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Objective: To investigate the effect of fetal growth restriction (FGR) on cerebrovascular autoregulation in preterm neonates during the first 3 days of life., Design: Case-control study., Setting: Neonatal intensive care unit of the Wilhelmina Children's Hospital, The Netherlands., Patients: 57 FGR (birth weight <10th percentile) and 57 appropriate for gestational age (AGA) (birth weight 20th-80th percentiles) preterm neonates, matched for gender, gestational age, respiratory and blood pressure support., Methods: The correlation between continuously measured mean arterial blood pressure and regional cerebral oxygen saturation was calculated to generate the cerebral oximetry index (COx). Mean COx was calculated for each patient for each postnatal day. The percentage of time with impaired autoregulation (COx>0.5) was also calculated., Results: FGR neonates had higher mean COx values than their AGA peers on day 2 (0.15 (95% CI 0.11 to 0.18) vs 0.09 (95% CI 0.06 to 0.13), p=0.029) and day 3 (0.17 (95% CI 0.13 to 0.20) vs 0.09 (95% CI 0.06 to 0.12), p=0.003) of life. FGR neonates spent more time with impaired autoregulation (COx value >0.5) than controls on postnatal day 2 (19% (95% CI 16% to 22%) vs 14% (95% CI 12% to 17%), p=0.035) and day 3 (20% (95% CI 17% to 24%) vs 15% (95% CI 12% to 18%), p=0.016)., Conclusion: FGR preterm neonates more frequently display impaired cerebrovascular autoregulation compared with AGA peers on days 2 and 3 of life which may predispose them to brain injury. Further studies are required to investigate whether this impairment persists beyond the first few days of life and whether this impairment is linked to poor neurodevelopmental outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aim: Caffeine improves neurodevelopmental outcome of preterm infants. This study analyses the effects of caffeine on the neonatal brain. We hypothesized that caffeine has a neuroprotective effect through an increase in oxygen metabolism; reflected by increased cerebral oxygen extraction, electrical function, and perfusion., Methods: Preterm infants <32 weeks gestation (GA) receiving their primary dose caffeine-base (10 mg/kg) were included. Ten minutes of stable monitoring were selected before, during, and every hour up to 6 h after caffeine. Near-infrared spectroscopy monitored regional cerebral oxygenation (rScO 2 ) and extraction (FTOE). Amplitude-integrated electroencephalogram (aEEG) monitored minimum, mean and maximum amplitudes. Spontaneous activity transients (SAT) rate and the interval between SATs (ISI) were calculated. Mean arterial blood pressure (MABP), heart rate (HR) and arterial oxygen saturation (SaO 2 ) were monitored. Arterial pCO 2 's were collected before and 4 h after caffeine. Brain perfusion was assessed 1 h before and 3 h after caffeine by Doppler-measured resistance-index (RI), peak systolic velocity (PSV) and end-diastolic velocity (EDV), in the anterior cerebral artery (ACA) and internal carotid artery (ICA). Results were presented in mean ± SD., Results: 34 infants, mean GA 28.8 ± 2.1 wk, were included. rScO 2 significantly decreased from 69 ± 11 to 63 ± 12 1 h after caffeine, and recovered at 6 h (66 ± 10). FTOE increased correspondingly. MABP and HR increased significantly. PSV in the ACA decreased slightly. Other Doppler variables, aEEG parameters, and SaO 2 were unaffected., Conclusion: Caffeine increases oxygen extraction, suggesting a (transient) stimulating effect on brain metabolism. However, no substantial changes were found in brain perfusion and in electrical brain activity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To evaluate the incidence of brain injury after neonatal surgery for noncardiac congenital anomalies using magnetic resonance imaging (MRI)., Study Design: An MRI was obtained in 101 infants at 7 days [range: 1-115] after neonatal surgery for major noncardiac congenital anomalies. Brain injury was assessed using T1, T2, diffusion weighted imaging, and susceptibility-weighted imaging., Results: Thirty-two preterm infants (<37 weeks of gestation) and 69 full-term infants were included. MRI abnormalities were found in 24 (75%) preterm and 40 (58%) full-term infants. Parenchymal lesions were noted in 23 preterm (72%) and 29 full-term infants (42%). These consisted of punctate white matter lesions (n = 45), punctate cerebellar lesions (n = 17), thalamic infarction (n = 5), and periventricular hemorrhagic infarction (n = 4). Nonparenchymal abnormalities were found in 9 (28%) preterm and 26 (38%) full-term infants. These included supra- and infratentorial subdural hemorrhages (n = 30), intraventricular hemorrhage grade II (n = 7), and asymptomatic sinovenous thrombosis (n = 1). A combination of parenchymal lesions was present in 21 infants. Of infants who had an MRI within 10 days after surgery, punctate white matter lesions were visible on diffusion weighted imaging in 22 (61%), suggestive of recent ischemic origin. Type of congenital anomaly and prematurity were most predictive of brain injury., Conclusions: Infants who have neonatal surgery for noncardiac congenital anomalies are at risk of brain injury, potentially accounting for the neurodevelopmental delay frequently observed in this population. Further research is warranted into potential mechanisms of brain injury and its timing of onset. Long-term neurodevelopmental follow-up is needed in this vulnerable population., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Drug administration on the neonatal intensive care unit is often associated with adverse events. This may be due to dosing errors caused by multi-infusion setups. We aim to investigate these dosing errors., Material and Methods: N=3 experiment using a medication schedule, multi-infusion setup (three pumps) and disposables as applied on the NICU. In-line and real-time absorption spectrophotometry was used with dyes as substitutes for pharmaceuticals. Three flow rate changes lasting 1h were initiated. Subsequently, the possible dosing errors were estimated in the parallel pumps. In addition, startup durations, the times the flow rates required to reach steady state after significant dosing errors, as well as the total dosing error were measured., Results: Contribution of the start-up delays to the cumulative dosing errors was the largest. However, initiated flow rate changes resulted in significant dosing errors in the parallel pumps as well. The total dosing error was not significant. The significant peak errors were between 48.2% and -32.5% at flow rate increase and decrease, respectively. Startup delays of up to 42.6min were measured., Conclusions: Applying multi-infusion while following a neonatal medication schedule may temporarily result in dosing errors, which can be relevant for fast-acting medications. Awareness may mitigate the risks., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The combined monitoring of oxygen supply and delivery using Near-InfraRed spectroscopy (NIRS) and cerebral activity using amplitude-integrated EEG (aEEG) could yield new insights into brain metabolism and detect potentially vulnerable conditions soon after birth. The relationship between NIRS and quantitative aEEG/EEG parameters has not yet been investigated. Our aim was to study the association between oxygen utilization during the first 6 h after birth and simultaneously continuously monitored brain activity measured by aEEG/EEG. Forty-four hemodynamically stable babies with a GA < 28 weeks, with good quality NIRS and aEEG/EEG data available and who did not receive morphine were included in the study. aEEG and NIRS monitoring started at NICU admission. The relation between regional cerebral oxygen saturation (rScO2) and cerebral fractional tissue oxygen extraction (cFTOE), and quantitative measurements of brain activity such as number of spontaneous activity transients (SAT) per minute (SAT rate), the interval in seconds (i.e. time) between SATs (ISI) and the minimum amplitude of the EEG in μV (min aEEG) were evaluated. rScO2 was negatively associated with SAT rate (β=-3.45 [CI=-5.76- -1.15], p=0.004) and positively associated with ISI (β=1.45 [CI=0.44-2.45], p=0.006). cFTOE was positively associated with SAT rate (β=0.034 [CI=0.009-0.059], p=0.008) and negatively associated with ISI (β=-0.015 [CI=-0.026- -0.004], p=0.007). Oxygen delivery and utilization, as indicated by rScO2 and cFTOE, are directly related to functional brain activity, expressed by SAT rate and ISI during the first hours after birth, showing an increase in oxygen extraction in preterm infants with increased early electro-cerebral activity. NIRS monitored oxygenation may be a useful biomarker of brain vulnerability in high-risk infants.

Background: The perfusion index (PI) derived from pulse oximetry readings represents the ratio of pulsatile (arterial blood) and nonpulsatile contributors to infrared light absorption. PI has been shown to correlate with cardiac performance. In theory, PI is readily available on every pulse oximeter; therefore, no additional sensors or infant handling are required. Currently, reference values are lacking in (preterm) neonates and the association with common clinical conditions is unclear., Objectives: To establish reference values for the PI in premature infants and at the same time determine the influence of common clinical conditions., Methods: PI was prospectively monitored on the lower limb for 72 h in 311 neonates born with a gestational age <32 weeks between January 2011 and December 2013. Longitudinal mixed-effects modeling was used. Linear, quadratic, and cubic models were explored. Main effects and interactions were investigated., Results: A squared model (0-24 h) followed by a linear model (24-72 h) provided the best fit of the data. PI was lowest around 12-18 h after birth and showed a steady increase thereafter. PI was positively related with female gender, gestational age, and pulse pressure. Negative associations were found with SIMV/HFOV ventilation, dopamine administration, mean arterial blood pressure, and arterial oxygen saturation. Although more complex, the general association with a patent ductus arteriosus was positive., Conclusion: PI varied according to several clinical conditions. The association with common clinical factors suggests that PI might be used for monitoring neonatal hemodynamics and possibly as an additional guidance for interventions., (© 2015 S. Karger AG, Basel.)

Background: Carbon monoxide (CO), a relaxant regulator of muscle tone and marker of oxidative stress and inflammation, can be measured in exhaled air by determination of end-tidal CO corrected for CO in ambient air (ETCOc)., Objective: Increased endogenous production of CO may influence patency of the ductus arteriosus, cerebral perfusion and, subsequently, cerebral oxygenation. The aim was to study the relation between early ETCOc levels, hemodynamically significant patent ductus arteriosus (hsPDA) and cerebral oxygenation (rScO2) in preterm infants <32 weeks' gestational age and determine predictive values of ETCOc for hsPDA., Methods: ETCOc was measured in 91 infants within the first 24 h after birth. A hsPDA was diagnosed according to echocardiographic indices. In 78/91 infants, rScO2 was monitored with near-infrared spectroscopy to assess cerebral oxygenation., Results: ETCOc values were significantly higher in infants who subsequently developed hsPDA (2.3 ± 0.7 ppm) vs. no-hsPDA (1.7 ± 0.6 ppm), p < 0.001. With a cut-off value of 2.5 ppm, positive and negative predictive values of ETCOc for hsPDA were 55 and 88%, respectively. rScO2 values were not different between the two groups (64 ± 1 vs. 65 ± 3%, NS)., Conclusions: The higher ETCOc values in hsPDA infants early after birth reflect the early relaxant state of ductal muscular tone. ETCOc <2.5 ppm within 24 h after birth may predict the subsequent absence of hsPDA. ETCOc showed no correlation with cerebral oxygenation in both groups., (© 2013 S. Karger AG, Basel.)

Background: Indomethacin has vasoactive properties in cerebral and systemic vascular beds, and it improves cerebral autoregulatory ability. We speculated that tocolytic indomethacin will improve cerebral autoregulatory ability in the very preterm infant in early postnatal life., Methods: Eighteen stable preterm infants gestational age (GA) 25.3-29.6 weeks, birth weight (BW) 660-1430 grams), whose mothers had received 50-150 mg of tocolytic indomethacin within 24 h before birth, and 18 individually matched controls (GA 25.0-29.7 weeks, BW 700-1390 grams) were studied four times for 15 min in the first 24 h of life. Autoregulation was assessed by determining correlations between mean arterial blood pressure (MABP (mm Hg)) and near-infrared spectroscopy-monitored cerebral oxygenation (rScO2)., Results: MABPs were significantly higher in the indomethacin infants than in the control infants (p=0.03). A decreased ability to autoregulate was found in four of the indomethacin infants, and in six of the control infants, which is not significantly different., Conclusions: Prenatally administered indomethacin, given as a tocolytic in doses of 50-150 mg per day, improved transitional circulation in very preterm infants by significantly raising the MABP. It did not have an effect on the ability to autoregulate the cerebral circulation. In this study, no differences in short-term outcomes, like haemorrhagic or ischaemic cerebral lesions, were observed.

Near-infrared spectroscopy is a noninvasive method for monitoring brain oxygenation. The aim of the study was to investigate differences between cerebral oxygenation in different brain regions in newborns. In a prospective study, we monitored simultaneously left and right frontoparietal and temporo-occipital regional cerebral oxygen saturation (rScO2) and cerebral fractional tissue extraction (cFTOE: (arterial oxygen saturation (SaO2) - rScO2)/SaO2) using near-infrared spectroscopy. A 2-h measurement was performed on d 1, 3, and 7. We included 10 very preterm (GA <32 wk), 10 preterm (GA: 32-37 wk), and 10 term (GA ≥37 wk) neonates. Limits of agreement for difference of the measurements between different places were determined using the Bland-Altman method. In all subgroups, the rScO2 and cFTOE values at different regions were not different. Limits of agreement were between ±14 and ±18% for all subgroups. Left-to-right differences were small between different postnatal and GAs. A decrease and increase over time for rScO2 and cFTOE values was detected for all four brain regions, most pronounced for infants with GA <32 wk. Cerebral oxygenation in stable preterm and term neonates seems not to differ between different regions of the brain during the early neonatal period. However, variability of individual measurements was quite high as indicated by large limits of agreement.

In a prospective study, we monitored simultaneously left and right parieto-frontal-cerebral oxygen saturation (rScO2) and cerebral fractional tissue oxygen extraction (cFTOE) using near-infrared spectroscopy in 36 very preterm neonates during the first 3 d of life. Simple regression analysis showed a close correlation between left and right rScO2 (r = 0.89, p < 0.01) and cFTOE (r = 0.88, p < 0.01), respectively. The Bland and Altman-determined limits of agreement found overall limits of agreement of -8.5 to +9.5% and of -0.10 to +0.093% between left and right for rScO2 and for cFTOE, respectively. However, we found that during stable systemic oxygenation (i.e., arterial oxygen saturation [SaO2 between 85 and 97%]) the limits of agreement between left and right improved from -7.8 to +8.2% and -0.088 to +0.084 for rScO2 and cFTOE, respectively (all p < 0.05). We conclude that bilateral near-infrared spectroscopy-measured rScO2 and cFTOE can reveal differences up to 10% between left and right hemisphere, especially during unstable arterial saturations, which may indicate uneven cerebral oxygenation.

Objectives: A hemodynamically important patent ductus arteriosus is a common problem in the first week of life in the preterm infant. Although patent ductus arteriosus induces alterations in organ perfusion, scarce information is available of the impact of patent ductus arteriosus and its subsequent treatment on the oxygen supply and oxygen extraction of the brain. We investigated the impact of patent ductus arteriosus and its treatment with indomethacin on regional cerebral oxygen saturation and fractional tissue oxygen extraction by using near-infrared spectroscopy., Patients and Methods: Twenty infants with patent ductus arteriosus (gestational age: <32 weeks), subsequently treated with indomethacin, were monitored for mean arterial blood pressure, arterial oxygen saturation, near-infrared spectroscopy-determined regional cerebral oxygen saturation, and fractional tissue oxygen extraction ([arterial oxygen saturation - regional cerebral oxygen saturation]/arterial oxygen saturation). Ten-minute periods were selected and averaged during patent ductus arteriosus, at 10, 20, 30, 60, and 120 minutes, and at 6,12, 24, and 36 hours after starting indomethacin treatment (to ductal closure) for mean arterial blood pressure, arterial oxygen saturation, regional cerebral oxygen saturation, and fractional tissue oxygen extraction. The patients with patent ductus arteriosus were matched for gestational age, birth weight, postnatal age, and severity of respiratory distress syndrome with infants without patent ductus arteriosus, who served as control subjects., Results: Mean arterial blood pressure and regional cerebral oxygen saturation were significantly lower and fractional tissue oxygen extraction significantly higher compared with the control infants during patent ductus arteriosus (mean arterial blood pressure: 33 +/- 5 vs 38 +/- 6 mmHg; regional cerebral oxygen saturation: 62% +/- 9% vs 72% +/- 10%; fractional tissue oxygen extraction: 0.34 +/- 0.1 vs 0.25 +/- 0.1, respectively). Regional cerebral oxygen saturation and fractional tissue oxygen extraction were lower and higher, respectively, up to 24 hours after the start of indomethacin but normalized to control values afterward. Indomethacin had no additional negative effect on cerebral oxygenation., Conclusions: A hemodynamically significant patent ductus arteriosus has a negative effect on cerebral oxygenation in the premature infant. Subsequent and adequate treatment of a patent ductus arteriosus may prevent diminished cerebral perfusion and subsequent decreased oxygen delivery, which reduces the change of damage to the vulnerable immature brain.

Haemodynamic factors play an important role in the etiology of cerebral lesions in preterm infants. Respiratory distress syndrome (RDS), a common problem in preterms, is strongly related with low and fluctuating arterial blood pressure. This study investigated the relation between mean arterial blood pressure (MABP), fractional cerebral oxygen saturation (ScO2) and fractional (cerebral) tissue oxygen extraction (FTOE), a measure of oxygen utilisation of the brain, during the first 72 h of life. Thirty-eight infants (gestational age < 32 week) were included, 18 with and 20 without RDS. Arterial oxygen saturation (SaO2), MABP and near infrared spectroscopy-determined ScO2 were continuously measured. FTOE was calculated as a ratio: (SaO2-ScO2)/SaO2. Gestational age and birth weight did not differ between groups, but assisted ventilation and use of inotropic drugs were more common in RDS infants (P<0.01). MABP was lower in RDS patients (P<0.05 from 12 up to 36 h after birth), but increased in both groups over time. ScO2 and FTOE were not different between groups over time, but in RDS infants ScO2 and FTOE had substantial larger variance (P<0.05 at all time points except at 36-48 h for ScO2 and P<0.05 at 12-18, 18-24, 36-48 and 48-60 h for FTOE). During the first 72 h of life, RDS infants showed more periods of positive correlation between MABP and ScO2 (P<0.05 at 18-24, 24-36 36-48 48-60 h) and negative correlation between MABP and FTOE (P<0.05 at 18-24, 36-48 h). Although we found that the patterns of cerebral oxygenation and extraction in RDS infants were not different as compared to infants without RDS, we suggest that the frequent periods with possible lack of cerebral autoregulation in RDS infants may make these infants more vulnerable to cerebral damage.