breathing signal quality, regular breathing, periodic breathing and confounding artefacts. The results were compared with the impedance pneumographic data. RESULTS: 26 recordings (mean duration: 210 min/infant) were conducted without bradycardia or apnea alarm. The gestational age at birth ranged 28.9 to 41.1 and at recording from 35.6 to 42.3 postmenstrual weeks. Motion patterns of quiet sleep with regular breathing, periodic breathing and active sleep with confounding body movements were found. The longitudinal and transversal gyroscope axes resulted in best signal quality. Periodic breathing was found in up to 80% of episodes and decreased inversely with gestational age showing significantly more periodic breathing in preterm infants. Respiration signals of the gyroscope vs. IP showed a low bias and highly variating frequencies. CONCLUSIONS: Standardized motion trackers may detect typical neonatal breathing and body-motion-patterns, that could help to classify neonatal sleep. Respiratory rates can only be determined during quiet sleep.

The effect of less invasive surfactant administration on cerebral oxygenation in preterm infants.

AIM: To determine the regional cerebral tissue oxygenation saturation (rcSO2 ) in a group of infants requiring less invasive surfactant administration (LISA) as compared to infants with continuous positive airway pressure (CPAP) only. METHODS: In preterm infants with a gestational age 26 0/7-31 6/7 weeks, we conducted an observational study using near-infrared spectroscopy (NIRS) in the first 120 hours of life. RESULTS: We analysed the data of 22 infants who never received surfactant (CPAP), 22 infants had LISA and CPAP (LISA) and 6 infants received surfactant via endotracheal tube (ETT). Four infants had both surfactant application modes including six LISA applications. In total, there were 32 successful LISA applications but 44 attempts; 13/44 (30%) of LISA attempts resulted in a 20% decrease of rcSO2 . During the first 120 hours of life, rcSO2 values of CPAP were similar to those of infants in the LISA group, that is median rcSO2 values 90% vs 85%, respectively (P = .126). Episodes with rcSO2 values <65% were 0.4% in the CPAP group as compared to 4.8% in the LISA group (P < .001). CONCLUSION: Our observational data indicate that rcSO2 values of infants in the LISA group were similar to the CPAP group.

A randomised controlled trial in preterm infants comparing prophylactic with selective "less invasive surfactant administration" (pro.LISA).

BACKGROUND: Respiratory distress syndrome is the main cause of mortality and morbidity in preterm infants. "Less invasive surfactant administration" (LISA), which describes intratracheal surfactant administration to spontaneously breathing infants via a small diameter tube, is recommended as the first-line treatment in preterm infants with more than 30% supplemental oxygen. Prophylactic use of LISA in preterm infants with less than 30% supplemental oxygen was not tested in randomised controlled trials yet, and long-term outcome data of the procedure are scarce. METHODS: Preterm infants with a gestational age between 25 weeks + 0 days and 28 weeks + 6 days who are breathing spontaneously on continuous positive airway pressure with supplemental oxygen at or below 30% in the first hour of life will be randomised to a prophylactic LISA treatment with 100-200 mg surfactant intratracheally per kilogramme bodyweight (intervention group) or will continue the continuous positive airway pressure treatment (control group). Participants will have follow-up until age 5 years. At that time, the children will be tested by spirometry, and forced expiratory volume within 1-s z-scores will be compared between the intervention and control groups as the primary outcome parameter of the trial. Secondary endpoints include additional lung function parameters, endurance, motor development, intelligence, and sensitivity for infectious lung diseases. Short-term safety assessment will be done after completed enrolment (n = 698) and discharge of all infants. This safety assessment will include in-hospital mortality and short-term complications. DISCUSSION: Robust data concerning the possible long-term benefits of prophylactic LISA treatment are lacking. The current observational data from the German Neonatal Network indicate that approximately 50% of preterm infants with supplemental oxygen at or below 30% within the first hour of life are treated with LISA. The pro.LISA trial will provide short- and long-term outcomes of preterm infants receiving prophylactic treatment and will clarify if prophylactic treatment should be given to all preterm infants or if the current practice of selective treatment if supplemental oxygen exceeds 30% is more appropriate. TRIAL REGISTRATION: German Clinical Trials Register DRKS00028086. Prospectively registered on 8 February 2022.

Lung Function of Preterm Children Parsed by a Polygenic Risk Score for Adult COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) in adults is a result of environmental risk factors and genetic factors. Polygenic COPD risk scores are highly predictive for lung function in adults. We hypothesized that a polygenic COPD risk score is also predictive for lung function in children who are born preterm. METHODS: Infants with a birth weight of less than 1500 g (n=17,394) were enrolled in the German Neonatal Network. Among these children, we included those with chip genotyping and 5-year follow-up assessment (n=1957) in this analysis. A polygenic COPD risk score derived in adults with COPD was calculated on the basis of 1,637,882 single-nucleotide polymorphisms associated with forced expiratory volume within 1 second (FEV1) and 1,179,331 single-nucleotide polymorphisms associated with FEV1/FVC (forced vital capacity). This score was related to FEV1, FVC, and FEV1/FVC z scores by linear regression analysis. RESULTS: At a mean age at follow-up of 5.8±0.4 years, the polygenic COPD risk score was strongly associated with FEV1 (−0.05 z score/decile, P=6.5 × 10−9) and FEV1/FVC (−0.07 z score/decile, P=4.4 × 10−11) but not FVC. Children in the 10th decile of the polygenic COPD risk score ­ that is, those at the highest risk ­ had a mean FEV1 z score of −1.74 (±1.1), indicating lower lung function by these measures and higher rates of obstructive bronchitis. CONCLUSIONS: The upper deciles of a polygenic COPD risk score derived in adults identified a subgroup of children who were born preterm and who are at high risk for obstructive pulmonary disease of prematurity. This finding supports the notion that COPD-associated genes strongly impact lung function in premature children. (Funded by the German Federal Ministry of Education and Research.)

ATP-binding cassette member A3 (E292V) gene mutation and pulmonary morbidity in very-low-birth-weight infants.

AIM: ATP-binding cassette member A 3 (ABCA3) plays a critical role for the transport of surfactant phospholipids into the lamellar bodies of type II alveolar epithelial cells. Term infants carrying the E292V missense mutation of the gene encoding ABCA3 are likely to develop respiratory distress syndrome, and the mutation has also been linked to interstitial lung disease in paediatric patients. The aim of this study was to investigate the association of the E292V genotype with pulmonary morbidity in a large cohort of very-low-birth-weight (VLBW) infants. METHODS: We performed a genetic association study with a prospective, population-based multi-centre cohort of 3177 VLBW infants born in 16 German study centres between 2003 and 2009 (German Neonatal Network). The ABCA3 genotype was determined by restriction fragment length polymorphism-PCR in genomic DNA samples derived from buccal swabs. RESULTS: In a large cohort of 3177 VLBW infants, 11 individuals were found to be heterozygote for the E292V mutation (0.34%). After stratification according to ABCA3 genotype, no differences were noted for clinical characteristics, necessary treatments and neonatal pulmonary outcomes. CONCLUSIONS: Within the size limits of our study cohort, the ABCA3 missense mutation E292V had no remarkable effect on pulmonary outcome in VLBW infants. Present results do not rule out the possibility that E292V phenotype is associated with minor difference in the morbidity.

Progressive Respiratory Insufficiency in a Teenager with Diaphragmatic Hypomotility Due to a Novel Combination of Gliomedin Gene Variants.

Lethal congenital contracture syndrome 11 (LCCS11) is a form of arthrogryposis multiplex congenita (AMC) which is associated with mutations in the gliomedin gene (GLDN) and has been known to be severely life-shortening, mainly due to respiratory insufficiency. Patients with this condition have been predominantly treated by pediatricians as they usually do not survive beyond childhood. In this case report, we present a young adult who developed severe progressive respiratory insufficiency as a teenager due to diaphragmatic hypomotility and was diagnosed with LCCS11 following the discovery of compound heterozygous pathogenic variants in GLDN. This case demonstrates the importance of screening for neuromuscular diseases in well-child visits and follow-ups of patients at risk for gross and fine motor function developmental delay. It also underscores the significance of including LCCS11 and other axonopathies in the differential diagnosis of juvenile onset of respiratory insufficiency, highlights that patients with this condition may present to adult practitioners and questions whether the nomenclature of this condition with various phenotypes should be reconsidered due to the stigmatizing term 'lethal'.

Characterization of phospholipid-modified lung surfactant in vitro and in a neonatal ARDS model reveals anti-inflammatory potential and surfactant lipidome signatures.

A strong inflammatory immune response drives the lung pathology in neonatal acute respiratory distress syndrome (nARDS). Anti-inflammatory therapy is therefore a promising strategy for improved treatment of nARDS. We demonstrate a new function of the anionic phospholipids POPG, DOPG, and PIP2 as inhibitors of IL-1ß release by LPS and ATP-induced inflammasome activation in human monocyte-derived and lung macrophages. Curosurf® surfactant was enriched with POPG, DOPG, PIP2 and the head-group derivative IP3, biophysically characterized and applicability was evaluated in a piglet model of nARDS. The composition of pulmonary surfactant from piglets was determined by shotgun lipidomics screens. After 72 h of nARDS, levels of POPG, DOPG, and PIP2 were enhanced in the respective treatment groups. Otherwise, we did not observe changes of individual lipid species in any of the groups. Surfactant proteins were not affected, with the exception of the IP3 treated group. Our data show that POPG, DOPG, and PIP2 are potent inhibitors of inflammasome activation; their enrichment in a surfactant preparation did not induce any negative effects on lipid profile and reduced biophysical function in vitro was mainly observed for PIP2. These results encourage to rethink the current strategies of improving surfactant preparations by inclusion of anionic lipids as potent anti-inflammatory immune regulators.

Lactoferrin and Human Neutrophil Protein (HNP) 1-3 Levels During the Neonatal Period in Preterm Infants.

Antimicrobial polypeptides (APPs) are part of the innate immune system, but their specific role in the context of preterm birth is not yet understood. The aim of this investigation was to determine the systemic expression of APPs, i.e., lactoferrin (LF) and human neutrophil protein (HNP) 1-3 in preterm infants in the period of highest vulnerability for infection and to correlate these biomarkers with short-term outcome. We therefore conducted a prospective two-center study including plasma samples of 278 preterm infants and 78 corresponding mothers. APP levels were analyzed on day 1, 3, 7, and 21 of life via enzyme-linked immunosorbent assay (ELISA). The levels of LF and HNP1-3 remained stable during the first 21 days of life and were not influenced by maternal levels. Elevated APP levels were found at day 1 in infants born to mothers with amniotic infection syndrome (AIS vs. no AIS, mean ± SD in ng/ml: LF 199.8 ± 300 vs. 124.1 ± 216.8, HNP 1-3 16,819 ± 36,124 vs. 8,701 ± 11,840; p = 0.021, n = 179). We found no elevated levels of APPs before the onset of sepsis episodes or in association with other short-term outcomes that are in part mediated by inflammation such as necrotizing enterocolitis (NEC) or retinopathy of prematurity (ROP). Interestingly, infants developing bronchopulmonary dysplasia (BPD) showed higher levels of HNP1-3 on day 21 than infants without BPD (13,473 ± 16,135 vs. 8,388 ± 15,938, n = 111, p = 0.008). In infants born without amniotic infection, levels of the measured APPs correlated with gestational age and birth weight. In our longitudinal study, systemic levels of LF and HNP 1-3 were not associated with postnatal infection and adverse short-term outcomes in preterm infants.

Lymphangioma of the fetal neck within the PIK3CA-related-overgrowth spectrum (PROS): A case report.

The delineation of the prenatal diagnostic key features of PIK3CA-related overgrowth spectrum disorders will assume a crucial part in future and a prenatal diagnosis of the causing mutations would provide physicians with a simplified interdisciplinary perinatal management.

Five Year Follow Up of Extremely Low Gestational Age Infants after Timely or Delayed Administration of Routine Vaccinations.

This study is aimed at detecting the rate of untimely immunization in a large cohort of extremely low gestational age neonates (ELGANs) of the German Neonatal Network (GNN) and at addressing risk factors for delayed vaccination and associated long-term consequences. We performed an observational study of the GNN between 1st January 2010 and 31st December 2019. The immunization status for the hexavalent and pneumococcal immunization was evaluated in n = 8401 preterm infants <29 weeks of gestation. Univariate analysis and logistic/linear regression models were used to identify risk factors for vaccination delay and outcomes at a 5-year follow-up. In our cohort n = 824 (9.8%) ELGANs did not receive a timely first immunization with the hexavalent and pneumococcal vaccine. Risk factors for delayed vaccination were SGA status (18.1% vs. 13.5%; OR 1.3; 95% CI: 1.1-1.7), impaired growth and surrogates for complicated clinical courses (i.e., need for inotropes, necrotizing enterocolitis). At 5 years of age, timely immunized children had a lower risk of bronchitis (episodes within last year: 27.3% vs. 37.7%; OR 0.60, 95% CI: 0.42-0.86) but spirometry measures were unaffected. In conclusion, a significant proportion of ELGANs are untimely immunized, specifically those with increased vulnerability, even though they might particularly benefit from the immune-promoting effects of a timely vaccination.

Prophylactic intratracheal polymyxin B/surfactant prevents bacterial growth in neonatal Escherichia coli pneumonia of rabbits.

In neonatal pneumonia, the surface activity of pulmonary surfactant is impaired and microorganisms may invade by passing the air-liquid interface. Previously, we have shown that addition of the antimicrobial peptide polymyxin B (PxB) to modified porcine surfactant (pSF) improves resistance to surfactant inactivation in vitro while antimicrobial activity of PxB is maintained. In this study, we investigated pSF/PxB in vivo. Neonatal near-term rabbits were treated with intratracheal pSF and/or PxB. Rabbits treated with only saline served as controls. Animals were ventilated with standardized tidal volumes and received ∼10(7) Escherichia coli intratracheally. Plethysmographic pressure-volume curves were recorded every 30 min. After 240 min, animals were killed, the right lung and left kidney were excised, and bacterial growth was determined. The left lung was used for histologic analysis. Intratracheal administration of PxB ± pSF significantly reduced the growth of E. coli compared with control animals or animals receiving only pSF. This was accompanied by reduction of severe inflammatory tissue destruction and significantly reduced bacterial translocation to the left kidney. Animals receiving pSF + PxB had no difference in lung compliance compared with the pSF- or PxB-treated group. Mixtures of PxB and pulmonary surfactant show antimicrobial effects in neonatal rabbits and prevent systemic spreading of E. coli.

Active perinatal care of preterm infants in the German Neonatal Network.

OBJECTIVE: To determine if survival rates of preterm infants receiving active perinatal care improve over time. DESIGN: The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016. SETTING: 43 German level III neonatal intensive care units (NICUs). PATIENTS: 8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care. INTERVENTIONS: Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (

Inactivation of pulmonary surfactant by silicone oil in vitro and in ventilated immature rabbits.

OBJECTIVE: Surface activity of pulmonary surfactant is impaired by exposure to syringes lubricated with silicone oil (SO). These syringes are used daily in clinical practice. DESIGN: In vitro experiments were used for detection of SO, determination of surface activity, and semiquantitative measurement of surfactant protein (SP)-B and -C in SO/surfactant mixtures. Randomized, controlled animal studies were applied for determination of in vivo activity. SETTING: University research laboratory. INTERVENTIONS: Mass spectrometry of SO originating from syringes with and without surfactant was performed. The surface activity of SO plus surfactant phospholipids (PLs) or modified natural surfactant (Curosurf) was measured. SO/Curosurf preparations were further analyzed for changes in the content of SP-B and SP-C using immunoblotting. Neonatal rabbits received mixtures of SO/Curosurf (ratio 0-1.3 mg/mg PL) intratracheally and were then ventilated with a standardized sequence of peak insufflation pressures. Tidal volume curves were recorded, gas volumes of excised lungs were measured, and histologic analysis was performed. MEASUREMENTS AND MAIN RESULTS: Dissolved SO was found after rinsing syringes with organic solvents or Curosurf. Surface activity of Curosurf was significantly reduced after addition of 0.13-1.3 mg SO/mg PL. Immunoblotting revealed interference of SO with SP-B, but not with SP-C. With increasing SO/Curosurf ratios, patchy alveolar air expansion was observed, lung gas volumes were reduced, and time to inflate the lungs was increased, whereas compliance and tidal volumes remained unimpaired. CONCLUSIONS: In vitro SO impairs surface activity of Curosurf and leads to interference with SP-B. SO contamination of exogenous surfactant impairs lung function in animal studies and should be avoided.

Natural Derived Surfactant Preparation As a Carrier of Polymyxin E for Treatment of Pseudomonas aeruginosa Pneumonia in a Near-Term Rabbit Model.

BACKGROUND: Pulmonary surfactant spreads rapidly over the airway epithelium, a property that could be harnessed to transport drugs into the lungs. For efficient drug delivery, an interaction between pulmonary surfactant and the drug to be administered is likely needed. On the other hand, the interaction should not compromise the activity of surfactant or the drug once delivered in vivo. The antibiotics gentamicin (an aminoglycoside) and polymyxin E represent drugs that could benefit from being delivered directly to the lung, thereby increasing local concentrations and reducing systemic side effects. Our aim was to study how the animal-derived surfactant poractant alfa (Curosurf®) affects the activities of polymyxin E and gentamicin against Pseudomonas aeruginosa. METHODS: In vitro antimicrobial assays and a neonatal near-term rabbit model were used to evaluate the combinations of antibiotics and surfactant against Pseudomonas aeruginosa. RESULTS: The bactericidal activity of polymyxin E, but not of gentamicin, against P. aeruginosa was partly reduced in vitro in the presence of poractant alfa. In contrast, in the rabbit model of P. aeruginosa pneumonia, polymyxin E administrated together with surfactant was superior in lowering the bacterial load in the lungs compared to polymyxin E alone, without affecting plethysmographically recorded lung compliance. CONCLUSIONS: The results suggest that polymyxin E interacts with poractant alfa, which reduces the antibacterial effect in vitro. However, when polymyxin E mixed with surfactant is used in the in vivo pneumonia model, increased bactericidal effect was observed. This may be due to a more efficient spreading mediated by interactions between polymyxin E and surfactant. These results warrant further studies of surfactant preparations for drug delivery against lung infections.

Surfactant proteins B and C are both necessary for alveolar stability at end expiration in premature rabbits with respiratory distress syndrome.

Modified natural surfactant preparations, used for treatment of respiratory distress syndrome in premature infants, contain phospholipids and the hydrophobic surfactant protein (SP)-B and SP-C. Herein, the individual and combined effects of SP-B and SP-C were evaluated in premature rabbit fetuses treated with airway instillation of surfactant and ventilated without positive end-expiratory pressure. Artificial surfactant preparations composed of synthetic phospholipids mixed with either 2% (wt/wt) of porcine SP-B, SP-C, or a synthetic poly-Leu analog of SP-C (SP-C33) did not stabilize the alveoli at the end of expiration, as measured by low lung gas volumes of approximately 5 ml/kg after 30 min of ventilation. However, treatment with phospholipids containing both SP-B and SP-C/SP-C33 approximately doubled lung gas volumes. Doubling the SP-C33 content did not affect lung gas volumes. The tidal volumes were similar in all groups receiving surfactant. This shows that SP-B and SP-C exert different physiological effects, since both proteins are needed to establish alveolar stability at end expiration in this animal model of respiratory distress syndrome, and that an optimal synthetic surfactant probably requires the presence of mimics of both SP-B and SP-C.