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.

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.

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.

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.

Automated versus Manual Oxygen Control with Different Saturation Targets and Modes of Respiratory Support in Preterm Infants.

OBJECTIVE: To determine the efficacy and safety of automated adjustment of the fraction of inspired oxygen (FiO2) in maintaining arterial oxygen saturation (SpO2) within a higher (91%-95%) and a lower (89%-93%) target range in preterm infants. STUDY DESIGN: Eighty preterm infants (gestational age [median]: 26 weeks, age [median] 18 days) on noninvasive (n = 50) and invasive (n = 30) respiratory support with supplemental oxygen, were first randomized to one of the SpO2 target ranges and then treated with automated FiO2 (A-FiO2) and manual FiO2 (M-FiO2) oxygen control for 24 hours each, in random sequence. RESULTS: The percent time within the target range was higher during A-FiO2 compared with M-FiO2 control. This effect was more pronounced in the lower SpO2 target range (62 ± 17% vs 54 ± 16%, P < .001) than in the higher SpO2 target range (62 ± 17% vs 58 ± 15%, P < .001). The percent time spent below the target or in hypoxemia (SpO2 <80%) was consistently reduced during A-FiO2, independent of the target range. The time spent above the target range or at extreme hyperoxemia (SpO2 >98%) was only reduced during A-FiO2 when targeting the lower SpO2 range (89%-93%). These outcomes did not differ between infants on noninvasive and invasive respiratory support. Manual adjustments were significantly reduced during A-FiO2 control. CONCLUSIONS: A-FiO2 control improved SpO2 targeting across different SpO2 ranges and reduced hypoxemia in preterm infants on noninvasive and invasive respiratory support. TRIAL REGISTRATION: ISRCTN 56626482.

A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants.

OBJECTIVE: To compare extubation failure rate with two ranges of nasal continuous positive airway pressure (NCPAP) in oxygen dependent preterm infants. STUDY DESIGN: Preterm infants of birth weight 500-1000 g and gestational age 23-30 weeks, extubated for the first time during the first 6 weeks while requiring fraction of inspired oxygen ≥ 0.25, were randomly assigned to a NCPAP range of 4-6 (low NCPAP) or 7-9 (high NCPAP) cmH2O. RESULTS: Infants were randomized to low (n = 47) or high NCPAP (n = 46) at day 16.3 ± 14.7 and 15.5 ± 12.4, respectively. Rates of extubation failure per criteria (24% vs 43%, P = .04, OR and 95% CI: 0.39 [0.16-0.96]) and re-intubation (17% vs 38%, P = .023, 0.33 [0.016-0.85]) within 96 hours were significantly lower in the high- compared with the low NCPAP group. This was mainly due to a strikingly lower failure rate in the 500-750 g birth weight strata. Duration of ventilation, bronchopulmonary dysplasia, or severe bronchopulmonary dysplasia did not differ significantly. No infant developed pneumothorax during 96 hours post-extubation. CONCLUSIONS: Extubation failure in preterm infants with residual lung disease was lower with NCPAP range of 7-9 compared with 4-6 cmH2O. These findings suggest the need for higher distending pressure post-extubation in the more immature infants who are still oxygen dependent.

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.

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 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.