Prophylactic Oropharyngeal Surfactant for Preterm Newborns at Birth: A Randomized Clinical Trial.

Importance: Preterm newborns at risk of respiratory distress syndrome are supported with continuous positive airway pressure (CPAP). Many newborns worsen despite CPAP and are intubated for surfactant administration, an effective therapy for treatment of respiratory distress syndrome. Endotracheal intubation is associated with adverse effects. Pharyngeal administration of surfactant to preterm animals and humans has been reported as an alternative. Objective: To assess whether giving prophylactic oropharyngeal surfactant to preterm newborns at birth would reduce the rate of intubation for respiratory failure. Design, Setting, and Participants: This unblinded, parallel-group randomized clinical trial (Prophylactic Oropharyngeal Surfactant for Preterm Infants [POPART]) was conducted from December 17, 2017, to September 11, 2020, at 9 tertiary neonatal intensive care units in 6 European countries. Newborns born before 29 weeks of gestation without severe congenital anomalies, for whom intensive care was planned, were eligible for inclusion. The data were analyzed from July 27, 2022, to June 20, 2023. Intervention: Newborns were randomly assigned to receive oropharyngeal surfactant at birth in addition to CPAP or CPAP alone. Randomization was stratified by center and gestational age (GA). Main Outcomes and Measures: The primary outcome was intubation in the delivery room for bradycardia and/or apnea or in the neonatal intensive care unit for prespecified respiratory failure criteria within 120 hours of birth. Caregivers were not masked to group assignment. Results: Among 251 participants (mean [SD] GA, 26 [1.5] weeks) who were well matched at study entry, 126 (69 [54.8%] male) with a mean (SD) birth weight of 858 (261) grams were assigned to the oropharyngeal surfactant group, and 125 (63 [50.4%] male) with a mean (SD) birth weight of 829 (253) grams were assigned to the control group. The proportion of newborns intubated within 120 hours was not different between the groups (80 [63.5%) in the oropharyngeal surfactant group and 81 [64.8%] in the control group; relative risk, 0.98 [95% CI, 0.81-1.18]). More newborns assigned to the oropharyngeal surfactant group were diagnosed with and treated for pneumothorax (21 [16.6%] vs 8 [6.4%]; P = .04). Conclusions and Relevance: This randomized clinical trial found that administration of prophylactic oropharyngeal surfactant to newborns born before 29 weeks' GA did not reduce the rate of intubation in the first 120 hours of life. These findings suggest that administration of surfactant into the oropharynx immediately after birth in addition to CPAP should not be routinely used. Trial Registration: EudraCT: 2016-004198-41.

Infant Milk Formula with Large, Milk Phospholipid-coated Lipid Droplets Enriched in Dairy Lipids Affects Body Mass Index Trajectories and Blood Pressure at School Age: Follow-up of a Randomized Controlled Trial.

BACKGROUND: Human milk comprises large fat globules enveloped by a native phospholipid membrane, whereas infant formulas contain small, protein-coated lipid droplets. Previous experimental studies indicated that mimicking the architecture of human milk lipid droplets in infant milk formula (IMF) alters lipid metabolism with lasting beneficial impact on later metabolic health. OBJECTIVES: To evaluate in a follow-up (FU) study of a randomized, controlled trial whether a Concept IMF with large, milk phospholipid-coated lipid droplets enriched with dairy lipids beneficially impacts long-term body mass index (BMI in kg/m2) trajectories and blood pressure at school age. METHODS: Fully formula-fed infants were randomly assigned to Concept IMF (n = 115) or Control IMF with conventional, small lipid droplets containing vegetable oils (n = 108) for the first 4 mo of age. A group of 88 breastfed infants served as a reference. During FU, anthropometrics were collected at 1, 3, 4, and 5 y of age, and blood pressure only at the last visit. RESULTS: Compared to Control, Concept group children had consistently lower mean BMI values during FU, with the most marked difference at 1 y of age (difference in means -0.71 kg/m2, 95% confidence interval (CI): -1.13, -0.29; P = 0.001); mean values were close to the breastfed group (P > 0.05). Contrary, the mean BMI values of the Control group were higher compared with the breastfed group during FU from 1 to 5 y of age (differences in means from 0.59 to 0.96 kg/m2, respectively; P < 0.02). At 5 y of age, the Concept group had a lower mean diastolic and arterial blood pressure compared with the Control group; -4.3mm Hg (95% CI: -7.3, -1.3; P = 0.005) and -3.7 mm Hg (95% CI: -6.5, -0.9; P = 0.01), respectively. CONCLUSIONS: Early life feeding of an innovative IMF with large, milk phospholipid-coated lipid droplets enriched with dairy lipids results in a BMI trajectory closer to breastfed infants and a lower blood pressure at school age. This trial was registered at the Dutch Trial Register as NTR3683 and NTR5538.

Rapid Whole Genome Sequencing Diagnoses and Guides Treatment in Critically Ill Children in Belgium in Less than 40 Hours.

Rapid Whole Genome Sequencing (rWGS) represents a valuable exploration in critically ill pediatric patients. Early diagnosis allows care to be adjusted. We evaluated the feasibility, turnaround time (TAT), yield, and utility of rWGS in Belgium. Twenty-one unrelated critically ill patients were recruited from the neonatal intensive care units, the pediatric intensive care unit, and the neuropediatric unit, and offered rWGS as a first tier test. Libraries were prepared in the laboratory of human genetics of the University of Liège using Illumina DNA PCR-free protocol. Sequencing was performed on a NovaSeq 6000 in trio for 19 and in duo for two probands. The TAT was calculated from the sample reception to the validation of results. Clinical utility data were provided by treating physicians. A definite diagnosis was reached in twelve (57.5%) patients in 39.80 h on average (range: 37.05-43.7). An unsuspected diagnosis was identified in seven patients. rWGS guided care adjustments in diagnosed patients, including a gene therapy, an off-label drug trial and two condition-specific treatments. We successfully implemented the fastest rWGS platform in Europe and obtained one of the highest rWGS yields. This study establishes the path for a nationwide semi-centered rWGS network in Belgium.

Ventilation devices for neonatal resuscitation at birth: A systematic review and meta-analysis.

Initial management of inadequate adaptation to extrauterine life relies on non-invasive respiratory support. Two types of devices are available: fixed pressure devices (FPD; T-pieces or ventilators) and hand driven pressure devices (HDPD; self- or flow-inflating bags). This systematic review and meta-analysis aims to compare clinical outcomes after neonatal resuscitation according to device type. METHODS: Four databases were searched from inception to 2022, January. Search strategies included Mesh/Emtree terms as well as free language without any restriction. Randomized, quasi-randomized studies and prospective cohorts comparing the use of the two types of devices in neonatal resuscitation were included. RESULTS: Nine studies recruiting 3621 newborns were included: 5 RCTs, 2 RCTs with interventions bundles and 2 prospective cohorts. Meta-analysis of the 5 RCTs demonstrated significant reductions in bronchopulmonary dysplasia (RR0,68[0,48-0,96]-NNT 31) and other respiratory outcomes: intubation in the delivery room (RR0,72[0,58-0,88]-NNT 13,4), mechanical ventilation requirements (RR0,81[0,67-0,96]-NNT 17) and duration (MD-1,54 days[-3,03- -0,05]), need for surfactant (RR0,79[0,64-0,96]-NNT 7,3). The overall analysis found a lower mortality in the FPD group (OR0,57[0,47-0,69]-NNT 12,7) and confirmed decreases in intubation, surfactant requirement and mechanical ventilation rates (OR 0,56[0,40-0,79]- NNT7,5; OR 0,67[0,55-0,82]-NNT10,7 and OR0,58[0,42-0,80]- NNT 7,4 respectively). The risk of cystic periventricular leukomalacia (cPVL) decreased significantly with FPD (OR0.59[0.41-0.85]-NNT 27). Pneumothorax rates were similar (OR0.82[0.44-1.52]). CONCLUSION AND RELEVANCE: Resuscitation at birth with FPD improves respiratory transition and decreases BPD with a very low to moderate certainty of evidence. There is suggestion of decreases in mortality and cPVL. Further studies are still needed to confirm those results.

Intranasal Analgosedation for Infants in the Neonatal Intensive Care Unit: A Systematic Review.

AIM: Pain management is important for newborns' immediate and long-term well-being. While intranasal analgesia and sedation have been well studied in children, their use could be extended to term and preterm infants. This systematic review aims to assess the use of intranasal medications for procedural analgesia or sedation in the neonatal intensive care unit. METHODS: MEDLINE via Ovid, Scopus, Embase, and Cochrane Library were searched independently by two reviewers for clinical studies on sedation or analgesia given intranasally. RESULTS: Seven studies, with 401 patients, were included. The studies described various molecules (midazolam, fentanyl, ketamine, or dexmedetomidine) for different procedures such as intubation in the delivery room, screening for retinopathy, or magnetic resonance imaging. All studies reported significant reduction in pain and sedation markers (based on clinical scales, skin conductance, and clinical variables such as heart rate and crying time). Adverse effects were uncommon and mostly consisted in desaturation, apnoea, hypotension, or paradoxical reactions. DISCUSSION AND CONCLUSION: The intranasal route seems a potential alternative for procedural pain management and sedation in neonates, especially when intravenous access is not available. However, data about safety remain limited. Reported sides effects could be attributed to molecules used rather than the intranasal route. Optimal drugs and doses still need to be characterized. Further studies are needed to ensure safety before promoting a widespread use of intranasal medications in neonatology.

Analgosedation before Less-Invasive Surfactant Administration: A Systematic Review.

BACKGROUND: Surfactant therapy is the cornerstone of respiratory distress syndrome management. "Less-invasive surfactant administration (LISA)" is now recommended for spontaneously breathing preterm infants. Analgosedation remains controversial as 52% of European neonatologists do not use any. This systematic review aims to describe the efficacy and safety of different drugs for analgosedation during LISA. METHODS: MEDLINE via Ovid, Embase, Scopus, and Cochrane Library of Trials were searched independently by 2 reviewers for studies on sedation or analgesia for LISA, without filters or limits. RESULTS: Eight studies (1 randomized controlled trial) recruiting 945 infants were included. Infant pain was significantly reduced, with more infants evaluated as comfortable. Failure, defined as need for intubation or for a second dose of surfactant, was not different between sedated and unsedated groups. Analgosedation was associated with a higher occurrence of desaturation and need for positive pressure ventilation during procedure, but the need for mechanical ventilation within 24 or 72 h of life was not significantly different. There does not seem to be any difference in clinical tolerance and complications (e.g., hypotension, mortality, air leaks, etc.). Procedural conditions were evaluated as good or excellent in 83% after sedation. DISCUSSION AND CONCLUSION: Analgesia or sedative drugs increase infant comfort and allow good procedural conditions, with a limited impact on the clinical evolution. Questions remain about the best choice of drugs and dosages, with the constraint to maintain spontaneous breathing and have a rapid offset. Further good quality studies are needed to provide additional evidence to supplement those limited existing data.

Neonatal Cancer Epidemiology and Outcome: A Retrospective Study.

OBJECTIVE: Our study aimed at describing neonatal cancer incidence, distribution by type, location, outcome, and long-term toxicity, by comparison with tumors occurring later in infancy. METHODS: The authors led a single-center retrospective analysis of 118 cases of tumors diagnosed in the first year of life and compared tumors' types incidence, presentation, location, and outcome according to age group at diagnosis (below or over 28 d of life). RESULTS: The most frequent neonatal tumor types in our series were germ cell tumors, mainly teratoma, followed by neuroblastoma and renal tumors, whereas in children below 1 year of age, brain tumors, neuroblastoma, and leukemia were the most common types. Genetic predisposition syndromes were present in 14% of these infants and antenatal sonography enabled 68% of diagnosis for tumors presenting at birth. Other patients presented with mass syndrome, hydrops, or skin lesions. Six percent of neonates with cancer died from their malignancies, and up to 18% experienced a chronic health condition as a consequence of therapy. CONCLUSIONS: Tumor pattern differs in neonates and infants, with a higher percentage of benign tumors in children below 28 days of life. Yet, long-term therapy-related toxicity is significant in younger patients. Enhancing knowledge of neonatal tumors, their epidemiology, clinical presentation, genetic background, and prognosis should help promote better management and introduce follow-up programs to improve surviving rates and the quality of life of survivors.

Growth Benefits of Own Mother's Milk in Preterm Infants Fed Daily Individualized Fortified Human Milk.

The influence of types of human milk (HM)-raw own mother's milk (OMM), pasteurized OMM, and donor milk (DM)-was evaluated for growth in premature infants fed exclusively HM with controlled nutritional intakes using daily individualized HM fortification (IHMF). Growth and nutritional intakes were prospectively collected in preterm infants (<32 weeks) fed IHMF and compared in infants fed predominantly (≥75%) OMM and DM. The influence of HM types (raw OMM, pasteurized OMM, and DM) on growth were also evaluated in the whole population. One-hundred and one preterm infants (birth weight 970 ± 255 g, gestational age 27.8 ± 1.9 weeks) were included. Energy (143 ± 8 vs. 141 ± 6 kcal/kg/day; p = 0.15) and protein intakes (4.17 ± 0.15 vs. 4.15 ± 0.14 g/kg/day; p = 0.51) were similar in both groups. Infants receiving predominantly OMM (n = 37), gained significantly more weight (19.8 ± 2.0 vs. 18.2 ± 2.2 g/kg/day; p = 0.002) and length (1.17 ± 0.26 vs. 0.99 ± 0.36 cm/week; p = 0.020) than those fed predominantly DM (n = 33). Stepwise multivariate analysis (n = 101) suggests that raw OMM was the major determinant of growth, contributing 22.7% of weight gain. Length gain was also related to OMM (raw + pasteurized) intakes, explaining 4.0% of length gain. In conclusion, at daily controlled similar protein and energy intakes, OMM had significant beneficial effects on weight and length versus DM in VLBW infants. This difference could be partially explained by the use of raw OMM.

Distances from vocal cords to mid-trachea for optimizing endotracheal tubes depth markers according to gestational age.

BACKGROUND: Adequate endotracheal tube positioning in preterm infants is complicated by the short length of the airway. Distal markers were designed to help with the insertion of endotracheal tubes at an appropriate depth below the vocal cords. However, those markers are not standardized between manufacturers, each tube size displays only one (sometimes 2) markers to provide information for infants of various gestational ages, and indicated distances are often too long for extremely preterm infants. AIMS: The study aims to describe vocal cords to mid-tracheal distance for different gestational ages and determine if depth markers should be adjusted accordingly. METHODS: Half the tracheal length added to the height of the posterior lamina of the cricoids approximates the distance between vocal cords and mid-trachea. Those dimensions were retrospectively retrieved from a database of laryngo-tracheal measurements obtained during autopsies of fetuses and newborn infants free of upper airway malformations. The equation of correlation between gestational age and distance from vocal cords to mid-trachea was used to calculate those distances for different gestational ages. RESULTS: Data were derived from 114 patients. Vocal cords to mid-trachea distance is linearly correlated with gestational age (r = .90; distance = 2.831 + 0.6208 × gestational age). We suggest depth markers at 17.7, 19.0, 20.8, 22.7, 24.6, and 26.4 mm for gestational ages of 24, 26, 29, 32, 35, and 38 weeks, respectively, indicated by contrasting colors. CONCLUSION: The linear relationship between laryngo-tracheal size and gestational age offers the opportunity to revise endotracheal tube depth markers for the smallest patients. Trials comparing those suggested markers with those currently in use are needed before implementation.

Five-country manikin study found that neonatologists preferred using the LISAcath rather than the Angiocath for less invasive surfactant administration.

AIM: Less invasive surfactant administration (LISA) has been shown to decrease the risk of death and bronchopulmonary dysplasia in preterm neonates. The LISAcath is the first catheter to be specifically developed for LISA, and we compared the clinical impressions of neonatologists using the LISAcath and the commonly used Angiocath in a simulated setting. METHODS: This was a multinational, multicentre study, conducted in October 2016, which involved 39 neonatologists who were recruited by employees of the sponsor from large, well-recognised neonatal intensive care units across Europe. LISA was not the standard of care in these units in Austria, Belgium, Poland, Spain and the United Kingdom at the time of the study. After training, participants simulated LISA on a neonatal manikin, once with the LISAcath and once with Angiocath, then answered a 10-item questionnaire. RESULTS: The responses to nine of 10 questions showed that 67-95% of the respondents preferred the LISAcath to the Angiocath, with most of the remainder indicating no preference. The only exception was the luer connection question, with two-thirds expressing no preference. The LISAcath was considered potentially safer by 33 of 39 participants, with no votes for the Angiocath. CONCLUSION: Overall, neonatologists preferred using the LISAcath rather than the Angiocath on a neonatal manikin.

Surfactant instillation in spontaneously breathing preterm infants: a systematic review and meta-analysis.

Less invasive surfactant therapies (LIST) use surfactant instillation through a thin tracheal catheter in spontaneously breathing infants. This review and meta-analysis investigates respiratory outcomes for preterm infants with respiratory distress syndrome treated with LIST rather than administration of surfactant through an endotracheal tube. Randomised controlled trial (RCT) full texts provided outcome data for bronchopulmonary dysplasia (BPD), death or BPD, early CPAP failure, invasive ventilation requirements and usual neonatal morbidities. Relative risks (RR) from pooled data, with subgroup analyses, were obtained from a Mantel-Haenszel analysis using a random effect model. Six RCTs evaluated LIST: 4 vs InSurE and 1 each vs delayed or immediate intubation for surfactant. LIST resulted in decreased risks of BPD (RR = 0.71 [0.52-0.99]; NNT = 21), death or BPD (RR = 0.74 [0.58-0.94]; NNT = 15) and early CPAP failure or invasive ventilation requirements (RR = 0.67 [0.53-0.84]; NNT = 8 and RR = 0.69 [0.53-0.88]; NNT = 6). Compared to InSurE, LIST decreased the risks of BPD or death (RR = 0.63 [0.44-0.92]; NNT = 11) and of early CPAP failure (RR = 0.71 [0.53-0.96]; NNT = 11). Common neonatal morbidities were not different. CONCLUSIONS: Respiratory management with LIST decreases the risks of BPD and BPD or death, and the need for invasive ventilation. This strategy appears safe, but long-term follow-up is lacking. What is Known: • Initial management of preterm infants with CPAP decreases the risk of death or BPD, but many still require surfactant or invasive ventilation. • Surfactant can be instilled through a tracheal thin catheter while the infant breathes on CPAP, but improvement in BPD is inconsistent between studies. What is New: • Less invasive surfactant therapy (LIST) strategies decrease the risks of BPD, of death or BPD, and of CPAP failure compared to strategies where surfactant is administered through an endotracheal tube. • LIST strategies decrease the risks of the composite outcome of BPD or death and of early CPAP failure when compared to "intubation-surfactant-extubation" approaches.

Automated respiratory cycles selection is highly specific and improves respiratory mechanics analysis.

OBJECTIVE: Selected optimal respiratory cycles should allow calculation of respiratory mechanic parameters focusing on patient-ventilator interaction. New computer software automatically selecting optimal breaths and respiratory mechanics derived from those cycles are evaluated. DESIGN: Retrospective study. SETTING: University level III neonatal intensive care unit. SUBJECTS: Ten mins synchronized intermittent mandatory ventilation and assist/control ventilation recordings from ten newborns. INTERVENTION: The ventilator provided respiratory mechanic data (ventilator respiratory cycles) every 10 secs. Pressure, flow, and volume waves and pressure-volume, pressure-flow, and volume-flow loops were reconstructed from continuous pressure-volume recordings. Visual assessment determined assisted leak-free optimal respiratory cycles (selected respiratory cycles). New software graded the quality of cycles (automated respiratory cycles). Respiratory mechanic values were derived from both sets of optimal cycles. We evaluated quality selection and compared mean values and their variability according to ventilatory mode and respiratory mechanic provenance. To assess discriminating power, all 45 "t" values obtained from interpatient comparisons were compared for each respiratory mechanic parameter. MEASUREMENTS AND MAIN RESULTS: A total of 11,724 breaths are evaluated. Automated respiratory cycle/selected respiratory cycle selections agreement is high: 88% of maximal κ with linear weighting. Specificity and positive predictive values are 0.98 and 0.96, respectively. Averaged values are similar between automated respiratory cycle and ventilator respiratory cycle. C20/C alone is markedly decreased in automated respiratory cycle (1.27 ± 0.37 vs. 1.81 ± 0.67). Tidal volume apparent similarity disappears in assist/control: automated respiratory cycle tidal volume (4.8 ± 1.0 mL/kg) is significantly lower than for ventilator respiratory cycle (5.6 ± 1.8 mL/kg). Coefficients of variation decrease for all automated respiratory cycle parameters in all infants. "t" values from ventilator respiratory cycle data are two to three times higher than ventilator respiratory cycles. CONCLUSIONS: Automated selection is highly specific. Automated respiratory cycle reflects most the interaction of both ventilator and patient. Improving discriminating power of ventilator monitoring will likely help in assessing disease status and following trends. Averaged parameters derived from automated respiratory cycles are more precise and could be displayed by ventilators to improve real-time fine tuning of ventilator settings.

Precision of continuous neonatal ventilator respiratory mechanics is improved with selected optimal respiratory cycles.

UNLABELLED: Given their high apparent variability, bedside continuous respiratory mechanics (RM) parameters [excepting tidal volume (V (T))] remain infrequently used for adjustment of neonatal ventilatory settings. RM parameters provided by ventilator (VRC) from ten recordings of newborns [10 min in synchronised intermittent mandatory ventilation and 10 min in assist/control (A/C)] were compared to those computed from visually selected assisted leak-free optimal respiratory cycles (SRC). Mean values, variability and ability to distinguish patients were compared between VRC and SRC. Dynamic resistances were more correlated (r(2) = 0.95) than compliances (r (2) = 0.42). V (T)s were correlated only in A/C (r(2) = 0.78). C20/C was significantly higher in VRC (1.81 ± 0.67) than in SRC (1.23 ± 0.36) and frequently out of neonatal reference range. In A/C ventilation, V(T) was higher in VRC (5.6 ± 1.8 ml/kg) than in SRC (4.8 ± 1.0 ml/kg) (p < 0.05). Displayed V (T)s do not reflect those found in optimal assisted breaths and therefore have incomplete value in assessing adequacy of ventilator settings. The variability of RM parameters provided by the ventilator is large, and coefficients of variation were significantly lower with optimal respiratory cycles (for resistance, compliance, V (T) and C20/C; 27%, 26%, 18%, 24% in SRC and 36%, 35%, 40% and 33% in VRC). Selecting optimal cycles yields RM with two to three times higher discriminating power between patients. CONCLUSION: Current ventilator's RM parameters have limited clinical use. Using optimal breaths to calculate RM parameters improves precision and discriminating power. For integration to ventilatory care, automation of this selection must be implemented first.

Secretory phospholipase A2 pathway in various types of lung injury in neonates and infants: a multicentre translational study.

BACKGROUND: Secretory phospholipase A2 (sPLA2) is a group of enzymes involved in lung tissue inflammation and surfactant catabolism. sPLA2 plays a role in adults affected by acute lung injury and seems a promising therapeutic target. Preliminary data allow foreseeing the importance of such enzyme in some critical respiratory diseases in neonates and infants, as well. Our study aim is to clarify the role of sPLA2 and its modulators in the pathogenesis and clinical severity of hyaline membrane disease, infection related respiratory failure, meconium aspiration syndrome and acute respiratory distress syndrome. sPLA2 genes will also be sequenced and possible genetic involvement will be analysed. METHODS/DESIGN: Multicentre, international, translational study, including several paediatric and neonatal intensive care units and one coordinating laboratory. Babies affected by the above mentioned conditions will be enrolled: broncho-alveolar lavage fluid, serum and whole blood will be obtained at definite time-points during the disease course. Several clinical, respiratory and outcome data will be recorded. Laboratory researchers who perform the bench part of the study will be blinded to the clinical data. DISCUSSION: This study, thanks to its multicenter design, will clarify the role(s) of sPLA2 and its pathway in these diseases: sPLA2 might be the crossroad between inflammation and surfactant dysfunction. This may represent a crucial target for new anti-inflammatory therapies but also a novel approach to protect surfactant or spare it, improving alveolar stability, lung mechanics and gas exchange.