Thomas Alderliesten

Cerebral near infrared spectroscopy oximetry in extremely preterm infants : Phase II randomised clinical trial

Objective To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. Design Phase II randomised, single blinded, parallel clinical trial. Setting Eight tertiary neonatal intensive care units in eight European countries. Participants 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support. Interventions Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control). Main outcome measures The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography. Randomisation Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥26 weeks). Blinding Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. Results The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device. Conclusions Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring. Trial registration ClinicalTrial.gov NCT01590316.

MR Imaging and Outcome of Term Neonates with Perinatal Asphyxia: Value of Diffusion-weighted MR Imaging and H MR Spectroscopy

PURPOSE To compare the association between neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy following perinatal asphyxia and (a) apparent diffusion coefficients (ADCs) in the thalamus and basal ganglia at diffusion-weighted (DW) magnetic resonance (MR) imaging and (b) hydrogen 1 (¹H) MR spectroscopic measurements in the basal ganglia. MATERIALS AND METHODS This retrospective study was approved by the local ethics committee, and the requirement to obtain informed consent was waived. Eighty-one term neonates with perinatal asphyxia underwent conventional and DW cranial MR imaging (median age, 4 days; age range, 1-14 days); 51 neonates also underwent ¹H MR spectroscopy. Neurodevelopment was assessed from 18 to 46 months. Patients with favorable and adverse outcomes were compared. Receiver operating characteristics analysis was performed in all patients, and uni- and multivariate logistic regression analyses were performed in 44 patients examined within 7 days of birth by using MR imaging scores, ADCs in the basal ganglia and thalamus, and ¹H MR spectroscopic measurements in the basal ganglia. RESULTS An adverse outcome was seen in 28 of all 81 neonates (20 died, seven developed cerebral palsy, and one had severe mental retardation) and 22 of the 44 neonates examined within 7 days of birth with both ADC and ¹H MR spectroscopy. Poor outcome was associated with (a) lower ADCs in the basal ganglia (P < .001) and thalamus (P = .001) of neonates examined within 7 days of birth and (b) a higher lactate (Lac)-N-acetylaspartate (NAA) ratio in the basal ganglia (P < .001). Multivariate analysis showed that MR imaging score combined with Lac/NAA ratios or ADCs in the basal ganglia within the 1st week of life had a better association with outcome than did MR imaging alone (P = .006, area under the receiver operating characteristic curve [AUC] = 0.85 with Lac/NAA ratio; P < .0001, AUC = 0.93 with ADCs in basal ganglia). CONCLUSION The combination of MR imaging score with ADCs or Lac/NAA ratios in the basal ganglia has a better association with outcome of asphyxiated term neonates than does MR imaging alone.

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.

Regional changes in brain perfusion during brain maturation measured non-invasively with Arterial Spin Labeling MRI in neonates.

PURPOSE The purpose of this study was to evaluate if non-invasive Arterial Spin Labeling MR imaging can be used to assess changes in brain perfusion with age which reflect neonatal brain development. For this purpose regional perfusion values obtained with ASL MR imaging were evaluated as a function of postmenstrual age. MATERIALS AND METHODS Pulsed ASL imaging was performed in 33 neonates with a postmenstrual age from 30 to 53 weeks. Whole brain cerebral blood flow (wbCBF), CBF in the basal ganglia and thalamus (BGT-CBF), in the occipital cortex (OC-CBF) and the frontal cortex (FC-CBF) were measured. Regional CBF values were expressed quantitatively (in ml/100 g min) and relative as a percentage of the wbCBF. RESULTS Mean wbCBF increased significantly from 7±2 ml/100 g min (mean±sd) at 31±2 weeks postmenstrual age to 12±3 ml/100 g min at term-equivalent age (TEA) and 29±9 ml/100 g min at 52±1 weeks postmenstrual age. Relative regional CBF was highest in the BGT at all time-points. Relative OC-and FC-CBF increased significantly from 31±2 weeks postmentrual age to TEA. A significant difference in relative BGT-CBF and OC-CBF was shown between infants at 31±2 weeks postmenstrual age and infants scanned at 52±1 weeks postmenstrual age. Relative perfusion in the BGT measured at TEA was significant different compared to 52±1 weeks postmenstrual age. CONCLUSION In conclusion, regional differences in CBF and changes with postmenstrual age could be detected with ASL in neonates. This suggests that ASL can be used as a non-invasive tool to investigate brain maturation in neonates.

Patent ductus arteriosus and brain volume

BACKGROUND AND OBJECTIVES: A hemodynamically significant patent ductus arteriosus (PDA) can compromise perfusion and oxygenation of the preterm brain. Reports suggest that PDA is associated with increased mortality and morbidity. We hypothesize that long-standing low cerebral oxygenation due to PDA might affect brain volume at term equivalent age. METHODS: Observational study in 140 infants investigating the relationship between near-infrared spectroscopy–monitored cerebral oxygen saturation (rSco2) and MRI-assessed regional brain volume and maturation of the posterior limb of the internal capsule at term-equivalent age in 3 groups: those whose PDA closed with indomethacin, those who needed additional surgical closure, and matched controls. RESULTS: The surgery group had the lowest rSco2 values before closure (n = 35), 48% ± 9.7% (mean ± SD) as compared with the indomethacin (n = 35), 59% ± 10.4 (P < .001), and control groups (n = 70), 66% ± 6.9 (P < .001); the highest postnatal age before effective treatment; and the lowest volumes of most brain regions at term-equivalent age. Multiple linear regression analysis showed a significant effect of preductal closure rSco2 on cerebellar volume in this group. No differences were found in maturation of the posterior limb of the internal capsule. CONCLUSIONS: Long-standing suboptimal cerebral oxygenation due to a PDA may negatively influence brain growth, affecting neurodevelopmental outcome.

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 (S100β, 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 S100β, 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.

Evaluation of perinatal arterial ischemic stroke using noninvasive arterial spin labeling perfusion MRI

Background:Arterial spin labeling (ASL) magnetic resonance imaging (MRI) can evaluate brain perfusion in neonates noninvasively. The aim of this study was to investigate whether ASL MRI can demonstrate perfusion abnormalities in neonates diagnosed with perinatal arterial ischemic stroke (PAIS).Methods:Pulsed ASL perfusion MR images were acquired in the subacute stage (5–6 d after birth) and at follow-up (13 d to 16 wk after birth) in four PAIS patients. Images were visually evaluated for hypo- and hyperperfusion. In addition, cerebral oxygenation was monitored using near infrared spectroscopy (NIRS).Results:In three PAIS patients, ASL images showed hypoperfusion in the stroke area. In one of these, hyperperfusion was visualized in the periphery of the stroke area. In one PAIS patient, hyperperfusion was seen in the stroke area. In all infants, cerebral oxygenation was higher in the infarcted hemisphere as compared with the contralateral hemisphere. Follow-up ASL images showed partial recovery of perfusion in the stroke area.Conclusion:ASL perfusion MRI is able to reliably detect hypo- and hyperperfusion in PAIS patients and can be used to monitor the evolution of perfusion after an ischemic event.

MRI and spectroscopy in (near) term neonates with perinatal asphyxia and therapeutic hypothermia

Background Previous studies have demonstrated the association of abnormalities on diffusion-weighted MRI (DW-MRI) and proton magnetic resonance spectroscopy (1H-MRS) in infants with perinatal asphyxia. The use of therapeutic hypothermia might change this association. Aim To study the association between DW-MRI and 1H-MRS and outcome after perinatal asphyxia and therapeutic hypothermia in infants with a gestational age of ≥36 weeks. Patients and methods Infants with perinatal asphyxia and therapeutic hypothermia (n=88) were included when an MR examination was performed within 7 days after birth. Apparent diffusion coefficient (ADC) values of the basal ganglia and thalamus were calculated, as were lactate/N-acetylaspartate (LAC/NAA) and N-acetylaspartate/choline (NAA/Cho) ratios. Death or an abnormal neurodevelopment at ≥24 months was considered an adverse outcome. Receiver operating characteristic analysis was performed to determine cut-off levels. Results Of the 88 infants, 22 died and 7 had an adverse neurodevelopmental outcome. In infants with an adverse outcome, ADC values of the basal ganglia and thalamus were significantly lower, and Lac/NAA ratios were significantly higher than in infants with a normal outcome. Areas under the curve of ADC of the basal ganglia, thalami and Lac/NAA ratio were 0.89, 0.88 and 0.87, respectively. NAA/Cho ratios were in this cohort not associated with outcome. Conclusions During and after therapeutic hypothermia, low ADC values and high Lac/NAA ratios of the basal ganglia and thalamus are associated with an adverse outcome in infants with perinatal asphyxia.

Antemortem cranial MRI compared with postmortem histopathologic examination of the brain in term infants with neonatal encephalopathy following perinatal asphyxia

Aim To compare antemortem cranial MRI with postmortem histopathological examination of the brain in full-term infants with neonatal encephalopathy following perinatal asphyxia. Patients and methods In this retrospective observational cohort study, 23 infants with neonatal encephalopathy who subsequently died, were analysed. Infants underwent antemortem cranial MRI and postmortem histopathological examination of the brain. MRI included T1, T2 and diffusion-weighted sequences. Histopathology included staining with H&E, and monoclonal antibodies to CD68 and HLA-DR. Histological abnormalities were compared with MRI in 10 different brain regions. Results All neonates underwent cranial MRI within 7 days after birth (median day 3, IQR 2–4 days). Infants died on median day 4 (IQR 2–5 days). Histopathology demonstrated significantly (p=0.0016) more abnormal regions (median 10, IQR 7–10) per patient than did MRI (median 8, IQR 5–9). The number of cases with abnormalities in the thalamus, basal ganglia, posterior limb of the internal capsule (PLIC), cerebral cortex and cerebellum were not significantly different between MRI and histopathology. By contrast, the hippocampus (70% vs 96%, p=0.047), cerebral white matter (anterior 65% vs 96%, p=0.022, posterior 61% vs 91%, p=0.035) and brainstem (57% vs 96%, p=0.004) were confirmed to be affected more often on histopathological examination than with MRI. Conclusions Whereas early postnatal MR imaging is excellent in detecting injury to the basal ganglia and thalamus, PLIC, cortex and cerebellum, it may underestimate injury to the hippocampus, cerebral white matter, and the brainstem in term infants with neonatal encephalopathy following perinatal asphyxia.

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.