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Background: An oxygen saturation (SpO2) histogram classification system has been shown to enable quantification of SpO2 instability into five types, based on histogram distribution and time spent at SpO2 ≤ 80%. We aimed to investigate this classification system as a tool to describe response to doxapram treatment in infants with severe apnea of prematurity. Methods: This retrospective study included 61 very-low-birth-weight infants who received doxapram. SpO2 histograms were generated over the 24-h before and after doxapram start. Therapy response was defined as a decrease of ≥1 histogram types after therapy start. Results: The median (IQR) histogram type decreased from 4 (3–4) before to 3 (2–3) after therapy start (p < 0.001). The median (IQR) FiO2 remained constant before (27% [24–35%]) and after (26% [22–35%]) therapy. Thirty-six infants (59%) responded to therapy within 24 h. In 34/36 (94%) of the responders, invasive mechanical ventilation (IMV) was not required during the first 72 h of therapy, compared to 15/25 (60%) of non-responders (p = 0.002). Positive and negative predictive values of the 24-h response for no IMV requirement within 72 h were 0.46 and 0.94, respectively. Conclusions: Classification of SpO2 histograms provides an objective bedside measure to assess response to doxapram therapy and can serve as a tool to detect changes in oxygenation status around respiratory interventions. Impact: The SpO2 histogram classification system provides a tool for quantifying response to doxapram therapy.The classification system allowed estimation of the probability of invasive mechanical ventilation requirement, already within a few hours of treatment.The SpO2 histogram classification system allows an objective bedside assessment of the oxygenation status of the preterm infant, making it possible to assess the changes in oxygenation status in response to respiratory interventions.

Background and objective: The most common respiratory complication of extreme prematurity is bronchopulmonary dysplasia(BPD), leading to structural lung changes and impaired respiratory outcomes. However, also extremely preterm children without BPD may show similar adverse respiratory outcomes. There is need for a safe imaging modality for preterm children with and without BPD for disease severity and risk stratification assessment. Our objective was to develop a chest Magnetic Resonance Imaging(MRI) protocol in preterm children with and without BPD at school age. Methods: Nine healthy volunteers (median age 11.6(range 8.8-12.8) years), eleven preterm children with BPD (11.0(7.2-15.6) years) and nine without BPD (11.1(10.7-12.6) years) underwent MRI. MR images were scored on hypo- and hyperintense abnormalities, bronchopathy and architectural distortion. MRI data were correlated to spirometry. Ventilation and perfusion defects were analysed using Fourier Decomposition (FD) MRI. Results: On MRI, children with BPD had a higher %diseased lung (9.1 (IQR 5.9-11.6)%) compared to preterm children without BPD (3.4 (IQR 2.5-5.4)%, p1 (r=-0.40, p=0.04), FEV1/FVC (r=-0.49, p=0.009) and FEF75 (r=-0.63, pConclusion: MRI can identify structural and functional lung damage at school age in preterm children with and without BPD, showing good correlation with spirometry. We propose chest MRI as a sensitive and safe imaging method (without ionising radiation, contrast agents or the use of anaesthesia) for the long-term follow up of preterm children.

Background: In neonates with post-asphyxial neonatal encephalopathy, further neuronal damage is prevented with therapeutic hypothermia (TH). In addition, fluctuations in carbon dioxide levels have been associated with poor neurodevelopmental outcome, demanding close monitoring. This study investigated the accuracy and clinical value of transcutaneous carbon dioxide (tcPCO2) monitoring during TH. Methods: In this retrospective cohort study in neonates, agreement between arterial carbon dioxide (PaCO2) values and tcPCO2 measurements during TH was determined. TcPCO2 levels during the first 24 h of hypothermia were tested for an association with ischemic brain injury on magnetic resonance imaging (MRI). Results: Thirty-four neonates were included. Agreement (bias (95% limits of agreement)) between tcPCO2 and PaCO2 levels was 3.9 (−12.4–20.2) mm Hg. No relation was found between the body temperature and tcPCO2 levels. TcPCO2 levels differed significantly between patients with considerable and minimal damage on MRI; after 6 h (P = 0.02) and 9 h (P = 0.04). Conclusions: Although tcPCO2 provided a limited estimation of PaCO2, it can be used for trend monitoring during TH. TcPCO2 levels after birth could provide an early indicator of ischemic brain injury. This relation should be investigated in large prospective studies, in which adjustments for confounders can be made. Impact: Transcutaneous carbon dioxide measurements during therapeutic hypothermia in neonates show limited accuracy similar to measurements reported in normothermic neonates and can be used for trend monitoring.Low transcutaneous carbon dioxide levels during the first 24 h were associated with considerable ischemic brain injury on MRI.The value of transcutaneous carbon dioxide measurements during the first 24 h as an indicator of considerable ischemic brain injury on MRI should be investigated in future studies, adjusting for confounders.Transcutaneous oxygen measurements during therapeutic hypothermia showed an inaccuracy that could not be related to a low body temperature.

Background: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. Methods: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0–28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin–clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. Findings: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin–clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [non-inferiority

Background and Purpose Recently pentoxifylline, a non-selective phosphodiesterase inhibitor and adenosine receptor antagonist, has attracted much interest for the treatment of the increased vascular resistance and endothelial dysfunction in pre-eclampsia. We therefore investigated the placental transfer, vascular effects and anti-inflammatory actions of pentoxifylline in healthy and pre-eclamptic human placentas. Experimental Approach The placental transfer and metabolism of pentoxifylline were studied using ex vivo placenta perfusion experiments. In wire myography experiments with chorionic plate arteries, pentoxifyllines vasodilator properties were investigated, focusing on the cGMP and cAMP pathways and adenosine receptors. Its effects on inflammatory factors were also studied in placental explants. Key Results Pentoxifylline transferred from the maternal to foetal circulation, reaching identical concentrations. The placenta metabolized pentoxifylline into its active metabolite lisofylline (M1), which was released into both circulations. In healthy placentas, pentoxifylline potentiated cAMP- and cGMP-induced vasodilation, as well as causing vasodilation by adenosine A(1) antagonism and via NO synthase and PKG. Pentoxifylline also reduced inflammatory factors secretion. In pre-eclamptic placentas, we observed that its vasodilator capacity was preserved, however not via NO-PKG but likely through adenosine signalling. Pentoxifylline neither potentiated vasodilation through cAMP and cGMP, nor suppressed the release of inflammatory factors from these placentas. Conclusion and Implications Pentoxifylline is transferred across and metabolized by the placenta. Its beneficial effects on the NO pathway and inflammation are not retained in pre-eclampsia, limiting its application in this disease, although it could be useful for other placenta-related disorders. Future studies might focus on selective A(1) receptor antagonists as a new treatment for pre-eclampsia.

With the development of highly sensitive bioanalytical techniques, the volume of samples necessary for accurate analysis has reduced. Microsampling, the process of obtaining small amounts of blood, has thus gained popularity as it offers minimal-invasiveness, reduced logistical costs and biohazard risks while simultaneously showing increased sample stability and a potential for the decentralization of the approach and at-home self-sampling. Although the benefits of microsampling have been recognised, its adoption in clinical practice has been slow. Several microsampling technologies and devices are currently available and employed in research studies for various biomedical applications. This review provides an overview of the state-of-the-art in microsampling technology with a focus on the latest developments and advancements in the field of microsampling. Research published in the year 2022, including studies (i) developing strategies for the quantitation of analytes in microsamples and (ii) bridging and comparing the interchangeability between matrices and choice of technology for a given application, is reviewed to assess the advantages, challenges and limitations of the current state of microsampling. Successful implementation of microsampling in routine clinical care requires continued efforts for standardization and harmonization. Microsampling has been shown to facilitate data-rich studies and a patient-centric approach to healthcare and is foreseen to play a central role in the future digital revolution of healthcare through continuous monitoring to improve the quality of life.

ImportanceQuantification of bilirubin in blood is essential for early diagnosis and timely treatment of neonatal hyperbilirubinemia. Handheld point-of-care (POC) devices may overcome the current issues with conventional laboratory-based bilirubin (LBB) quantification.ObjectiveTo systematically evaluate the reported diagnostic accuracy of POC devices compared with LBB quantification.Data SourcesA systematic literature search was conducted in 6 electronic databases (Ovid MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, CINAHL, and Google Scholar) up to December 5, 2022.Study SelectionStudies were included in this systematic review and meta-analysis if they had a prospective cohort, retrospective cohort, or cross-sectional design and reported on the comparison between POC device(s) and LBB quantification in neonates aged 0 to 28 days. Point-of-care devices needed the following characteristics: portable, handheld, and able to provide a result within 30 minutes. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline.Data Extraction and SynthesisData extraction was performed by 2 independent reviewers into a prespecified, customized form. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was performed of multiple Bland-Altman studies using the Tipton and Shuster method for the main outcome.Main Outcomes and MeasuresThe main outcome was mean difference and limits of agreement in bilirubin levels between POC device and LBB quantification. Secondary outcomes were (1) turnaround time (TAT), (2) blood volumes, and (3) percentage of failed quantifications.ResultsTen studies met the inclusion criteria (9 cross-sectional studies and 1 prospective cohort study), representing 3122 neonates. Three studies were considered to have a high risk of bias. The Bilistick was evaluated as the index test in 8 studies and the BiliSpec in 2. A total of 3122 paired measurements showed a pooled mean difference in total bilirubin levels of −14 μmol/L, with pooled 95% CBs of −106 to 78 μmol/L. For the Bilistick, the pooled mean difference was −17 μmol/L (95% CBs, −114 to 80 μmol/L). Point-of-care devices were faster in returning results compared with LBB quantification, whereas blood volume needed was less. The Bilistick was more likely to have a failed quantification compared with LBB.Conclusions and RelevanceDespite the advantages that handheld POC devices offer, these findings suggest that the imprecision for measurement of neonatal bilirubin needs improvement to tailor neonatal jaundice management.

Aims To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. Methods and results Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was Conclusion These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

Objectives: To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging markers and survival. Design: Retrospective cohort study. Setting: Multicentre study in large referral centres. Population: Infants with an isolated unilateral CDH, live born at 32.0 weeks or less of gestation, between January 2009 and January 2020. Methods: Neonatal outcomes were evaluated for infants that were expectantly managed during pregnancy and infants that underwent fetoscopic endoluminal tracheal occlusion (FETO) therapy, separately. We evaluated the association between prenatal imaging markers and survival to discharge. Prenatal imaging markers included observed to expected lung-to-head ratio (o/e LHR), side of the defect, liver position, stomach position grade, and observed to expected total fetal lung volume (o/e TFLV). Main Outcome Measure: Survival to discharge. Results: We included 53 infants born at 30 +4 (interquartile range 29 +1–31 +2) weeks. Survival in fetuses expectantly managed during pregnancy was 48% (13/27) in left-sided CDH and 33% (2/6) in right-sided CDH. Survival in fetuses that underwent FETO therapy was 50% (6/12) in left-sided CDH and 25% (2/8) in right-sided CDH. The o/e LHR at baseline was positively associated with survival in cases expectantly managed during pregnancy (odds ratio [OR] 1.20, 95% CI 1.07–1.42, p < 0.01), but not in cases that received FETO therapy (OR 1.01, 95% CI 0.88–1.15, p = 0.87). Stomach position grade (p = 0.03) and o/e TFLV were associated with survival (p = 0.02); liver position was not (p = 0.13). Conclusions: In infants with CDH born at or before 32 weeks of gestation, prenatal imaging markers of disease severity were associated with postnatal survival.

BACKGROUND AND OBJECTIVE: Clavulanic acid is a commonly used β-lactam inhibitor in pediatrics for a variety of infections. Clear insight into its mode of action is lacking, however, and a target has not been identified. The dosing of clavulanic acid is currently based on that of the partner drug (amoxicillin or ticarcillin). Still, proper dosing of the compound is needed because clavulanic acid has been associated with adverse effects. In this systematic review, we aim to describe the current literature on the pharmacokinetics of clavulanic acid in the pediatric population METHODS: We performed a systematic search in MEDLINE, Embase.com, Cochrane Central, Google Scholar, and Web of Science. We included all published studies reporting pharmacokinetic data on clavulanic acid in neonates and children 0-18 years of age. RESULTS: The search resulted in 18 original studies that met the inclusion criteria. In general, the variation in drug exposure was large, which can be partly explained by differences in disease state, route of administration, or age. Unfortunately, the studies' limited background information hampered in-depth assessment of the observed variability. CONCLUSION: The pharmacokinetics of clavulanic acid in pediatric patients is highly variable, similar to reports in adults, but more pronounced. Significant knowledge gaps remain with regard to the population-specific explanation for this variability. Model-based pharmacokinetic studies that address both maturational and disease-specific changes in the pediatric population are therefore needed. Furthermore, additional pharmacodynamic studies are needed to define a clear target. The combined outcomes will eventually lead to pharmacokinetic-pharmacodynamic modeling of clavulanic acid and targeted exposure. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42020137253. ispartof: CLINICAL PHARMACOKINETICS vol:61 issue:5 pages:637-653 ispartof: location:Switzerland status: published

Background: Iron plays a role in many key processes in the developing brain. During pregnancy, iron supplementation is widely recommended to prevent and treat iron deficiency; however, the prevalence of iron deficiency and the risk of iron overload vary greatly between populations. Evidence on the role of high levels of maternal ferritin, a storage iron marker during pregnancy in relation to offspring neurodevelopment is lacking. Objective: Our main objective was to examine if maternal ferritin levels during pregnancy are associated with child cognitive and motor abilities. Methods: We included Dutch mother-child dyads from the prospective population-based Generation R Study, born in 2002–2006. We compared children whose mothers had high (standard deviation score >+1) or low (standard deviation score 3 (95% confidence interval -30.57, -1.48) smaller brain volume. Results remained similar after excluding mothers with high C-reactive protein. Low maternal ferritin was not associated with child cognitive abilities. Maternal ferritin was unrelated to child motor outcomes. Conclusion: High maternal ferritin during pregnancy was associated with poorer child cognitive abilities and smaller brain volume. Maternal iron status during pregnancy may be associated with offspring neurodevelopment.

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).Conclusion: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a “rebound” vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action. What is Known:• In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo. What is New:• The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension.• The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

The study objective was to explore associations of fetal and infant weight patterns and preterm birth with sleep and 24-h activity rhythm parameters at school-age. In our prospective population-based study, 1327 children were followed from birth to age 10–15 years. Fetal weight was estimated using ultrasound in the second and third trimester of pregnancy. Birth weight and gestational age were available from midwife registries. Infant weight was measured at 6, 12 and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change of >0.67 standard deviation between the corresponding age intervals. At school-age, sleep duration, sleep efficiency, wake after sleep onset, social jetlag, inter-daily stability, and intra-daily variability were assessed using tri-axial wrist actigraphy for 9 consecutive nights. We observed that low birth weight (

Introduction Human pregnancy is considered term from 37+0/7 to 41+6/7 weeks. Within this range, both maternal, fetal and neonatal risks may vary considerably. This study investigates how gestational age per week is related to the components of perinatal mortality and parameters of adverse neonatal and maternal outcome at term. Material and Methods A registry-based study was made of all singleton term pregnancies in the Netherlands from January 2014 to December 2017. Stillbirth and early neonatal mortality, as components of perinatal mortality, were defined as primary outcomes; adverse neonatal and maternal events as secondary outcomes. Neonatal adverse outcomes included birth trauma, 5-minute Apgar score

Infections by meningococcal species are extremely rare in the first days of life. We present a fatal case of early-onset sepsis presenting at birth, caused by intrauterine transmission of serogroup Y N. meningitidis, evidenced clinically and histologically by corresponding chorioamnionitis and N. meningitidis-positive amniotic fluid. This case confirms a long-standing suspicion that N. meningitidis can be transmitted in utero.

Purpose Parents of infants admitted to a neonatal intensive care unit (NICU) experience additional stress due to restrictions on their presence and visits by other family members during the COVID-19 pandemic. Our study aims to describe how this impacted parents and how NICU staff could support them. Design and methods This was a cross-sectional study in which 25 parents (16 mothers, 9 fathers) of infants admitted to our NICU during the first COVID-19 lockdown completed online questionnaires with socio-demographic questions, the Parental Stressor Scale:NICU (PSS:NICU) and questions related to COVID-19. Results Being separated from, and not being able to hold their infant at all times were among the most important PSS:NICU stressors. Parents experienced additional stress because other family members were not allowed to visit. They indicated that NICU staff could support them by clearly explaining the reasons for visitor restrictions and by ensuring that they felt heard. Most parents supported the restrictions, but also mentioned that less strict measures would really help them. Conclusions Parents who participated in this study found it very stressful that they could not be with their infant together with their partner and other family members. Furthermore, parents recommended the hospital management to continuously reconsider whether particular restrictions could be lifted in case of a new lockdown. Together with clear communication, this would result in less parenteral stress. Practice implications Hospital management should be cautious on restricting the presence of parents and other family members and scale restrictions back whenever possible.

BackgroundVolumes of cerebellar posterior lobes have been associated with cognitive skills, such as language functioning. Children born very preterm (VPT) often have language problems. However, only total cerebellar volume has been associated with language functioning, with contradicting results. The objective of this study was to ascertain whether total cerebellar structures or specific posterior lobular structures are associated with language ability of school-aged VPT children.MethodsThis is a prospective cohort study of 42 school-aged VPT children without major handicaps. Structural MRI was performed and the cerebellum segmentation pipeline was used for segmentation of separate lobules. Narrative retelling assessment was performed and language content and language structure scores were extracted. Linear regression analyses were used to associate language scores with whole gray matter (GM) cerebellar volume and right Crus I+II GM volume.ResultsWhole cerebellar GM volume was not significantly associated with language content nor with language structure; however, right Crus I+II GM volume was significantly associated with language content (β = 0.192 (CI = 0.033, 0.351), p = 0.020).ConclusionsGM volume of Crus I+II appears to be associated with language functions in school-aged VPT children without major handicaps, while whole cerebellar volume is not. This study showed the importance of studying cerebellar lobules separately, rather than whole cerebellar volume only, in relation to VPT children’s language functions.ImpactGM volume of Crus I+II is associated with semantic language functions in school-aged very preterm children without overt brain injury, whereas whole cerebellar volume is not.This study showed the importance of studying cerebellar lobules separately, rather than whole cerebellar volume only, in relation to very preterm children’s language functions.This study might impact future research in very preterm children. Lobular structures rather than whole cerebellar structures should be the region of interest in relation to language functions.

Background International guidelines recommend delayed umbilical cord clamping (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However, clamping the cord prior to lung aeration may severely limit circulatory adaptation resulting in a reduction in cardiac output and hypoxia. Delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) allows for an adequately established pulmonary circulation and results in a more stable circulatory transition. The decline in cardiac output following time-based delayed cord clamping (TBCC) may thus be avoided. We hypothesise that PBCC, compared to TBCC, results in a more stable transition in very preterm infants, leading to improved clinical outcomes. The primary objective is to compare the effect of PBCC on intact survival with TBCC. Methods The Aeriation, Breathing, Clamping 3 (ABC3) trial is a multicentre randomised controlled clinical trial. In the interventional PBCC group, the umbilical cord is clamped after the infant is stabilised, defined as reaching heart rate > 100 bpm and SpO2 > 85% while using supplemental oxygen Discussion The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management in very preterm infants at birth. Trial registration ClinicalTrials.gov NCT03808051. First registered on January 17, 2019.

Background: Language difficulties of very preterm (VPT) children might be related to weaker cerebral hemispheric lateralization of language. Language lateralization refers to the development of an expert region for language processing in the left hemisphere during the first years of life. Children born VPT might not develop such a dominant left hemisphere for language processing. A dichotic listening task may be a functional task to show the dominance of the left hemisphere during language processing. During this task, different acoustic events are simultaneously presented to both ears. Due to crossing fibers in the brain, right ear stimuli are transferred directly to the left hemisphere, and left ear stimuli are transferred first to the right hemisphere and then, through the corpus callosum (CC), to the left hemisphere. Dichotic listening typically shows a right ear advantage, assuming to reflect left hemispherical language dominance. The CC, in particular the splenium, is associated with auditory processing and is considered important for language lateralization. The objective of this work was to explore whether dichotic listening performance in school-aged VPT children are associated with language performance and interhemispheric connectivity. Methods: This is a cross-sectional study of 58 VPT children and 30 full term controls at age 10 years. Language performance and dichotic digit test (DDT) were assessed. In 44 VPT children, additionally diffusion weighted imaging (DWI) was performed using a 3 T MRI scanner. Fractional anisotropy (FA) and mean diffusivity (MD) values of the splenium of the CC were extracted. Results: Poorer right ear DDT scores were associated with poorer language performance in VPT children only (p = 0.015). Association between right ear DDT scores and MD of the splenium approached the level of significance (p = 0.051). Conclusions: These results support the hypothesis that poor language performance in VPT children may be a consequence of weaker lateralized language organization, due to a poorly developed splenium of the CC. Dichotic listening may reflect the level of language lateralization in VPT children. Impact: Poor language performance in VPT children may be a consequence of weaker lateralized language organization, due to a poorly developed splenium of the CC.Dichotic listening performance may reflect the level of language lateralization in VPT children and right ear scores of a dichotic listening task are associated with both the splenium of the corpus callosum and language performance.If our results could be validated in future research, it suggests that poor CC development may indicate VPT children at risk for long-term language problems.

Contains fulltext : 234037.pdf (Publisher’s version ) (Open Access) AIM: Patent ductus arteriosus (PDA) is treated with ibuprofen and it is known that the clearance of ibuprofen increases with postnatal age. We aimed to study whether postnatal age-adjusted ibuprofen dosages improve the effectiveness of treatment compared to standard ibuprofen dosages after the first days of life. METHODS: A historical cohort of 207 preterm neonates treated with standard ibuprofen dosages (Group A; 2011-2015) was compared to a prospective cohort of 66 preterm neonates treated with postnatal age-adjusted ibuprofen dosages (Group B; 2015-2016). RESULTS: Both groups had comparable background characteristics. Treatment was started after median 6 (25-75th percentile: 4-11) and 5 (25-75th percentile: 4-11) days and effectiveness was 33.2 and 44.7% (p = .17) in groups A and B, respectively. No hemodynamically significant PDA was found in 23/49 (46.9%) of the patients born before 28 weeks after adjusted ibuprofen dosages compared to 48/162 (29.6%) after standard ibuprofen dosages (p = .04). There were significantly more reversible side effects with the postnatal age-adjusted ibuprofen dosages (p = .04). CONCLUSIONS: There seems to be a trend to higher effectiveness with the adjusted ibuprofen dosages in preterm neonates before 28 weeks, but it is associated with more reversible side effects.

Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

Placental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a specific histiocytic intervillositis. Placental fibrin depositions can decrease the maternal-fetal interface causing fetal distress. Coronavirus disease 2019-related placental inflammation can lead to SARS-CoV-2-associated pediatric inflammatory multisystem syndrome., Background In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is not considered to be an increased risk for severe maternal outcomes but has been associated with an increased risk for fetal distress. Maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain; however, recently a few cases of vertical transmission have been reported. The intrauterine mechanisms, besides direct vertical transmission, leading to the perinatal adverse outcomes are not well understood. Methods Multiple maternal, placental, and neonatal swabs were collected for the detection of SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR). Serology of immunoglobulins against SARS-CoV-2 was tested in maternal, umbilical cord, and neonatal blood. Placental examination included immunohistochemical investigation against SARS-CoV-2 antigen expression, with SARS-CoV-2 ribonucleic acid (RNA) in situ hybridization and transmission electron microscopy. Results RT-qPCRs of the oropharynx, maternal blood, vagina, placenta, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples tested negative. Placental findings showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts. Conclusions Placental infection by SARS-CoV-2 leads to fibrin depositions hampering fetal-maternal gas exchange with resulting fetal distress necessitating a premature emergency cesarean section. Postpartum, the neonate showed a fetal or pediatric inflammatory multisystem-like syndrome with coronary artery ectasia temporarily associated with SARS-CoV-2 for which admittance and care on the neonatal intensive care unit (NICU) were required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current coronavirus disease 2019 pandemic, especially considering that the majority of pregnant women appear asymptomatic.

Current haemodynamic monitoring is mainly aimed at the macrocirculation. Multiple studies have demonstrated the importance of the microcirculation in relation to the patient’s condition and impact of treatment strategies. However, continuous monitoring of the microcirculation is not yet possible in the neonatal field. A novel dynamic light scattering (DLS) sensor technology for continuous monitoring of the microcirculation was investigated in the neonatal population. Thirty-one haemodynamically stable infants were included. Sequential measurements at the forehead, upper extremity, thorax, abdomen and lower extremity were conducted with the DLS sensor. For analyses stable measurements were selected. The DLS parameters, total blood flow (TBF) and relative blood velocity (RBV), were compared between measurement locations. Changes in relative haemodynamic indices (relHIs), indicating the distribution of blood flow in the microcirculatory blood vessels, were associated with heart rate decelerations. Measurements performed at the forehead had significantly lower TBF levels, compared to measurements at other locations. Early changes in relHIs around a heart rate deceleration were recorded a median (IQR) of 22.0 (13.5–27.0) s before the onset. Measurement of the currently unavailable parameters TBF, RBV and relHIs is possible with DLS technology. Validation of the DLS technology is needed for clinical implementation.

IntroductionPulmonary hypertension is a major determinant of postnatal survival in infants with a congenital diaphragmatic hernia (CDH). The current care during the perinatal stabilisation period in these infants might contribute to the development of pulmonary hypertension after birth—in particular umbilical cord clamping before lung aeration. An ovine model of diaphragmatic hernia demonstrated that cord clamping after lung aeration, called physiological-based cord clamping (PBCC), avoided the initial high pressures in the lung vasculature while maintaining adequate blood flow, thereby avoiding vascular remodelling and aggravation of pulmonary hypertension. We aim to investigate if the implementation of PBCC in the perinatal stabilisation period of infants born with a CDH could reduce the incidence of pulmonary hypertension in the first 24 hours after birth.Methods and analysisWe will perform a multicentre, randomised controlled trial in infants with an isolated left-sided CDH, born at ≥35.0 weeks. Before birth, infants will be randomised to either PBCC or immediate cord clamping, stratified by treatment centre and severity of pulmonary hypoplasia on antenatal ultrasound. PBCC will be performed using a purpose-built resuscitation trolley. Cord clamping will be performed when the infant is considered respiratory stable, defined as a heart rate >100 bpm, preductal oxygen saturation >85%, while using a fraction of inspired oxygen of Ethics and disseminationCentral ethical approval was obtained from the Medical Ethical Committee of the Erasmus MC, Rotterdam, The Netherlands (METC 2019-0414). Local ethical approval will be obtained by submitting the protocol to the regulatory bodies and local institutional review boards.Trial registration numberNCT04373902.

Background Suboptimal maternal health already from preconception onwards is strongly linked to an increased risk of birth complications. To enable identification of women at risk of birth complications, we aimed to develop a prediction model for birth complications using maternal preconception socio-demographic, lifestyle, medical history and early-pregnancy clinical characteristics in a general population. Methods In a population-based prospective cohort study among 8340 women, we obtained information on 33 maternal characteristics at study enrolment in early-pregnancy. These characteristics covered the preconception period and first half of pregnancy ( Results The basic preconception model included easy obtainable maternal characteristics in the preconception period including age, ethnicity, parity, body mass index and smoking. This basic preconception model had an area under the receiver operating characteristics curve (AUC) of 0.63 (95% confidence interval (CI) 0.61 to 0.65) and 0.64 (95% CI 0.62 to 0.66) for preterm birth/SGA and LGA, respectively. Further extension to more complex models by adding maternal socio-demographic, lifestyle, medical history and early-pregnancy clinical characteristics led to small, statistically significant improved models. The full model for prediction of preterm birth/SGA had an AUC 0.66 (95% CI 0.64 to 0.67) with a sensitivity of 22% at a 90% specificity. The full model for prediction of LGA had an AUC of 0.67 (95% CI 0.65 to 0.69) with sensitivity of 28% at a 90% specificity. The developed models had a reasonable level of calibration within highly different socio-economic subsets of our population and predictive performance for various secondary maternal, delivery and neonatal complications was better than for primary outcomes. Conclusions Prediction of birth complications is limited when using maternal preconception and early-pregnancy characteristics, which can easily be obtained in clinical practice. Further improvement of the developed models and subsequent external validation is needed.

Introduction: Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. Methods: KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. Results: KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor a (IL-6Ra) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. Conclusion: KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Ra signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

Clinical improvement after red blood cell (RBC) transfusions in preterm infants remains debated. This study aims to investigate the effect of RBC transfusion on the occurrence of desaturations and hypoxia, and other cardiorespiratory outcomes in preterm infants. In this longitudinal observational study, prospectively stored cardiorespiratory parameters of preterm infants who received at least one RBC transfusion between July 2016 and June 2017 were retrospectively analyzed. Sixty infants with 112 RBC transfusions, median GA of 26.7 weeks, were included. The number of desaturations and area 2 limit, as a measure of the hypoxic burden, were calculated in 24 h before and after RBC transfusion. A mixed effects model was used to account for repeated measurements. Overall, the mean (SE) number of desaturations per hour decreased from 3.28 (0.55) to 2.25 (0.38; p 2 limit decreased from 0.14 (0.04) to 0.08 (0.02) %/s (p = 0.02). These outcomes were stratified for the number of desaturations in 24 h prior to RBC transfusion. The largest effect was observed in the group with the highest mean number of desaturations (≥ 6) prior to RBC transfusion, with a decrease from 7.50 (0.66) to 4.26 (0.38) (p 2. Perfusion index increased significantly after RBC transfusion (p Conclusions: RBC transfusions in preterm newborns could help decrease the incidence of desaturations and the area 2 as a measure of the hypoxic burden. The higher the number of desaturations prior to the RBC transfusion, the larger the effect observed. What is Known:•Red blood cell transfusions potentially prevent hypoxia in anemic preterm infants by increasing the circulatory hemoglobin concentration and improving tissue oxygenation.•There is not a predefined hemoglobin concentration cut-off for the occurrence of symptomatic anemia in preterm infants. What is New:•Oxygen desaturations and hypoxia in anemic preterm infants can be improved by RBC transfusions, especially if more desaturations have occurred before transfusion.•Cardiorespiratory monitor data may help identify infants who will benefit most from red blood cell transfusions.

Prematurely born young adults who experienced neonatal oxidative injury (NOI) of the lungs have increased incidence of cardiovascular disease. Here, we investigated the long-term effects of NOI on cardiopulmonary function in piglets at the age of 10–12 weeks. To induce NOI, term-born piglets (1.81 ± 0.06 kg) were exposed to hypoxia (10–12% (Formula presented.)), within 2 days after birth, and maintained for 4 weeks or until symptoms of heart failure developed (range 16–28 days), while SHAM piglets were normoxia raised. Following recovery (>5 weeks), NOI piglets were surgically instrumented to measure haemodynamics during hypoxic challenge testing (HCT) and exercise with modulation of the nitric-oxide system. During exercise, NOI piglets showed a normal increase in cardiac index, but an exaggerated increase in pulmonary artery pressure and a blunted increase in left atrial pressure – suggesting left atrial under-filling – consistent with an elevated pulmonary vascular resistance (PVR), which correlated with the duration of hypoxia exposure. Moreover, hypoxia duration correlated inversely with stroke volume (SV) during exercise. Nitric oxide synthase inhibition and HCT resulted in an exaggerated increase in PVR, while the PVR reduction by phosphodiesterase-5 inhibition was enhanced in NOI compared to SHAM piglets. Finally, within the NOI piglet group, prolonged duration of hypoxia was associated with a better maintenance of SV during HCT, likely due to the increase in RV mass. In conclusion, duration of neonatal hypoxia appears an important determinant of alterations in cardiopulmonary function that persist further into life. These changes encompass both pulmonary vascular and cardiac responses to hypoxia and exercise. (Figure presented.). Key points: Children who suffered from neonatal oxidative injury, such as very preterm born infants, have increased risk of cardiopulmonary disease later in life. Risk stratification requires knowledge of the mechanistic underpinning and the time course of progression into cardiopulmonary disease. Exercise and hypoxic challenge testing showed that 10- to 12-week-old swine that previously experienced neonatal oxidative injury had increased pulmonary vascular resistance and nitric oxide dependency. Duration of neonatal oxidative injury was a determinant of structural and functional cardiopulmonary remodelling later in life. Remodelling of the right ventricle, as a result of prolonged neonatal oxidative injury, resulted in worse performance during exercise, but enabled better performance during the hypoxic challenge test. Increased nitric oxide dependency together with age- or comorbidity-related endothelial dysfunction may contribute to predisposition to pulmonary hypertension later in life.

Lausanne : Frontiers Media 9, 793531 (2022). doi:10.3389/fped.2021.793531, Published by Frontiers Media, Lausanne

The aim of this study was to investigate the association between the implementation of a local heart rate variability (HRV) monitoring guideline combined with determination of inflammatory biomarkers and mortality, measures of sepsis severity, frequency of sepsis testing, and antibiotic usage, among very preterm neonates. In January 2018, a guideline was implemented for early detection of late-onset neonatal sepsis using HRV monitoring combined with determination of inflammatory biomarkers. Data on all patients admitted with a gestational age at birth of n = 1,135; n = 515 pre-implementation, n = 620 post-implementation). Outcomes of interest were (sepsis-related) mortality, sepsis severity (neonatal sequential organ failure assessment (nSOFA)), sepsis testing, and antibiotic usage. Differences before and after implementation of the guideline were assessed using logistic and linear regression analysis for binary and continuous outcomes respectively. All analyses were adjusted for gestational age and sex. Mortality within 10 days of a sepsis episode occurred in 39 (10.3%) and 34 (7.6%) episodes in the pre- and post-implementation period respectively (P = 0.13). The nSOFA course during a sepsis episode was significantly lower in the post-implementation group (P = 0.01). We observed significantly more blood tests for determination of inflammatory biomarkers, but no statistically significant difference in number of blood cultures drawn and in antibiotic usage between the two periods.Conclusion: Implementing HRV monitoring with determination of inflammatory biomarkers might help identify patients with sepsis sooner, resulting in reduced sepsis severity, without an increased use of antibiotics or number of blood cultures. What is Known:• Heart rate variability (HRV) monitoring might be used as an early warning system to diagnose preterm neonates at risk of developing sepsis.• It has already been shown that HRV monitoring could reduce mortality; however, there are concerns that HRV monitoring alone could lead to higher rates of blood cultures and overuse of antibiotics. What is New:• Implementing HRV monitoring with determination of inflammatory biomarkers might help identify patients with sepsis sooner, resulting in reduced sepsis severity, without an increased use of antibiotics or number of blood cultures.

To identify distinctive multidisciplinary neurodevelopmental profiles of relatively healthy children born very preterm (VPT) and describe the longitudinal course of these profiles up to age 10. At 2 years of corrected age, 84 children born VPT underwent standardized testing for cognitive, language, speech, motor, behavioral, and auditory nerve function. These data were submitted to factor and cluster analysis. Sixty-one of these children underwent cognitive, language, and behavioral assessment again at age 10. Descriptive statistics were used to analyze longitudinal trajectories for each profile. Four neurodevelopmental profiles were identified at age 2. Profile 1 children (n = 22/26%) had excellent cognitive-language-motor function, normal behavioral and auditory nerve function, but showed an unexpected severe decline up to age 10. Profile 2 children (n = 16/19%) had very low behavioral function, low cognitive-language-motor function, and accelerated auditory nerve function. Their scores remained low up until age 10. Profile 3 children (n = 17/20%) had delayed auditory nerve function, low behavioral function, and slightly lower cognitive-language-motor function. They showed the most increasing trajectory. Profile 4 children (n = 29/35%) had very low cognitive-language-motor function, normal behavioral and auditory nerve function, but showed wide variation in their trajectory. Our preliminary study showed that a multidisciplinary profile-oriented approach may be important in children born VPT to improve counseling and provide targeted treatment for at risk children. High performers at age 2 may not be expected to maintain their favorable development. Behavioral problems might negatively impact language development. Delayed auditory nerve function might represent a slow start and catch-up development.

ObjectiveTo find propofol doses providing effective sedation without side effects in neonates of different gestational ages (GA) and postnatal ages (PNA).Design and settingProspective multicentere dose-finding study in 3 neonatal intensive care units.PatientsNeonates with a PNA InterventionsNeonates were stratified into 8 groups based on GA and PNA. The first 5 neonates in every group received a dose of 1.0 mg/kg propofol. Based on sedative effect and side effects, the dose was increased or decreased in the next 5 patients until the optimal dose was found.Main outcome measuresThe primary outcome was the optimal single propofol starting dose that provides effective sedation without side effects in each age group.ResultsAfter inclusion of 91 patients, the study was prematurely terminated because the primary outcome was only reached in 13% of patients. Dose-finding was completed in 2 groups, but no optimal propofol dose was found. Effective sedation without side effects was achieved more often after a starting dose of 2.0 mg/kg (28%) than after 1.0 mg/kg (3%) and 1.5 mg/kg (9%). Propofol-induced hypotension occurred in 59% of patients. Logistic regression analyses showed that GA and PNA did not predict effective sedation or the occurrence of hypotension.ConclusionsEffective sedation without side effects is difficult to achieve with propofol and the optimal dose in different age groups of neonates could not be determined. The sedative effect of propofol and the occurrence of hypotension are unpredictable and show large inter-individual variability in the neonatal population.

BACKGROUND: Language is a complex neurodevelopmental phenomenon. Approximately 45% of children born very preterm (VP) show mild-to-severe language problems throughout childhood. Nevertheless, in most hospitals in Europe language functions are not routinely assessed at follow-up.OBJECTIVE: To give clear indications for extensive language assessment in school-aged children born VP, based on routinely assessed intelligence and behavioral problems.METHOD: Language functions of 63 10-year-old children born VP (RESULTS: The mean language score was significantly lower than the verbal intelligent quotient (VIQ; mean difference = 6.4, p < .001, d=.48) and the mean vocabulary knowledge (mean difference = 9.3, p < .001, d=.70). Besides, VIQ (β = .649, p = .001) and performance IQ (PIQ; β = .260, p = .035) were significantly associated with language scores. Significant predictors of language scores were number of days of assisted ventilation (β = -.592, p = .015) and mother's vocabulary knowledge (β =.473, p = .014), rather than mother's educational level (β =.139, p = .956).CONCLUSIONS: Children born VP had language problems that were not expected from their significantly higher VIQ and vocabulary knowledge. Clinicians assessing these children should be aware of possible language problems, which cannot be detected with a simple vocabulary task. Our findings provide evidence of the need for adequate language assessments by a speech-language pathologist in children born VP, especially in those with VIQ scores in the low average range.

Aim: To analyse the effects of different propofol starting doses as premedication for endotracheal intubation on blood pressure in neonates. Methods: Neonates who received propofol starting doses of 1.0 mg/kg (n = 30), 1.5 mg/kg (n = 23) or 2.0 mg/kg (n = 26) as part of a previously published dose-finding study were included in this analysis. Blood pressure in the 3 dosing groups was analysed in the first 60 minutes after start of propofol. Results: Blood pressure declined after the start of propofol in all 3 dosing groups and was not restored 60 minutes after the start of propofol. The decline in blood pressure was highest in the 2.0 mg/kg dosing group. Blood pressure decline was mainly dependent on the initial propofol starting dose rather than the cumulative propofol dose. Conclusion: Propofol causes a dose-dependent profound and prolonged decrease in blood pressure. The use of propofol should be carefully considered. When using propofol, starting with a low dose and titrating according to sedative effect seems the safest strategy.

Introduction: Traditional transcutaneous oxygen (tcPO2) measurements are affected by measurement drift, limiting accuracy and usability. The new potentially drift-free oxygen fluorescence quenching technique has been combined in a single sensor with conventional transcutaneous carbon dioxide (tcPCO2) monitoring. This study aimed to validate optical tcPO2 and conventional tcPCO2 against arterial blood gas samples in preterm neonates and determine measurement drift. Methods: In this prospective observational study, during regular care, transcutaneous measurements were paired to arterial blood gases from preterm neonates aged 24–31 weeks of gestational age (GA) with an arterial catheter. Samples were included based on stability criteria and stratified for sepsis status. Agreement was assessed using the Bland-Altman analysis. Measurement drift per hour was calculated. Results: Sixty-eight premature neonates were included {median (interquartile range [IQR]) GA of 26 4/7 [25 3/7–27 5/7] weeks}, resulting in 216 stable paired samples. Agreement of stable samples in neonates without sepsis (n = 38) and with suspected sepsis (n = 112) was acceptable for tcPO2 and good for tcPCO2. However, in stable samples of neonates with sepsis (n = 66), tcPO2 agreement (bias and 95% limits of agreement) was −32.6 (−97.0 to 31.8) mm Hg and tcPCO2 agreement was 4.2 (−10.5 to 18.9) mm Hg. The median (IQR) absolute drift values were 0.058 (0.0231–0.1013) mm Hg/h for tcPO2 and 0.30 (0.11–0.64) mm Hg/h for tcPCO2. Conclusion: The accuracy of optical tcPO2 in premature neonates was acceptable without sepsis, while electrochemically measured tcPCO2 remained accurate under all circumstances. Measurement drift was negligible for tcPO2 and highly acceptable for tcPCO2.

This study investigated the accuracy, drift, and clinical usefulness of a new optical transcutaneous oxygen tension (tcPO2) measuring technique, combined with a conventional electrochemical transcutaneous carbon dioxide (tcPCO2) measurement and reflectance pulse oximetry in the novel transcutaneous OxiVenT™ Sensor. In vitro gas studies were performed to measure accuracy and drift of tcPO2and tcPCO2. Clinical usefulness for tcPO2and tcPCO2monitoring was assessed in neonates. In healthy adult volunteers, measured oxygen saturation values (SpO2) were compared with arterially sampled oxygen saturation values (SaO2) during controlled hypoxemia. In vitro correlation and agreement with gas mixtures of tcPO2(r= 0.999, bias 3.0 mm Hg, limits of agreement − 6.6 to 4.9 mm Hg) and tcPCO2(r= 0.999, bias 0.8 mm Hg, limits of agreement − 0.7 to 2.2 mm Hg) were excellent. In vitro drift was negligible for tcPO2(0.30 (0.63 SD) mm Hg/24 h) and highly acceptable for tcPCO2(− 2.53 (1.04 SD) mm Hg/12 h). Clinical use in neonates showed good usability and feasibility. SpO2-SaO2correlation (r= 0.979) and agreement (bias 0.13%, limits of agreement − 3.95 to 4.21%) in healthy adult volunteers were excellent. The investigated combined tcPO2, tcPCO2, and SpO2sensor with a new oxygen fluorescence quenching technique is clinically usable and provides good overall accuracy and negligible tcPO2drift. Accurate and low-drift tcPO2monitoring offers improved measurement validity for long-term monitoring of blood and tissue oxygenation.