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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., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: Apnea is common among infants in the neonatal intensive care unit (NICU). Our group previously developed an automated algorithm to quantitate central apneas with associated bradycardia and desaturation (ABDs). Sex differences in lung disease are well described in preterm infants, but the influence of sex on apnea has not been established., Study Design: This study includes infants < 34 weeks' gestation admitted to the University of Virginia NICU from 2009 to 2014 with at least 1 day of bedside monitor data available when not on mechanical ventilation. Waveform and vital sign data were analyzed using a validated algorithm to detect ABD events of low variance in chest impedance signal lasting at least 10 seconds with associated drop in heart rate to < 100 beats/minute and drop in oxygen saturation to < 80%. Male and female infants were compared for prevalence of at least one ABD event during the NICU stay, treatment with caffeine, occurrence of ABDs at each week of postmenstrual age, and number of events per day., Results: Of 926 infants studied (median gestational age 30 weeks, 53% male), median days of data analyzed were 19 and 22 for males and females, respectively. There was no sex difference in prevalence of at least one ABD event during the NICU stay (males 62%, females 64%, p  = 0.47) or in the percentage of infants treated with caffeine (males 64%, females 67%, p  = 0.40). Cumulative prevalence of ABDs from postmenstrual ages 24 to 36 weeks was comparable between sexes. Males had 18% more ABDs per day of data, but this difference was not statistically significant ( p  = 0.16)., Conclusion: In this large cohort of infants < 34 weeks' gestation, we did not detect a sex difference in prevalence of central ABD events. There was a nonsignificant trend toward a greater number of ABDs per day in male infants., Key Points: · Central apnea is pervasive among preterm infants in the NICU, but potential disparities between males and females have not been thoroughly studied.. · Identification of risk factors for central apnea can lead to improved treatment protocols.. · The rate and prevalence of central apnea events accompanied by bradycardia and desaturation does not significantly differ between male and female preterm infants.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: We previously showed, in a single-center study, that early heart rate (HR) characteristics predicted later adverse outcomes in very low birth weight (VLBW) infants. We sought to improve predictive models by adding oxygenation data and testing in a second neonatal intensive care unit (NICU)., Methods: HR and oxygen saturation (SpO 2 ) from the first 12 hours and first 7 days after birth were analyzed for 778 VLBW infants at two NICUs. Using multivariate logistic regression, clinical predictive scores were developed for death, severe intraventricular hemorrhage (sIVH), bronchopulmonary dysplasia (BPD), treated retinopathy of prematurity (tROP), late-onset septicemia (LOS), and necrotizing enterocolitis (NEC). Ten HR-SpO 2 measures were analyzed, with first 12 hours data used for predicting death or sIVH and first 7 days for the other outcomes. HR-SpO 2 models were combined with clinical models to develop a pulse oximetry predictive score (POPS). Net reclassification improvement (NRI) compared performance of POPS with the clinical predictive score., Results: Models using clinical or pulse oximetry variables alone performed well for each outcome. POPS performed better than clinical variables for predicting death, sIVH, and BPD (NRI > 0.5, p  < 0.01), but not tROP, LOS, or NEC., Conclusion: Analysis of early HR-SpO 2 characteristics adds to clinical risk factors to predict later adverse outcomes in VLBW infants., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objectives: To determine whether an early heart rate characteristics (HRC) index (HeRO score), measured in the first day and week after birth predicts death and morbidities compared with established illness severity scores., Study Design: For all very low birth weight infants in a single neonatal intensive care unit from 2004-2014, the average first day HRC index was calculated within 24 hours of birth (aHRC-24h) and the average first week HRC index within 7 days of birth (aHRC-7d). The Score for Neonatal Acute Physiology (SNAP-II) and Clinical Risk Indicator for Babies (CRIB-II) were calculated when data were available. The aHRC was compared with the SNAP-II and CRIB-II for predicting death, late-onset septicemia, necrotizing enterocolitis, bronchopulmonary dysplasia, severe intraventricular hemorrhage, or severe retinopathy of prematurity., Results: All 4 scores were associated with death and severe intraventricular hemorrhage (P < .01). The OR and 95% CI for every 1-point increase in aHRC for predicting mortality, adjusted for gestational age, was 1.59 (1.25-2.00) for aHRC-24h and 2.61 (1.58-4.33) for aHRC-7d. High aHRC-7d, SNAP-II, and CRIB-II were associated with bronchopulmonary dysplasia (P < .001). High aHRC-7d was associated with late-onset septicemia (P < .05). None of the scores predicted necrotizing enterocolitis or severe retinopathy of prematurity., Conclusions: HRC assessed in the first day or first week after birth compares favorably to established risk scores to predict death and morbidities in very low birth weight infants., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purposes: Heart rate characteristics monitoring for early detection of late-onset neonatal sepsis was first described in 2003. This technique, which uses mathematical methods to report the fold-increase in the risk of imminent neonatal sepsis, adds independent information to laboratory tests and clinical findings, and, in a large randomized trial, reduced NICU mortality of very low birth weight infants. Through re-analysis and new secondary analyses of published studies, we have systematically evaluated the utility of this new risk marker for screening the growing population of premature infants., Methods: We followed the guidelines proposed by Hlatky et al. (Circulation, 119:2408-2416, 2009), reviewed past works, and re-analyzed data from 1,489 patients receiving conventional monitoring alone, 348 of whom had 488 episodes of proven sepsis, in the large randomized trial., Results: Heart rate characteristics monitoring passed all phases of risk marker development from proof of concept to improvement of clinical outcomes. The predictiveness curve affirmed good calibration, and addition of the heart rate characteristics index to predictive models using standard risk factors favorably impacted the receiver operating characteristic curve area (increase of 0.030), continuous net reclassification index (0.389) and the integrated discrimination index (0.008), and compares well to other modern risk factors., Conclusion: Heart rate characteristics monitoring is a validated risk marker for sepsis in the NICU.

Objective: To identify clinical conditions associated with a large increase (spike) in the heart rate characteristics index in very low birth weight (VLBW) infants., Study Design: Retrospective medical record review within a day of all large heart rate characteristics index spikes (increase of ≥3 from the previous 5-day average) in VLBW infants at a single center enrolled from 2007 to 2010 in a multicenter trial of heart rate characteristics monitoring. In the trial, infants were randomized to having their heart rate characteristics index displayed to clinicians or not displayed., Results: Of 274 eligible infants, 224 large heart rate characteristics spikes occurred in 105 infants. Thirty-three spikes were associated with surgery or procedures requiring anesthetic or anticholinergic medications, and infection-related conditions were the most common clinical association with the other spikes. Of the first spikes in 47 infants randomized to conventional monitoring (heart rate characteristics index not displayed to clinicians), 53% were associated with suspected or proven infection. Respiratory deterioration without suspected infection occurred with 34%, and no association was identified in 13%. Infants randomized to having their heart rate characteristics index displayed were more likely to have antibiotics initiated around the time of a large heart rate characteristics index spike., Conclusions: Sepsis, other infectious or systemic inflammatory conditions, respiratory deterioration, and surgical procedures are the most common clinical associations with a large increase in the heart rate characteristics index in VLBW infants. This information may improve use of heart rate characteristics monitors in patients in the neonatal intensive care unit., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: In 2006 the apnea of prematurity (AOP) consensus group identified inaccurate counting of apnea episodes as a major barrier to progress in AOP research. We compare nursing records of AOP to events detected by a clinically validated computer algorithm that detects apnea from standard bedside monitors., Study Design: Waveform, vital sign, and alarm data were collected continuously from all very low-birth-weight infants admitted over a 25-month period, analyzed for central apnea, bradycardia, and desaturation (ABD) events, and compared with nursing documentation collected from charts. Our algorithm defined apnea as > 10 seconds if accompanied by bradycardia and desaturation., Results: Of the 3,019 nurse-recorded events, only 68% had any algorithm-detected ABD event. Of the 5,275 algorithm-detected prolonged apnea events > 30 seconds, only 26% had nurse-recorded documentation within 1 hour. Monitor alarms sounded in only 74% of events of algorithm-detected prolonged apnea events > 10 seconds. There were 8,190,418 monitor alarms of any description throughout the neonatal intensive care unit during the 747 days analyzed, or one alarm every 2 to 3 minutes per nurse., Conclusion: An automated computer algorithm for continuous ABD quantitation is a far more reliable tool than the medical record to address the important research questions identified by the 2006 AOP consensus group., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

We have applied principles of statistical signal processing and nonlinear dynamics to analyze heart rate time series from premature newborn infants in order to assist in the early diagnosis of sepsis, a common and potentially deadly bacterial infection of the bloodstream. We began with the observation of reduced variability and transient decelerations in heart rate interval time series for hours up to days prior to clinical signs of illness. We find that measurements of standard deviation, sample asymmetry and sample entropy are highly related to imminent clinical illness. We developed multivariable statistical predictive models, and an interface to display the real-time results to clinicians. Using this approach, we have observed numerous cases in which incipient neonatal sepsis was diagnosed and treated without any clinical illness at all. This review focuses on the mathematical and statistical time series approaches used to detect these abnormal heart rate characteristics and present predictive monitoring information to the clinician.

Background: Sepsis in very low birth weight (VLBW) infants has been associated with an increased risk of adverse developmental outcome. We have identified abnormal heart rate characteristics (HRCs) that are predictive of impending sepsis, and we have developed a summary measure of an infant's abnormal HRCs during the neonatal hospitalization that we refer to as the cumulative HRC score (cHRC)., Objective: In this study, we tested the hypothesis that increasing cHRC is associated with an increasing risk of adverse neurodevelopmental outcome in VLBW infants., Method: Data were collected on 65 VLBW infants whose HRCs were monitored while in the neonatal intensive care unit and who were examined at 12 to 18 months adjusted age. Using the Bayley Scale of Infant Development-II, we identified delays in early cognitive function (i.e., Mental Developmental Index <70) and psychomotor development (i.e., Psychomotor Developmental Index <70). Cerebral palsy (CP) was diagnosed using a standard neurological examination., Result: Increasing cHRC score was associated with an increased risk of CP (odds ratio per 1 standard deviation increase in cHRC: 2.6, 95% confidence limits: 1.42, 5.1) and delayed early cognitive development [odds ratio: 2.3 (1.3; 4.3)]. These associations remain statistically significant when adjusted for major cranial ultrasound abnormality. There was an association of increasing cHRC and delayed psychomotor development, which did not reach statistical significance [odds ratio: 1.7 (1.0, 3.0)]., Conclusion: Among VLBW infants, the cumulative frequency of abnormal HRCs, which can be assessed non-invasively in the neonatal intensive care unit, is associated with an increased risk of adverse neurodevelopmental outcome.

Objective: Monitoring of regulated physiologic processes using physiomarkers such as heart rate variability may be important in the early diagnosis of subacute, potentially catastrophic illness. Early in the course of neonatal sepsis, there are physiomarkers of reduced heart rate variability and transient decelerations similar to fetal distress. The goal of this study was to determine the degree of increased risk for sepsis, urinary tract infection (UTI), and death when these abnormal heart rate characteristics (HRC) were observed., Methods: We monitored 1022 infants at 2 tertiary care NICUs, 458 of whom were very low birth weight. We calculated an HRC index from validated regression models relating mathematical features of heart rate time series and histograms to episodes of illness. We calculated the risks for adverse events of sepsis, UTI, and death for infants stratified by HRC measurements., Results: Compared with infants with low-risk HRC measurements, infants with high-risk HRC measurements had 5- to 6-fold increased risk for an adverse event in the next day and 3-fold increased risk in the next week. Laboratory tests that were relevant to infection added information to HRC measurements. Infants with both high-risk HRC and abnormal laboratory tests had 6- to 7-fold increased risk for an adverse event in the next day compared with infants who had neither., Conclusion: HRC are noninvasively monitored physiomarkers that identify infants in the NICU who are at high risk for sepsis, UTI, and death.