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

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in interorgan communication in diverse pathological processes. ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of the alveolar macrophage (AM) markers CD11b, CD11c, and CD206 as well as 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 of inspired oxygen therapy (HO2⩾30%) had increased concentrations of AM-derived EV-ASC compared with infants on lower fraction of inspired oxygen (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 cross-talk 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.

Highly comparative time series analysis of oxygen saturation and heart rate to predict respiratory outcomes in extremely preterm infants.

Objective.Highly comparative time series analysis (HCTSA) is a novel approach involving massive feature extraction using publicly available code from many disciplines. The Prematurity-Related Ventilatory Control (Pre-Vent) observational multicenter prospective study collected bedside monitor data from>700extremely preterm infants to identify physiologic features that predict respiratory outcomes.Approach. We calculated a subset of 33 HCTSA features on>7 M 10 min windows of oxygen saturation (SPO2) and heart rate (HR) from the Pre-Vent cohort to quantify predictive performance. This subset included representatives previously identified using unsupervised clustering on>3500HCTSA algorithms. We hypothesized that the best HCTSA algorithms would compare favorably to optimal PreVent physiologic predictor IH90_DPE (duration per event of intermittent hypoxemia events below 90%).Main Results.The top HCTSA features were from a cluster of algorithms associated with the autocorrelation of SPO2 time series and identified low frequency patterns of desaturation as high risk. These features had comparable performance to and were highly correlated with IH90_DPE but perhaps measure the physiologic status of an infant in a more robust way that warrants further investigation. The top HR HCTSA features were symbolic transformation measures that had previously been identified as strong predictors of neonatal mortality. HR metrics were only important predictors at early days of life which was likely due to the larger proportion of infants whose outcome was death by any cause. A simple HCTSA model using 3 top features outperformed IH90_DPE at day of life 7 (.778 versus .729) but was essentially equivalent at day of life 28 (.849 versus .850).Significance. These results validated the utility of a representative HCTSA approach but also provides additional evidence supporting IH90_DPE as an optimal predictor of respiratory outcomes.

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.

Highly comparative time series analysis of oxygen saturation and heart rate to predict respiratory outcomes in extremely preterm infants.

Objective: Highly comparative time series analysis (HCTSA) is a novel approach involving massive feature extraction using publicly available code from many disciplines. The Prematurity-Related Ventilatory Control (Pre-Vent) observational multicenter prospective study collected bedside monitor data from > 700 extremely preterm infants to identify physiologic features that predict respiratory outcomes. We calculated a subset of 33 HCTSA features on > 7M 10-minute windows of oxygen saturation (SPO2) and heart rate (HR) from the Pre-Vent cohort to quantify predictive performance. This subset included representatives previously identified using unsupervised clustering on > 3500 HCTSA algorithms. Performance of each feature was measured by individual area under the receiver operating curve (AUC) at various days of life and binary respiratory outcomes. These were compared to optimal PreVent physiologic predictor IH90 DPE, the duration per event of intermittent hypoxemia events with threshold of 90%. Main Results: The top HCTSA features were from a cluster of algorithms associated with the autocorrelation of SPO2 time series and identified low frequency patterns of desaturation as high risk. These features had comparable performance to and were highly correlated with IH90_DPE but perhaps measure the physiologic status of an infant in a more robust way that warrants further investigation. The top HR HCTSA features were symbolic transformation measures that had previously been identified as strong predictors of neonatal mortality. HR metrics were only important predictors at early days of life which was likely due to the larger proportion of infants whose outcome was death by any cause. A simple HCTSA model using 3 top features outperformed IH90_DPE at day of life 7 (.778 versus .729) but was essentially equivalent at day of life 28 (.849 versus .850). These results validated the utility of a representative HCTSA approach but also provides additional evidence supporting IH90_DPE as an optimal predictor of respiratory outcomes.

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

Objectives: Detection of changes in cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, may facilitate earlier detection of sepsis. Our objective was to examine the association of cardiorespiratory events with late-onset sepsis for extremely preterm infants (<29 weeks' gestational age (GA)) on versus off invasive mechanical ventilation. Study Design: Retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in five level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean GA 26.4w, 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 >72h after birth and ≥5d 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 IH80 events 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 predicted sepsis with an AUC 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.

Towards a harmonized bronchopulmonary dysplasia definition: a study protocol for an international Delphi procedure.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth with lifelong consequences. Multiple BPD definitions are currently used in daily practice. Uniformity in defining BPD is important for clinical care, research and benchmarking. The aim of this Delphi procedure is to determine what clinicians and researchers consider the key features for defining BPD. With the results of this study, we hope to advance the process of reaching consensus on the diagnosis of BPD. METHODS AND ANALYSIS: A Delphi procedure will be used to establish why, when and how clinicians propose BPD should be diagnosed. This semi-anonymous iterative technique ensures an objective approach towards gaining these insights. An international multidisciplinary panel of clinicians and researchers working with preterm infants and/or patients diagnosed with BPD will participate. Steering committee members will recruit potential participants in their own region or network following eligibility guidelines to complete a first round survey online. This round will collect demographic information and opinions on key features of BPD definitions. Subsequent rounds will provide participants with the results from the previous round, for final acceptance or rejection of key features. Statements will be rated using a 5-point Likert scale. After completing the Delphi procedure, an (online) consensus meeting will be organised to discuss the results. ETHICS AND DISSEMINATION: For this study, ethical approval a waiver has been provided. However, all participants will be asked to provide consent for the use of personal data. After the Delphi procedure is completed, it will be published in a peer-reviewed journal and disseminated at international conferences.

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.

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.

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.

Effect of the Target Range on Arterial Oxygen Saturation Stability in Extremely Premature Infants.

OBJECTIVE: The aim of this study was to compare the effect of targeting arterial oxygen saturation (SpO2) in the high (93-95%) versus the low portion (90-92%) of the recommended range of 90-95% on oxygenation stability in extremely premature infants. METHODS: Premature infants of ≤28 weeks of gestational age who received a fraction of inspired oxygen (FiO2) > 0.21 after day 14 were eligible. FiO2 was adjusted by a dedicated investigator to keep SpO2 between 90-92% and 93-95% for 2 h each in random sequence. Episodes of intermittent hypoxemia (IH) were defined as SpO2 <90% for ≥10 s; severe IH episodes were defined as SpO2 <80% for ≥10 s. Hyperoxemia was defined as SpO2 >95% or >98%. RESULTS: Eighteen premature infants were enrolled. Their (mean ± SD) GA was 26 ± 1.5 w. Seven infants were on mechanical ventilation, 4 infants on nasal ventilation, and 7 infants on nasal cannula. They were on a mean FiO2 0.38 ± 0.12 at study entry. Episodes of IH and severe IH were more frequent during the low compared to the high target (36.6 [27.0-41.3] vs. 16.0 [7.8-19.0], p < 0.001; 8.4 ± 9.3 vs. 3.2 ± 4.3, p = 0.002). The proportions of time with SpO2 >95% and >98% were greater with the high target (13.9 ± 11 vs. 34.1 ± 15.4%, p < 0.001; 0.9 [0-5.7] vs. 3.4 [0.5-16.1]%, p = 0.002). CONCLUSION: In this group of extremely premature infants, targeting SpO2 at the lower portion of the recommended range resulted in more frequent episodes of IH. However, targeting the higher SpO2 range led to more hyperoxemia. This trade-off warrants further investigation.

Caffeine: Some of the Evidence behind Its Use and Abuse in the Preterm Infant.

Apnea of prematurity is a developmental disorder affecting most extremely preterm infants. The consequences of apnea of prematurity on neurodevelopment are not well established, but several reports suggest that apnea and hypoxemia episodes may be associated with worse neurological outcome. Caffeine is the only FDA-approved drug for the prevention and treatment of apnea of prematurity. Besides its clear effectiveness to reduce apnea, the use of caffeine appears to have a wide margin of safety and has been associated with possible beneficial effects on later neurodevelopmental outcome. At the same time, there are also many studies in experimental animals and some in preterm infants suggesting potential serious adverse effects from caffeine administration, especially when using higher doses. Because of these uncertainties, there is a wide variation in caffeine use across institutions. This review summarizes some of the available evidence on caffeine use in this population, its indications and best timing of initiation and discontinuation, appropriate dosing, and some of the possible adverse effects of caffeine administration. Because of the many gaps in knowledge, especially as it relates to efficacy and safety, we encourage further basic and clinical studies to provide stronger evidence, not only on its potential beneficial effects but also its side effects.

New Modes of Respiratory Support for the Premature Infant: Automated Control of Inspired Oxygen Concentration.

Most extremely premature infants have respiratory instability that can manifest as frequent episodes of intermittent hypoxemia. Although caregivers target clinically recommended ranges of arterial oxygen saturation (oxygen saturation as measured by pulse oximetry [Spo2]), consistent maintenance of these ranges is not always achieved. Excessive administration of supplemental oxygen combined with limited staff resources increases exposure to extreme Spo2 levels. In this population, exposure to hyperoxemia and prolonged episodes of intermittent hypoxemia have been associated with damage to the eye and lung and impaired neurodevelopment. To improve Spo2 targeting, various systems for automated control of inspired oxygen have been developed recently.

Efficacy of late postnatal dexamethasone on weaning from invasive mechanical ventilation in extreme premature infants.

OBJECTIVE: To evaluate the short-term respiratory effects of PND in a cohort of ventilator-dependent premature infants. STUDY DESIGN: Clinical data from 106 infants 23-28 weeks gestation who received PND for weaning from MV during 2011-2017 were evaluated. PND was started at a dose of 0.1 mg/kg/d tapered over 5-7 d. Treatment success was defined as extubated and free from MV on d14 after start of treatment. RESULT: Treatment was successful in 83 (78%) infants. Demographics and age of treatment did not differ between groups. In the failure group, a higher proportion were on HFOV and FiO2 ≥ 0.50 before treatment, compared to the successful group. CONCLUSION: In most infants, PND resulted in successful weaning from MV. Reduced need for oxygen in infants not extubated may be beneficial, but it is unknown if this offsets the risks. The long-term effects PND in ventilator dependent infants need to be evaluated.