Objective:To independently validate an empirically optimized algorithm for calculating estimated Oxygenation Index (eOI) using noninvasive parameters from pediatric intensive care populations. Design:Retrospective observational cohort study using an integrated patient data repository spanning over 12 years (August 2012-December 2024). Setting:Single tertiary children's hospital with general pediatric ICU (PICU) and cardiothoracic ICU (CTICU). Key measures:Arterial blood gas measurements were paired with coincident SpO2, heart rate, pulse rate, FiO2, and mean airway pressure measurements. The primary analyses used SpO2 observations between 80%-100%. Using these values eOI was calculated. The primary outcome was the Bias and Limits of Agreement of the difference between measured OI and eOI. Discrimination performance of eOI for severity of hypoxemia was evaluated using receiver operating characteristic curves at OI thresholds of 4, 8, and 16. Results:Analysis included 68,915 observations from 7,109 subjects (44,133 CTICU, 24,782 PICU observations). Bias was minimal in both populations: PICU 0.06 (95% CI; 0.03, 0.10) and CTICU 0.12 (95% CI; 0.09, 0.14). Limits of agreement were -5.2 to 5.4 (PICU) and -4.9 to 5.2 (CTICU). Discrimination performance was excellent, at 3 hypoxemia thresholds (AUROC; 0.91-0.98), and in the CTICU for OI ≥4 when SpO2 >97% (AUROC; 0.83). Conclusions:The new eOI algorithm provides accurate, but not precise, estimation of OI in both general pediatric and cardiothoracic ICU populations. Noninvasive OI monitoring may be shown clinically useful.

INTRODUCTION:There is a broad awareness of shifts in the oxygen hemoglobin dissociation (ODC) relationship associated with fetal hemoglobin (HbF) changes. However, quantification of the shift has been limited. Aim was to quantify the shift of partial oxygen tension (PO2) associated with HbF and with changes after transfusion of adult erythrocytes (TAE) in preterm infants. METHODS:This is a single-center, retrospective observational analysis of blood gas samples. The shifts of ODC and PO2 related to HbF were evaluated in two models. Either HbF or TAE status (0, 1, ≥2) were used as the independent variable. Multivariate analysis was used to correct for confounding effects (gestational age, postnatal age, source of blood gas sample as well as pH, SO2, and PCO2). RESULTS:There were 3,452 blood gas observations analyzed from 2,464 infants whose median gestational age was 334 weeksdays (IQR 296-363). With SpO2 between 90 and 95%, the ODC was shifted to the left (13 mm Hg, 1.3 kPa). After adjusting for confounding variables, the number of TAEs (0, 1, ≥2), was highly significantly related to a shift (p < 0.001), consistent with the percent HbF level (p < 0.001). Based on the multivariate model (i.e., holding confounding parameters constant), with a SpO2 of 92% the PaO2 could be expected to shift markedly higher with 2 or more TAEs in an extremely preterm infant (7.3 mm Hg, 0.97 kPa). CONCLUSION:While preliminary, these data suggest that in vulnerable preterm infants a change to a slightly lower SpO2 target range following TAE could maintain equivalent PaO2 exposure.

Objective 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).Design Multicentre randomised cross-over study.Setting Five neonatal intensive care units experienced with automated control of FiO2 and the fabian ventilator.Patients 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.Intervention Randomised sequential 24-hour periods of automated and manual FiO2 control.Main outcome measures 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.Results 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.Conclusions 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.

Objective This randomised study in preterm infants on non-invasive respiratory support investigated the effectiveness of automated oxygen control (A-FiO 2 ) in keeping the oxygen saturation (SpO 2 ) within a target range (TR) during a 28-day period compared with manual titration (M-FiO 2 ). Design A single-centre randomised control trial. Setting A level III neonatal intensive care unit. Patients Preterm infants (<28 weeks’ gestation) on non-invasive respiratory support. Interventions A-FiO 2 versus M-FiO 2 control. Methods Main outcomes were the proportion of time spent and median area of episodes in the TR, hyperoxaemia, hypoxaemia and the trend over 28 days using a linear random intercept model. Results 23 preterm infants (median gestation 25.7 weeks; birth weight 820 g) were randomised. Compared with M-FiO 2 , the time spent within TR was higher in the A-FiO 2 group (68.7% vs 48.0%, p<0.001). Infants in the A-FiO 2 group spent less time in hyperoxaemia (13.8% vs 37.7%, p<0.001), but no difference was found in hypoxaemia. The time-based analyses showed that the A-FiO 2 efficacy may differ over time, especially for hypoxaemia. Compared with the M-FiO 2 group, the A-FiO 2 group had a larger intercept but with an inversed slope for the daily median area below the TR (intercept 70.1 vs 36.3; estimate/day −0.70 vs 0.69, p<0.001). Conclusion A-FiO 2 control was superior to manual control in keeping preterm infants on non-invasive respiratory support in a prespecified TR over a period of 28 days. This improvement may come at the expense of increased time below the TR in the first days after initiating A-FiO 2 control. Trial registration number NTR6731.

ObjectiveOur aim was to confirm whether extreme hyperoxemic events had been associated with excess mortality in our diverse critical care population.MethodsRetrospective analysis of 9 years of data collected in the pediatric and cardiothoracic ICUs in Children's Hospital Los Angeles was performed. The analysis was limited to those mechanically ventilated for at least 24 h, with at least 1 arterial blood gas measurement. An extreme hyperoxemic event was defined as a PaO2 of ≥300 torr. Multivariable logistic regression was used to assess the association of extreme hyperoxemia events and mortality, adjusting for confounding variables. Selected a-priori, these were Pediatric Risk of Mortality III predicted mortality, general or cardiothoracic ICU, number of blood gas measurements, as well as an abnormal blood gas measurements (pH < 7.25, pH > 7.45, and PaO2 < 50 torr).ResultsThere were 4,003 admissions included with a predicted mortality of 7.1% and an actual mortality of 9.7%. Their care was associated with 75,129 blood gas measurements, in which abnormal measurements were common. With adjustments for these covariates, any hyperoxemic event was associated with excess mortality (p < 0.001). Excess mortality increased with multiple hyperoxemic events (p < 0.046). Additionally, treatment resulting in SpO2 > 98% markedly increased the risk of a hyperoxemic event.ConclusionRetrospective analysis of critical care admissions showed that extreme hyperoxemic events were associated with higher mortality. Supplemental oxygen levels resulting in SpO2 > 98% should be avoided.

Objective To evaluate the efficacy of automatic oxygen control (A-FiO 2 ) in reducing the extremes of oxygen saturations (SpO 2 <80% and SpO 2 >98%) in preterm infants on high-flow nasal cannula (HFNC) respiratory support using Vapotherm Precision Flow. Design A parallel-arm randomised controlled trial. Setting A level-III neonatal intensive care unit. Patients Preterm infants born <33 (23+0 to 32+6) weeks receiving HFNC as respiratory support. Interventions A-FiO 2 versus manual (M-FiO 2 ) oxygen control during the full course of HFNC support. Outcomes The primary outcome of this study is percentage of time spent in extreme oxygen saturations (<80% and >98%) in preterm infants when receiving HFNC as respiratory support. Secondary outcomes were time with SpO 2 between 90% and 95% plus time >95% without supplemental oxygen. Results 60 infants were randomised equally to either A-FiO 2 or M-FiO 2 arm. Their baseline characteristics were comparable. They spent a median of 5.3 (IQR: 2.0–8.4) and 6.5 (IQR: 2.9–13.7) days in the study, A-FiO 2 and M-FiO 2 , respectively. The percentage of time spent in SpO 2 <80% (median of 0.4% (0.1%–0.8%) vs 1.6% (0.6%–2.6%), p=0.002) and >98% (median 0.2% (0.1%–0.9%) vs 1.9% (0.7%–4%), p<0.001) were significantly lower in A-FiO 2 compared with M-FiO 2 . The difference in median percentage of time in target range between the two arms was 26% (81% (74%–93%) in A-FiO 2 vs 55% (48%–72%) in M-FiO 2 ). Conclusion A-FiO 2 was associated with statistically significant reduction in the percentage of time spent in extremes of saturation when compared with M-FiO 2 in preterm infants receiving HFNC. Trial registration number NCT04687618 .

BackgroundPremature newborns often require oxygen support as part of their therapy. Systems for oxygen administration are developed to assure adequate oxygenation of newborns. Several factors were identified in the systems that contribute to the time delay between the change in the set inspiratory oxygen fraction and its actual delivery to tissues. In this study, we aimed to reduce the physical delay in oxygen delivery to newborns.MethodsWe developed an O2 Flush System (O2-FS) that brings the source of oxygen as close to a patient as possible to make oxygen available for rapid delivery that compensates for the physical delay in the ventilator circuit. The O2-FS system is built around an electromechanical on/off valve. We validated the O2-FS concept in experiments with non-invasive Continuous Positive Airways Pressure (CPAP) ventilators.ResultsThe O2-FS accelerated oxygen delivery with all the tested systems and arrangements, typically by 5–15 s. We also observed that the application of supplemental oxygen increased the pressure in the ventilator circuit by 3–4 cmH2O which may mitigate the apneic pauses that are common in premature newborns.ConclusionsThe O2-FS system may work as a universal accessory of the CPAP lung ventilator and shorten the distribution of oxygen to the patient during oxygen desaturation events, possibly eliminating or interrupting apneic pauses in neonates, for whom oxygen therapy is an essential treatment. In clinical practice, the O2-FS could help maintain normoxemic saturation values through adequate oxygen dosing in preterm neonates, thus reducing morbidity and mortality.

Although smartwatches are not considered medical devices, experimental validation of their accuracy in detecting hypoxemia is necessary due to their potential use in monitoring conditions manifested by a prolonged decrease in peripheral blood oxygen saturation (SpO2), such as chronic obstructive pulmonary disease, sleep apnea syndrome, and COVID-19, or at high altitudes, e.g., during sport climbing, where the use of finger-sensor-based pulse oximeters may be limited. The aim of this study was to experimentally compare the accuracy of SpO2 measurement of popular smartwatches with a clinically used pulse oximeter according to the requirements of ISO 80601-2-61. Each of the 18 young and healthy participants underwent the experimental assessment three times in randomized order-wearing Apple Watch 8, Samsung Galaxy Watch 5, or Withings ScanWatch-resulting in 54 individual experimental assessments and complete datasets. The accuracy of the SpO2 measurements was compared to that of the Radical-7 (Masimo Corporation, Irvine, CA, USA) during short-term hypoxemia induced by consecutive inhalation of three prepared gas mixtures with reduced oxygen concentrations (14%, 12%, and 10%). All three smartwatch models met the maximum acceptable root-mean-square deviation (≤4%) from the reference measurement at both normal oxygen levels and induced desaturation with SpO2 less than 90%. Apple Watch 8 reached the highest reliability due to its lowest mean bias and root-mean-square deviation, highest Pearson correlation coefficient, and accuracy in detecting hypoxemia. Our findings support the use of smartwatches to reliably detect hypoxemia in situations where the use of standard finger pulse oximeters may be limited.

ObjectiveChanges in oximeter averaging times have been noted to affect alarm settings. Automated algorithms (A-FiO2) assess FiO2 faster than oximeter averaging, potentially impacting their effectiveness.MethodsIn a single NICU routinely using 15 fabian-PRICO A-FiO2 systems, neonates were randomly exposed to SpO2 averaging time settings switched every 12 h among short (2–4 s), medium (10 s), and long (16 s) oximeter averaging times for the entire duration of their A-FiO2 exposure. Primary endpoints were the percent time in the set SpO2 target range (dependent on PMA), SpO2 < 80%, and SpO2 > 98%, excluding FiO2 = 0.21.ResultsTen VLBW neonates were enrolled over 11 months. At entry, they were 17 days old (IQR: 14–19), with an adjusted gestational age of 29 weeks (IQR: 27–30). The study included data from 272 days of A-FiO2 control (34% short, 32% medium, and 34% long). Respiratory support was predominantly non-invasive (53% NCPAP, 40% HFNC, and 6% NIPPV). The aggregate SpO2 exposure levels were 67% (IQR: 55–82) in the target range, 5.4% (IQR: 2.0–10) with SpO2 < 80%, and 1.2% (IQR: 0.4–3.1) with SpO2 > 98%. There were no differences in the target range time between the SpO2 averaging time settings. There were differences at the SpO2 extremes (p ≤ 0.001). The medium and long averaging were both lower than the short, with the difference larger than predicted. Multivariate analysis revealed that these findings were independent of subject, ventilation mode, target range, and overall stability.ConclusionsThis A-FiO2 algorithm is effective regardless of the SpO2 averaging time setting. There is an advantage to the longer settings, which suggest an interaction with the controller.

Objective The objective of this study was to evaluate the efficacy of the automatic oxygen control (A-Fio2) in reducing the percentage of time spent in severe hypoxaemia (Spo2 <80%) in preterm infants for the time period on invasive ventilation and/or nasal continuous positive airway pressure (NCPAP) delivered by AVEA ventilator. Design A parallel arm randomised controlled trial. Setting A level-III neonatal intensive care unit. Patients Preterm infants (<33 weeks birth gestation) who received invasive ventilation or NCPAP in the first 72 hours of age. Interventions A-Fio2 vs manual (M-Fio2) oxygen control. Outcomes The primary outcome of the study was percentage of time spent in severe hypoxaemia (Spo2 <80%). Results 44 infants were randomised to either A-Fio2 or M-Fio2 arm and continued in the study for the period of respiratory support (invasive ventilation and/or NCPAP). The total number of study days in A-Fio2 and M-Fio2 arm were 194 and 204 days, respectively. The percentage of time spent in Spo2 <80% was significantly lower with A-Fio2 compared with M-Fio2 (median of 0.1% (IQR: 0.07–0.7) vs 0.6% (0.2–2); p=0.03). The number of prolonged episodes (>60 s) of Spo2 <80% per day was also significantly lower in A-Fio2 (0.3 (0.0–2) vs 2 (0.6–6); p=0.02). Conclusion A-Fio2 was associated with statistically significant reduction in the percentage of time spent in severe hypoxaemia when compared with M-Fio2 in preterm infants receiving respiratory support. Trial registration number NCT04223258. In this randomised controlled trial that included 44 infants, servo controlled adjustment of FiO2 improved oxygen targeting over the duration of ventilation and nasal CPAP treatment.

Objective:The performance of automated control of inspired oxygen (A-FiO2) has been confirmed in dozens of studies but reports of routine use are limited. Broadly adopted in Poland, our aim is to share that experience.Methods:We used a prospectively planned observational study of the performance, general use patterns, unit practices, and problems with A-FiO2, based on a web registry of case reports, complemented by surveys of subjective impressions.Results:In 2019, a total of 92 A-FiO2 systems were in routine use in 38 centers. Of the 38 centers, 20 had agreed in 2013 to participate in the project. In these centers, A-FiO2 was applied in infants of all weights, but some centers restricted its use to weaning from oxygen and unstable infants. A cohort had reported their experience with each use (5/20 centers, 593 cases). A quarter of those infants were managed with a lower target range and three-quarters with alarms looser than European guidelines for manual SpO2 control. The perceived primary advantages of A-FiO2 were as follows: keeping the readings in the target range, reducing exposure to SpO2 extremes, reducing risk from nurse distraction, reducing workload, and reducing alarm fatigue. Practices did evolve with experience, including implementing changes in the alarm strategy, indications for use, and target range. The potential for over-reliance on automation was cited as a risk. There were a few reports of limited effectiveness (moderate 12/593 and poor 2/593).Conclusions:Automated oxygen control is broadly perceived by users as an improvement in controlling SpO2 with infrequent problems.

The utility of decision tree machine learning in exploring the interactions among the SpO2 target range, neonatal maturity, and oxemic-risk is demonstrated. METHODS: This observational study used 3 years of paired age-SpO2-PaO2 data from a neonatal ICU. The CHAID decision tree method was used to explore the interaction of postmenstrual age (PMA) on the risk of extreme arterial oxygen levels at six different potential SpO2 target ranges (88–92%, 89–93%, 90–94%, 91–95%, 92–96% and 93–97%). Risk was calculated using a severity-weighted average of arterial oxygen outside the normal range for neonates (50–80 mmHg). RESULTS: In total, 7500 paired data points within the potential target range envelope were analyzed. The two lowest target ranges were associated with the highest risk, and the ranges of 91–95% and 92–96% were associated with the lowest risk. There were shifts in the risk associated with PMA. All the target ranges showed the lowest risk at ≥42 weeks PMA. The lowest risk for preterm infants was within a target range of 92–96% with a PMA of ≤34 weeks. CONCLUSIONS: This study demonstrates the utility of decision tree analytics. These results suggest that SpO2 target ranges that are different from typical range might reduce morbidity and mortality. Further research, including prospective randomized trials, is warranted.

Oxygen is the most common drug used in the critical care of infants. There is significant morbidity and mortality associated with excess or inadequate levels. For this reason, an important element of many therapeutic interventions in the ICU requires assessment of their acute impact on oxygenation. It is common to normalize the arterial level of oxygen with the fraction of inspired oxygen (PF-ratio). Further, a change may often be more important than the absolute level. Though the PF-ratio is often reported, it was surmised that the rarely reported, relative magnitude of change in PF-ratio might be a useful metric for assessing the stability and effectiveness of therapy. Therefore, individual patient data from two different studies were evaluated. The cases included periods of therapeutic intervention and periods without intervention, thus permitting the evaluation of the PF-ratio's potential sensitivity to change and thresholds for relevant change. During surfactant administration in extremely preterm infants, the PF-ratio improved at least 25% in 91% of the infants, while 9% showed less than a 10% change. During high-frequency oscillatory rescue in children, the PF-ratio improved at least 25% in 76% of the infants, while 8% showed less than a 10% change. Consideration of thresholds of 50% and 5% reflected low prevalence. In periods of routine care, the prevalence of marked changes was less prevalent but still common (6% and 55%) and periods of little change more prevalent (21% and 21%). We believe this initial work supports the feasibility of using the magnitude of change in PF-ratio and provides a useful stimulus for additional evaluations.

ObjectiveThe objective of this study was to compare two different modes of ventilation in maintaining oxygen saturation (SpO2) in target range (90%–95%) in ventilated preterm infants cared for with automatic control of oxygen delivery (A-FiO2).DesignA single-centre randomised crossover study.SettingsA level III neonatal intensive care unit.PatientsPreterm infants receiving mechanical ventilation and oxygen requirement >21%.InterventionsVolume guarantee (VG) vs volume controlled ventilation (VCV) modes with automatic oxygen control (A-FiO2).OutcomesThe primary outcome of this study was the proportion of time spent with oxygen saturations in the target range (90%–95%) .ResultsNineteen preterm infants with a median gestation age 25 weeks (IQR: 24–28) and birth weight 685 g (IQR: 595–980) were enrolled in the study. There was no significant difference in primary outcome of median proportion of time spent in target saturation between the two arms (72% (57–81) in VG vs 75% (58–83) in VCV; p=0.98). There was no significant difference in the secondary outcomes of time spent in SpO2 <80% (0.03% vs 0.14%; p=0.51), time spent in SpO2 >98% (0.50% vs 0.08%; p=0.54), the median FiO2 (31% vs 29%; p=0.51) or manual adjustments carried out between VG and VCV, respectively. The number of episodes of prolonged hypoxaemia and hyperoxaemia were similar in the two groups.ConclusionThere was no significant difference in time spent in target SpO2 range between VG and VCV when A-FiO2 was used as the FiO2 controller in this crossover randomised control study.Trial registration numberNCT03865069.

Continuous monitoring with pulse oximetry is the standard of care for titrating inspired oxygen in the neonatal ICU. However titrating supplemental oxygen to address frequent desaturations is a challenging task for caregivers. Increasing exposure to SpO2 extremes is associated with increasingly poorer long-term outcomes. More recently the prevalence of prolonged episodes at extremes and cluster of short episodes have been reported to be also associated with bad outcomes. We speculated that more complex episodes might also have an impact on outcomes. We defined two sets of these: clusters and swings. Automatic control of inspired oxygen based on continuous pulse oximetry, is available on many neonatal ventilators. Some have expressed concern that continuous adjustment of inspired oxygen, without observing the infant, might cause instability and thus increased prevalence of clusters and oscillations. The aim of this study was to determine the prevalence of these complex events and determine if they were more common during automated control. To accomplish this we analyzed data of 58 extremely preterm newborns that were ventilated at least 24 hours with manual inspiratory oxygen control and at least 24 hours with automated FiO2 control, in random order. We found that clusters and swings were quite prevalent, that is similar to the prevalence of prolonged episodes that have been shown to be associated with bad outcomes. We also found that these complex events were reduced during automated control, rather than increased. Finally, we suggest that additional research in this area is warranted.

Objective We investigated how a commercially available smartwatch that measures peripheral blood oxygen saturation (SpO 2 ) can detect hypoxemia compared to a medical-grade pulse oximeter. Methods We recruited 24 healthy participants. Each participant wore a smartwatch (Apple Watch Series 6) on the left wrist and a pulse oximeter sensor (Masimo Radical-7) on the left middle finger. The participants breathed via a breathing circuit with a three-way non-rebreathing valve in three phases. First, in the 2-minute initial stabilization phase, the participants inhaled the ambient air. Then in the 5-minute desaturation phase, the participants breathed the oxygen-reduced gas mixture (12% O 2 ), which temporarily reduced their blood oxygen saturation. In the final stabilization phase, the participants inhaled the ambient air again until SpO 2 returned to normal values. Measurements of SpO 2 were taken from the smartwatch and the pulse oximeter simultaneously in 30-s intervals. Results There were 642 individual pairs of SpO 2 measurements. The bias in SpO 2 between the smartwatch and the oximeter was 0.0% for all the data points. The bias for SpO 2 less than 90% was 1.2%. The differences in individual measurements between the smartwatch and oximeter within 6% SpO 2 can be expected for SpO 2 readings 90%–100% and up to 8% for SpO 2 readings less than 90%. Conclusions Apple Watch Series 6 can reliably detect states of reduced blood oxygen saturation with SpO 2 below 90% when compared to a medical-grade pulse oximeter. The technology used in this smartwatch is sufficiently advanced for the indicative measurement of SpO 2 outside the clinic. Trial Registration ClinicalTrials.gov NCT04780724

A pulse oximeter model linking arterial (SaO2) and peripheral (SpO2) oxygen saturation is the terminal part of a mathematical model of neonatal oxygen transport. Previous studies have confirmed the overestimation of oxygen saturation measured by pulse oximetry in neonates compared to arterial oxygen saturation and the large variability of measured values over time caused by measurement inaccuracies. This work aimed to determine the SpO2 measurement noise that affects the biased SpO2 value at each time point and integrate the noise description with the systematic bias between SaO2 and SpO2. The SaO2–SpO2 bias was based on previously published clinical data from pathological patients younger than 60 days requiring ventilatory support. The statistical properties of the random SpO2 measurement noise were estimated from the SpO2 continuous recordings of 21 pathological and 21 physiological neonates. The result of the work is a comprehensive characterization of the properties of a pulse oximeter model describing the transfer of the input SaO2 value to the output SpO2 value, including the bias and noise typical for the bedside monitoring of neonates. These results will help to improve a computer model of neonatal oxygen transport.

Objective Neonatal exposure to episodic hypoxemia and hyperoxemia is highly relevant to outcomes. Our goal was to investigate the differences in the frequency and duration of extreme low and high SpO(2) episodes between automated and manual inspired oxygen control. Design Post-hoc analysis of a cohort from prospective randomized cross-over studies. Setting Seven tertiary care neonatal intensive care units. Patients Fifty-eight very preterm neonates (32 or less weeks PMA) receiving respiratory support and supplemental oxygen participating in an automated versus manual oxygen control cross-over trial. Main measures Extreme hypoxemia was defined as a SpO(2) < 80%, extreme hyperoxemia as a SpO(2) > 98%. Episode duration was categorized as < 5 seconds, between 5 to < 30 seconds, 30 to < 60 seconds, 60 to < 120 seconds, and 120 seconds or longer. Results The infants were of a median postmenstrual age of 29 (28-31) weeks, receiving a median FiO(2) of 0.28 (0.25-0.32) with mostly receiving non-invasive respiratory support (83%). While most of the episodes were less than 30 seconds, longer episodes had a marked effect on total time exposure to extremes. The time differences in each of the three longest durations episodes (30, 60, and 120 seconds) were significantly less during automated than during manual control (p < 0.001). Nearly two-third of the reduction of total time spent at the extremes between automated and manual control (3.8 to 2.1% for < 80% SpO(2) and 3.0 to 1.6% for > 98% SpO(2)) was seen in the episodes of at least 60 seconds. Conclusions This study shows that the majority of episodes preterm infants spent in SpO(2) extremes are of short duration regardless of manual or automated control. However, the infrequent longer episodes not only contribute the most to the total exposure, but also their reduction in frequency to the improvement associated with automated control.

Oxygen is the most common drug used in the neonatal intensive care. It has a narrow therapeutic range in preterm infants. Too high (hyperoxemia) or low oxygen (hypoxemia) is associated with adverse neonatal outcomes. It is not only prudent to maintain oxygen saturations in the target range, but also to avoid extremes of oxygen saturations. In routine practice when done manually by the staff, it is challenging to maintain oxygen saturations within the target range. Automatic control of oxygen delivery is now feasible and has shown to improve the time spent with in the target range of oxygen saturations. In addition, it also helps to avoid extremes of oxygen saturation. However, there are no studies that evaluated the clinical outcomes with automatic control of oxygen delivery. In this narrative review article, we aim to present the current evidence on automatic oxygen control and the future directions.

Introduction: Increased proliferation and survival of pulmonary vascular cells in small pulmonary arteries (PA) are key pathological features of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH).We recently reported that LATS1, a member of HIPPO growth-suppressor pathway, acts as a negative regulator of proliferative, apoptosis-resistant PA vascular smooth muscle cells (PAVSMC) phenotype in PAH.The role of other key protein-kinases of HIPPO cassette, mammalian Ste20-like kinases (MST) 1/2, in PAH remains unknown.Methods and results: Here we report that, in contrast to canonical anti-proliferative/pro-apoptotic roles, MST1 and MST2 act as pro-proliferative/pro-survival molecules in human PAH PAVSMC and PA adventitial fibroblasts (PAAF).Using MST1/2 kinase-dead constructs and specific ATP-competitive inhibitor XMU-MP-1, we demonstrated that catalytically active MST1/2 are required for increased proliferation and survival in PAH PAVSMC and PAAF.Immunoblot and immunocytochemical analyses revealed overexpression of MST1/2 in PAH PAAF and significant increase of cytoplasmic MST1 in PAH PAVSMC as evidenced by twice lower nucleus/cytoplasm ratio.MST1/2 supported up-regulated AKT and MTOR signaling in PAVSMC and were required for FOXO deficiency in both PAAF (FOXO3) and PAVSMC (FOXO1).Unbiased mass spectrometry analysis revealed that, in contrast to control cells, in PAH PAVSMC MST1/2 form a disease-specific interactions with BUB3 and USP10.BUB3 was significantly up-regulated in human PAH PAVSMC by MST1/2 in extracellular matrix-and USP10-dependent manner, and, in turn, supported activation of Akt-mTORC1, sustained cell growth and inhibited apoptosis.In PAH PAAF, MST1/2 pro-proliferative function was caused by IL-6/STAT3-dependent MST1/2 over-expression, which induced PSMC6-dependent down-regulation of FOXO3 and hyper-proliferation.Confirming our in vitro data, smooth muscle-specific tamoxifen-induced depletion of Mst1/2 in mice with already developed SuHx-induced Pulmonary Hypertension (PH) reversed pulmonary vascular remodeling and significantly reduced systolic right ventricular pressure (sRVP), pulmonary arterial pressure (PAP) and contractility (max dP/dT) demonstrating that MST1/2 support pulmonary vascular remodeling and PH in vivo.Conclusion: In aggregate, our data demonstrate the novel, non-canonical pro-proliferative/pro-survival function of MST1/2 in PAH pulmonary vasculature, identify BUB3 and FOXO as MST1/2 downstream effectors in PAH, and suggest that MST1/2 is an attractive potential target for PAH therapy.