Oxygen (O2) is vital for cellular development, function, proliferation, and repair, underscoring its critical role in organogenesis. Both hypoxia (reduced tissue O2) and hyperoxia (excess tissue O2), when prolonged, can trigger inflammation and oxidative stress, contributing to acute and long-term cardiopulmonary and neurodevelopmental morbidity. In sick neonates, immature defense mechanisms and coexisting morbidities demand nuanced and sometimes opposing strategies for O2 saturation targets and therapeutic titration. Most current neonatal O2 targeting guidelines are based on animal models or small clinical studies, resulting in recommendations with limited evidence. This narrative review aims to provide an updated overview of the physiological roles of O2 in development, its delivery and consumption, approaches to O2 saturation monitoring, and therapeutic targeting in neonates under both normal and pathological conditions. We also highlight key knowledge gaps and propose directions for future research on neonatal O2 saturation targeting.

To evaluate the association between intermittent hypoxemia (IH) and hyperoxemia (HOX) during the first 28 days with peripheral and central chemoreception at 36 weeks of postmenstrual age among infants born extremely preterm.

For this observational study, 52 infants born at 23-28 weeks of gestational age were enrolled. Mean daily IH frequency (arterial oxygen saturation <80% for ≥10 seconds) and percent of time in HOX (arterial oxygen saturation ≥98% while the fraction of inspired oxygen was >0.21) were calculated for the first 28 days of life. At 36 weeks of postmenstrual age, respiratory control tests assessed peripheral chemoreception by ventilatory response to 100% O2 for 30 seconds in which decreased ventilation caused by inhibition of peripheral chemoreceptors reflects their contribution to respiratory drive. Central chemoreception was evaluated by ventilatory response to 4% inspired CO2 for 10 minutes.

Multivariable generalized linear models showed increasing IH and HOX were independently associated with an attenuated ventilatory response to 100% O2 at 36 weeks of postmenstrual age. IH and HOX were not significantly associated with an attenuated ventilatory response to CO2.

In these infants born extremely preterm, neonatal IH and HOX were independently associated with attenuated peripheral chemoreception at near-term corrected age. This may reflect reduced peripheral chemoreceptor oxygen sensitivity and may be in part responsible for persistence of respiratory instability in infants born preterm. Neonatal IH or HOX were not associated with reduced central chemoreception.

This review outlines the prevalence and complications of apneas and intermittent hypoxemic events in preterm infants, examines current monitoring limitations in neonatal ICUs (NICUs), and explores emerging technologies addressing these challenges.

New evidence from the Prematurity-Related Ventilatory Control (Pre-Vent) study, which analyzed cardiorespiratory data from 717 extremely preterm infants, exposes the varying frequency, duration, and severity of apneas, intermittent hypoxemia, bradycardias, and periodic breathing during hospitalization, and highlights the negative impact of intermittent hypoxemia on pulmonary outcomes at discharge. Although traditional monitoring methods cannot differentiate between apnea types and quantify their burden, recent advancements in sensor technologies and data integration hold promise for improving real-time detection and evaluation of apneas in the NICU. Notably, small wearable mechano-acoustic sensors could improve apnea monitoring through continuous detection of airflow and respiratory efforts. Additionally, integrating bedside physiological data with modalities such as near-infrared spectroscopy, diaphragmatic activity, and electrical impedance tomography could help predict adverse outcomes by monitoring regional oxygen saturation and lung function in relation to apneas.

Enhancing our understanding of neonatal apneas and overcoming the current limitations in apnea monitoring through advanced sensor technologies and data integration could lead to more personalized management and improved outcomes for preterm infants.

To compare the effect of liberal versus restrictive transfusion strategies on the proportion of time (%time) spent with intermittent hypoxaemia (IH, ie, arterial haemoglobin oxygen saturation measured by pulse oximetry (SpO2) <80% lasting ≥60 s) in the 'Effects of Transfusion Thresholds on Neurocognitive Outcome' (ETTNO) population, and to investigate whether infants with above-median exposure to IH might benefit more from liberal transfusion strategies than those with lower exposure.

Secondary analysis in all 554/1013 infants of <1000 g birth weight recruited into the ETTNO trial (mean gestational age 26.2 weeks) with >80% completeness of SpO2 recordings during postnatal days 8-49.

Randomly assigned liberal (n=268) or restrictive (n=286) transfusion strategies, defining transfusion triggers based on postnatal age and health status.

%time with IH, rate and mean duration of IH episodes during postnatal days 8-49. Interaction between exposure to IH and transfusion strategies with respect to ETTNO's composite primary outcome, death or disability at 24 months corrected age.

The median (quartile 1-quartile 3) %time with IH was similar between treatment groups (0.91% (0.13%-2.83%) with liberal vs 0.79% (0.16%-2.44%) with restrictive transfusions). There was no interaction between exposure to IH and transfusion strategies on outcome at 24 months.

In infants <1000 g birth weight, a liberal transfusion strategy did not reduce IH. Blood transfusions should not be administered 'liberally' to reduce IH or to improve neurocognitive outcome in infants with above-average exposure to IH.

NCT01393496.

Sleep apnea that leads to chronic intermittent hypoxia (CIH) is an independent risk factor for advanced, debilitating ischemic proliferative retinopathies, such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP). The underlying mechanisms are unknown. Here we investigated the consequences of CIH on the ischemic retina of the oxygen-induced retinopathy model. We show that experimental CIH inhibited colony stimulating factor 1 (CSF1) expression, blunting the reactive microgliosis during the ischemic phase of OIR. CIH severely delayed beneficial revascularization of the ischemic retina and increased pathological neovascularization. CIH also induced photoreceptor segment thinning and accentuated OIR-induced inner and outer retinal functional deficits. Mechanistically we demonstrated that local CSF1R inhibition during ischemic retinopathy reduced the number of microglial cells, inhibited revascularization, and exacerbated pathological neovascularization, recapitulating the effects of CIH. Our findings provide a novel mechanism by which sleep apnea and CIH aggravate ischemic retinopathies, underscoring the importance of treating apnea in DR and ROP to help prevent sight threatening severe disease.

In neonatal care, maintaining oxygen levels in the target range is essential to minimize adverse outcomes. Both episodes of hyperoxemia and hypoxemia are associated with adverse neonatal outcomes. Criteria to determine the hypoxemic and hyperoxemic burden are currently not standardized or generally applied in clinical care. This results in difficulty to identify clinically relevant events in preterm infants. Clinical decisions and interventions are therefore mostly based on the experience of the clinical team. This systematic review aims to provide an overview of the used definitions for hypoxemia and hyperoxemia in preterm infants, based on continuous monitoring techniques and the relation to neonatal outcome (PROSPERO: CRD42023493201).

Caffeine is a proven medication used for the prevention and treatment of apnea in premature infants, offering both short- and long-term benefits. International guidelines provide a range of recommendations regarding the preterm population eligible for caffeine prophylaxis, including the timing, dosage, and duration of treatment. Our national guidelines, published prior to the most recent updates of the international guidelines, recommend the use of caffeine citrate starting from the first day after delivery for preterm infants with a gestational age of <28 weeks. For infants up to 32 weeks, if positive pressure ventilation is required, the decision should be made on an individual basis. This study aims to describe the variability in caffeine usage across neonatal intensive care units in our country.

An online survey was sent to neonatologist who are members of the Turkish Neonatology Society to describe the variability in caffeine usage in neonatal intensive care units in our country.

We collected responses from 74 units. Prophylactic caffeine usage was observed as; GA ≤276/7: 98.6%, GA 280/7-286/7: 89.0%, GA 290/7-296/7: 75.3%, GA 300/7-316/7: 53.4%. 62.2% of units reported administering loading dose within the first two hours. The initial maintenance dose was 5 mg/kg in 64.8% of units, 10 mg/kg in 32.4% of units, and intermediate dose in 5.3% of units. 47.3% of units reported no routine dose adjustment. The postmenstrual age that caffeine treatment was stopped was found to be 34 (min-max; 32-36) weeks for infants without apnea and respiratory support, 36 (min-max; 34-52) weeks for infants without apnea but any respiratory support. The time to discharge after treatment cessation was found as; 1-4 days: 37.8%, 5-7 days: 68.9%. Among the 56 units with multiple responsible physicians, 32.1% reported intra-unit variations.

The significant differences in caffeine usage characteristics between and within units highlight the need for clear recommendations provided by standardized guidelines.

To describe the trends in percentage oxygen requirement and mode of respiratory support delivered to extremely premature infants in the 12 weeks after birth.

This is a retrospective study of extremely premature infants (≤276/7 weeks) discharged from neonatal intensive care units managed by Pediatrix Medical Group between January 1, 2016, and December 31, 2021. Demographic and daily clinical data (mode of respiratory support and fraction of inspired oxygen [FiO2]) were extracted from the Pediatrix Clinical Data Warehouse.

A total of 16 386 infants with a median gestational age of 25 weeks and birthweight of 765 g were included. There were 3808 (23.2%) infants who died. Of the cohort, 6019 (43.1%) infants who survived to 36 weeks' gestation had bronchopulmonary dysplasia. Median FiO2 at all gestations followed a biphasic pattern with a peak on day of life 1, reduction to a nadir by day 4 to 5, and an increase to a second peak around day 14. Infants born at lower gestational ages had a higher median FiO2 at each time point. At lower gestations, there were higher proportions of infants receiving mechanical ventilation and a later introduction of noninvasive modes.

Extremely premature infants show a consistent biphasic pattern in percentage of supplemental oxygen required after birth.

Incubator oxygen may improve respiratory stability in preterm infants compared with nasal cannula oxygen.

Single center randomized trial of infants <29 weeks' gestation on supplemental oxygen at ≥32 weeks' postmenstrual age. Infants were crossed-over every 24 hours for 96 hours between incubator oxygen and nasal cannula ≤1.0 L/kg/min. We measured episodes of intermittent hypoxemia (oxygen saturations (SpO2) < 85% ≥10 seconds), bradycardia, cerebral and abdominal hypoxemia, and end-tidal carbon dioxide.

We enrolled 25 infants with a gestational age of 26 weeks 4 days±15 days (mean ± SD) and birth weight 805 ± 202 grams. There were no differences in episodes of intermittent hypoxemia, bradycardia, or cerebral hypoxemia between groups. There were fewer episodes of abdominal hypoxemia <40% ≥10 seconds with incubator oxygen compared with nasal cannula (132 ± 130 versus 158 ± 125; p < 0.01). Time with SpO2 < 85% and abdominal hypoxemia was lower among infants on incubator oxygen. Carbon dioxide values were higher while on incubator oxygen (41 ± 11 versus 36 ± 10 mmHg; p < 0.02).

There was no difference in intermittent hypoxemia between incubator and nasal cannula oxygen among preterm infants on supplemental oxygen. Infants had higher levels of carbon dioxide while on incubator oxygen, which may have improved some measures of respiratory stability. CLINCALTRIALS.

NCT03333174 and NCT03174301.

In this randomized cross-over trial of preterm infants on supplemental oxygen, incubator oxygen did not decrease episodes of intermittent hypoxemia compared with nasal cannula oxygen. Incubator oxygen reduced time with oxygen saturations less than 85%, reduced abdominal hypoxemia, and increased carbon dioxide levels. Differences in measures of respiratory stability on incubator oxygen may be partly due to higher carbon dioxide levels compared with nasal cannula oxygen. The mode of supplemental oxygen administration may impact control of breathing in preterm infants through its effect on hypopharyngeal oxygen stability and carbon dioxide levels.

Approximately 5% of very premature infants delivered at less than 30 weeks' gestation have systemic hypertension. In adult human and animal models, intermittent hypoxemia events are associated with systemic hypertension. In neonates, intermittent hypoxemia events are associated with adverse outcomes, but it is unknown if they are a risk factor for hypertension. We hypothesize that early intermittent hypoxemia events in very preterm neonates are associated with systemic hypertension at 34-36 weeks' postmenstrual age.

Secondary analysis of a single-center cohort study of 164 infants, <31 weeks' gestational age. Intermittent hypoxemia events were continuously recorded during the first 21 days of age.

There was a significant association between the number of intermittent hypoxemia events (per 100) and systemic hypertension (OR (95% CI) = 1.08 (1.01-1.15)), and both the number of intermittent hypoxemia events (per 100 β (95% CI) = 0.22 (0.10-0.34)) and percent of time with hypoxemia (β (95% CI) = 0.10 (0.01-0.19)) and systolic blood pressure at 34-36 weeks' postmenstrual age.

This study demonstrated a higher incidence of early intermittent hypoxemia events in preterm infants with hypertension. Decreasing intermittent hypoxemia during this critical period may reduce incidence of later vascular stress in this population.

Intermittent hypoxemia events are very common in premature infants and increased frequency of intermittent hypoxemia events is associated with morbidity. Intermittent hypoxemia events in adult human as well as adult and neonatal animal models are associated with systemic hypertension. This study demonstrated an association between early intermittent hypoxemia events and systemic hypertension in very preterm neonates, adding to the body of literature of possible morbidities caused by intermittent hypoxemia events. This study addresses the common, though under-recognized, issue of neonatal hypertension, and suggests increased intermittent hypoxemia events may be contributory.

Retinopathy of prematurity (ROP) is a major cause of preventable blindness in preterm infants. The association between red blood cell (RBC) parameters and the development of ROP remains unclear. The objectives of the present study were to evaluate the association between RBC parameters and ROP treatment. This single-center, retrospective cohort study included preterm infants born at < 30 weeks of gestation. Data pertaining to RBC parameters and ROP treatment were obtained from the medical records. A receiver operating characteristic (ROC) analysis was performed to determine the cut-off values of the RBC parameters according to the need for ROP treatment. Multiple logistic regression analyses assessed the association between ROP treatment and RBC parameters at birth and on day of life (DOL) 28. We included 202 infants, and 44.1% were treated for ROP. After adjusting for confounders, we observed associations between ROP treatment and mean corpuscular volume (MCV) values > 117.3 fL at birth (adjusted odds ratio [aOR]:2.3; 95% confidence intervals CI 1.0-5.3). Additionally, on DOL 28, hemoglobin (Hb) values < 9.9 g/dL (aOR:3.0; 95% CI 1.4-6.7), hematocrit (Hct) values < 31.0% (aOR:2.7; 95% CI 1.3-5.6), and red cell distribution width (RDW) values > 18.5% (aOR:2.6; 95% CI 1.1-6.2) were associated with ROP treatment. In conclusion, our study indicated that infants born at < 30 weeks of gestation with an MCV > 117.3 fL at birth, along with Hb < 9.9 g/dL, Hct < 31.0%, and RDW > 18.5% on DOL 28, had an increased risk of requiring ROP, warranting treatment.

To assess the efficacy of the DIGIROP-Birth algorithm in identifying infants at risk for developing retinopathy of prematurity (ROP).

In a retrospective study, we included preterm infants over 11 years, 2010-2020, meeting the inclusion criteria for the DIGIROP-Birth calculator (24 + 0/7 to 30 + 6/7 weeks of gestational age). We assessed the validity of DIGIROP-Birth using receiver-operating characteristic (ROC) curves and calculated area-under-curve (AUC), sensitivity, specificity, and positive and negative predictive values.

897 infants were included in the analysis. The median age of the first ophthalmological examination was 40 days (IQR 32-50), the median gestational age was 198 days (IQR 185-209; corresponding to 28 + 2/7 gestational weeks), median birth weight was 1000 g (IQR 790-1300). Of 897 screened children, 458 (51.1%) were diagnosed with ROP, and 34 of 897 (3.8%) required treatment.Analysis of ROP requiring treatment predicted by DIGIROP showed an AUC of 0.860 [95%-CI 0.795-0.925]. An equilibrium of sensitivity and specificity existed at a probability of 4.12%. The positive predictive value was 10.95%, and the negative predictive value was 99.36%. Independent significant peri- and postnatal risk factors were emergency cesarean section and mass blood transfusions.

The DIGIROP-Birth calculator showed good predictive power in our studied population, with an incidence of 3.79% for therapy-requiring ROP. Peri- and postnatal risk factors should be included in ROP screening.

Pulmonary air leak may cause serious complications and mortality in neonates, especially preterm infants. Its incidence and perinatal risk factors in preterm infants might differ from those in term infants. We investigated the incidence, perinatal risk factors and morbidities associated with pulmonary air leak in very-low-birth-weight (VLBW) preterm infants in Taiwan.

Data from 2011 to 2015 from the nationwide multihospital registry of the Taiwan Premature Infant Follow-up Network were analyzed. Preterm infants with pulmonary air leak, including pneumothorax and pneumomediastinum, were enrolled. Data on perinatal characteristics, the course of resuscitation in the delivery room, the management of respiratory distress syndrome (RDS), and the clinical outcomes of pulmonary air leak were collected and compared between VLBW preterm infants with and without pulmonary air leak.

We included 5906 VLBW preterm infants with a mean gestational age of 28.6 ± 3 weeks and mean birth weight of 1078 ± 284 g. Of them, 379 neonates (6.4%) had pulmonary air leak, with 5.4% and 1% having isolated pneumothorax and isolated pneumomediastinum, respectively. Independent risk factors for pulmonary air leak in VLBW preterm infants were male sex, a 5-min Apgar score <7, and RDS treated with surfactant. VLBW preterm infants who had higher gestational age or received nasal continuous positive airway pressure (NCPAP) had a lower risk of pulmonary air leak. However, pulmonary air leak was associated with higher rates of severe retinopathy of prematurity, severe intraventricular hemorrhage, chronic lung disease, and mortality.

NCPAP appeared to protect against pulmonary air leak in VLBW preterm infants. Clinicians should be aware of the risk factors for pulmonary air leak in such infants and promptly initiate meticulous ventilation strategies as needed.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of methylxanthines in preventing or treating intermittent hypoxemia or respiratory insufficiency in late preterm infants.

Extremely low gestational age neonates (ELGANs, i.e. those born before 28 weeks postmenstrual age (PMA)) often require supplemental oxygen and frequently experience intermittent hypo- and hyperoxemic episodes. Exposure to episodes with inadequate oxygen concentrations has been shown to be associated with an increased risk of retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI) and death. Closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) reduces number and duration of hypo- and hyperoxemic episodes in ELGANs. Its impacts on clinically important short- and long-term outcomes such as ROP, BPD, NEC, NDI and mortality have not yet been studied.

An outcome-assessor-blinded, multicentre, randomized-controlled, parallel-group trial for superiority was designed to study the effects of FiO2-C (provided by standard infant ventilators) in addition to routine manual control (RMC) during respiratory support, compared to RMC only, on short- and long-term clinical outcomes in ELGANs. Two co-primary composite outcomes were defined: (i) death, severe ROP, BPD or NEC, assessed at 36 weeks PMA or, in case of ROP, until complete vascularization of the retina; (ii) death or NDI (defined as language/cognitive delay, motor impairment, severe visual impairment or hearing impairment), assessed at 2 years corrected age.

Primary outcomes will be compared between the two intervention groups using a Cochran-Mantel-Haenszel test. The factors considered for randomization (centre, sex and gestational age at birth (< 26 weeks and ≥ 26 weeks)) will be used to define strata. Results will be presented as adjusted odds ratios with two-sided 95% and 97.5% confidence intervals and two-sided p values.

The statistical analyses for the FiO2-C trial were defined in the study protocol and specified in detail in this statistical analysis plan published prior to any statistical analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

ClinicalTrials.gov NCT03168516. Registered on May 30, 2017.

Apnea of prematurity (AOP) occurs in 85% of neonates ≤34 weeks of gestational age. AOP is frequently associated with intermittent hypoxia (IH). This narrative review reports on the putative relationship of AOP with IH and the resulting oxidative stress (OS). Preterm infants are susceptible to OS due to an imbalance between oxidant and antioxidant systems with the excessive free radical load leading to serious morbidities that may include retinopathy of prematurity, bronchopulmonary dysplasia, and neurodevelopmental delay. Current therapeutic approaches to minimize the adverse effects of AOP and optimize oxygen delivery include noninvasive ventilation and xanthine inhibitor therapy, but these approaches have only been partially successful in decreasing the incidence of AOP and associated morbidities.

To evaluate whether kangaroo mother care (KMC) in preterm infants on non-invasive respiratory support improves indices of cardiorespiratory wellbeing.

Prospective quasi-experimental observational study.

Tertiary perinatal neonatal unit.

50 very preterm infants being managed with nasal continuous positive airway pressure.

Continuous high-resolution preductal pulse-oximetry recordings using Masimo Radical-7 oximeter for 1 hour (incubator care) followed by 1 hour during KMC performed on the same day.

Measures of cardiorespiratory stability (dips in oxygen saturations (SpO2)) of ≥5% less than baseline, % time spent with oxygen saturations <90%, SpO2 variability and heart rate fluctuation and incidence of bradycardias.

The gestational age and birth weight of the cohort were 28.4±2.1 weeks and 1137±301 g, respectively. Dips in SpO2 of ≥5% less than baseline were significantly fewer with KMC, median (IQR) 24 (12 to 42) vs 13 (3 to 25), p=0.001. SpO2 variability (Delta 12 s and 2 s), (1.24±0.6 vs 0.9±0.4, p=0.005 and 4.1±1.7 vs 2.8±1.2, p<0.0001) and rapid resaturation and desaturation indices were significantly lower during KMC, compared with incubator care. Percentage time spent in oxygen saturations <90% was less with KMC (7.5% vs 2.7%, p=0.04). Mean heart rate was comparable although fluctuations in heart rate (rise by >8 bpm) were lower with KMC (43±22 vs 33±20, p=0.03). Seven (14%) infants had bradycardias during incubator care and none during KMC, p=0.012.

KMC improves cardiorespiratory stability in ventilated preterm infants. Regular KMC has the potential to improve clinical outcomes in this vulnerable cohort.

We assessed the associations between retinopathy of prematurity (ROP) and continuous measurements of oxygen saturation (SpO2), and developed a risk prediction model for severe ROP using birth data and SpO2 data.

This retrospective study included infants who were born before 30 weeks of gestation between August 2009 and January 2019 and who were screened for ROP at a single hospital in Japan. We extracted data on birth weight (BW), birth length, gestational age (GA) and minute-by-minute SpO2 during the first 20 days from the medical records. We defined four SpO2 variables using sequential measurements. Multivariate logistic regression was used to develop a model that combined birth data and SpO2 data to predict treatment-requiring ROP (TR-ROP). The model's performance was evaluated using the area under the receiver operating characteristic curve (AUC).

Among 350 infants, 83 (23.7%) required ROP treatment. The SpO2 variables in infants with TR-ROP differed significantly from those with non-TR-ROP. The average SpO2 and high SpO2 showed strong associations with GA (r=0.73 and r=0.70, respectively). The model incorporating birth data and the four SpO2 variables demonstrated good discriminative ability (AUC=0.83), but it did not outperform the model incorporating BW and GA (AUC=0.82).

Data obtained by continuous SpO2 monitoring demonstrated valuable associations with severe ROP, as well as with GA. Differences in the distribution of average SpO2 and high SpO2 between infants with TR-ROP and non-TR-ROP could be used to establish efficient cut-off values for risk determination.

To compare the effect of peripheral oxygen saturation (SpO2) target range (TR) (either 91%-95% and 92%-96%) on the frequency and duration of hypoxic and hyperoxic episodes while on automated oxygen control using the OxyGenie controller.

Randomised cross-over study.

Tertiary-level neonatal unit in the Netherlands.

Infants (n=27) with a median (IQR) gestational age of 27+0 (25+5-27+3) weeks and postnatal age of 16 (10-22) days, receiving invasive or non-invasive respiratory support.

In both groups supplemental oxygen was titrated to a TR of 91%-95% (TRlow) or 92%-96% (TRhigh) by the OxyGenie controller (SLE6000 ventilator) for 24 hours each, in random sequence. After a switch in TR, a 1-hour washout period was applied to prevent carry-over bias.

Frequency and duration of hypoxic (SpO2<80% for ≥1 s) and hyperoxic episodes (SpO2>98% for ≥1 s).

Hypoxic episodes were less frequent when the higher range was targeted (TRhigh vs TRlow: 2.5 (0.7-6.2)/hour vs 2.4 (0.9-10.2)/hour, p=0.02), but hyperoxic episodes were more frequent (5.3 (1.8-12.3)/hour vs 2.9 (1.0-7.1)/hour, p<0.001). The duration of the out-of-range episodes was not significantly different (hypoxia: 4.7 (2.8-7.1) s vs 4.4 (3.7-6.5) s, p=0.67; hyperoxia: 4.3 (3.3-4.9) s vs 3.9 (2.8-5.5) s, p=0.89).

Targeting a higher SpO2 TR with the OxyGenie controller reduced hypoxic episodes but increased hyperoxic episodes. This study highlights the feasibility of using an automated oxygen titration device to explore the effects of subtle TR adjustments on clinical outcomes in neonatal care.

NL9662.

Intermittent hypoxemia (IH) may influence retinopathy of prematurity (ROP) development in preterm infants, however, previous studies had mixed results. This study tests the hypothesis that increased IH is associated with Type 1 ROP; a stage beyond which treatment is indicated.

IH was quantified by continuously monitoring oxygen saturation (SpO2) using high-resolution pulse oximeters during the first 10 weeks of life. Statistical analyses assessed the relationship and predictive ability of weekly and cumulative IH for Type 1 ROP development.

Most analyses showed no association between IH and Type 1 ROP adjusting for gestational age (GA) and birth weight (BW). However, cumulative IH of longer duration during weeks 5-10, 6-10, and 7-10 were significantly associated with Type 1 ROP adjusting for GA and BW, e.g., the adjusted odds ratio of Type 1 ROP was 2.01 (p = 0.03) for every 3.8 seconds increase in IH duration from week 6-10. IH did not provide statistically significant added predictive ability above GA and BW.

For most analyses there was no significant association between IH and Type 1 ROP adjusting for GA and BW. However, infants with longer IH duration during the second month of life had higher risk for Type 1 ROP.

The relationship and predictive ability of intermittent hypoxemia (IH) on retinopathy of prematurity (ROP) is controversial. This study shows no significant association between IH events and Type 1 ROP after adjusting for gestational age (GA) and birth weight (BW), except for cumulative IH of longer duration in the second month of life. In this cohort, IH does not provide a statistically significant improvement in ROP prediction over GA and BW. This study is the first to assess the cumulative impact of IH measures on Type 1 ROP. Interventions for reducing IH duration during critical postnatal periods may improve ROP outcomes.

Although nearly half of preterm survivors display persistent neurobehavioral dysfunction including memory impairment without overt gray matter injury, the underlying mechanisms of neuronal or glial dysfunction, and their relationship to commonly observed cerebral white matter injury are unclear. We developed a mouse model to test the hypothesis that mild hypoxia during preterm equivalence is sufficient to persistently disrupt hippocampal neuronal maturation related to adult cellular mechanisms of learning and memory. Methods: Neonatal (P2) mice were exposed to mild hypoxia (8%O 2 ) for 30 min and evaluated for acute injury responses or survived until adulthood for assessment of learning and memory and hippocampal neurodevelopment.

Neonatal mild hypoxia resulted in clinically relevant oxygen desaturation and tachycardia without bradycardia and was not accompanied by cerebral gray or white matter injury. Neonatal hypoxia exposure was sufficient to cause hippocampal learning and memory deficits and abnormal maturation of CA1 neurons that persisted into adulthood. This was accompanied by reduced hippocampal CA3-CA1 synaptic strength and LTP and reduced synaptic activity of calcium-sensitive SK2 channels, key regulators of spike timing dependent neuroplasticity, including LTP. Structural illumination microscopy revealed reduced synaptic density, but intact SK2 localization at the synapse. Persistent loss of SK2 activity was mediated by altered casein kinase 2 (CK2) signaling.

Clinically relevant mild hypoxic exposure in the neonatal mouse is sufficient to produce morphometric and functional disturbances in hippocampal neuronal maturation independently of white matter injury. Additionally, we describe a novel persistent mechanism of potassium channel dysregulation after neonatal hypoxia. Collectively our findings suggest an unexplored explanation for the broad spectrum of neurobehavioral, cognitive and learning disabilities that paradoxically persist into adulthood without overt gray matter injury after preterm birth.

This study aims to evaluate the performance of the fabian-Predictive-Intelligent-Control-of-Oxygenation (PRICO) system for automated control of the fraction of inspired oxygen (FiO2).

Multicentre randomised cross-over study.

Five neonatal intensive care units experienced with automated control of FiO2 and the fabian ventilator.

39 infants: median gestational age of 27 weeks (IQR: 26-30), postnatal age 7 days (IQR: 2-17), weight 1120 g (IQR: 915-1588), FiO2 0.32 (IQR: 0.22-0.43) receiving both non-invasive (27) and invasive (12) respiratory support.

Randomised sequential 24-hour periods of automated and manual FiO2 control.

Proportion (%) of time in normoxaemia (90%-95% with FiO2>0.21 and 90%-100% when FiO2=0.21) was the primary endpoint. Secondary endpoints were severe hypoxaemia (<80%) and severe hyperoxaemia (>98% with FiO2>0.21) and prevalence of episodes ≥60 s at these two SpO2 extremes.

During automated control, subjects spent more time in normoxaemia (74%±22% vs 51%±22%, p<0.001) with less time above and below (<90% (9%±8% vs 12%±11%, p<0.001) and >95% with FiO2>0.21 (16%±19% vs 35%±24%) p<0.001). They spent less time in severe hyperoxaemia (1% (0%-3.5%) vs 5% (1%-10%), p<0.001) but exposure to severe hypoxaemia was low in both arms and not different. The differences in prolonged episodes of SpO2 were consistent with the times at extremes.

This study demonstrates the ability of the PRICO automated oxygen control algorithm to improve the maintenance of SpO2 in normoxaemia and to avoid hyperoxaemia without increasing hypoxaemia.

Cardiorespiratory control is immature in infants born preterm compared to those born at term. Animal studies have shown that repetitive hypoxia associated with periodic breathing can alter autonomic control. We aimed to elucidate if the amount of time spent with apnoea and periodic breathing in the neonatal unit was associated with longitudinal changes in autonomic control assessed using heart rate variability.

Twenty-nine very preterm infants (10 M 19F) were studied during supine daytime sleep on 4 occasions. Study 1: 32-36 weeks post menstrual age (PMA) (n = 29), Study 2: 36-40 weeks PMA (n = 27), Study 3: 3-months corrected age (CA) (n = 20) and Study 4: 6-months CA (n = 26). The percentage total sleep time (%TST) spent having apnoeas in active (AS) and quiet sleep (QS) at each study was calculated. Total power, low frequency (LF, sympathetic + parasympathetic activity) high frequency (HF, parasympathetic activity), and LF/HF (sympathovagal balance) were calculated. Infants were divided into two groups based on the %TST spent with apnoeas above and below the median in AS and QS at Study 1. Data were normalised and compared with two-way ANOVA with Bonferroni post-hoc tests.

When apnoeas were included in the analysis, in QS Total power and HF power were higher, and when apnoeas were excluded HF power was higher in QS but lower in AS in the above median group at Study 4.

This study provides new evidence that short apnoeas, particularly periodic breathing, which is currently not detected or treated in the neonatal unit can affect autonomic cardiovascular control.

With a wide therapeutic index, efficacy, ease of use, and other neuroprotective and respiratory benefits, caffeine citrate(CC) is currently the drug of choice for preterm neonates (PTNs). Caffeine-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side-effects (CC-APSEs) result in lower daily-weight gain (WG) in premature neonates. This study aimed to evaluate the risk factors for daily-WG in neonates exposed to different dose regimens of caffeine in ICU.

This retrospective cohort study included neonates of ≤ 36weeks gestational age (GA) and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I (received; standard-doses = 5 mg/kg/day), group-II (received;>5-7 mg/kg/day), and group-III (received;>7 mg/kg/day). Prenatal and postnatal clinical characteristics, CC-regimen, daily-WG, CC-APSEs, and concomitant risk-factors, including daily-caloric intake, Parenteral-Nutrition duration, steroids, diuretics, and ibuprofen exposure, were analyzed separately for group-II and group-III using group-I as standard. Regression analysis was performed to evaluate the risk factors for daily-WG.

Included 314 PTNs. During 15-28 DOL, the mean-daily-WG(MD-WG) was significantly higher in group-I than group-II [19.9 ± 0.70 g/kg/d vs. 17.7 ± 0.52 p = 0.036] and group-III [19.9 ± 0.70 g/kg/d vs. 16.8 ± 0.73 p < 0.001]. During 29-42 DOL the MD-WG of group-I was only significantly higher than group-III [21.7 ± 0.44 g/kg/d vs. 18.3 ± 0.41 g/kg/d p = 0.003] and comparable with group-II. During 15-28 DOL, observed CC-APSEs was significantly higher in group-II and III but during 29-42 DOL it was only significant in group-III. In the adjusted regression analysis for daily-WG during 15-28DOL, with respect to standard-dose, 5-7 mg/kg/day (β=-1.04; 95%CI:-1.62,-0.93) and > 7-10 mg/kg/day (β=-1.36; 95%CI:-1.56,-1.02) were associated with a lower daily-WG. However, during 29-42DOL, this association was present only for > 7-10 mg/kg/day (β=-1.54; 95%CI:-1.66,-1.42). The GA ≤ 27weeks (β=-1.03 95%CI:-1.24, -0.88) was associated with lower daily-WG only during 15-28DOL. During both periods of therapy, higher cumulative-caffeine dose and presence of culture proven sepsis, tachypnea, hyponatremia, and feeding intolerance were significantly associated with lower daily-WG. Conversely, daily kcal intake was found to be linked with an increase in daily-WG in both periods.

In this study cohort exposure to higher caffeine daily and cumulative doses is associated with lower postnatal daily-WG in PTNs than standard-daily doses, which may be due to its catabolic effects and CC-APSEs.

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.

This study aimed to compare oxygenation instability, as documented by the oxygen saturation (SpO2) histograms, during bolus (over 30 minutes) versus continuous (over 2 hours) feeding among very low birth weight (VLBW) premature infants, supported with noninvasive ventilation (NIV).

This was a randomized prospective study. VLBW infants supported with NIV received three consecutive feeds in a random order of bolus-continuous-bolus or continuous-bolus-continuous. During each feed, 30 minutes and 2 hours histograms were documented.

Twenty-four infants (birth weight [mean ± standard deviation, SD] 820 ± 168 g, gestational age [mean ± SD] 27.0 ± 1.6 weeks) were included in our study (12 infants started with bolus feeding and 12 with continuous feeding) and 72 histograms were obtained (36 during bolus feeding and 36 during continuous feeding). No differences in mean fraction of inspired oxygen (FiO2), and number of apnea events were observed between the two feeding modes. Oxygenation instability as assessed by time spent in different SpO2 ranges and histogram types (stable or unstable) was comparable during bolus and continuous feedings. Changing feeding mode from bolus to continuous or vice versa did not significantly change the oxygenation instability of the group, though individual infants did show a consistence response to feeding length changes.

Among VLBW infants supported with NIV, oxygenation instability, as documented by SpO2 histograms, was comparable between bolus and continuous feedings. Individual infants may benefit from specific feeding length, and this can be easily demonstrated by the SpO2 histograms.

· Feeding length did not affect oxygenation instability of preterm infants on noninvasive respiratory Support.. · Oxygen saturation histograms allow objective quantification of oxygenation instability at the bedside.. · Individual infants benefit from specific feeding length, as demonstrated by SpO2 histograms..

Notch ligands and receptors are important for cell specification and angiogenesis, but their role in oxygen-induced retinopathy (OIR) is not well studied. Delta-like ligand (DLL)-4/Notch inhibits angiogenesis, while Jagged-1/Notch promotes angiogenesis. We tested the hypothesis that early supplementation with antioxidants and/or fish oil curtails severe OIR by inducing DLL-4/Notch and reducing Jagged-1/Notch. Newborn rats were exposed to brief intermittent hypoxia (IH) during hyperoxia, during which they received daily oral supplements of (1) fish oil, (2) coenzyme Q10 (CoQ10) in olive oil (OO), (3) glutathione nanoparticles (nGSH), (4) fish oil + CoQ10, or (5) OO (controls) from birth (P0) to P14. At P14, the pups were placed in room air (RA) until P21, with no further treatment. Oxidative stress, apoptosis, ocular histopathology, and Notch signaling were assessed. Neonatal IH resulted in severe retinal damage consistent with retinopathy of prematurity (ROP). Retinal damage was associated with induced oxidative stress and Jagged-1/Notch signaling, as well as reduced DLL-4/Notch signaling. All treatments reversed these outcomes, but nGSH produced the most beneficial outcomes. Severe OIR promoted the induction of Jagged-1/Notch and curtailed DLL-4/Notch, which was an effect that could be reversed with nGSH supplementation. These findings may indicate a potential alternate pathway for ROP treatment and/or prevention.

Length of hospitalization varies widely in preterm infants and can be affected by multiple maternal and neonatal factors including respiratory instability. Therefore, we aimed to determine the association between postnatal intermittent hypoxemia (IH) and prolonged hospitalization.

This prospective single-center cohort study followed infants born at <31 weeks of gestational age through 2 years corrected age with detailed oxygen saturation data captured from days 7 to 30 of age.

51/164 (31%) of infants were discharged after 400/7 weeks of corrected gestational age (CGA). A greater average daily number of IH events (OR per 10 events/day 1.33 [95% CI 1.03-1.72]), duration of events (OR per minute 1.14 [1.07-1.21]), and percent time with oxygen saturation <80% (OR per percent 1.88 [1.25-2.85]) on days 7-30 of age were all significantly associated with prolonged hospitalization past 400/7 weeks CGA. In survival analyses, infants with a greater average daily number of IH events (HR per 10 events/day 0.89 [0.81-0.98]), percent time with oxygen saturation <80% (HR per percent 0.79 [0.67-0.94]), and duration of events (HR per minute 0.93 [0.91-0.95]) on days 7-30 of age all had significantly lower probability of earlier discharge. In addition, there was a significant interaction with gestational age; the association between IH and prolonged hospitalization was stronger in more mature infants (p = 0.024).

Physiological instability on days 7-30 of age, as manifested by IH, is significantly associated with prolonged hospitalization. IH likely represents both a marker of initial severity of illness and the beginning of biological cascades, leading to prematurity-associated morbidities.

Retinopathy of prematurity (ROP) is one of the leading causes of blindness in children. Although the role of oxygen in the pathophysiology of ROP is well established, a precise understanding of the dynamic relationship between oxygen exposure ROP incidence and severity is lacking. The purpose of this study was to evaluate the correlation between time-dependent oxygen variables and the onset of ROP.

Retrospective cohort study.

Two hundred thirty infants who were born at a single academic center and met the inclusion criteria were included. Infants are mainly born between January 2011 and October 2022.

Patient data were extracted from electronic health records (EHRs), with sufficient time-dependent oxygen data. Clinical outcomes for ROP were recorded as none/mild or moderate/severe (defined as type II or worse). Mixed-effects linear models were used to compare the 2 groups in terms of dynamic oxygen variables, such as daily average and the coefficient of variation (COV) fraction of inspired oxygen (FiO2). Support vector machine (SVM) and long-short-term memory (LSTM)-based multimodal models were trained with fivefold cross-validation to predict which infants would develop moderate/severe ROP. Gestational age (GA), birth weight, and time-dependent oxygen variables were used to develop predictive models.

Model cross-validation performance was evaluated by computing the mean area under the receiver operating characteristic (AUROC) curve, precision, recall, and F1 score.

We found that both daily average and COV of FiO2 were associated with more severe ROP (adjusted P < 0.001). With fivefold cross-validation, the multimodal LSTM models had higher performance than the best static models (SVM using GA and 3 average FiO2 features) and SVM models trained on GA alone (mean AUROC = 0.89 ± 0.04 vs. 0.86 ± 0.05 vs. 0.83 ± 0.04).

The development of severe ROP might not only be influenced by oxygen exposure but also by its fluctuation, which provides direction for future study of pathophysiological factors associated with severe ROP development. Additionally, we demonstrated that multimodal neural networks can be a method to extract useful information from time-series data, which may be a valuable methodology for the investigation of other diseases using EHR data.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Tremendous advancements in neonatal respiratory care have contributed to the improved survival of extremely preterm infants (gestational age ≤ 28 weeks). While mechanical ventilation is often considered one of the most important breakthroughs in neonatology, it is also associated with numerous short and long-term complications. For those reasons, clinical research has focused on strategies to avoid or reduce exposure to mechanical ventilation. Nonetheless, in the extreme preterm population, 70-100% of infants born 22-28 weeks of gestation are exposed to mechanical ventilation, with nearly 50% being ventilated for ≥ 3 weeks. As contemporary practices have shifted towards selectively reserving mechanical ventilation for those patients, mechanical ventilation weaning and extubation remain a priority yet offer a heightened challenge for clinicians. In this review, we will summarize the evidence for different strategies to expedite weaning and assess extubation readiness in preterm infants, with a particular focus on extremely preterm infants.

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.

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.

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.

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.

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.

Retinopathy of prematurity (ROP) is a proliferative vascular ailment affecting the retina. It is the main risk factor for visual impairment and blindness in infants and young children worldwide. If left undiagnosed and untreated, it can progress to retinal detachment and severe visual impairment. Geographical variations in ROP epidemiology have emerged over recent decades, attributable to differing levels of care provided to preterm infants across countries and regions. Our understanding of the causes of ROP, screening, diagnosis, treatment, and associated risk factors continues to advance. This review article aims to present the pathophysiological mechanisms of ROP, including its treatment. Specifically, it delves into the latest cutting-edge treatment approaches targeting hypoxia and redox signaling pathways for this condition.

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%.

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.