Ventilatory Assistance Before Umbilical Cord Clamping in Extremely Preterm Infants: A Randomized Clinical Trial.

Importance: Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants. Objective: To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death. Design, Setting, and Participants: This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth. Intervention: After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation. Main Outcomes and Measures: The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs. Results: Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort. Conclusions and Relevance: This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight. Trial Registration: ClinicalTrials.gov Identifier: NCT02742454.

Systematic review and network meta-analysis with individual participant data on cord management at preterm birth (iCOMP): study protocol.

INTRODUCTION: Timing of cord clamping and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups. Previous and current trials compare various policies, including time-based or physiology-based deferred cord clamping, and cord milking. Individual participant data (IPD) enable exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. OBJECTIVES: (1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis. (2) To evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. METHODS AND ANALYSIS: Systematic searches of Medline, Embase, clinical trial registries, and other sources for all ongoing and completed randomised controlled trials comparing cord management strategies at preterm birth (before 37 weeks' gestation) have been completed up to 13 February 2019, but will be updated regularly to include additional trials. IPD will be sought for all trials; aggregate summary data will be included where IPD are unavailable. First, deferred clamping and cord milking will be compared with immediate clamping in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for prespecified participant subgroups. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes. Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. ETHICS AND DISSEMINATION: Ethics approval for this project has been granted by the University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline developers and policy-makers, and will be disseminated via publications, presentations and media releases. REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001305112) and International Prospective Register of Systematic Reviews (PROSPERO, CRD42019136640).

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.

Ventilation of Preterm Infants during Delayed Cord Clamping (VentFirst): A Pilot Study of Feasibility and Safety.

Background Establishing lung inflation prior to umbilical cord clamping may improve the cardiovascular transition and reduce the risk of intraventricular hemorrhage in preterm infants. We developed a pilot feasibility and safety study in which infants < 33 weeks' gestation received assisted ventilation during delayed cord clamping (DCC). Methods Infants born between 24 0/7 and 32 6/7 weeks' gestation whose mothers consented were enrolled. All infants received continuous positive airway pressure or positive pressure ventilation during 90 seconds of DCC. Outcomes included feasibility (ability to complete protocol and maintain a sterile field during cesarean deliveries) and safety variables (Apgar scores, umbilical cord pH and base deficit, admission temperature, and postcesarean infection). Results A total of 29 infants were enrolled, including one set of twins (median gestation: 30 weeks; 72% cesarean births). In all cases, the protocol was completed. Heart rate at 60 seconds was more than 100 beats per minute in all infants. Apgar scores, cord blood gas values, and admission temperature were comparable to other preterm deliveries at our institution. Conclusion Assisting ventilation of very preterm infants during 90 seconds of DCC is challenging but feasible and appears to be safe in this small pilot study. A randomized clinical trial is warranted to determine clinical benefit.

Vital signs and their cross-correlation in sepsis and NEC: a study of 1,065 very-low-birth-weight infants in two NICUs.

BACKGROUND: Subtle changes in vital signs and their interactions occur in preterm infants prior to overt deterioration from late-onset septicemia (LOS) or necrotizing enterocolitis (NEC). Optimizing predictive algorithms may lead to earlier treatment. METHODS: For 1,065 very-low-birth-weight (VLBW) infants in two neonatal intensive care units (NICUs), mean, SD, and cross-correlation of respiratory rate, heart rate (HR), and oxygen saturation (SpO2) were analyzed hourly (131 infant-years' data). Cross-correlation (cotrending) between two vital signs was measured allowing a lag of ± 30 s. Cases of LOS and NEC were identified retrospectively (n = 186) and vital sign models were evaluated for ability to predict illness diagnosed in the ensuing 24 h. RESULTS: The best single illness predictor within and between institutions was cross-correlation of HR-SpO2. The best combined model (mean SpO2, SDHR, and cross-correlation of HR-SpO2,) trained at one site with ROC area 0.695 had external ROC area of 0.754 at the other site, and provided additive value to an established HR characteristics index for illness prediction (Net Reclassification Improvement: 0.205; 95% confidence interval (CI): 0.113, 0.328). CONCLUSION: Despite minor inter-institutional differences in vital sign patterns of VLBW infants, cross-correlation of HR-SpO2 and a 3-variable vital sign model performed well at both centers for preclinical detection of sepsis or NEC.

Stochastic modeling of central apnea events in preterm infants.

A near-ubiquitous pathology in very low birth weight infants is neonatal apnea, breathing pauses with slowing of the heart and falling blood oxygen. Events of substantial duration occasionally occur after an infant is discharged from the neonatal intensive care unit (NICU). It is not known whether apneas result from a predictable process or from a stochastic process, but the observation that they occur in seemingly random clusters justifies the use of stochastic models. We use a hidden-Markov model to analyze the distribution of durations of apneas and the distribution of times between apneas. The model suggests the presence of four breathing states, ranging from very stable (with an average lifetime of 12 h) to very unstable (with an average lifetime of 10 s). Although the states themselves are not visible, the mathematical analysis gives estimates of the transition rates among these states. We have obtained these transition rates, and shown how they change with post-menstrual age; as expected, the residence time in the more stable breathing states increases with age. We also extrapolated the model to predict the frequency of very prolonged apnea during the first year of life. This paradigm-stochastic modeling of cardiorespiratory control in neonatal infants to estimate risk for severe clinical events-may be a first step toward personalized risk assessment for life threatening apnea events after NICU discharge.

Clinical associations with immature breathing in preterm infants: part 2-periodic breathing.

BACKGROUND: Periodic breathing (PB) is a normal immature breathing pattern in neonates that, if extreme, may be associated with pathologic conditions. METHODS: We used our automated PB detection system to analyze all bedside monitor chest impedance data on all infants <35 wk' gestation in the University of Virginia Neonatal Intensive Care Unit from 2009-2014 (n = 1,211). Percent time spent in PB was calculated hourly (>50 infant-years' data). Extreme PB was identified as a 12-h period with PB >6 SDs above the mean for gestational age (GA) and postmenstrual age and >10% time in PB. RESULTS: PB increased with GA, with the highest amount in infants 30-33 wk' GA at about 2 wk' chronologic age. Extreme PB was identified in 76 infants and in 45% was temporally associated with clinical events including infection or necrotizing enterocolitis (NEC), immunizations, or caffeine discontinuation. In 8 out of 28 cases of septicemia and 10 out of 21 cases of NEC, there was a >2-fold increase in %PB over baseline on the day prior to diagnosis. CONCLUSION: Infants <35 wk GA spend, on average, <6% of the time in PB. An acute increase in PB may reflect illness or physiological stressors or may occur without any apparent clinical event.

Clinical associations of immature breathing in preterm infants: part 1-central apnea.

BACKGROUND: Apnea of prematurity (AOP) is nearly universal among very preterm infants, but neither the apnea burden nor its clinical associations have been systematically studied in a large consecutive cohort. METHODS: We analyzed continuous bedside monitor chest impedance and electrocardiographic waveforms and oxygen saturation data collected on all neonatal intensive care unit (NICU) patients <35 wk gestation from 2009 to 2014 (n = 1,211; >50 infant-years of data). Apneas, with bradycardia and desaturation (ABDs), defined as central apnea ≥10 s associated with both bradycardia <100 bpm and oxygen desaturation <80%, were identified using a validated automated algorithm. RESULTS: Number and duration of apnea events decreased with increasing gestational age (GA) and postmenstrual age (PMA). ABDs were more frequent in infants <31 wk GA at birth but were not more frequent in those with severe retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), or severe intraventricular hemorrhage (IVH) after accounting for GA. In the day before diagnosis of late-onset septicemia and necrotizing enterocolitis, ABD events were increased in some infants. Many infants continued to experience short ABD events in the week prior to discharge home. CONCLUSION: Frequency of apnea events is a function of GA and PMA in infants born preterm, and increased apnea is associated with acute but not with chronic pathologic conditions.

Quantification of periodic breathing in premature infants.

Periodic breathing (PB), regular cycles of short apneic pauses and breaths, is common in newborn infants. To characterize normal and potentially pathologic PB, we used our automated apnea detection system and developed a novel method for quantifying PB. We identified a preterm infant who died of sudden infant death syndrome (SIDS) and who, on review of her breathing pattern while in the neonatal intensive care unit (NICU), had exaggerated PB.We analyzed the chest impedance signal for short apneic pauses and developed a wavelet transform method to identify repetitive 10-40 second cycles of apnea/breathing. Clinical validation was performed to distinguish PB from apnea clusters and determine the wavelet coefficient cutoff having optimum diagnostic utility. We applied this method to analyze the chest impedance signals throughout the entire NICU stays of all 70 infants born at 32 weeks' gestation admitted over a two-and-a-half year period. This group includes an infant who died of SIDS and her twin.For infants of 32 weeks' gestation, the fraction of time spent in PB peaks 7-14 d after birth at 6.5%. During that time the infant that died of SIDS spent 40% of each day in PB and her twin spent 15% of each day in PB.This wavelet transform method allows quantification of normal and potentially pathologic PB in NICU patients.

Very long apnea events in preterm infants.

Apnea is nearly universal among very low birth weight (VLBW) infants, and the associated bradycardia and desaturation may have detrimental consequences. We describe here very long (>60 s) central apnea events (VLAs) with bradycardia and desaturation, discovered using a computerized detection system applied to our database of over 100 infant years of electronic signals. Eighty-six VLAs occurred in 29 out of 335 VLBW infants. Eighteen of the 29 infants had a clinical event or condition possibly related to the VLA. Most VLAs occurred while infants were on nasal continuous positive airway pressure, supplemental oxygen, and caffeine. Apnea alarms on the bedside monitor activated in 66% of events, on average 28 s after cessation of breathing. Bradycardia alarms activated late, on average 64 s after cessation of breathing. Before VLAs oxygen saturation was unusually high, and during VLAs oxygen saturation and heart rate fell unusually slowly. We give measures of the relative severity of VLAs and theoretical calculations that describe the rate of decrease of oxygen saturation. A clinical conclusion is that very long apnea (VLA) events with bradycardia and desaturation are not rare. Apnea alarms failed to activate for about one-third of VLAs. It appears that neonatal intensive care unit (NICU) personnel respond quickly to bradycardia alarms but not consistently to apnea alarms. We speculate that more reliable apnea detection systems would improve patient safety in the NICU. A physiological conclusion is that the slow decrease of oxygen saturation is consistent with a physiological model based on assumed high values of initial oxygen saturation.

Accurate automated apnea analysis in preterm infants.

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.

Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial.

BACKGROUND: Abnormal heart rate characteristics (HRC) wax and wane in early stages of culture-positive, late-onset septicemia (LOS) in patients in the neonatal intensive care unit (NICU). Continuously monitoring an HRC index leads to a reduction in mortality among very low birth weight (VLBW) infants. We hypothesized that the reduction in mortality was due to a decrease in septicemia-associated mortality. METHODS: This is a secondary analysis of clinical and HRC data from 2,989 VLBW infants enrolled in a randomized clinical trial of HRC monitoring in nine NICUs from 2004 to 2010. RESULTS: LOS was diagnosed 974 times in 700 patients, and the incidence and distribution of organisms were similar in HRC display and nondisplay groups. Mortality within 30 d of LOS was lower in the HRC display as compared with the nondisplay group (11.8 vs. 19.6%; relative risk: 0.61; 95% confidence interval: 0.43, 0.87; P < 0.01), but mortality reduction was not statistically significant for patients without LOS. There were fewer large, abrupt increases in the HRC index in the days leading up to LOS diagnosis in infants whose HRC index was displayed. CONCLUSION: Continuous HRC monitoring is associated with a lower septicemia-associated mortality in VLBW infants, possibly due to diagnosis earlier in the course of illness.