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.

Artificial and human intelligence for early identification of neonatal sepsis.

Artificial intelligence may have a role in the early detection of sepsis in neonates. Machine learning can identify patterns that predict high or increasing risk for clinical deterioration from a sepsis-like illness. In developing this potential addition to NICU care, careful consideration should be given to the data and methods used to develop, validate, and evaluate prediction models. When an AI system alerts clinicians to a change in a patient's condition that warrants a bedside evaluation, human intelligence and experience come into play to determine an appropriate course of action: evaluate and treat or wait and watch closely. With intelligently developed, validated, and implemented AI sepsis systems, both clinicians and patients stand to benefit. IMPACT: This narrative review highlights the application of AI in neonatal sepsis prediction. It describes issues in clinical prediction model development specific to this population. This article reviews the methods, considerations, and literature on neonatal sepsis model development and validation. Challenges of AI technology and potential barriers to using sepsis AI systems in the NICU are discussed.

Impact of race on heart rate characteristics monitoring in very low birth weight infants.

BACKGROUND: A multicenter RCT showed that displaying a heart rate characteristics index (HRCi) predicting late-onset sepsis reduced mortality for VLBW infants. We aimed to assess whether HRCi display had a differential impact for Black versus White infants. METHODS: We performed secondary data analysis of Black and White infants enrolled in the HeRO RCT. We evaluated the predictive performance of the HRCi for infants with Black or White maternal race. Using models adjusted for birth weight, we assessed outcomes and interventions for a race × randomization interaction. RESULTS: Among 2607 infants, Black infants had lower birth weight, gestational age, length of stay, and ventilator days, while sepsis and mortality were similar. The HRCi performed equally for sepsis prediction in Black and White infants. We found no differential effect of randomization by race on sepsis, mortality, antibiotic days, length of stay, or ventilator days. However, there was a differential randomization effect by race for blood cultures per patient: White RR 1.11 (95% CrI 1.04-1.18), Black RR 1.00 (0.93-1.07). CONCLUSIONS: The HRCi performed similarly for sepsis prediction in Black and White infants. Randomization to HRCi display increased blood cultures in White but not in Black infants, while the impact on other outcomes or interventions was similar. IMPACT: Predictive analytics, such as heart rate characteristics (HRC) monitoring for late-onset neonatal sepsis, should have equal impact among patients of different race. Infants with Black or White maternal race randomized to HRC display had similar outcomes, but randomization to the study arm increased a related clinical intervention, blood cultures, in White but not in Black infants. This study provides evidence of a differential effect of predictive models on clinical care by race. The work will promote consideration and analysis of equity in the implementation of predictive analytics.

Heart rate patterns predicting cerebral palsy in preterm infants.

BACKGROUND: Heart rate (HR) patterns can inform on central nervous system dysfunction. We previously used highly comparative time series analysis (HCTSA) to identify HR patterns predicting mortality among patients in the neonatal intensive care unit (NICU) and now use this methodology to discover patterns predicting cerebral palsy (CP) in preterm infants. METHOD: We studied NICU patients <37 weeks' gestation with archived every-2-s HR data throughout the NICU stay and with or without later diagnosis of CP (n = 57 CP and 1119 no CP). We performed HCTSA of >2000 HR metrics and identified 24 metrics analyzed on HR data from two 7-day periods: week 1 and 37 weeks' postmenstrual age (week 1, week 37). Multivariate modeling was used to optimize a parsimonious prediction model. RESULTS: Week 1 HR metrics with maximum AUC for CP prediction reflected low variability, including "RobustSD" (AUC 0.826; 0.772-0.870). At week 37, high values of a novel HR metric, "LongSD3," the cubed value of the difference in HR values 100 s apart, were added to week 1 HR metrics for CP prediction. A combined birthweight + early and late HR model had AUC 0.853 (0.805-0.892). CONCLUSIONS: Using HCTSA, we discovered novel HR metrics and created a parsimonious model for CP prediction in preterm NICU patients. IMPACT: We discovered new heart rate characteristics predicting CP in preterm infants. Using every-2-s HR from two 7-day periods and highly comparative time series analysis, we found a measure of low variability HR week 1 after birth and a pattern of recurrent acceleration in HR at term corrected age that predicted CP. Combined clinical and early and late HR features had AUC 0.853 for CP prediction.

Cardiorespiratory signature of neonatal sepsis: development and validation of prediction models in 3 NICUs.

BACKGROUND: Heart rate characteristics aid early detection of late-onset sepsis (LOS), but respiratory data contain additional signatures of illness due to infection. Predictive models using cardiorespiratory data may improve early sepsis detection. We hypothesized that heart rate (HR) and oxygenation (SpO2) data contain signatures that improve sepsis risk prediction over HR or demographics alone. METHODS: We analyzed cardiorespiratory data from very low birth weight (VLBW, <1500 g) infants admitted to three NICUs. We developed and externally validated four machine learning models to predict LOS using features calculated every 10 m: mean, standard deviation, skewness, kurtosis of HR and SpO2, and cross-correlation. We compared feature importance, discrimination, calibration, and dynamic prediction across models and cohorts. We built models of demographics and HR or SpO2 features alone for comparison with HR-SpO2 models. RESULTS: Performance, feature importance, and calibration were similar among modeling methods. All models had favorable external validation performance. The HR-SpO2 model performed better than models using either HR or SpO2 alone. Demographics improved the discrimination of all physiologic data models but dampened dynamic performance. CONCLUSIONS: Cardiorespiratory signatures detect LOS in VLBW infants at 3 NICUs. Demographics risk-stratify, but predictive modeling with both HR and SpO2 features provides the best dynamic risk prediction. IMPACT: Heart rate characteristics aid early detection of late-onset sepsis, but respiratory data contain signatures of illness due to infection. Predictive models using both heart rate and respiratory data may improve early sepsis detection. A cardiorespiratory early warning score, analyzing heart rate from electrocardiogram or pulse oximetry with SpO2, predicts late-onset sepsis within 24 h across multiple NICUs and detects sepsis better than heart rate characteristics or demographics alone. Demographics risk-stratify, but predictive modeling with both HR and SpO2 features provides the best dynamic risk prediction. The results increase understanding of physiologic signatures of neonatal sepsis.

Continuous ECG monitoring should be the heart of bedside AI-based predictive analytics monitoring for early detection of clinical deterioration.

The idea that we can detect subacute potentially catastrophic illness earlier by using statistical models trained on clinical data is now well-established. We review evidence that supports the role of continuous cardiorespiratory monitoring in these predictive analytics monitoring tools. In particular, we review how continuous ECG monitoring reflects the patient and not the clinician, is less likely to be biased, is unaffected by changes in practice patterns, captures signatures of illnesses that are interpretable by clinicians, and is an underappreciated and underutilized source of detailed information for new mathematical methods to reveal.

Sepsis and Mortality Prediction in Very Low Birth Weight Infants: Analysis of HeRO and nSOFA.

OBJECTIVE: Scores to predict sepsis or define sepsis severity could improve care for very low birth weight (VLBW) infants. The heart rate characteristics (HRC) index (HeRO score) was developed as an early warning system for late-onset sepsis (LOS), and also rises before necrotizing enterocolitis (NEC). The neonatal sequential organ failure assessment (nSOFA) was developed to predict sepsis-associated mortality using respiratory, hemodynamic, and hematologic data. The aim of this study was to analyze the HRC index and nSOFA near blood cultures in VLBW infants relative to diagnosis and sepsis-associated mortality. STUDY DESIGN: Retrospective, single-center study of VLBW infants from 2011 to 2019. We analyzed HRC index and nSOFA around blood cultures diagnosed as LOS/NEC. In a subgroup of the cohort, we analyzed HRC and nSOFA near the first sepsis-like illness (SLI) or sepsis ruled-out (SRO) compared with LOS/NEC. We compared scores by diagnosis and mortality during treatment. RESULTS: We analyzed 179 LOS/NEC, 93 SLI, and 96 SRO blood culture events. In LOS/NEC, the HRC index increased before the blood culture, while nSOFA increased at the time of culture. Both scores were higher in nonsurvivors compared with survivors and in LOS/NEC compared with SRO. The nSOFA 12 hours after the time of blood culture predicted mortality during treatment better than any other time point analyzed (area under the curve 0.91). CONCLUSION: The HRC index provides earlier warning of imminent sepsis, whereas nSOFA after blood culture provides better prediction of mortality. KEY POINTS: · The HRC index and nSOFA provide complementary information on sepsis risk and sepsis-related mortality risk.. · This study adds to existing literature evaluating these risk scores independently by analyzing them together and in cases of not only proven but also suspected infections.. · The impact of combining risk models could be improved outcomes for premature infants..

Early Vital Sign Differences in Very Low Birth Weight Infants with Severe Intraventricular Hemorrhage.

OBJECTIVE: Severe intraventricular hemorrhage (sIVH, grades 3 and 4) is a serious complication for very low birth weight (VLBW) infants and is often clinically silent requiring screening cranial ultrasound (cUS) for detection. Abnormal vital sign (VS) patterns might serve as biomarkers to identify risk or occurrence of sIVH. STUDY DESIGN: This retrospective study was conducted in VLBW infants admitted to two level-IV neonatal intensive care units (NICUs) between January 2009 and December 2018. Inclusion criteria were: birth weight <1.5 kg and gestational age (GA) <32 weeks, at least 12 hours of systemic oxygen saturation from pulse oximetry (SpO2) data over the first 24 hours and cUS imaging. Infants were categorized as early sIVH (sIVH identified in the first 48 hours), late sIVH (sIVH identified after 48 hours and normal imaging in the first 48 hours), and no IVH. Infants with grades 1 and 2 or unknown timing IVH were excluded. Mean heart rate (HR), SpO2, mean arterial blood pressure (MABP), number of episodes of bradycardia (HR < 100 bpm), and desaturation (SpO2 < 80%) were compared. RESULTS: A total of 639 infants (mean: 27 weeks' gestation) were included (567 no IVH, 34 early sIVH, and 37 late sIVH). In the first 48 hours, those with sIVH had significantly higher HR compared with those with no IVH. Infants with sIVH also had lower mean SpO2 and MABP and more desaturations <80%. No significant differences in VS patterns were identified in early versus late sIVH. Logistic regression identified higher HR and greater number of desaturations <80% as independently associated with sIVH. CONCLUSION: VLBW infants who develop sIVH demonstrate VS differences with significantly lower SpO2 and higher mean HR over the first 48 hours after birth compared with VLBW infants with no IVH. Abnormalities in early VS patterns may be a useful biomarker for sIVH. Whether VS abnormalities predict or simply reflect sIVH remains to be determined. KEY POINTS: · A higher HR in the first 48 hours is seen in infants with severe IVH.. · Infants with sIVH have lower blood pressure in the first 48 hours.. · Infants with sIVH have more oxygen desaturations in the first 48 hours..

Vital signs as physiomarkers of neonatal sepsis.

Neonatal sepsis accounts for significant morbidity and mortality, particularly among premature infants in the Neonatal Intensive Care Unit. Abnormal vital sign patterns serve as physiomarkers of sepsis and provide early warning of illness before overt clinical decompensation. The systemic inflammatory response to pathogens signals the autonomic nervous system, leading to changes in temperature, respiratory rate, heart rate, and blood pressure. In infants with comorbidities of prematurity, vital sign abnormalities often occur in the absence of infection, which confounds sepsis diagnosis. This review will cover the mechanisms of vital sign changes in neonatal sepsis, including the cholinergic anti-inflammatory pathway mediated by the vagus nerve, which is critical to the host response to infectious and inflammatory insults. We will also review the clinical implications of vital sign changes in neonatal sepsis, including their use in early warning scores and systems to direct clinicians to the bedside of infants with physiologic changes that might be due to sepsis. IMPACT: This manuscript summarizes and reviews the relevant literature on the physiological manifestations of neonatal sepsis and how we monitor and analyze these through vital signs and advanced analytics.

Heart Rate and Pulse Oximetry Dynamics in the First Week after Birth in Neonatal Intensive Care Unit Patients and the Risk of Cerebral Palsy.

OBJECTIVE: Infants in the neonatal intensive care unit (NICU) are at high risk of adverse neuromotor outcomes. Atypical patterns of heart rate (HR) and pulse oximetry (SpO2) may serve as biomarkers for risk assessment for cerebral palsy (CP). The purpose of this study was to determine whether atypical HR and SpO2 patterns in NICU patients add to clinical variables predicting later diagnosis of CP. STUDY DESIGN: This was a retrospective study including patients admitted to a level IV NICU from 2009 to 2017 with archived cardiorespiratory data in the first 7 days from birth to follow-up at >2 years of age. The mean, standard deviation (SD), skewness, kurtosis and cross-correlation of HR and SpO2 were calculated. Three predictive models were developed using least absolute shrinkage and selection operator regression (clinical, cardiorespiratory and combined model), and their performance for predicting CP was evaluated. RESULTS: Seventy infants with CP and 1,733 controls met inclusion criteria for a 3.8% population prevalence. Area under the receiver operating characteristic curve for CP prediction was 0.7524 for the clinical model, 0.7419 for the vital sign model, and 0.7725 for the combined model. Variables included in the combined model were lower maternal age, outborn delivery, lower 5-minute Apgar's score, lower SD of HR, and more negative skewness of HR. CONCLUSION: In this study including NICU patients of all gestational ages, HR but not SpO2 patterns added to clinical variables to predict the eventual diagnosis of CP. Identification of risk of CP within the first few days of life could result in improved therapy resource allocation and risk stratification in clinical trials of new therapeutics. KEY POINTS: · SD and skewness of HR have some added predictive value of later diagnosis of CP.. · SpO2 measures do not add to CP prediction.. · Combining clinical variables with early HR measures may improve the prediction of later CP..

Low Variability of Blood Pressure Predicts Abnormal Electroencephalogram in Infants with Hypoxic Ischemic Encephalopathy.

OBJECTIVE: This study aimed to evaluate the role of an objective physiologic biomarker, arterial blood pressure variability, for the early identification of adverse short-term electroencephalogram (EEG) outcomes in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: In this multicenter observational study, we analyzed blood pressure of infants meeting these criteria: (1) neonatal encephalopathy determined by modified Sarnat exam, (2) continuous mean arterial blood pressure (MABP) data between 18 and 27 hours after birth, and (3) continuous EEG performed for at least 48 hours. Adverse outcome was defined as moderate-severe grade EEG at 48 hours. Standardized signal preprocessing was used; the power spectral density was computed without interpolation. Multivariate binary logistic regression was used to identify which MABP time and frequency domain metrics provided improved predictive power for adverse outcomes compared with standard clinical predictors (5-minute Apgar score and cord pH) using receiver operator characteristic analysis. RESULTS: Ninety-one infants met inclusion criteria. The mean gestational age was 38.4 ± 1.8 weeks, the mean birth weight was 3,260 ± 591 g, 52/91 (57%) of infants were males, the mean cord pH was 6.95 ± 0.21, and 10/91 (11%) of infants died. At 48 hours, 58% of infants had normal or mildly abnormal EEG background and 42% had moderate or severe EEG backgrounds. Clinical predictor variables (10-minute Apgar score, Sarnat stage, and cord pH) were modestly predictive of 48 hours EEG outcome with area under curve (AUC) of 0.66 to 0.68. A composite model of clinical and optimal time- and frequency-domain blood pressure variability had a substantially improved AUC of 0.86. CONCLUSION: Time- and frequency-domain blood pressure variability biomarkers offer a substantial improvement in prediction of later adverse EEG outcomes over perinatal clinical variables in a two-center cohort of infants with HIE. KEY POINTS: · Early outcome prediction in HIE is suboptimal.. · Patterns in blood pressure physiology may be predictive of short-term outcomes.. · Early time- and frequency-domain measures of blood pressure variability predict short-term EEG outcomes in HIE infants better than perinatal factors alone..

Video-Assisted Informed Consent in a Clinical Trial of Resuscitation of Extremely Preterm Infants: Lessons Learned.

OBJECTIVE: Obtaining informed consent for clinical trials is challenging in acute clinical settings. For the VentFirst randomized clinical trial (assisting ventilation during delayed cord clamping for infants <29 weeks' gestation), we created an informational video that sites could choose to use to supplement the standard in-person verbal and written consent. Using a postconsent survey, we sought to describe the impact of the video on patient recruitment, satisfaction with the consent process, and knowledge about the study. STUDY DESIGN: This is a descriptive survey-based substudy. RESULTS: Of the sites participating in the VentFirst trial that obtained institutional review board (IRB) approval to allow use of the video to supplement the standard informed consent process, three elected to participate in the survey substudy. From February 2018 to January 2021, 82 women at these three sites were offered the video and completed the postconsent survey. Overall, 73 of these 82 women (89%) consented to participate in the primary study, 78 (95%) indicated the study was explained to them very well or extremely well, and the range of correct answers on five knowledge questions about the study was 63 to 98%. Forty-six (56%) of the 82 women offered the video chose to watch it. There were no major differences in study participation, satisfaction with the consent process, or knowledge about the study between the women who chose to watch or not watch the video. CONCLUSION: Watching an optional video to supplement the standard informed consent process did not have a major impact on outcomes in this small substudy. The ways in which audiovisual tools might modify the traditional informed consent process deserve further study. KEY POINTS: · Informed consent in acute clinical contexts is difficult.. · Videos offer an alternative communication tool.. · Continued research is necessary to optimize the consent process..

Framework for Considering Abnormal Heart Rate Characteristics and Other Signs of Sepsis in Very Low Birth Weight Infants.

OBJECTIVE: A heart rate characteristics index (HeRO score), incorporating low variability and superimposed decelerations, was developed as a sepsis risk indicator for preterm infants in the neonatal intensive care unit (NICU). A rise in the risk score should prompt consideration of other clinical changes that may be signs of sepsis to decide whether a workup and antibiotics are needed. We aimed to develop a framework to systematically consider signs potentially indicating sepsis in very low birth weight (VLBW) infants. STUDY DESIGN: We developed easy-recall acronyms for 10 signs of sepsis in VLBW infants. Over 12 months in a level IV NICU, neonatology fellows completed a brief survey after each shift to document changes prompting sepsis workups. We analyzed associations between survey data, hourly heart rate characteristic data, and the diagnosis of the workup, grouped as culture-positive sepsis (CXSEP, positive blood or urine culture), clinical sepsis (CLINSEP, negative cultures treated with antibiotics ≥5 days), or sepsis ruled out (SRO, negative cultures and <3 days antibiotics). RESULTS: We analyzed 93 sepsis workups in 48 VLBW infants (35 CXSEP, 20 CLINSEP, and 38 SRO). The most frequently cited changes prompting the workups were heart rate patterns and respiratory deterioration, which were common in all three categories. Low blood pressure and poor perfusion were uncommonly cited but were more likely to be associated with CXSEP than the other signs. A rise in the HeRO score ≥1 from 0 to 12 hours before compared with 12to 72 hours prior the blood culture occurred in 31% of workups diagnosed as CXSEP, 16% CLINSEP, and 31% SRO. CONCLUSION: The HeRO score can alert clinicians to VLBW infants at high or increasing risk of a sepsis-like illness, but heart rate characteristic patterns are highly variable in individual babies. The easy-recall NeoSEP-10 framework can assist clinicians in considering other clinical changes when making decisions about sepsis workups and the duration of antibiotics. KEY POINTS: · Abnormal heart rate characteristics can indicate sepsis or other pathologies in preterm infants.. · We developed a simple bedside tool to consider clinical signs potentially associated with sepsis.. · Considering vital sign trends together with clinical changes is a key to right-timing antibiotics..

Autism risk in neonatal intensive care unit patients associated with novel heart rate patterns.

BACKGROUND: Neonatal intensive care unit (NICU) patients are at increased risk for autism spectrum disorder (ASD). Autonomic nervous system aberrancy has been described in children with ASD, and we aimed to identify heart rate (HR) patterns in NICU patients associated with eventual ASD diagnosis. METHODS: This retrospective cohort study included NICU patients from 2009 to 2016 with archived HR data and follow-up beyond age 3 years. Medical records provided clinical variables and ASD diagnosis. HR data were compared in infants with and without ASD. RESULTS: Of the 2371 patients, 88 had ASD, and 689,016 h of data were analyzed. HR skewness (HRskw) was significantly different between ASD and control infants. Preterm infants at early postmenstrual ages (PMAs) had negative HRskw reflecting decelerations, which increased with maturation. From 34 to 42 weeks PMA, positive HRskw toward accelerations was higher in males with ASD. In 931 males with at least 4 days of HR data, overall ASD prevalence was 5%, whereas 11% in the top 5th HRskw percentile had ASD. CONCLUSION: High HRskw in NICU males, perhaps representing autonomic imbalance, was associated with increased ASD risk. Further study is needed to determine whether HR analysis identifies highest-risk infants who might benefit from earlier screening and therapies. IMPACT: In a large retrospective single-center cohort of NICU patients, we found that high positive skewness of heart rate toward more accelerations was significantly associated with increased risk of eventual autism spectrum disorder diagnosis in male infants but not in females. Existing literature describes differences in heart rate characteristics in children, adolescents, and adults with autism spectrum disorders, but the finding from our study in NICU infants is novel. Heart rate analysis during the NICU stay might identify, among an inherently high-risk population, those infants with especially high risk of ASD who might benefit from earlier screening and therapies.

Vital sign metrics of VLBW infants in three NICUs: implications for predictive algorithms.

BACKGROUND: Continuous heart rate (HR) and oxygenation (SpO2) metrics can be useful for predicting adverse events in very low birth weight (VLBW) infants. To optimize the utility of these tools, inter-site variability must be taken into account. METHODS: For VLBW infants at three neonatal intensive care units (NICUs), we analyzed the mean, standard deviation, skewness, kurtosis, and cross-correlation of electrocardiogram HR, pulse oximeter pulse rate, and SpO2. The number and durations of bradycardia and desaturation events were also measured. Twenty-two metrics were calculated hourly, and mean daily values were compared between sites. RESULTS: We analyzed data from 1168 VLBW infants from birth through day 42 (35,238 infant-days). HR and SpO2 metrics were similar at the three NICUs, with mean HR rising by ~10 beats/min over the first 2 weeks and mean SpO2 remaining stable ~94% over time. The number of bradycardia events was higher at one site, and the duration of desaturations was longer at another site. CONCLUSIONS: Mean HR and SpO2 were generally similar among VLBW infants at three NICUs from birth through 6 weeks of age, but bradycardia and desaturation events differed in the first 2 weeks after birth. This highlights the importance of developing predictive analytics tools at multiple sites. IMPACT: HR and SpO2 analytics can be useful for predicting adverse events in VLBW infants in the NICU, but inter-site differences must be taken into account in developing predictive algorithms. Although mean HR and SpO2 patterns were similar in VLBW infants at three NICUs, inter-site differences in the number of bradycardia events and duration of desaturation events were found. Inter-site differences in bradycardia and desaturation events among VLBW infants should be considered in the development of predictive algorithms.

Central Apnea of Prematurity: Does Sex Matter?

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..

Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial.

OBJECTIVE: To test whether the composite outcome of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age for infants ≤1000 g at birth is decreased by continuous monitoring of heart rate characteristics during neonatal intensive care. STUDY DESIGN: We studied a subset of participants enrolled in a multicenter randomized trial of heart rate characteristics monitoring. Survivors were evaluated at 18-22 months corrected age with a standardized neurologic examination and the Bayley Scales of Infant Development-III (BSID-III). NDI was defined as Gross Motor Function Classification System of >2 (moderate or severe cerebral palsy), BSID-III language or cognitive scores of <70, severe bilateral hearing impairment, and/or bilateral blindness. RESULTS: The composite outcome, death or NDI, was obtained for 628 of 884 study infants (72%). The prevalence of this outcome was 44.4% (136/306) among controls (infants randomized to heart rate characteristics monitored but not displayed) and 38.9% (125/322) among infants randomized to heart rate characteristics monitoring displayed (relative risk, 0.87; 95% CI, 0.73-1.05; P = .17). Mortality was reduced from 32.0% (99/307) among controls to 24.8% (81/326) among monitoring displayed infants (relative risk, 0.75; 95% CI, 0.59 to 0.97; P = .028). The composite outcomes of death or severe CP and death or mildly low Bayley cognitive score occurred less frequently in the displayed group (P < .05). CONCLUSIONS: We found no difference in the composite outcome of death or NDI for extremely preterm infants whose heart rate characteristics were and were not displayed during neonatal intensive care. Two outcomes that included mortality or a specific NDI were less frequent in the displayed group.

Continuous vital sign analysis for predicting and preventing neonatal diseases in the twenty-first century: big data to the forefront.

In the neonatal intensive care unit (NICU), heart rate, respiratory rate, and oxygen saturation are vital signs (VS) that are continuously monitored in infants, while blood pressure is often monitored continuously immediately after birth, or during critical illness. Although changes in VS can reflect infant physiology or circadian rhythms, persistent deviations in absolute values or complex changes in variability can indicate acute or chronic pathology. Recent studies demonstrate that analysis of continuous VS trends can predict sepsis, necrotizing enterocolitis, brain injury, bronchopulmonary dysplasia, cardiorespiratory decompensation, and mortality. Subtle changes in continuous VS patterns may not be discerned even by experienced clinicians reviewing spot VS data or VS trends captured in the monitor. In contrast, objective analysis of continuous VS data can improve neonatal outcomes by allowing heightened vigilance or preemptive interventions. In this review, we provide an overview of the studies that have used continuous analysis of single or multiple VS, their interactions, and combined VS and clinical analytic tools, to predict or detect neonatal pathophysiology. We make the case that big-data analytics are promising, and with continued improvements, can become a powerful tool to mitigate neonatal diseases in the twenty-first century.

Correction: Oxygen desaturations in the early neonatal period predict development of bronchopulmonary dysplasia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction: Recovery from bradycardia and desaturation events at 32 weeks corrected age and NICU length of stay: an indicator of physiologic resilience?

An amendment to this paper has been published and can be accessed via a link at the top of the paper.