Non-Invasive Ventilatory Support in Preterm Neonates in the Delivery Room and the Neonatal Intensive Care Unit: A Short Narrative Review of What We Know in 2024.

BACKGROUND: Guidelines recommend non-invasive ventilatory (NIV) support as first-line respiratory support mode in preterm infants as NIV is superior to intubation and mechanical ventilation in preventing death or bronchopulmonary dysplasia. However, with an ever-expanding variety of NIV modes available, there is much debate about which NIV modality should ideally be used, how, and when. The aims of this work were to summarise the evidence on different NIV modalities for both primary and secondary respiratory support: nCPAP, nasal high-flow therapy (nHFT), and nasal intermittent positive airway pressure ventilation (nIPPV), bi-level positive airway pressure (BiPAP), nasal high-frequency oscillatory ventilation (nHFOV), and nasally applied, non-invasive neurally adjusted ventilatory assist (NIV-NAVA) modes, with particular focus on their use in preterm infants. SUMMARY: This is a narrative review with reference to published guidelines by European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update. nCPAP is currently the most commonly used primary and secondary NIV modality for premature infants. However, there is increasing evidence on the superiority of nIPPV over nCPAP. No beneficial effect was found for BiPAP over nCPAP. For the use of nHFT, nHFOV, and NIV-NAVA, more studies are needed to establish their place in neonatal respiratory care. KEY MESSAGES: The superiority of nIPPV over nCPAP needs to be confirmed by contemporaneous trials comparing nCPAP to nIPPV at comparable mean airway pressures. Future trials should study NIV modalities in preterm infants with comparable respiratory pathology and indications, at comparable pressure settings and with different modes of synchronisation. Importantly, future trials should not exclude infants of the smallest gestational ages.

The role of nutritional interventions in the prevention and treatment of chronic lung disease of prematurity.

Chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Nutrition may affect incidence and severity of BPD. In this context, the Section on Nutrition, Gastroenterology and Metabolism, the Pulmonary Section of the European Society for Paediatric Research (ESPR) and SPR have joined forces to review the current knowledge on nutritional issues related to BPD. The aim of this narrative review is to discuss the clinical implications for nutritional practice. Nutrient deficiencies may influence pathogenesis of BPD. Adequate nutrition and growth can play a crucial role in the prevention of and recovery from BPD. Optimal nutrition strategy is an important principle, especially in the early postnatal period. As optimal energy intake in infants at risk of BPD or with evolving BPD is not yet defined, further research with well-designed studies on nutritional strategies for preterm infants with BPD is urgently needed. IMPACT: Based on current evidence it seems reasonable to recommend that BPD diagnosed infants should receive an energy supply ranging from 120 to 150 Kcal/kg/d. Exclusive MOM feed with adequate fortification should be encouraged as this is associated with a significant reduction in the risk of BPD. Suboptimal nutritional delivery is often seen in preterm infants with BPD compared to controls.

State of the art on neonatal noninvasive respiratory support: How physiological and technological principles explain the clinical outcomes.

Noninvasive respiratory support has gained significant popularity in neonatal units because of its potential to reduce lung injury associated with invasive mechanical ventilation. To minimize lung injury, clinicians aim to apply for noninvasive respiratory support as early as possible. However, the physiological background and the technology behind such support modes are not always clear, and many open questions remain regarding the indications of use and clinical outcomes. This narrative review discusses the currently available evidence for various noninvasive respiratory support modes applied in Neonatal Medicine in terms of physiological effects and indications. Reviewed modes include nasal continuous positive airway pressure, nasal high-flow therapy, noninvasive high-frequency oscillatory ventilation, nasal intermittent positive pressure ventilation (NIPPV), synchronized NIPPV and noninvasive neurally adjusted ventilatory assist. To enhance clinicians' awareness of each support mode's strengths and limitations, we summarize technical features related to the functioning mechanisms of devices and the physical properties of the interfaces commonly used for providing noninvasive respiratory support to neonates. We finally address areas of current controversy and suggest possible areas of research for implementing noninvasive respiratory support in neonatal intensive care units.

Assessment of Postnatal Corticosteroids for the Prevention of Bronchopulmonary Dysplasia in Preterm Neonates: A Systematic Review and Network Meta-analysis.

Importance: The safety of postnatal corticosteroids used for prevention of bronchopulmonary dysplasia (BPD) in preterm neonates is a controversial matter, and a risk-benefit balance needs to be struck. Objective: To evaluate 14 corticosteroid regimens used to prevent BPD: moderately early-initiated, low cumulative dose of systemic dexamethasone (MoLdDX); moderately early-initiated, medium cumulative dose of systemic dexamethasone (MoMdDX); moderately early-initiated, high cumulative dose of systemic dexamethasone (MoHdDX); late-initiated, low cumulative dose of systemic dexamethasone (LaLdDX); late-initiated, medium cumulative dose of systemic dexamethasone (LaMdDX); late-initiated, high cumulative dose of systemic dexamethasone (LaHdDX); early-initiated systemic hydrocortisone (EHC); late-initiated systemic hydrocortisone (LHC); early-initiated inhaled budesonide (EIBUD); early-initiated inhaled beclomethasone (EIBEC); early-initiated inhaled fluticasone (EIFLUT); late-initiated inhaled budesonide (LIBUD); late-initiated inhaled beclomethasone (LIBEC); and intratracheal budesonide (ITBUD). Data Sources: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, World Health Organization's International Clinical Trials Registry Platform (ICTRP), and CINAHL were searched from inception through August 25, 2020. Study Selection: In this systematic review and network meta-analysis, the randomized clinical trials selected included preterm neonates with a gestational age of 32 weeks or younger and for whom a corticosteroid regimen was initiated within 4 weeks of postnatal age. Peer-reviewed articles and abstracts in all languages were included. Data Extraction and Synthesis: Two independent authors extracted data in duplicate. Network meta-analysis used a bayesian model. Main Outcomes and Measures: Primary combined outcome was BPD, defined as oxygen requirement at 36 weeks' postmenstrual age (PMA), or mortality at 36 weeks' PMA. The secondary outcomes included 15 safety outcomes. Results: A total of 62 studies involving 5559 neonates (mean [SD] gestational age, 26 [1] weeks) were included. Several regimens were associated with a decreased risk of BPD or mortality, including EHC (risk ratio [RR], 0.82; 95% credible interval [CrI], 0.68-0.97); EIFLUT (RR, 0.75; 95% CrI, 0.55-0.98); LaHdDX (RR, 0.70; 95% CrI, 0.54-0.87); MoHdDX (RR, 0.64; 95% CrI, 0.48-0.82); ITBUD (RR, 0.73; 95% CrI, 0.57-0.91); and MoMdDX (RR, 0.61; 95% CrI, 0.45-0.79). Surface under the cumulative ranking curve (SUCRA) value ranking showed that MoMdDX (SUCRA, 0.91), MoHdDX (SUCRA, 0.86), and LaHdDX (SUCRA, 0.76) were the 3 most beneficial interventions. ITBUD (RR, 4.36; 95% CrI, 1.04-12.90); LaHdDX (RR, 11.91; 95% CrI, 1.64-44.49); LaLdDX (RR, 6.33; 95% CrI, 1.62-18.56); MoHdDX (RR, 4.96; 95% CrI, 1.14-14.75); and MoMdDX (RR, 3.16; 95% CrI, 1.35-6.82) were associated with more successful extubation from invasive mechanical ventilation. EHC was associated with a higher risk of gastrointestinal perforation (RR, 2.77; 95% CrI, 1.09-9.32). MoMdDX showed a higher risk of hypertension (RR, 3.96; 95% CrI, 1.10-30.91). MoHdDX had a higher risk of hypertrophic cardiomyopathy (RR, 5.94; 95% CrI, 1.95-18.11). Conclusions and Relevance: This study suggested that MoMdDX may be the most appropriate postnatal corticosteroid regimen for preventing BPD or mortality at a PMA of 36 weeks, albeit with a risk of hypertension. The quality of evidence was low.

Pulmonary hypertension in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

Variations in preterm stabilisation practices and caffeine therapy between two European tertiary level neonatal units.

AIM: To investigate interinstitutional differences in preterm infant stabilisation between two European tertiary neonatal centres with particular focus on intubation timing, surfactant administration, caffeine therapy and neonatal morbidity and mortality. METHODS: Retrospective (2012-2014) study of very low birth weight (VLBW) preterm infants admitted to John Radcliffe Hospital (UK centre) and Charité Medical Centre (German centre). Timing of intubation, surfactant and caffeine administration and respiratory outcomes were examined. RESULTS: Gestational age, birth weight and five-minute Apgar scores of VLBW infants from the UK centre (n = 86) were comparable to those from the German centre (n = 96). Significant differences in antenatal steroid therapy, intubation timing and surfactant therapy were noted. Timing of caffeine initiation differed significantly between centres (median 0 [0-2.5] UK vs. 2 [1.5-4] days German centre); however, caffeine was discontinued at a similar corrected gestational age of 34.7 weeks. Mechanical ventilation was significantly longer at the UK centre, but there was no difference in bronchopulmonary dysplasia (BPD) (44% UK vs. 36% German centre) or mortality (15% UK vs. 13% German centre). CONCLUSION: Timing of primary intubation and caffeine therapy differed significantly between centres. However, earlier intubation and caffeine administration in the UK centre were not associated with a changed incidence of BPD.

Nasal High-Flow Therapy as Primary Respiratory Support for Preterm Infants without the Need for Rescue with Nasal Continuous Positive Airway Pressure.

AIM: To evaluate the effectiveness of nasal high-flow therapy (nHFT) as primary respiratory support for preterm infants with respiratory distress syndrome (RDS) in two tertiary neonatal units. METHODS: A retrospective outcome analysis of initial respiratory support strategies was performed in two tertiary neonatal units in the UK: John Radcliffe Hospital (JRH), Oxford and St Peter's Hospital (SPH), Chertsey. Infants born between 28+0 and 36+6 weeks gestational age (GA) between May 2013 and June 2015 were included. RESULTS: A total of 381 infants, 191 from JRH and 190 from SPH, were analysed. Infants were stabilised in the delivery room using mask continuous positive airway pressure followed by nHFT. Endotracheal intubation was performed according to local protocols, depending on the severity of RDS. There were significant differences in initial intubation rates according to GA (26% JRH vs. 16.9% SPH, p < 0.001 for babies < 32 weeks GA, and 8.2% JRH vs. 6.5% SPH, p < 0.001 for babies > 32 weeks GA); however, most infants were successfully transitioned to nHFT. Intubation rates during the first 72 h were comparable between centres (14.7% JRH vs. 11.1% SPH, p = 0.29). There were no differences in neonatal morbidities, including air leak, duration of oxygen supplementation, bronchopulmonary dysplasia, sepsis, retinopathy of prematurity, intraventricular haemorrhage, necrotising enterocolitis, or median time to full-suck feeds. CONCLUSION: Use of nHFT for primary respiratory support, without use of nasal continuous positive airway pressure as "rescue" treatment, resulted in intubation rates lower or comparable to published data from randomised controlled trials.

Lung hypoplasia in newborn rabbits with a diaphragmatic hernia affects pulmonary ventilation but not perfusion.

BackgroundA congenital diaphragmatic hernia (DH) can result in severe lung hypoplasia that increases the risk of morbidity and mortality after birth; however, little is known about the cardiorespiratory transition at birth.MethodsUsing phase-contrast X-ray imaging and angiography, we examined the cardiorespiratory transition at birth in rabbit kittens with DHs. Surgery was performed on pregnant New Zealand white rabbits (n=18) at 25 days' gestation to induce a left-sided DH. Kittens were delivered at 30 days' gestation, intubated, and ventilated to achieve a tidal volume (Vt) of 8 ml/kg in control and 4 ml/kg in DH kittens while they were imaged.ResultsFunctional residual capacity (FRC) recruitment and Vt in the hypoplastic left lung were markedly reduced, resulting in a disproportionate distribution of FRC into the right lung. Following lung aeration, relative pulmonary blood flow (PBF) increased equally in both lungs, and the increase in pulmonary venous return was similar in both control and DH kittens.ConclusionThese findings indicate that nonuniform lung hypoplasia caused by DH alters the distribution of ventilation away from hypoplastic and into normally grown lung regions. During transition, the increase in PBF and pulmonary venous return, which is vital for maintaining cardiac output, is not affected by lung hypoplasia.

Dead space reduction by Kolobow's endotracheal tube does not justify the waiving of volume monitoring in small, ventilated lungs.

In ventilated preterm infants the flow sensor contributes significantly to the total apparatus dead space, which may impair gas exchange. The aim of the study was to quantify to which extent a dead space reduced Kolobow tube (KB) without flow sensor improves the gas exchange compared with a conventional ventilator circuit with flow sensor [Babylog 8000 (BL)]. In a cross-over trial in 14 tracheotomized, surfactant-depleted (saline lavage) and mechanically ventilated newborn piglets (age <12 h; body weight 705-1200 g) BL and KB was applied alternately for 15 min and blood gases were recorded. The inner diameter of the endotracheal tube was 3.6 mm and the apparatus dead space of BL and KB including the endotracheal tube were 3.0 and 1.34 mL. Despite a 50 % apparatus dead space reduction with KB compared to BL statistically significant improvements were only observed for body weights <900 g. In this weight group median paCO2 was decreased by 5 mmHg (p < 0.01), whereas the improvement decreased with decreasing baseline paCO2. Furthermore, median paO2 was increased by 4 mmHg (p < 0.05) and O2 saturation was increased by 2.5 % (p < 0.05). No significant changes were seen in the circulatory parameters. In very small, ventilated lungs the use of KB improved the gas exchange; however, the improvement was moderate and does not justify the waiving of volume monitoring.

Differential effects of immaturity and neonatal lung disease on the lung function of very low birth weight infants at 48-52 postconceptional weeks.

BACKGROUND: The pathogenesis of chronic lung disease of prematurity involves maturational arrest and neonatal lung disease (NLD) followed by mechanical ventilation (MV). However, the effect of these factors on postnatal lung function is not well established. Therefore, the aim of this study was to examine the differential effects of immaturity and NLD requiring MV on lung function test (LFT) parameters within 4 months after discharge. PATIENTS AND METHODS: A total of 386 very low birth weight (VLBW) infants (birth weight <1,500 g) were examined at a median postmenstrual age of 49 weeks. Two hundred twenty-six infants (59%) were born before the 28th week of gestation, and 247 infants (64%) had NLD requiring invasive MV. LFTs included tidal breathing measurements, measurement of respiratory mechanics assessed by occlusion test, body plethysmography, SF6 multiple breath washout, forced expiratory flow (VmaxFRC') by rapid thoraco-abdominal compression technique, end-expiratory CO2 (Pet CO2 ), exhaled NO (FeNO), and arterialized capillary blood gas analysis. MAIN RESULTS: Multivariate analysis indicated that severe immaturity was mainly associated with changes in the breathing pattern (reduced tidal volume (P = 0.003) and increased respiratory rate (P = 0.03)), a reduced VmaxFRC' (P = 0.004) and lower respiratory compliance (P < 0.001). NLD requiring MV, but not immaturity, was significantly and independently associated with increased respiratory and airway resistances (both P = 0.003), reduced FRCSF6 (P = 0.03), increased Pet CO2 (P = 0.019) and lower FeNO (P < 0.001). Both immaturity and NLD requiring MV caused a lower paO2 (P < 0.001) and higher a paCO2 . CONCLUSIONS: Lung function after discharge of VLBW infants is differentially affected by both immaturity and NLD requiring MV. With increasing prematurity, intubated and mechanically ventilated infants are at increased risk of developing impaired lung function which can be detected by LFT.