Neonatal Chronic Lung Disease Research Articles

Current Status of Neonatal Music Therapy Services Within the US

Abstract Over the past 30 years, music therapy services in the neonatal intensive care units (NICUs) have expanded, yet there is still limited literature available that captures current practice trends in this setting. The purpose of this paper was to obtain descriptive data about current demographics, consultation, and clinical practice trends in NICU music therapy clinical practice in the US. A questionnaire was sent to 9,222 Board-Certified Music Therapists. Those providing music therapy services in the NICU and choosing to participate (N = 87) completed the questionnaire. Results showed that a majority of music therapists working in the NICU who responded to the questionnaire have completed additional training to provide specialized services. Most NICU music therapists reported spending less than 20 hr a week on the unit and providing a variety of family-centered interventions to infants starting at 28 weeks postmenstrual age (PMA). Common diagnoses for referral besides prematurity were Neonatal Opioid Withdrawal Syndrome and Chronic Lung Disease. Music therapists are well integrated within treatment teams with a majority reporting collaborating and/or co–treating with other therapies and/or clinical staff.

Inhibition of lysophosphatidic acid receptor 2 attenuates neonatal chronic lung disease in mice by preserving vascular and alveolar development

AimBronchopulmonary dysplasia (BPD) is a common morbidity in extremely premature infants. Previous studies demonstrated the important role of lysophosphatidic acid (LPA) in inflammation in BPD. However, the role of LPA and its receptors in hyperoxia-induced vascular malformations in BPD remains to be elucidated. Methods and ResultsElevated plasma LPA levels were observed in mice with BPD compared to controls (792 vs. 607 ng/mL, p < 0.05). Inhibition of LPA signaling protected against hyperoxia-induced lung injury in neonatal mice, demonstrated by a 2.8-fold increase in pulmonary vascular density and a 14% reduction in alveolar enlargement. In vitro studies showed that LPA suppressed tube formation in human umbilical vein endothelial cells (HUVECs) by approximately 50%. LPA receptor 2 (LPA2) was identified as a functional LPA receptor in primary endothelial cells from the lungs of hyperoxic mice and in HUVECs under hyperoxic conditions. The LPA2 antagonist H2L5186303 enhanced the tube formation ability of HUVECs exposed to LPA, both under normoxia (4-fold) and hyperoxia (5-fold). Moreover, H2L5186303 significantly protected against hyperoxia-induced vascular malformation (2-fold) and improved alveolarization in neonatal mice (12% decrease in mean linear intercept, MLI). Early growth response 1 (EGR1) was characterized as a downstream target of LPA2, silencing EGR1 restored tube formation in HUVECs exposed to LPA and hyperoxia. ConclusionsOur in vitro and in vivo findings demonstrate that the inhibition of LPA/LPA2 signaling mitigates hyperoxia-induced pulmonary vascular malformations, suggesting the LPA/LPA2-dependent signaling pathway has therapeutic potential for extremely premature infants with BPD.

Bronchopulmonary Dysplasia in Children. An Up-to-Date View of Disease Outcomes

Introduction. Bronchopulmonary dysplasia (BPD) is a chronic neonatal lung disease, with oxygen dependence by 36 weeks post conceptual age (PCA). Over the past decade, the frequency of the disease has increased. More and more modern scientific data are published that BPD has an adverse effect not just the development of the lungs, but also on the cardiovascular system. There is a large amount of information in the literature about the outcomes of BPD, but there is not enough information about the consequences of cardiovascular disorders in children with a history of BPD. Lack of clear criteria to predict and prevent to demonstrate cardiovascular disorders, were the basis for a detailed study of the literature concerning this issue.Purpose of the study based on study of the results of studies by local and foreign authors, to analyze the nature of cardiovascular disorders in children with a history of BPD, and to determine directions for more detailed scientific and practical search for a solution to this problem.Materials and methods. Research articles were searched for keywords “bronchopulmonary dysplasia” and “сardiovascular disorders” in the PubMed, UpToDate, Google Scholar databases, eLibrary.ru. At least 80 publications have been extracted from search results for simplification. Analyses of the results of studies by local and foreign authors on outcomes, BPD, including cardiovascular disorders, was carried out.Results and discussion. At the moment, the outcomes of BPD are well understood, while few information on cardiovascular disorders and possible prognosis for children who have undergone BPD.Conclusion. Cardiovascular disorders in children with a history of BPD are a pressing problem in pediatric practice. The presented literature review summarizes the information accumulated over several years on the outcomes of cardiovascular changes and determines the direction for further study of the problem, involving pediatricians and doctors of other specialties in order to identify groups at increased risk for the development of these diseases in children.

The number of blood transfusions received and the incidence and severity of chronic lung disease among NICU patients born >31 weeks gestation.

We previously reported the possible pathogenic role, among infants born ≤29 weeks, of transfusions in bronchopulmonary dysplasia. The present study examined this association in infants born >31 weeks. Analysis of red blood cell (RBC) and platelet transfusions in five NICUs to infants born >31 weeks, and chronic neonatal lung disease (CNLD) at six-weeks of age. Seven-hundred-fifty-one infants born >31 weeks were still in the NICU when six-weeks of age. CNLD was identified in 397 (53%). RBC and platelet transfusions were independently associated with CNLD after controlling for potential confounders. For every transfusion, the adjusted odds of developing CNLD increased by a factor of1.64 (95% CI, 1.38-2.02; p < 0.001). Among NICU patients born >31 weeks, transfusions received by six weeks are associated with CNLD incidence and severity. Though we controlled for known confounding variables in our regression models, severity of illness is an important confounder that limits our conclusions.

Influence of Gut and Lung Microbiota and the Gut-Lung Axis on Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease, is a common respiratory disease in preterm infants. Preterm infants with BPD often exhibit changes in gut and lung microbiota. In recent years, with the development of high-throughput sequencing technology, more and more mechanisms of the gut-lung axis have been confirmed, helping to explore new directions for the treatment of BPD using microecological agents. This paper reviews the roles of gut microbiota, lung microbiota, and the gut-lung axis in the pathogenesis of BPD in preterm infants, providing new research avenues for the prevention and treatment of BPD.

Recombinant fragment of human surfactant protein D to prevent neonatal chronic lung disease (RESPONSE): a protocol for a phase I safety trial in a tertiary neonatal unit

IntroductionChronic respiratory morbidity from bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth and has consequences for later respiratory, cardiovascular and neurodevelopmental outcomes. The early phases of respiratory...

DDIT4L regulates mitochondrial and innate immune activities in early life.

Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Taken together, these data show that DDIT4L regulates mitochondrial activity and provide what we believe to be the first direct evidence for its potential role supressing innate immune activity in myeloid cells during development.

Infants with neonatal Chronic Lung Disease are associated with delayed auditory conduction in the rostral brainstem after term

AimsVery Low Birthweight (VLBW) infants with neonatal Chronic Lung Disease (CLD) have been found to have functional impairment of the brainstem auditory pathway at term. This study investigated the functional status of the brainstem auditory pathway in VLBW infants with CLD after term for any abnormality. MethodsFifty-two VLBW infants were recruited at 50 weeks of Postconceptional Age: 25 with neonatal CLD and 27 without CLD. None had any other major complications to minimize confounding effects. Brainstem Auditory Evoked Responses were studied at 21‒91/s click rates. ResultsCompared with those without CLD, VLBW infants with CLD had relatively shorter latencies of BAER waves I and III, associated with a slightly lower BAER threshold. Wave V latency and I‒V interpeak interval did not differ significantly between the two groups of infants. The I‒III interval in infants with CLD was shorter than in those without CLD at 91/s clicks. However, the III‒V interval was significantly longer than in those without CLD at all click rates (all p < 0.05). There were no significant differences in the amplitudes of BAER wave components between the two groups of infants. ConclusionsThe main BAER abnormality in VLBW infants with CLD was a prolonged III‒V interval. Auditory conduction is delayed or impaired at more central regions of the brainstem in CLD infants. After term central auditory function is adversely affected by neonatal CLD. Monitoring post-term change is required to provide valuable information for post-term care of CLD infants.

Improved survival at the cost of more chronic lung disease? Current management and outcomes in extremely preterm infants born in New South Wales and the Australian Capital Territory: 2010-2020.

Since 2010, most tertiary care hospitals in Australia have changed how they care for extremely premature infants. However, in-hospital and longer-term outcome data have suggested unchanged or even worse health outcomes in later epochs, especially respiratory outcomes. This study examined the trend in outcomes since these changes were introduced, particularly the prevalence of chronic neonatal lung disease (CLD). This is a retrospective cross-sectional analysis of data from the Neonatal Intensive Care Units' (NICUS) database of all perinatal intensive care units in New South Wales and the Australian Capital Territory, including infants born at ≥ 24 and ≤ 28weeks of gestational age in tertiary perinatal units between January 1, 2010, and December 31, 2020. Temporal trends and changes in primary outcome were examined by linear and adjusted multivariable logistic regression models. This study included 3258 infants. We saw significant changes in antenatal magnesium sulfate (75% increase), delayed cord clamping (66% increase), delivery room intubations (30% decrease), any time (20% decrease), duration on mechanical ventilation (100-hour decrease), and hours on noninvasive ventilation (200-hour increase). Mortality decreased from 17% to 6%. The incidence of CLD increased significantly even when adjusted for confounders (15% increase). Any time and mean hours spent on mechanical ventilation significantly increased the odds of CLD. This study could not find a significant association of any of the protective antenatal treatments on CLD. The last decade saw a significant improvement in survival and survival to discharge without major morbidity. There was increased use of magnesium sulfate, delayed cord clamping, and less invasive respiratory management of extremely preterm infants. The avoidance of mechanical ventilation may impact the incidence of CLD.

CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia

Preterm infants with oxygen supplementation are at high risk for bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Inflammation with macrophage activation is central to the pathogenesis of BPD. CXCL10, a chemotactic and pro-inflammatory chemokine, is elevated in the lungs of infants evolving BPD and in hyperoxia-based BPD in mice. Here, we tested if CXCL10 deficiency preserves lung growth after neonatal hyperoxia by preventing macrophage activation. To this end, we exposed Cxcl10 knockout (Cxcl10−/−) and wild-type mice to an experimental model of hyperoxia (85% O2)-induced neonatal lung injury and subsequent regeneration. In addition, cultured primary human macrophages and murine macrophages (J744A.1) were treated with CXCL10 and/or CXCR3 antagonist. Our transcriptomic analysis identified CXCL10 as a central hub in the inflammatory network of neonatal mouse lungs after hyperoxia. Quantitative histomorphometric analysis revealed that Cxcl10−/− mice are in part protected from reduced alveolar. These findings were related to the preserved spatial distribution of elastic fibers, reduced collagen deposition, and protection from macrophage recruitment/infiltration to the lungs in Cxcl10−/− mice during acute injury and regeneration. Complimentary, studies with cultured human and murine macrophages showed that hyperoxia induces Cxcl10 expression that in turn triggers M1-like activation and migration of macrophages through CXCR3. Finally, we demonstrated a temporal increase of macrophage-related CXCL10 in the lungs of infants with BPD. In conclusion, our data demonstrate macrophage-derived CXCL10 in experimental and clinical BPD that drives macrophage chemotaxis through CXCR3, causing pro-fibrotic lung remodeling and arrest of alveolarization. Thus, targeting the CXCL10-CXCR3 axis could offer a new therapeutic avenue for BPD.

Improved Cardiac Performance with Dexamethasone Therapy in Premature Neonates: Novel Insights Using Serial Echocardiographic Assessments

(1) Background: dexamethasone is used for the prevention and treatment of chronic lung disease (CLD) in premature neonates, and its impact on cardiac performance and pulmonary vascular resistance has not been well studied. (2) Methods: eligible neonates of &lt;30 weeks gestational age (GA) had echocardiograms performed on them at three time points—before the initiation of dexamethasone (Echo-1), 24–48 h post the completion of dexamethasone therapy (Echo-2), and 7–14 days after course completion (Echo-3). (3) Results: 28 neonates with a 25.2 week mean GA and 652.9 g birthweight were included. The mean cumulative dose of dexamethasone was 0.98 mg/kg, given over 8–10 days. Echo-1 and Echo-2 showed a significant improvement in the right ventricular fractional area change (RV FAC 44.88 vs. 49.71, p = 0.025), tricuspid annular plane systolic excursion (TAPSE 0.65 cm vs. 0.70 cm, p = 0.013), and RV S’ (7.18 vs. 8.56, p = 0.05). The left ventricular (LV) ejection fraction was similar but with a significant increase in the LV S’ (4.77 vs. 6.01, p = 0.006). A longitudinal analysis at three time points showed a significant increase in RV FAC (0.02 units 95% CI (0.00–0.04), p = 0.037), TAPSE (0.09 units 95% CI (0.06–0.13), p &lt; 0.001), RV S’ (0.97 units (95% CI = 0.11–1.84), p = 0.028), a reduction in the eccentricity index (0.07 units 95% CI (−0.14–−0.01), p = 0.030), and an increase in the LV S’ (0.56 units (95% CI = 0.18–0.94)). (4) Conclusion: The use of postnatal dexamethasone for the prevention/treatment of CLD in premature neonates resulted in an expected improvement in respiratory status along with a significant improvement in the echocardiographic measures of biventricular heart performance.

Nutrition-based implications and therapeutics in the development and recovery of bronchopulmonary dysplasia

Premature births account for over 10% of live births worldwide. Bronchopulmonary dysplasia (BPD) represents a severe sequela in neonates born very prematurely and remains the most common chronic neonatal lung disease, often leading to serious adverse consequences in adulthood. Nutrition plays a crucial role in lung development and repair. Ongoing research has primarily focused on the pathogenesis and prevention of BPD in preterm birth. However, infants with established BPD need specialist medical care that persists throughout their hospitalization and continues after discharge. This manuscript aims to highlight the impact of growth and nutrition on BPD and highlight research gaps to provide direction for future studies. Protective practices include ensuring adequate early energy delivery through parenteral nutrition and enteral feedings while carefully monitoring total fluid intake and the use of breast milk over formula. These nutritional strategies remain the same for infants with established BPD with the addition of limiting the use of diuretics and steroids; but if employed, monitoring carefully without compromising total energy delivery. Functional nutrient supplements with a potential protective role against BPD are revisited, despite the limited evidence of their efficacy, including vitamins, trace elements, zinc, lipids, and sphingolipids. Planning post-intensive care and outpatient longitudinal nutrition support is critical in caring for an infant with established BPD.

A Novel Phenotype of Calvarial Thickening and Increased Rates of Premature Calvarial Suture Closure in Children With Chronic Lung Disease.

The purpose of this study was to characterize a novel type of calvarial thickening and provide objective measurements of skull thickness and calvarial suture morphology in patients with bronchopulmonary dysplasia. Infants with severe bronchopulmonary dysplasia who also had undergone computed tomography (CT) scans were identified from the neonatal chronic lung disease program database. Thickness analysis was performed using Materialise Mimics. The chronic lung disease team treated 319 patients during the study interval of which, 58 patients (18.2%) had head CT available. Twenty-eight (48.3%) were found to have calvarial thickening. The rate of premature suture closure in the study population was 36.2% (21 of 58 patients), with 50.0% of affected cohort having evidence of premature suture closure on the first CT scan. Multivariate logistic regression identified 2 risk factors, requiring invasive ventilation at 6 months of age and fraction of inspired oxygen requirement at 6 months of age. Increased head circumference at birth protected against the development of calvarial thickening. We have described a novel subset of patients with chronic lung disease of prematurity who have calvarial thickening with remarkably high rates of premature closure of cranial sutures. The exact etiology of the association is unknown. In this patient population with radiographic evidence of premature suture closure, operative decision should be made after considering unequivocal evidence of elevated intracranial pressure or dysmorphology and balanced against the risk of the procedure.

Long-term vs short-term tocolysis with ritodrine hydrochloride: Propensity score-matched analysis

ObjectiveTo investigate whether the short-term tocolysis protocol is as effective as the traditional long-term tocolysis protocol with intravenous ritodrine hydrochloride for preterm labour. Study designThis single-centre, retrospective, observational study was conducted at Kitano Hospital, Osaka, Japan between April 2016 and July 2021. At the study hospital, the management protocol for preterm labour after 26 weeks of gestation was changed from the long-term tocolysis protocol to the short-term tocolysis protocol in November 2019. This study compared patients managed with the two protocols, using propensity score analysis to overcome the potential weaknesses of a retrospective study. The primary outcome was the frequency of preterm birth before 34 weeks of gestation before and after the protocol was revised. The secondary outcomes were frequency of neonatal intensive care unit admission and frequency of neonatal chronic lung disease. ResultsThe study population consisted of 82 patients managed by the long-term tocolysis protocol and 56 patients managed by the short-term tocolysis protocol. After propensity score-weighted adjustment, the median durations of intravenous ritodrine administration in the long-term and short-term protocols were 18 days and 3 days, respectively. Differences were not detected between the long-term and short-term protocols in terms of the frequency of preterm delivery before 34 weeks of gestation [23.7 % vs 21.6 %, risk ratio (RR) 0.91, 95 % confidence interval (CI) 0.47–1.77], frequency of neonatal intensive care unit admission due to preterm birth (49.5 % vs 39.3 %, RR 0.79, 95 % CI 0.53–1.19) and frequency of neonatal chronic lung disease (4.4 % vs 9.2 %, RR 2.07, 95 % CI 0.51–8.48). ConclusionUsing propensity score analysis, changing from the long-term tocolysis protocol to the short-term tocolysis protocol for the management of preterm labour after 26 weeks of gestation did not have a negative effect on the frequency of preterm birth or neonatal prognosis.

Home continuous positive airway pressure therapy in infants: a single-center experience.

There are limited data on indications and outcomes of home continuous positive airway pressure (CPAP) therapy in the first year of life. We aimed to analyze the clinical, demographic, and polysomnographic characteristics of a cohort of children initiated on home CPAP for treatment of sleep-disordered breathing and as respiratory support in the first year of life. Children started on CPAP in the first year of life at the Queensland Children's Hospital were retrospectively evaluated for clinical and demographic parameters, underlying diagnoses, respiratory support, airway surgical intervention, and polysomnography results at baseline and on CPAP. Twenty-nine infants (median age [interquartile range] at CPAP initiation, 182 days [126-265.5 days]) were included. The underlying etiology included Trisomy 21 (n = 6), craniofacial syndromes (n = 5), hypotonia (n = 8; 5 with noncraniofacial syndrome), airway malacia (n = 5), skeletal dysplasia (n = 2), nonsyndromic upper airway obstruction (n = 2), and chronic neonatal lung disease (n = 1). The median (interquartile range) obstructive apnea-hypopnea index was 14 events/h (6.2-31 events/h) at CPAP initiation, which improved on CPAP to 3.4 events/h (1.4-6.4 events/h). The median (interquartile range) transcutaneous CO2 max remained unchanged on CPAP (56.6 mm Hg [49-66.5 mm Hg] pre-CPAP vs 54.9 mm Hg [47-62 mm Hg] on CPAP). Fifteen children needed surgical airway intervention (11 pre-CPAP and 4 post-CPAP). CPAP therapy could be successfully stopped in 9 children, 2 children needed tracheostomy, and 1 child died during the follow-up period. Home CPAP as respiratory support is an effective long-term therapy in infancy, and these patients can be weaned from CPAP therapy even if it was initiated early. Prospective studies with predefined criteria for CPAP initiation and cessation would help ascertain long-term outcomes in this poorly researched group. Joshi SS, Sivapalan D, Leclerc M-J, Kapur N. Home continuous positive airway pressure therapy in infants: a single-center experience. J Clin Sleep Med. 2023;19(3):473-477.

Magnetic resonance imaging-based scoring of the diseased lung in the preterm infant with bronchopulmonary dysplasia: UNiforme Scoring of the disEAsed Lung in BPD (UNSEAL BPD).

Neonatal chronic lung disease lacks standardized assessment of lung structural changes. We addressed this clinical need by the development of a novel scoring system [UNSEAL BPD (UNiforme Scoring of the disEAsed Lung in BPD)] using T2-weighted single-shot fast-spin-echo sequences from 3 T MRI in very premature infants with and without bronchopulmonary dysplasia (BPD). Quantification of interstitial and airway remodeling, emphysematous changes, and ventilation inhomogeneity was achieved by consensus scoring on a five-point Likert scale. We successfully identified moderate and severe disease by logistic regression [area under the curve (AUC), 0.89] complemented by classification tree analysis revealing gestational age-specific structural changes. We demonstrated substantial interreader reproducibility (weighted Cohen's κ 0.69) and disease specificity (AUC = 0.91). Our novel MRI score enables the standardized assessment of disease-characteristic structural changes in the preterm lung exhibiting significant potential as a quantifiable endpoint in early intervention clinical trials and long-term disease monitoring.

Co-expression network analysis for identification of novel biomarkers of bronchopulmonary dysplasia model.

Bronchopulmonary dysplasia (BPD) is the most common neonatal chronic lung disease. However, its exact molecular pathogenesis is not understood. We aimed to identify relevant gene modules that may play crucial roles in the occurrence and development of BPD by weighted gene co-expression network analysis (WGCNA). We used RNA-Seq data of BPD and healthy control rats from our previous studies, wherein data from 30 samples was collected at days 1, 3, 7, 10, and 14. Data for preprocessing analysis included 17,613 differentially expressed genes (DEGs) with false discovery rate <0.05. We grouped the highly correlated genes into 13 modules, and constructed a network of mRNA gene associations, including the 150 most associated mRNA genes in each module. Lgals8, Srpra, Prtfdc1, and Thap11 were identified as the key hub genes. Enrichment analyses revealed Golgi vesicle transport, coated vesicle, actin-dependent ATPase activity and endoplasmic reticulum pathways associated with these genes involved in the pathological process of BPD in module. This is a study to analyze data obtained from BPD animal model at different time-points using WGCNA, to elucidate BPD-related susceptibility modules and disease-related genes.

Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia.

Lung development is precisely controlled by underlying gene regulatory networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD) - a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin's development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird's eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

Non-standard therapeutic methods for severe bronchopulmonary dysplasia in a premature newborn – case report

Bronchopulmonary dysplasia is a lung disease that is the most common complication of prematurity and the most common chronic lung disease in neonates treated with mechanical ventilation and/or oxygen therapy. Children with bronchopulmonary dysplasia are at risk of cardiovascular complications, such as pulmonary arterial hypertension and left ventricular hypertrophy. The presented case concerns a premature infant born at 24 weeks gestation with severe bronchopulmonary dysplasia complicated by pulmonary arterial hypertension, interstitial emphysema and emphysema. The patient was subject to non-standard therapeutic procedures including L-citrulline, which may have a beneficial effect on the treatment of complications of severe bronchopulmonary dysplasia. Despite proper treatment, it is not always possible to avoid severe complications of bronchopulmonary dysplasia. Currently, available therapies are not always fully effective and it is necessary to continue searching and implementing new treatments to lower the risk of infant death and minimise long-term complications.

Respiratory responses to hypoxia during rest and exercise in individuals born pre-term: a state-of-the-art review.

The pre-term birth survival rate has increased considerably in recent decades, and research investigating the long-term effects of premature birth is growing. Moreover, altitude sojourns are increasing in popularity and are often accompanied by various levels of physical activity. Individuals born pre-term appear to exhibit altered acute ventilatory responses to hypoxia, potentially predisposing them to high-altitude illness. These impairments are likely due to the use of perinatal hyperoxia stunting the maturation of carotid body chemoreceptors, but may also be attributed to limited lung diffusion capacity and/or gas exchange inefficiency. Aerobic exercise capacity also appears to be reduced in this population. This may relate to the aforementioned respiratory impairments, or could be due to physiological limitations in pulmonary blood flow or at the exercising muscle (e.g. mitochondrial efficiency). However, surprisingly, the debilitative effects of exercise when performed at altitude do not seem to be exacerbated by premature birth. In fact, it is reasonable to speculate that pre-term birth could protect against the consequences of exercise combined with hypoxia. The mechanisms that underlie this assertion might relate to differences in oxidative stress responses or in cardiopulmonary morphology in pre-term individuals, compared to their full-term counterparts. Further research is required to elucidate the independent effects of neonatal treatment, sex differences and chronic lung disease, and to establish causality in some of the proposed mechanisms that could underlie the differences discussed throughout this review. A more in-depth understanding of the acclimatisation responses to chronic altitude exposures would also help to inform appropriate interventions in this clinical population.