Machine Learning-Derived Active Sleep as an Early Predictor of White Matter Development in Preterm Infants.

White matter dysmaturation is commonly seen in preterm infants admitted to the neonatal intensive care unit (NICU). Animal research has shown that active sleep is essential for early brain plasticity. This study aimed to determine the potential of active sleep as an early predictor for subsequent white matter development in preterm infants. Using heart and respiratory rates routinely monitored in the NICU, we developed a machine learning-based automated sleep stage classifier in a cohort of 25 preterm infants (12 females). The automated classifier was subsequently applied to a study cohort of 58 preterm infants (31 females) to extract active sleep percentage over 5-7 consecutive days during 29-32 weeks of postmenstrual age. Each of the 58 infants underwent high-quality T2-weighted magnetic resonance brain imaging at term-equivalent age, which was used to measure the total white matter volume. The association between active sleep percentage and white matter volume was examined using a multiple linear regression model adjusted for potential confounders. Using the automated classifier with a superior sleep classification performance [mean area under the receiver operating characteristic curve (AUROC) = 0.87, 95% CI 0.83-0.92], we found that a higher active sleep percentage during the preterm period was significantly associated with an increased white matter volume at term-equivalent age [ß = 0.31, 95% CI 0.09-0.53, false discovery rate (FDR)-adjusted p-value = 0.021]. Our results extend the positive association between active sleep and early brain development found in animal research to human preterm infants and emphasize the potential benefit of sleep preservation in the NICU setting.

Delayed Surgical Closure of the Patent Ductus Arteriosus: Does the Brain Pay the Price?

OBJECTIVE: To investigate the relation between duration of hemodynamically significant patent ductus arteriosus (PDA), cerebral oxygenation, magnetic resonance imaging-determined brain growth, and 2-year neurodevelopmental outcome in a cohort of infants born preterm whose duct was closed surgically. STUDY DESIGN: Infants born preterm at <30 weeks of gestational age who underwent surgical ductal closure between 2008 and 2018 (n = 106) were included in this observational study. Near infrared spectroscopy-monitored cerebral oxygen saturation during and up to 24 hours after ductal closure and a Bayley III developmental test at the corrected age of 2 years is the institutional standard of care for this patient group. Infants also had magnetic resonance imaging at term-equivalent age. RESULTS: In total, 90 infants fulfilled the inclusion criteria (median [range]: 25.9 weeks [24.0-28.9]; 856 g [540-1350]. Days of a PDA ranged from 1 to 41. Multivariable linear regression analysis showed that duration of a PDA negatively influenced cerebellar growth and motor and cognitive outcome at 2 years of corrected age. CONCLUSIONS: Prolonged duration of a PDA in this surgical cohort is associated with reduced cerebellar growth and suboptimal neurodevelopmental outcome.

Additional Value of 3-Month Cranial Magnetic Resonance Imaging in Infants with Neonatal Encephalopathy following Perinatal Asphyxia.

OBJECTIVE: To assess the evolution of neonatal brain injury noted on magnetic resonance imaging (MRI), develop a score to assess brain injury on 3-month MRI, and determine the association of 3-month MRI with neurodevelopmental outcome in neonatal encephalopathy (NE) following perinatal asphyxia. METHODS: This was a retrospective, single-center study including 63 infants with perinatal asphyxia and NE (n = 28 cooled) with cranial MRI <2 weeks and 2-4 months after birth. Both scans were assessed using biometrics, a validated injury score for neonatal MRI, and a new score for 3-month MRI, with a white matter (WM), deep gray matter (DGM), and cerebellum subscore. The evolution of brain lesions was assessed, and both scans were related to 18- to 24-month composite outcome. Adverse outcome included cerebral palsy, neurodevelopmental delay, hearing/visual impairment, and epilepsy. RESULTS: Neonatal DGM injury generally evolved into DGM atrophy and focal signal abnormalities, and WM/watershed injury evolved into WM and/or cortical atrophy. Although the neonatal total and DGM scores were associated with composite adverse outcomes, the 3-month DGM score (OR 1.5, 95% CI 1.2-2.0) and WM score (OR 1.1, 95% CI 1.0-1.3) also were associated with composite adverse outcomes (occurring in n = 23). The 3-month multivariable model (including the DGM and WM subscores) had higher positive (0.88 vs 0.83) but lower negative predictive value (0.83 vs 0.84) than neonatal MRI. Inter-rater agreement for the total, WM, and DGM 3-month score was 0.93, 0.86, and 0.59. CONCLUSIONS: In particular, DGM abnormalities on 3-month MRI, preceded by DGM abnormalities on the neonatal MRI, were associated with 18- to 24-month outcome, indicating the utility of 3-month MRI for treatment evaluation in neuroprotective trials. However, the clinical usefulness of 3-month MRI seems limited compared with neonatal MRI.

Evaluation of Sleep Practices and Knowledge in Neonatal Healthcare.

BACKGROUND: Developmental care is designed to optimize early brain maturation by integrating procedures that support a healing environment. Protecting preterm sleep is important in developmental care. However, it is unclear to what extent healthcare professionals are aware of the importance of sleep and how sleep is currently implemented in the day-to-day care in the neonatal intensive care unit (NICU). PURPOSE: Identifying the current state of knowledge among healthcare professionals regarding neonatal sleep and how this is transferred to practice. METHODS: A survey was distributed among Dutch healthcare professionals. Three categories of data were sought, including (1) demographics of respondents; (2) questions relating to sleep practices; and (3) objective knowledge questions relating to sleep physiology and importance of sleep. Data were analyzed using Spearman's rho test and Cramer's V test. Furthermore, frequency tables and qualitative analyses were employed. RESULTS: The survey was completed by 427 participants from 34 hospitals in 25 Dutch cities. While healthcare professionals reported sleep to be especially important for neonates admitted in the NICU, low scores were achieved in the area of knowledge of sleep physiology. Most healthcare professionals (91.8%) adapted the timing of elective care procedures to sleep. However, sleep assessments were not based on scientific knowledge. Therefore, the difference between active sleep and wakefulness may often be wrongly assessed. Finally, sleep is rarely discussed between colleagues (27.4% regularly/always) and during rounds (7.5%-14.3% often/always). IMPLICATIONS: Knowledge about sleep physiology should be increased through education among neonatal healthcare professionals. Furthermore, sleep should be considered more often during rounds and handovers.

Respiratory Rate Extraction from Neonatal Near-Infrared Spectroscopy Signals.

Background: Near-infrared spectroscopy (NIRS) relative concentration signals contain 'noise' from physiological processes such as respiration and heart rate. Simultaneous assessment of NIRS and respiratory rate (RR) using a single sensor would facilitate a perfectly time-synced assessment of (cerebral) physiology. Our aim was to extract respiratory rate from cerebral NIRS intensity signals in neonates admitted to a neonatal intensive care unit (NICU). Methods: A novel algorithm, NRR (NIRS RR), is developed for extracting RR from NIRS signals recorded from critically ill neonates. In total, 19 measurements were recorded from ten neonates admitted to the NICU with a gestational age and birth weight of 38 ± 5 weeks and 3092 ± 990 g, respectively. We synchronously recorded NIRS and reference RR signals sampled at 100 Hz and 0.5 Hz, respectively. The performance of the NRR algorithm is assessed in terms of the agreement and linear correlation between the reference and extracted RRs, and it is compared statistically with that of two existing methods. Results: The NRR algorithm showed a mean error of 1.1 breaths per minute (BPM), a root mean square error of 3.8 BPM, and Bland-Altman limits of agreement of 6.7 BPM averaged over all measurements. In addition, a linear correlation of 84.5% (p < 0.01) was achieved between the reference and extracted RRs. The statistical analyses confirmed the significant (p < 0.05) outperformance of the NRR algorithm with respect to the existing methods. Conclusions: We showed the possibility of extracting RR from neonatal NIRS in an intensive care environment, which showed high correspondence with the reference RR recorded. Adding the NRR algorithm to a NIRS system provides the opportunity to record synchronously different physiological sources of information about cerebral perfusion and respiration by a single monitoring system. This allows for a concurrent integrated analysis of the impact of breathing (including apnea) on cerebral hemodynamics.

Ultra-Wideband Radar for Simultaneous and Unobtrusive Monitoring of Respiratory and Heart Rates in Early Childhood: A Deep Transfer Learning Approach.

Unobtrusive monitoring of children's heart rate (HR) and respiratory rate (RR) can be valuable for promoting the early detection of potential health issues, improving communication with healthcare providers and reducing unnecessary hospital visits. A promising solution for wireless vital sign monitoring is radar technology. This paper presents a novel approach for the simultaneous estimation of children's RR and HR utilizing ultra-wideband (UWB) radar using a deep transfer learning algorithm in a cohort of 55 children. The HR and RR are calculated by processing radar signals via spectrogram from time epochs of 10 s (25 sample length of hamming window with 90% overlap) and then transforming the resultant representation into 2-dimensional images. These images were fed into a pre-trained Visual Geometry Group-16 (VGG-16) model (trained on ImageNet dataset), with weights of five added layers fine-tuned using the proposed data. The prediction on the test data achieved a mean absolute error (MAE) of 7.3 beats per minute (BPM < 6.5% of average HR) and 2.63 breaths per minute (BPM < 7% of average RR). We also achieved a significant Pearson's correlation of 77% and 81% between true and extracted for HR and RR, respectively. HR and RR samples are extracted every 10 s.

Cerebral near-infrared spectroscopy monitoring (NIRS) in children and adults: a systematic review with meta-analysis.

BACKGROUND: Cerebral oxygenation monitoring utilising near-infrared spectroscopy (NIRS) is increasingly used to guide interventions in clinical care. The objective of this systematic review with meta-analysis and Trial Sequential Analysis is to evaluate the effects of clinical care with access to cerebral NIRS monitoring in children and adults versus care without. METHODS: This review conforms to PRISMA guidelines and was registered in PROSPERO (CRD42020202986). Methods are outlined in our protocol (doi: 10.1186/s13643-021-01660-2). RESULTS: Twenty-five randomised clinical trials were included (2606 participants). All trials were at a high risk of bias. Two trials assessed the effects of NIRS during neonatal intensive care, 13 during cardiac surgery, 9 during non-cardiac surgery and 1 during neurocritical care. Meta-analyses showed no significant difference for all-cause mortality (RR 0.75, 95% CI 0.51-1.10; 1489 participants; I2 = 0; 11 trials; very low certainty of evidence); moderate or severe, persistent cognitive or neurological deficit (RR 0.74, 95% CI 0.42-1.32; 1135 participants; I2 = 39.6; 9 trials; very low certainty of evidence); and serious adverse events (RR 0.82; 95% CI 0.67-1.01; 2132 participants; I2 = 68.4; 17 trials; very low certainty of evidence). CONCLUSION: The evidence on the effects of clinical care with access to cerebral NIRS monitoring is very uncertain. IMPACT: The evidence of the effects of cerebral NIRS versus no NIRS monitoring are very uncertain for mortality, neuroprotection, and serious adverse events. Additional trials to obtain sufficient information size, focusing on lowering bias risk, are required. The first attempt to systematically review randomised clinical trials with meta-analysis to evaluate the effects of cerebral NIRS monitoring by pooling data across various clinical settings. Despite pooling data across clinical settings, study interpretation was not substantially impacted by heterogeneity. We have insufficient evidence to support or reject the clinical use of cerebral NIRS monitoring.

Brain proton magnetic resonance spectroscopy and neurodevelopment after preterm birth: a systematic review.

BACKGROUND: Preterm infants are at risk of neurodevelopmental impairments. At present, proton magnetic resonance spectroscopy (1H-MRS) is used to evaluate brain metabolites in asphyxiated term infants. The aim of this review is to assess associations between cerebral 1H-MRS and neurodevelopment after preterm birth. METHODS: PubMed and Embase were searched to identify studies using 1H-MRS and preterm birth. Eligible studies for this review included 1H-MRS of the brain, gestational age ≤32 weeks, and neurodevelopment assessed at a corrected age (CA) of at least 12 months up to the age of 18 years. RESULTS: Twenty papers evaluated 1H-MRS in preterm infants at an age between near-term and 18 years and neurodevelopment. 1H-MRS was performed in both white (WM) and gray matter (GM) in 12 of 20 studies. The main regions were frontal and parietal lobe for WM and basal ganglia for GM. N-acetylaspartate/choline (NAA/Cho) measured in WM and/or GM is the most common metabolite ratio associated with motor, language, and cognitive outcome at 18-24 months CA. CONCLUSIONS: NAA/Cho in WM assessed at term-equivalent age was associated with motor, cognitive, and language outcome, and NAA/Cho in deep GM was associated with language outcome at 18-24 months CA. IMPACT: In preterm born infants, brain metabolism assessed using 1H-MRS at term-equivalent age is associated with motor, cognitive, and language outcomes at 18-24 months. 1H-MRS at term-equivalent age in preterm born infants may be used as an early indication of brain development. Specific findings relating to NAA were most predictive of outcome.

Normal regional tissue oxygen saturation in neonates: a systematic qualitative review.

BACKGROUND: The aim of this systematic qualitative review was to give an overview of reference ranges defined as normal values or centile charts of regional tissue oxygen saturation measured by near-infrared spectroscopy (NIRS) in term and preterm neonates. METHODS: A systematic search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials was performed. Additional articles were identified by manual search of cited references. Only human studies in neonates were included. RESULTS: Nineteen studies were identified. Eight described regional tissue oxygen saturation during fetal-to-neonatal transition, six during the first 3 days after birth, four during the first 7 days after birth, and one during the first 8 weeks after birth. Nine described regional tissue oxygen saturation in term, nine in preterm neonates, and one in both. Eight studies published centile charts for cerebral regional tissue oxygen saturation, and only five included large cohorts of infants. Eleven studies described normal values for cerebral, muscle, renal, and abdominal regional tissue oxygen saturation, the majority with small sample sizes. Four studies of good methodological quality were identified describing centile charts of cerebral regional tissue oxygen saturation. CONCLUSIONS: In clinical settings, quality centile charts are available and should be the preferred method when using NIRS monitoring. IMPACT: Near-infrared spectroscopy (NIRS) enables a bed-side non-invasive continuous monitoring of tissue oxygenation. When using NIRS monitoring in a clinical setting, centile charts with good quality are available and should be preferred to normal values. High-quality reference ranges of regional tissue oxygenation in term and preterm born neonates are an important step toward routine clinical application of NIRS.

Cerebellar injury in term neonates with hypoxic-ischemic encephalopathy is underestimated.

BACKGROUND: Postmortem examinations frequently show cerebellar injury in infants with severe hypoxic-ischemic encephalopathy (HIE), while it is less well visible on MRI. The primary aim was to investigate the correlation between cerebellar apparent diffusion coefficient (ADC) values and histopathology in infants with HIE. The secondary aim was to compare ADC values in the cerebellum of infants with HIE and infants without brain injury. METHODS: ADC values in the cerebellar vermis, hemispheres and dentate nucleus (DN) of (near-)term infants with HIE (n = 33) within the first week after birth were compared with neonates with congenital non-cardiac anomalies, normal postoperative MRIs and normal outcome (n = 22). Microglia/macrophage activation was assessed using CD68 and/or HLA-DR staining and Purkinje cell (PC) injury using H&E-stained slices. The correlation between ADC values and the histopathological measures was analyzed. RESULTS: ADC values in the vermis (p = 0.021) and DN (p < 0.001) were significantly lower in infants with HIE compared to controls. ADC values in the cerebellar hemispheres were comparable. ADC values in the vermis were correlated with the number and percentage of normal PCs; otherwise ADC values and histology were not correlated. CONCLUSION: Histopathological injury in the cerebellum is common in infants with HIE. ADC values underestimate histopathological injury. IMPACT: ADC values might underestimate cerebellar injury in neonates with HIE. ADC values in the vermis and dentate nucleus of infants with HIE are lower compared to controls, but not in the cerebellar hemispheres. Abnormal ADC values are only found when cytotoxic edema is very severe. ADC values in the vermis are correlated with Purkinje cell injury in the vermis; furthermore, there were no correlations between ADC values and histopathological measures.

Brain temperature of infants with neonatal encephalopathy following perinatal asphyxia calculated using magnetic resonance spectroscopy.

BACKGROUND: Little is known about brain temperature of neonates during MRI. Brain temperature can be estimated non-invasively with proton Magnetic Resonance Spectroscopy (1H-MRS), but the most accurate 1H-MRS method has not yet been determined. The primary aim was to estimate brain temperature using 1H-MRS in infants with neonatal encephalopathy (NE) following perinatal asphyxia. The secondary aim was to compare brain temperature during MRI with rectal temperatures before and after MRI. METHODS: In this retrospective study, brain temperature in 36 (near-)term infants with NE was estimated using short (36 ms) and long (288 ms) echo time (TE) 1H-MRS. Brain temperature was calculated using two different formulas: formula of Wu et al. and a formula based on phantom calibration. The methods were compared. Rectal temperatures were collected <3 hours before and after MRI. RESULTS: Brain temperatures calculated with the formula of Wu et al. and the calibrated formula were similar as well as brain temperatures derived from short and long TE 1H-MRS. Rectal temperature did not differ before and after MRI. CONCLUSIONS: Brain temperature can be measured using 1H-MRS in daily clinical practice using the formula of Wu et al. with both short and long TE 1H-MRS. Brain temperature remained within physiological range during MRI.

Brain Activity and Cerebral Oxygenation After Perinatal Arterial Ischemic Stroke Are Associated With Neurodevelopment.

Background and Purpose- In infants with perinatal arterial ischemic stroke (PAIS), early prognosis of neurodevelopmental outcome is important to adequately inform parents and caretakers. Early continuous neuromonitoring after PAIS may improve early prognosis. Our aim was to study early cerebral electrical activity and oxygenation measured by amplitude-integrated electroencephalography (aEEG) and near-infrared spectroscopy in term neonates with PAIS and relate these to the development of cerebral palsy and cognitive deficit. Methods- aEEG patterns and regional cerebral oxygen saturation (rScO2) levels of both hemispheres were studied for 120 hours from the first clinical symptoms of PAIS (ie, seizures) onward. Multivariable analyses were used to investigate the association between aEEG, near-infrared spectroscopy, clinical variables, and neurodevelopmental outcome. Results- In 52 patients with PAIS (gestational age, 40.4±1.4 weeks; birth weight, 3282±479 g), median time to a continuous background pattern was longer in the ipsilesional compared with the contralesional hemisphere (13.5 versus 10.0 hours; P<0.05). rScO2 decreased over time in both hemispheres but less in the ipsilesional one, resulting in a rScO2 asymmetry ratio of 4.5% (interquartile range, -4.3% to 5.9%; P<0.05) between hemispheres from day 3 after symptoms onward. Both time to normal background pattern and asymmetry in rScO2 were negatively affected by gestational age, size of the PAIS, use of antiepileptic drugs, and mechanical ventilation. After correction for size of the PAIS on magnetic resonance imaging, a slower recovery of background pattern on ipsilesional aEEG and increased rScO2 asymmetry between hemispheres was related with an increased risk for cognitive deficit (<-1 SD) at a median of 24.0 (interquartile range, 18.4-24.4) months of age. Conclusions- Recovery of background pattern on aEEG and cerebral oxygenation are both affected by PAIS and related to neurocognitive development. Both measurements may provide valuable early prognostic information. Additionally, monitoring cerebral activity and oxygenation may be useful in identifying infants eligible for early neuroprotective interventions and to detect early effects of these interventions.

Low Cerebral Oxygenation in Preterm Infants Is Associated with Adverse Neurodevelopmental Outcome.

OBJECTIVE: To assess whether high and low levels of cerebral oxygenation (regional cerebral oxygenation [rScO2]) in infants born at <32 weeks of gestation were associated with adverse long-term outcome. STUDY DESIGN: Observational cohort study including preterm infants born at <32 weeks of gestation at the Wilhelmina Children's Hospital, The Netherlands, between April 2006 and April 2013. The rScO2 was continuously monitored for 72 hours after birth using near-infrared spectroscopy. Outcome was assessed at 15 and 24 months of corrected age by certified investigators. An unfavorable composite outcome was defined as an outcome score below -1 SD or death. Various rScO2 thresholds were explored. RESULTS: In total, 734 infants were eligible for analysis, 60 of whom died. Associations with an unfavorable cognitive outcome in multivariable analysis were comparable for time spent with a rScO2 below 55% and -1.5 SD (according to published reference values), with an OR of 1.4 (CI 1.1-1.7) for 20% of time below either threshold. Results at 15 months were comparable with results at 24 months. Results were not statistically significant for thresholds defining high values of rScO2. The composite motor outcome was not significantly related to either low or high values or rScO2. CONCLUSIONS: Low, but not high, rScO2 was associated with an unfavorable cognitive outcome. This suggests the use of a threshold of rScO2 <55% for future clinical studies when using adult near-infrared sensors (rScO2 <65% for neonatal sensors, approximately).

No neurodevelopmental benefit of cerebral oximetry in the first randomised trial (SafeBoosC II) in preterm infants during the first days of life.

AIM: Cerebral hypoxia has been associated with neurodevelopmental impairment. We studied whether reducing cerebral hypoxia in extremely preterm infants during the first 72 hours of life affected neurological outcomes at two years of corrected age. METHODS: In 2012-2013, the phase II randomised Safeguarding the Brains of our smallest Children trial compared visible cerebral near-infrared spectroscopy (NIRS) monitoring in an intervention group and blinded NIRS monitoring in a control group. Cerebral hypoxia was significantly reduced in the intervention group. We followed up 115 survivors from eight European centres at two years of corrected age, by conducting a medical examination and assessing their neurodevelopment with the Bayley Scales of Infant and Toddler Development, Second or Third Edition, and the parental Ages and Stages Questionnaire (ASQ). RESULTS: There were no differences between the intervention (n = 65) and control (n = 50) groups with regard to the mean mental developmental index (89.6 ± 19.5 versus 88.4 ± 14.7, p = 0.77), ASQ score (215 ± 58 versus 213 ± 58, p = 0.88) and the number of children with moderate-to-severe neurodevelopmental impairment (10 versus six, p = 0.58). CONCLUSION: Cerebral NIRS monitoring was not associated with long-term benefits or harm with regard to neurodevelopmental outcome at two years of corrected age.

T2-prepared velocity selective labelling: A novel idea for full-brain mapping of oxygen saturation.

BACKGROUND AND AIM: Disturbances in cerebral oxygenation saturation (SO2) have been linked to adverse outcome in adults, children, and neonates. In intensive care, the cerebral SO2 is increasingly being monitored by Near-InfraRed Spectroscopy (NIRS). Unfortunately NIRS has a limited penetration depth. The "modified T2-prepared Blood Imaging of Oxygen Saturation" (T2-BIOS) MR sequence provides a step towards full brain SO2 measurement. MATERIALS AND METHODS: Tissue SO2, and venous SO2 (SvO2) were obtained simultaneously by T2-BIOS during a respiratory challenge in ten healthy volunteers. These two measures were compared to SO2 that was obtained by a single probe MR-compatible NIRS setup, and to cerebral blood flow and venous SO2 that were obtained by arterial spin labelling and T2-TRIR, respectively. RESULTS: SO2-T2-BIOS and SO2-NIRS had a mean bias of -4.0% (95% CI -21.3% to 13.3%). SvO2-T2-BIOS correlated with SO2-NIRS (R2=0.41, p=0.002) and SvO2-T2-TRIR (R2=0.87, p=0.002). In addition, SO2-NIRS correlated with SvO2-T2-TRIR (R2=0.85, p=0.003) Frontal cerebral blood flow correlated with SO2-T2-BIOS (R2=0.21, p=0.04), but was not significant in relation to SO2-NIRS. DISCUSSION/CONCLUSION: Full brain SO2 assessment by any technique may help validating NIRS and may prove useful in guiding the clinical management of patient populations with cerebral injury following hypoxic-ischaemic events. The agreement between NIRS and T2-BIOS provides confidence in measuring cerebral SO2 by either technique. As it stands now, the T2-BIOS represents a novel idea and future work will focus on improvements to make it a reliable tool for SO2 assessment.

Magnetic resonance imaging based noninvasive measurements of brain hemodynamics in neonates: a review.

Perinatal disturbances of brain hemodynamics can have a detrimental effect on the brain's parenchyma with consequently adverse neurodevelopmental outcome. Noninvasive, reliable tools to evaluate the neonate's brain hemodynamics are scarce. Advances in magnetic resonance imaging have provided new methods to noninvasively assess brain hemodynamics. More recently these methods have made their transition to the neonatal population. The aim of this review is twofold. Firstly, to describe these newly available noninvasive methods to investigate brain hemodynamics in neonates. Secondly, to discuss the results that were obtained with these techniques, identifying both potential clinical applications as well as gaps of knowledge.

Reference values of regional cerebral oxygen saturation during the first 3 days of life in preterm neonates.

BACKGROUND: Currently, reliable reference values of regional cerebral oxygen saturation (rScO2) for different gestational age (GA) groups are lacking, which hampers the implementation of near-infrared spectroscopy (NIRS) alongside monitoring arterial oxygen saturation (SaO2) and blood pressure in neonatal intensive care. The aim of this study was to provide reference values for rScO2 and cerebral fractional tissue oxygen extraction (cFTOE; (SaO2 - rScO2)/SaO2) for small adult and neonatal NIRS sensors. METHODS: In this study, 999 infants born preterm (GA <32 wk) were monitored with NIRS during the first 72 h of life. Mixed modeling was used to generate reference curves grouped per 2 wk of GA. In addition, the influence of a hemodynamically significant patent ductus arteriosus, gender, and birth weight were explored. RESULTS: Average rScO2 was ~65% at admission, increased with GA (1% per week) and followed a parabolic curve in relation to postnatal age with a peak at ~36 h. The cFTOE showed similar but inverse effects. On average, the neonatal sensor measured 10% higher than the adult sensor. CONCLUSION: rScO2 and cFTOE reference curves are provided for the first 72 h of life in preterm infants, which might support the broader implementation of NIRS in neonatal intensive care.

Brain injury in the international multicenter randomized SafeBoosC phase II feasibility trial: cranial ultrasound and magnetic resonance imaging assessments.

BACKGROUND: Abnormal cerebral perfusion during the first days of life in preterm infants is associated with higher grades of intraventricular hemorrhages and lower developmental score. In SafeBoosC II, we obtained a significant reduction of cerebral hypoxia by monitoring cerebral oxygenation in combination with a treatment guideline. Here, we describe (i) difference in brain injury between groups, (ii) feasibility of serial cranial ultrasound (cUS) and magnetic resonance imaging (MRI), (iii) local and central cUS assessment. METHODS: Hundred and sixty-six extremely preterm infants were included. cUS was scheduled for day 1, 4, 7, 14, and 35 and at term-equivalent age (TEA). cUS was assessed locally (unblinded) and centrally (blinded). MRI at TEA was assessed centrally (blinded). Brain injury classification: no, mild/moderate, or severe. RESULTS: Severe brain injury did not differ significantly between groups: cUS (experimental 10/80, control 18/77, P = 0.32) and MRI (5/46 vs. 3/38, P = 0.72). Kappa values for local and central readers were moderate-to-good for severe and poor-to-moderate for mild/moderate injuries. At TEA, cUS and MRI were assessed in 72 and 64%, respectively. CONCLUSION: There was no difference in severe brain injury between groups. Acquiring cUS and MRI according the standard operating procedures must be improved for future trials. Whether monitoring cerebral oxygenation during the first 72 h of life prevents brain injury should be evaluated in larger multicenter trials.

The SafeBoosC II randomized trial: treatment guided by near-infrared spectroscopy reduces cerebral hypoxia without changing early biomarkers of brain injury.

BACKGROUND: The SafeBoosC phase II multicentre randomized clinical trial investigated the benefits and harms of monitoring cerebral oxygenation by near-infrared spectroscopy (NIRS) combined with an evidence-based treatment guideline vs. no NIRS data and treatment as usual in the control group during the first 72 h of life. The trial demonstrated a significant reduction in the burden of cerebral hypoxia in the experimental group. We now report the blindly assessed and analyzed treatment effects on electroencephalographic (EEG) outcomes (burst rate and spectral edge frequency 95% (SEF95)) and blood biomarkers of brain injury (S100ß, brain fatty acid-binding protein, and neuroketal). METHODS: One hundred and sixty-six extremely preterm infants were randomized to either experimental or control group. EEG was recorded at 64 h of age and blood samples were collected at 6 and 64 h of age. RESULTS: One hundred and thirty-three EEGs were evaluated. The two groups did not differ regarding burst rates (experimental 7.2 vs. control 7.7 burst/min) or SEF95 (experimental 18.1 vs. control 18.0 Hz). The two groups did not differ regarding blood S100ß, brain fatty acid-binding protein, and neuroketal concentrations at 6 and 64 h (n = 123 participants). CONCLUSION: Treatment guided by NIRS reduced the cerebral burden of hypoxia without affecting EEG or the selected blood biomarkers.

A New Framework for the Assessment of Cerebral Hemodynamics Regulation in Neonates Using NIRS.

We present a new framework for the assessment of cerebral hemodynamics regulation (CHR) in neonates using near-infrared spectroscopy (NIRS). In premature infants, NIRS measurements have been used as surrogate variables for cerebral blood flow (CBF) in the assessment of cerebral autoregulation (CA). However, NIRS measurements only reflect changes in CBF under constant changes in arterial oxygen saturation (SaO2). This condition is unlikely to be met at the bedside in the NICU. Additionally, CA is just one of the different highly coupled mechanisms that regulate brain hemodynamics. Traditional methods for the assessment of CA do not take into account the multivariate nature of CHR, producing inconclusive results. In this study we propose a newly developed multivariate methodology for the assessment of CHR. This method is able to effectively decouple the influences of SaO2 from the NIRS measurements, and at the same time, produces scores indicating the strength of the coupling between the systemic variables and NIRS recordings. We explore the use of this method, and its derived scores, for the monitoring of CHR using data from premature infants who developed a grade III-IV intra-ventricular hemorrhage during the first 3 days of life.