Extracellular Vesicle ASC: A Novel Mediator for Lung-Brain Axis in Preterm Brain Injury.

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI) are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor NDI, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in inter-organ communication in diverse pathological processes. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of alveolar macrophage (AM) markers, CD11b, CD11c, and CD206, and ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction inspired oxygen (FiO2) therapy (HO2, ≥30%) had increased levels of AM-derived EV-ASC compared with infants on lower FiO2 (LO2, <30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier and the EVs from infants on HO2 caused inflammation, reduced cell survival, and increased cell death with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain crosstalk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Maturation of cardioventilatory physiological trajectories in extremely preterm infants.

BACKGROUND: In extremely preterm infants, persistence of cardioventilatory events is associated with long-term morbidity. Therefore, the objective was to characterize physiologic growth curves of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants during the first few months of life. METHODS: The Prematurity-Related Ventilatory Control study included 717 preterm infants <29 weeks gestation. Waveforms were downloaded from bedside monitors with a novel sharing analytics strategy utilized to run software locally, with summary data sent to the Data Coordinating Center for compilation. RESULTS: Apnea, periodic breathing, and intermittent hypoxemia events rose from day 3 of life then fell to near-resolution by 8-12 weeks of age. Apnea/intermittent hypoxemia were inversely correlated with gestational age, peaking at 3-4 weeks of age. Periodic breathing was positively correlated with gestational age peaking at 31-33 weeks postmenstrual age. Females had more periodic breathing but less intermittent hypoxemia/bradycardia. White infants had more apnea/periodic breathing/intermittent hypoxemia. Infants never receiving mechanical ventilation followed similar postnatal trajectories but with less apnea and intermittent hypoxemia, and more periodic breathing. CONCLUSIONS: Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. IMPACT: Physiologic curves of cardiorespiratory events in extremely preterm-born infants offer (1) objective measures to assess individual patient courses and (2) guides for research into control of ventilation, biomarkers and outcomes. Presented are updated maturational trajectories of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in 717 infants born <29 weeks gestation from the multi-site NHLBI-funded Pre-Vent study. Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Different time courses for apnea and periodic breathing suggest different maturational mechanisms.

Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

Etiology and Mechanism of Intermittent Hypoxemia Episodes in Spontaneously Breathing Extremely Premature Infants.

OBJECTIVE: To evaluate the mechanisms leading to intermittent hypoxemia (IH) episodes in spontaneously breathing extremely premature infants at 32 weeks and 36 weeks postmenstrual age (PMA). METHODS: We studied spontaneously breathing premature infants born at 23-28 weeks of gestational age who presented with IH episodes while on noninvasive respiratory support at 32 or 36 weeks PMA. Daytime recordings of arterial oxygen saturation (SpO2), esophageal pressure, respiratory inductive plethysmography of the abdomen, chest wall, and their sum were obtained during 4 hours at 32 weeks and 36 weeks PMA. IH episodes (SpO2 <90% for ≥5 seconds) and severe IH episodes (SpO2 < 80% for ≥5 seconds) were classified as resulting from apnea, active exhalation and breath holding, reduced tidal volume (VT), or reduced respiratory rate (RR) during the preceding 60 seconds. RESULTS: Fifty-one infants with a mean gestational age of 25.9 ± 1.5 weeks and a mean birth weight of 846 ± 185 g were included. Of these, 31 and 41 were included in the analysis at 32 weeks and 36 weeks PMA, respectively. At both 32 weeks and 36 weeks PMA, greater proportions of all IH episodes and severe IH episodes were associated with active exhalation and breath holding than with apnea, reduced RR, or reduced VT. The severity and duration of the IH episodes did not differ between mechanisms. CONCLUSIONS: In this group of premature infants, the predominant mechanism associated with daytime IH was active exhalation and breath holding. This etiology is more closely associated with behavioral factors than abnormal respiratory control and can have implications for prevention.

Pulse oximetry reliability for detection of hypoxemia under motion in extremely premature infants.

BACKGROUND: Episodes of intermittent hypoxemia (IH) in extremely premature infants are detected by pulse oximetry (SpO2) but motion artifact can cause falsely low readings. OBJECTIVES: To evaluate the reliability of SpO2 during IH episodes associated with motion in premature infants of ≤28 weeks GA monitored with 2 pulse oximeters. METHODS: IH episodes (defined as SpO2 < 90%, >10 s and SpO2 < 80%, >10 s) were classified by an analytic tool based on distortion caused by motion in the pulse plethysmograph (Pleth) as: A (true hypoxemia), both SpO2 decreased (only one Pleth showed motion); B (false hypoxemia), one SpO2 decreased (Pleth showed motion) and the other didn't (Pleth didn't show motion); C (suspected hypoxemia), both SpO2 decreased (both Pleth showed motion); D (true hypoxemia-motion free), both SpO2 decreased (neither Pleth showed motion). RESULTS: In 24-72 h data from 20 infants of 25.4 ± 1.5 weeks GA, 14.1 ± 5.7 episodes with SpO2 < 90% and 7.9 ± 5.5 episodes with SpO2 < 80% per infant were identified. 29 ± 15% of episodes with SpO2 < 90% were type A, 1 ± 2% B, 43 ± 21% C and 27 ± 23% D, while 26 ± 22% of episodes with SpO2 < 80% were type A, 0.3 ± 1.2% B, 45 ± 29% C, and 19 ± 25% D [p < 0.001 type B vs. rest (GLM-repeated measures)]. CONCLUSION: In extremely premature infants SpO2 with motion artifact is more likely to indicate true- than false hypoxemia. IMPACT: Uncertainty on the effect of motion on SpO2 accuracy during hypoxemia episodes in premature infants can influence the caregiver's trust on SpO2 and influence their response. This study evaluated data from two pulse oximeters used simultaneously in different extremities to determine the reliability of SpO2 during motion artifact in premature infants. Data from this study showed that in extremely premature infants SpO2 is more likely to indicate true- than false hypoxemia during episodes of hypoxemia associated with motion artifact.

Changes in Patent Ductus Arteriosus Treatment Strategy and Respiratory Outcomes in Premature Infants.

OBJECTIVE: To evaluate whether change in patent ductus arteriosus (PDA) management strategies over time had an impact on respiratory outcomes in premature infants. STUDY DESIGN: Prospectively collected data were included from all preterm infants born at 23-30 weeks gestational age with PDA admitted to the Children's Hospital of the University of Miami/Jackson Memorial Medical Center from January 1, 2005 to December 31, 2007 (epoch 1) and January 1, 2011 to December 31, 2015 (epoch 2). The 2 epochs were compared for approach with PDA diagnosis and subsequent management strategies and respiratory outcomes. RESULTS: Significantly fewer infants were treated for PDA in epoch 2 (54%) compared with epoch 1 (90%). Multivariable logistic regression analysis demonstrated that infants in epoch 2, with later PDA diagnosis and less frequent PDA treatment, had greater odds of bronchopulmonary dysplasia (BPD), composite of BPD or death, and more treatment with postnatal steroids than in epoch 1. CONCLUSIONS: The change in approach to diagnosis and management of PDA, from a more proactive and aggressive approach during the earlier epoch 1 to a more expectant approach during the subsequent epoch 2, was associated with worse respiratory outcomes, including increase in BPD and in BPD or death.

Equity in coronavirus disease 2019 vaccine development and deployment.

The coronavirus disease 2019 pandemic exposed weaknesses in multiple domains and widened gender-based inequalities across the world. It also stimulated extraordinary scientific achievement by bringing vaccines to the public in less than a year. In this article, we discuss the implications of current vaccination guidance for pregnant and lactating women, if their exclusion from the first wave of vaccine trials was justified, and if a change in the current vaccine development pathway is necessary. Pregnant and lactating women were not included in the initial severe acute respiratory syndrome coronavirus 2 vaccine trials. Therefore, perhaps unsurprisingly, the first vaccine regulatory approvals have been accompanied by inconsistent advice from public health, governmental, and professional authorities around the world. Denying vaccination to women who, although pregnant or breastfeeding, are fully capable of autonomous decision making is a throwback to a paternalistic era. Conversely, lack of evidence generated in a timely manner, upon which to make an informed decision, shifts responsibility from research sponsors and regulators and places the burden of decision making upon the woman and her healthcare advisor. The World Health Organization, the Task Force on Research Specific to Pregnant Women and Lactating Women, and others have highlighted the long-standing disadvantage experienced by women in relation to the development of vaccines and medicines. It is uncertain whether there was sufficient justification for excluding pregnant and lactating women from the initial severe acute respiratory syndrome coronavirus 2 vaccine trials. In future, we recommend that regulators mandate plans that describe the development pathway for new vaccines and medicines that address the needs of women who are pregnant or lactating. These should incorporate, at the outset, a careful consideration of the balance of the risks of exclusion from or inclusion in initial studies, patient and public perspectives, details of "developmental and reproductive toxicity" studies, and approaches to collect data systematically from participants who are unknowingly pregnant at the time of exposure. This requires careful consideration of any previous knowledge about the mode of action of the vaccine and the likelihood of toxicity or teratogenicity. We also support the view that the default position should be a "presumption of inclusion," with exclusion of women who are pregnant or lactating only if justified on specific, not generic, grounds. Finally, we recommend closer coordination across countries with the aim of issuing consistent public health advice.

Meningitis, urinary tract, and bloodstream infections in very low birth weight infants enrolled in a heart rate characteristics monitoring trial.

BACKGROUND: Displaying heart rate characteristic (HRC) scores was associated with lower sepsis-associated mortality in very low birth weight (VLBW) infants in a multicenter randomized controlled trial (HeRO trial). The aim of this study was to test whether HRC indices rise before diagnosis of urinary tract infection (UTI) or meningitis, with and without concomitant BSI. METHODS: Blood, urine, and cerebrospinal fluid (CSF) culture data after 3 days of age and within 120 days of study enrollment were analyzed from 2989 VLBW infants. The HRC index was analyzed 12 h prior to positive cultures compared to 36 h prior, using paired signed-rank tests. RESULTS: UTI, meningitis, and BSI were diagnosed in 10%, 2%, and 24% of infants, respectively. The mean hourly HRC index was significantly higher 12 h prior to diagnosis of UTI and BSI compared to 36 h prior (UTI 2.07 versus 1.81; BSI 2.62 versus 2.25, both p < 0.0001). The baseline HRC index was higher for meningitis, compared to UTI or BSI, but without a statistically significant rise in the day prior to meningitis diagnosis. CONCLUSIONS: In a large cohort of VLBW infants enrolled in the HeRO trial, the HRC index increased in the 24-h period prior to diagnosis of UTI and BSI but not meningitis.

Antenatal Infections and Respiratory Outcome in Preterm Infants.

Fetal exposure to infection and inflammation can result in accelerated lung maturation and simultaneously altered lung development. This alteration is characterized by reduced alveolar and vascular formation that is one of the hallmarks of the changes observed in animal models and in infants with bronchopulmonary dysplasia (BPD). These opposite effects on maturation and on lung development can explain the reduced severity of respiratory distress syndrome (RDS) but increased incidence of BPD observed in infants exposed to antenatal infections. This also explains why infants born to mothers with chorioamnionitis or colonized with ureaplasma urealitycum have an increased risk of lung injury and BPD. Despite the negative effects of infection on lung development, there is no clear evidence that antibiotic therapy improves the respiratory course in these infants. While the administration of azithromycin to ureaplasma colonized infants is effective in eradicating airway colonization, the effect on BPD is inconclusive. One of the few interventions that have been shown to improve respiratory outcome and reduce BPD in infants with severe RDS is the modulation of inflammation by the administration of systemic or intratracheal steroids early after birth. KEY POINTS: · Antenatal infection can reduce RDS.. · Fetal exposure to infection can alter lung development and increase BPD.. · The detrimental effect of infection is enhanced by mechanical ventilation..

Maternal preeclampsia and respiratory outcomes in extremely premature infants.

BACKGROUND: Preeclampsia (PE) is a pregnancy complication characterized by an anti-angiogenic environment. This can affect fetal pulmonary vascular and alveolar development but data of the impact of PE on respiratory outcome in extremely premature infants are inconclusive. The objective of this study was to determine if PE is associated with an increased risk for severe respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in extremely premature infants. METHODS: Prospectively collected single center data from a cohort of infants born at 23-28 w gestational age between January 2005 and December 2015 were analyzed. Logistic regression analysis and generalized estimating equations were used to model the association between PE and severe RDS (≥30% supplemental oxygen on d1), BPD and severe BPD [supplemental oxygen and ≥30% oxygen at 36 w postmenstrual age (PMA), respectively]. RESULTS: The cohort included 1218 infants of whom 23% were exposed to PE. PE was associated with increased risk for severe RDS as well as severe BPD among infants alive at 36w PMA. CONCLUSION: Exposure to preeclampsia is independently associated with an increased risk for severe RDS and adverse respiratory outcome in extreme premature infants. The mechanisms behind these associations need to be investigated.

Cerebral oxygenation in preterm infants receiving transfusion.

BACKGROUND: The influence of severity of anemia and cardiac output (CO) on cerebral oxygenation (CrSO2) and on the change in CrSO2 following packed red blood cell (PRBC) transfusion in preterm infants has not been evaluated. The objectives of the current study were to evaluate the effect of pre-transfusion hemoglobin (Hb) and CO-weighted oxygen delivery index (ODI) on CrSO2 and on the post-transfusion CrSO2 change. METHODS: Preterm infants of <32 weeks gestational age (GA) receiving PRBC transfusion were enrolled. Infants received 15 ml/kg PRBC over 3 h. CrSO2 by near-infrared spectroscopy and CO by electrical velocimetry were recorded for 1 h pre-ransfusion and post transfusion. ODI was defined as pre-transfusion Hb × CO. RESULTS: Thirty infants of 26.6 ± 2.0 weeks GA were studied at 19 ± 12 days. Pre-transfusion Hb was 9.8 ± 0.6 g/dl. Pre-transfusion CrSO2 correlated with pre-transfusion ODI (R2 = 0.1528, p = .044) but not with Hb level. The pre-transfusion to post-transfusion CrSO2 change correlated with pre-transfusion ODI (R2 = 0.1764, p = .029) but not with Hb level. CrSO2 increased from 66 ± 6% to 72 ± 7% post transfusion (p < .001), while arterial oxygen saturation, heart rate, and CO did not change. CONCLUSION: In these infants, the pre-transfusion ODI was a better indicator of brain oxygenation and its improvement post transfusion than Hb alone. The role of CO and tissue oxygenation monitoring in assessing the need for transfusion should be evaluated.

Pre-Vent: the prematurity-related ventilatory control study.

BACKGROUND: The increasing incidence of bronchopulmonary dysplasia in premature babies may be due in part to immature ventilatory control, contributing to hypoxemia. The latter responds to ventilation and/or oxygen therapy, treatments associated with adverse sequelae. This is an overview of the Prematurity-Related Ventilatory Control Study which aims to analyze the under-utilized cardiorespiratory continuous waveform monitoring data to delineate mechanisms of immature ventilatory control in preterm infants and identify predictive markers. METHODS: Continuous ECG, heart rate, respiratory, and oxygen saturation data will be collected throughout the NICU stay in 500 infants < 29 wks gestation across 5 centers. Mild permissive hypercapnia, and hyperoxia and/or hypoxia assessments will be conducted in a subcohort of infants along with inpatient questionnaires, urine, serum, and DNA samples. RESULTS: Primary outcomes will be respiratory status at 40 wks and quantitative measures of immature breathing plotted on a standard curve for infants matched at 36-37 wks. Physiologic and/or biologic determinants will be collected to enhance the predictive model linking ventilatory control to outcomes. CONCLUSIONS: By incorporating bedside monitoring variables along with biomarkers that predict respiratory outcomes we aim to elucidate individualized cardiopulmonary phenotypes and mechanisms of ventilatory control contributing to adverse respiratory outcomes in premature infants.

New Developments in Respiratory Support for Preterm Infants.

The evolution of neonatal respiratory support has been one of the cornerstones for the advancements in neonatal-perinatal medicine, allowing survival of infants previously considered not viable. There is an increasing focus on developing strategies which are not only lifesaving but also minimize lung and other organ systems injury, thereby reducing long-term morbidities. Respiratory support immediately after birth is an area that had lagged behind in terms of evidence base and technological advancements until recently. Some of these advancements include use of a respiratory function monitors for measuring flow and tidal volume, new evidence for oxygen supplementation and monitoring, and the efforts to formulate an ideal strategy for establishing functional residual capacity after birth. Increasing evidence for the benefits of avoiding invasive ventilation on reduction of bronchopulmonary dysplasia has resulted in efforts to further reduce the need for endotracheal intubation by applying newer strategies such as less invasive surfactant instillation, noninvasive high-frequency oscillatory ventilation, or use of high flow nasal cannula oxygen. For infants requiring mechanical ventilation, newer strategies such as volume targeted ventilation or neurally adjusted ventilation are being evaluated to reduce ventilator induced lung injury. Despite these advances, there are significant challenges, including lack of conclusive evidence base for many of currently used respiratory strategies, no reduction in the incidence of bronchopulmonary dysplasia in the last decade, and difficulties in defining outcome measures that better reflect long-term respiratory health.

Early Caffeine and Weaning from Mechanical Ventilation in Preterm Infants: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: To evaluate in a randomized, double-blind, placebo-controlled trial the effect of early caffeine on the age of first successful extubation in preterm infants. STUDY DESIGN: Preterm infants born at 23-30 weeks of gestation requiring mechanical ventilation in the first 5 postnatal days were randomized to receive a 20 mg/kg loading dose followed by 5 mg/kg/day of caffeine or placebo until considered ready for extubation. The placebo group received a blinded loading dose of caffeine before extubation. RESULTS: Infants were randomized to receive caffeine (n = 41) or placebo (n = 42). Age at first successful extubation did not differ between early caffeine (median, 24 days; IQR, 10-41 days) and control groups (median, 20 days; IQR, 9-43 days; P = .7). An interim analysis at 75% enrollment showed a trend toward higher mortality in 1 of the groups and the data safety and monitoring board recommended stopping the trial. Unblinded analysis revealed mortality did not differ significantly between the early caffeine (9 [22%]) and control groups (5 [12%]; P = .22). CONCLUSIONS: Early initiation of caffeine in this group of premature infants did not reduce the age of first successful extubation. A nonsignificant trend toward higher mortality in the early caffeine group led to a cautious decision to stop the trial. These findings suggest caution with early use of caffeine in mechanically ventilated preterm infants until more efficacy and safety data become available. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01751724.

Neonatal Intensive Care Unit Length of Stay Reduction by Heart Rate Characteristics Monitoring.

OBJECTIVE: To examine the effect of heart rate characteristics (HRC) monitoring on length of stay among very low birth weight (VLBW; <1500 g birth weight) neonates in the HeRO randomized controlled trial (RCT). STUDY DESIGN: We performed a retrospective analysis of length of stay metrics among 3 subpopulations (all patients, all survivors, and survivors with positive blood or urine cultures) enrolled in a multicenter, RCT of HRC monitoring. RESULTS: Among all patients in the RCT, infants randomized to receive HRC monitoring were more likely than controls to be discharged alive and prior to day 120 (83.6% vs 80.1%, P = .014). The postmenstrual age at discharge for survivors with positive blood or urine cultures was 3.2 days lower among infants randomized to receive HRC monitoring when compared with controls (P = .026). Although there were trends in other metrics toward reduced length of stay in HRC-monitored patients, none reached statistical significance. CONCLUSIONS: HRC monitoring is associated with reduced mortality in VLBW patients and a reduction in length of stay among infected surviving VLBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00307333.

Bronchopulmonary Dysplasia: Can We Agree on a Definition?

The advances in obstetric and neonatal care over the last half century have resulted in changes in pathophysiology and clinical presentation of bronchopulmonary dysplasia (BPD). In contrast to the original description of BPD by Northway et al as a severe lung injury in relatively mature preterm infants, the most common form of BPD currently is characterized by chronic respiratory insufficiency in extremely preterm infants. This evolution in the presentation of BPD, along with changes in respiratory support strategies such as increased use of nasal cannula oxygen, has presented a unique challenge to find a definition that describes the severity of lung damage and predict the long-term respiratory outcomes with some accuracy.The limitations of current definitions of BPD include inconsistent correlation with long-term respiratory outcomes, inability to classify infants dying from severe respiratory failure prior to 36 weeks' postmenstrual age, and potential inappropriate categorization of infants on nasal cannula oxygen or with extrapulmonary causes of respiratory failure. In the long term, the aim for a new definition of BPD is to develop a classification based on the pathophysiology and objective lung function evaluation providing a more accurate assessment for individual patients. Until then, a consensus definition that encompasses current clinical practices, provides reasonable prediction of later respiratory outcomes, and is relatively simple to use should be achieved.

Respiratory Instability and Hypoxemia Episodes in Preterm Infants.

Oxygenation instability is a very common problem in the premature infant that manifests as intermittent hypoxemia episodes (HEs). These are particularly frequent in premature infants who are on mechanical ventilation beyond the first weeks after birth. However, they can also occur in spontaneously breathing infants. Some of these episodes are due to central apnea, but in ventilated infants, they are frequently due to contractions of the abdominal musculature that can splint the respiratory pump, resulting in periods of decreased lung volume and hypoventilation. HEs are often followed by periods of hyperoxemia that results from excessive oxygen supplementation given to correct the hypoxemia. These episodes increase in frequency with postnatal age and are more common in infants with chronic lung disease. Although the evidence is not conclusive, their detrimental effects on the infant's neurologic, ocular, and respiratory system may be significant. There is no specific treatment for HEs, but several interventions are available to ameliorate the severity and duration of the episodes. Further research is needed to define the impact of HEs on the preterm infant's developing central nervous system and other organ systems and to develop effective strategies to prevent these episodes.