Use of neonatal lung ultrasound in European neonatal units: a survey by the European Society of Paediatric Research.

OBJECTIVE: Regarding the use of lung ultrasound (LU) in neonatal intensive care units (NICUs) across Europe, to assess how widely it is used, for what indications and how its implementation might be improved. DESIGN AND INTERVENTION: International online survey. RESULTS: Replies were received from 560 NICUs in 24 countries between January and May 2023. LU uptake varied considerably (20%-98% of NICUs) between countries. In 428 units (76%), LU was used for clinical indications, while 34 units (6%) only used it for research purposes. One-third of units had <2 years of experience, and only 71 units (13%) had >5 years of experience. LU was mainly performed by neonatologists. LU was most frequently used to diagnose respiratory diseases (68%), to evaluate an infant experiencing acute clinical deterioration (53%) and to guide surfactant treatment (39%). The main pathologies diagnosed by LU were pleural effusion, pneumothorax, transient tachypnoea of the newborn and respiratory distress syndrome. The main barriers for implementation were lack of experience with technical aspects and/or image interpretation. Most units indicated that specific courses and an international guideline on neonatal LU could promote uptake of this technique. CONCLUSIONS: Although LU has been adopted in neonatal care in most European countries, the uptake is highly variable. The main indications are diagnosis of lung disease, evaluation of acute clinical deterioration and guidance of surfactant. Implementation may be improved by developing courses and publishing an international guideline.

Pulmonary Hypertension in Developmental Lung Diseases.

Diverse genetic developmental lung diseases can present in the neonatal period with hypoxemic respiratory failure, often associated with with pulmonary hypertension. Intractable hypoxemia and lack of sustained response to medical management should increase the suspicion of a developmental lung disorder. Genetic diagnosis and lung biopsy are helpful in establishing the diagnosis. Early diagnosis can result in optimizing management and redirecting care if needed. This article reviews normal lung development, various developmental lung disorders that can result from genetic abnormalities at each stage of lung development, their clinical presentation, management, prognosis, and differential diagnoses.

Towards personalized therapies for genetic disorders of surfactant dysfunction.

Genetic disorders of surfactant dysfunction are a rare cause of chronic, progressive or refractory respiratory failure in term and preterm infants. This review explores genetic mechanisms underpinning surfactant dysfunction, highlighting specific surfactant-associated genes including SFTPB, SFTPC, ABCA3, and NKX2.1. Pathogenic variants in these genes contribute to a range of clinical presentations and courses, from neonatal hypoxemic respiratory failure to childhood interstitial lung disease and even adult-onset pulmonary fibrosis. This review emphasizes the importance of early recognition, thorough phenotype assessment, and assessment of variant functionality as essential prerequisites for treatments including lung transplantation. We explore emerging treatment options, including personalized pharmacological approaches and gene therapy strategies. In conclusion, this comprehensive review offers valuable insights into the pathogenic mechanisms of genetic disorders of surfactant dysfunction, genetic fundamentals, available and emerging therapeutic options, and underscores the need for further research to develop personalized therapies for affected infants and children.

Cyanoacrylate glue as part of a new bundle to decrease neonatal PICC-related complications.

A "bundle" is defined as a combination of evidence-based interventions that, if followed collectively and reliably, improve patient outcomes. The aim of this quasi-experimental study, conducted in a level-III NICU in Belgium, was to assess the impact of central line dressing and maintenance bundle implementation on the rate of catheter-related mechanical complications. We performed a quality improvement (QI) project. Prior to bundle implementation, neonatal PICC lines were secured by Steri-Strip® and occlusive dressing. We implemented a new PICC bundle consisting of the use of glue, sutureless device (Griplock®), and a transparent dressing to secure the catheter to the skin. We compared the rate of infections, mechanical complications, and dislocations before and after bundle implementation (periods 1 and 2, respectively). The use of glue resulted in a significantly decreased rate of central line-associated bloodstream infection (CLABSI) (p < 0.001), dislocations, and mechanical complications (p < 0.0001). During period 2, there was a significant increase for the average number of days the catheter stayed in place (p < 0.05). We did not observe catheter breakage or patient skin irritations attributable to the use of glue (not even in ELBW infants). CONCLUSION: The implementation of the new bundle to secure neonatal PICCs in our NICU was associated with a significant reduction in CLABSI and dislodgment rates, without glue-related complications. Active surveillance of CVC placement procedure, positioning, and management, as well as analysis of related complications is crucial for improving patient safety. Continuous implementation of up-to-date central line bundles based on best practice recommendations is a key for quality improvement in NICUs. WHAT IS KNOWN: • Stable vascular access is crucial in the NICU. Neonatal PICC securement issues can have serious consequences and are associated with device failure. WHAT IS NEW: • Catheter securement with tissue adhesive is safe and effective in reducing failure and complication rates in the neonatal population.

BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy.

BACKGROUND AND OBJECTIVES: BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis. METHODS: Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed. RESULTS: We included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers. DISCUSSION: BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

Implementing intact cord resuscitation in very preterm infants: feasibility and pitfalls.

The purpose of this study is to evaluate the feasibility of intact cord resuscitation (ICR) in very preterm infants using a custom-equipped mobile resuscitation trolley (LifeStart®). We collected maternal and neonatal data of all inborn infants < 32 weeks eligible for ICR per our protocol over 9 months from ICR implementation. We compared rates of ICR between the beginning and the end of the study period. We reviewed maternal and neonatal adverse events related to the procedure and direct outcomes. In order to assess potential quality improvements related to the procedure, we collected the same data in the infants born in the 9-month period preceding ICR implementation. Out of 44 infants born < 32 weeks during the period, 27 were eligible for ICR. Failure to initiate ICR occurred in 9/27, exclusively in the first 5.5 months of the study. In one infant, ICR was interrupted prior to 2 min due to placental abruption. No ICR procedure had to be interrupted due to insufficient cord length. Among the 18 infants who completed ICR, cord clamping timing increased significantly over the study period, from 3.0 [2.5-3.5] to 4.2 min [3.1-8.3] (p = 0.02). No significant maternal blood loss or wound complications were noted. No infant deaths were attributable to failure or direct consequence of ICR, and no infant experienced hypoxic respiratory failure (intubation, FiO2 ≥ 0.4), asphyxia (pH < 7.2), or blood pressure instability (< 2 SD) following stabilization. Hemoglobin level after cord clamping was higher in the ICR cohort than in the pre-implementation group. Seven out of 18 infants exposed to ICR had a temperature < 36.5 °C on admission.   Conclusion: ICR is feasible in very preterm infants. Temperature management requires special attention. Multidisciplinary simulation training before implementation and systematic post-implementation quality improvement meetings may significantly increase ICR program success. What is Known: • Because infants born < 32 weeks often require cardiorespiratory resuscitation at birth, they are not offered delayed cord clamping in the majority of neonatal intensive care units. • Recently, fully equipped mobile trolleys have been developed in order to allow bedside resuscitation with an intact cord. What is New: • Variable timing of cord clamping based on the infant's transition and respiratory stability, i.e., "physiology-based cord clamping," is safely achievable in very preterm infants. • Intact cord resuscitation requires specific equipment, operational protocols, and a high level of preparation from both obstetrical and neonatal teams, with a learning curve that can be streamlined by multidisciplinary simulation training.

First Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease.

Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.

Defective Leukocyte ß2 Integrin Expression and Reactive Oxygen Species Production in Neonates.

Neonates are highly susceptible to bacterial infections, which represent a major source of mortality and morbidity in this age category. It is recognized that ß2 integrins play a critical role in innate immunity by mediating leukocyte vascular adhesion, transmigration and bacterial phagocytosis. Therefore, we aimed to assess if the impaired immune functions seen in newborns may derive, in part, from a transient insufficient ß2 integrin expression. In the present study we measured baseline lymphocyte function-associated antigen-1 (LFA-1 or CD11a/CD18), macrophage-1 antigen (MAC-1 or CD11b/CD18) and leukocyte integrin p150-95 (CD11c/CD18) expression on cord blood, and on the third day of life in a cohort of 35 healthy neonates, compared with a control group of 12 healthy adults. For any of the three ß2 integrins, the expression on polymorphonuclear cells was significantly lower on cord blood than in adults and increased from birth to day 3. We also compared superoxide radical (SR) production in these neonates with 28 non-smoking adults. SR production in response to integrin stimulation by Zymosan was significantly lower at birth than in adults, and it decreased further in the third day of life. These findings suggest that innate immune impairment in newborns may be, in part, accounted for by a lower ß2 integrin expression on phagocytes in the neonatal period, but also by a functional impairment of free radical production.

Torsade de pointe due to QT prolongation following erythromycin administration in a preterm infant.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality in preterm infants. Chorioamnionitis is an important risk factor for the development of sepsis, therefore neonates born to mothers developing signs of amnionitis need to be treated with antibiotics immediately after birth. Ureaplasma spp can be a causative agent of vaginal or intra amniotic infection needing antibiotic treatment. Macrolides are frequently used to treat maternal intrauterine infection, but antibiotic treatment of the neonate should be consciously chosen with consideration of potential side effects. Indeed, macrolides are great purveyors of heart rhythm disorders. CASE PRESENTATION: We describe the case of a 29 weeks preterm infant born to a mother with Ureaplasma spp infection. The baby was treated with erythromycin immediately after birth. During the second day of life, the baby presented some episodes of tachyarrhythmia with premature ventricular beats (PVBs) that were followed by a non-sustained ventricular tachycardia as high as 270 bpm leading to a cardiac arrest. After resuscitation, tachycardia resolved but the rhythm was characterised by numerous PVBs and an electrocardiogram (ECG) diagnosed a Long QT Syndrome (LQTS). Erythromycin was discontinued, and the rhythm normalised a few days after withdrawal. CONCLUSIONS: Erythromycin should be administered in neonates only if no other choice is available, as although generally well tolerated, its administration can be associated with QTc interval prolongation. When no other option is available, paediatricians should be aware to perform cardiac monitoring or at least serial ECGs before and during erythromycin administration.

Early diagnosis and targeted approaches to pulmonary vascular disease in bronchopulmonary dysplasia.

Pulmonary hypertension has emerged as a life-threatening disease in preterm infants suffering from bronchopulmonary dysplasia (BPD). Its development is closely linked to respiratory disease, as vasculogenesis and alveologenesis are closely interconnected. Once clinically significant, BPD-associated pulmonary hypertension (BPD-PH) can be challenging to manage, due to poor reversibility and multiple comorbidities frequently associated. The pulmonary vascular disease process underlying BPD-PH is the result of multiple innate and acquired factors, and emerging evidence suggests that it progressively develops since birth and, in certain instances, may begin as early as fetal life. Therefore, early recognition and intervention are of great importance in order to improve long-term outcomes. Based on the most recent knowledge of BPD-PH pathophysiology, we review state-of-the-art screening and diagnostic imaging techniques currently available, their utility for clinicians, and their applicability and limitations in this specific population. We also discuss some biochemical markers studied in humans as a possible complement to imaging for the detection of pulmonary vascular disease at its early stages and the monitoring of its progression. In the second part, we review pharmacological agents currently available for BPD-PH treatment or under preclinical investigation, and discuss their applicability, as well as possible approaches for early-stage interventions in fetuses and neonates. IMPACT: BPD-associated PH is a complex disease involving genetic and epigenetic factors, as well as environmental exposures starting from fetal life. The value of combining multiple imaging and biochemical biomarkers is emerging, but requires larger, multicenter studies for validation and diffusion. Since "single-bullet" approaches have proven elusive so far, combined pharmacological regimen and cell-based therapies may represent important avenues for research leading to future cure and prevention.

Bronchopulmonary dysplasia and wnt pathway-associated single nucleotide polymorphisms.

AIM: Genetic variants contribute to the pathogenesis of bronchopulmonary dysplasia (BPD). The aim of this study is to evaluate the association of 45 SNPs with BPD susceptibility in a Turkish premature infant cohort. METHODS: Infants with gestational age <32 weeks were included. Patients were divided into BPD or no-BPD groups according to oxygen need at 28 days of life, and stratified according to the severity of BPD. We genotyped 45 SNPs, previously identified as BPD risk factors, in 192 infants. RESULTS: A total of eight SNPs were associated with BPD risk at allele level, two of which (rs4883955 on KLF12 and rs9953270 on CHST9) were also associated at the genotype level. Functional relationship maps suggested an interaction between five of these genes, converging on WNT5A, a member of the WNT pathway known to be implicated in BPD pathogenesis. Dysfunctional CHST9 and KLF12 variants may contribute to BPD pathogenesis through an interaction with WNT5A. CONCLUSIONS: We suggest investigating the role of SNPs on different genes which are in relation with the Wnt pathway in BPD pathogenesis. We identified eight SNPs as risk factors for BPD in this study. In-silico functional maps show an interaction of the genes harboring these SNPs with the WNT pathway, supporting its role in BPD pathogenesis. TRIAL REGISTRATION: NCT03467828. IMPACT: It is known that genetic factors may contribute to the development of BPD in preterm infants. Further studies are required to identify specific genes that play a role in the BPD pathway to evaluate them as a target for therapeutic interventions. Our study shows an association of BPD predisposition with certain polymorphisms on MBL2, NFKBIA, CEP170, MAGI2, and VEGFA genes at allele level and polymorphisms on CHST9 and KLF12 genes at both allele and genotype level. In-silico functional mapping shows a functional relationship of these five genes with WNT5A, suggesting that Wnt pathway disruption may play a role in BPD pathogenesis.

Treatment with Micafungin in a Preterm Neonate with an Invasive Candida parapsilosis Infection after a Severe Terlipressin-Induced Skin Necrosis.

Candida parapsilosis infections are increasingly reported in preterm neonates, but the optimal treatment remains uncertain. We report the clinical history of an extremely preterm neonate, who developed a devastating skin necrosis due to terlipressin administration, with subsequent superinfection by Candida parapsilosis. The infant underwent multiple curettages and skin grafts to resolve skin lesions and was treated with systemic micafungin administration at a high dose (8 mg/kg/day), with resolution of the fungal infection.

Clinical and in Vitro Evidence against Placenta Infection at Term by Severe Acute Respiratory Syndrome Coronavirus 2.

Despite occasional reports of vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy, the question of placental infection and its consequences for the newborn remain unanswered. Herein, we analyzed the placentas of 31 coronavirus disease 2019-positive mothers by reverse transcriptase PCR, immunohistochemistry, and in situ hybridization. Only one case of placental infection was detected, which was associated with intrauterine demise of the fetus. Differentiated primary trophoblasts were then isolated from nonpathologic human placentas at term, differentiated, and exposed to SARS-CoV-2 virions. Unlike for positive control cells Vero E6, the virus inside cytotrophoblasts and syncytiotrophoblasts or in the supernatant 4 days after infection was undetectable. As a mechanism of defense, we hypothesized that trophoblasts at term do not express angiotensin-converting enzyme 2 and transmembrane protease serine 2 (TMPRSS2), the two main host membrane receptors for SARS-CoV-2 entry. The quantification of these proteins in the placenta during pregnancy confirmed the absence of TMPRSS2 at the surface of the syncytium. Surprisingly, a transiently induced experimental expression of TMPRSS2 did not allow the entry or replication of the virus in differentiated trophoblasts. Altogether, these results underline that trophoblasts are not likely to be infected by SARS-CoV-2 at term, but raise concern about preterm infection.

How to minimize central line-associated bloodstream infections in a neonatal intensive care unit: a quality improvement intervention based on a retrospective analysis and the adoption of an evidence-based bundle.

Central line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in neonatal intensive care units (NICUs). A "bundle" is defined as a combination of evidence-based interventions that provided they are followed collectively and reliably, are proven to improve patient outcomes. The aim of this quasi-experimental study was to assess the impact of new central line insertion, dressing, and maintenance "bundles" on the rate of CLABSI and catheter-related complications. We performed a quality improvement (QI), prospective, before-after study. In the first 9-month period, the old "bundles" and pre-existing materials were used/applied. An intervention period then occurred with changes made to materials used and the implementation of new "bundles" related to various aspects of central lines care. A second 6-month period was then assessed and the CLABSI rates were measured in the NICU pre- and post-intervention period. The QI measures were the rate of CLABSI and catheter-related complications. Data are still being collected after the study to verify sustainability. The implementation of the new "bundles" and the change of certain materials resulted in a significantly decreased rate of CLABSI (8.4 to 1.8 infections per 1000 central venous catheter (CVC) days, p = 0.02,) as well as decreased catheter-related complications (47 to 10, p < 0.007).Conclusions: The analysis of pre-existing "bundles" and the implementation of updated central line "bundles" based on best practice recommendations are crucial for reducing the rate of CLABSI in the NICU. The implementation of the new evidence-based central line "bundles" was associated with a significant reduction in CLABSI rate in our unit soon after implementation. What is Known: • Central line-associated bloodstream infection (CLABSI) is a major cause of morbidity and mortality in the neonatal population. • The implementation of evidence-based "bundles" in the NICU is associated with a reduction in the incidence of CLABSI. What is New: • For the improvement in quality care in the NICU, audits are necessary to assess the existing systems. • The "Plan-Do-Study-Act cycle" is an effective tool to use when tackling challenges in an existing system. Using this tool assisted in the approach to reducing CLABSI in our NICU.

Novel Coronavirus disease (COVID-19) in newborns and infants: what we know so far.

Recently, an outbreak of viral pneumonitis in Wuhan, Hubei, China successively spread as a global pandemia, led to the identification of a novel betacoronavirus species, the 2019 novel coronavirus, successively designated 2019-nCoV then SARS-CoV-2). The SARS-CoV-2 causes a clinical syndrome designated coronavirus disease 2019 (COVID19) with a spectrum of manifestations ranging from mild upper respiratory tract infection to severe pneumonitis, acute respiratory distress syndrome (ARDS) and death. Few cases have been observed in children and adolescents who seem to have a more favorable clinical course than other age groups, and even fewer in newborn babies. This review provides an overview of the knowledge on SARS-CoV-2 epidemiology, transmission, the associated clinical presentation and outcomes in newborns and infants up to 6 months of life.

Nutrients and Microbiota in Lung Diseases of Prematurity: The Placenta-Gut-Lung Triangle.

Cardiorespiratory function is not only the foremost determinant of life after premature birth, but also a major factor of long-term outcomes. However, the path from placental disconnection to nutritional autonomy is enduring and challenging for the preterm infant and, at each step, will have profound influences on respiratory physiology and disease. Fluid and energy intake, specific nutrients such as amino-acids, lipids and vitamins, and their ways of administration -parenteral or enteral-have direct implications on lung tissue composition and cellular functions, thus affect lung development and homeostasis and contributing to acute and chronic respiratory disorders. In addition, metabolomic signatures have recently emerged as biomarkers of bronchopulmonary dysplasia and other neonatal diseases, suggesting a profound implication of specific metabolites such as amino-acids, acylcarnitine and fatty acids in lung injury and repair, inflammation and immune modulation. Recent advances have highlighted the profound influence of the microbiome on many short- and long-term outcomes in the preterm infant. Lung and intestinal microbiomes are deeply intricated, and nutrition plays a prominent role in their establishment and regulation. There is an emerging evidence that human milk prevents bronchopulmonary dysplasia in premature infants, potentially through microbiome composition and/or inflammation modulation. Restoring antibiotic therapy-mediated microbiome disruption is another potentially beneficial action of human milk, which can be in part emulated by pre- and probiotics and supplements. This review will explore the many facets of the gut-lung axis and its pathophysiology in acute and chronic respiratory disorders of the prematurely born infant, and explore established and innovative nutritional approaches for prevention and treatment.

Surfactant replacement therapy: from biological basis to current clinical practice.

This review summarizes the current knowledge on the physiological action of endogenous and exogenous pulmonary surfactant, the role of different types of animal-derived and synthetic surfactants for RDS therapy, different modes of administration, potential risks and strategies of ventilation, and highlights the most promising aims for future development. Scientists have clarified the physicochemical properties and functions of the different components of surfactant, and part of this successful research is derived from the characterization of genetic diseases affecting surfactant composition or function. Knowledge from functional tests of surfactant action, its immunochemistry, kinetics and homeostasis are important also for improving therapy with animal-derived surfactant preparations and for the development of modified surfactants. In the past decade newly designed artificial surfactants and additives have gained much attention and have proven different advantages, but their particular role still has to be defined. For clinical practice, alternative administration techniques as well as postsurfactant ventilation modes, taking into account alterations in lung mechanics after surfactant placement, may be important in optimizing the potential of this most important drug in neonatology.