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Functional near-infrared spectroscopy (fNIRS) and functional MRI (fMRI) are non-invasive techniques used to relate activity in different brain regions to certain tasks. Respiratory calibration of the blood oxygen level dependent (BOLD) signal, and combined fNIRS–fMRI approaches have been used to quantify physiological subcomponents giving rise to the BOLD signal. A comparison of absolute oxygen metabolism parameters between MRI and NIRS, using spatially resolved (SRS) NIRS and respiratory calibrated MRI, could yield additional insight in the physiology underlying activation. Changes in the BOLD signal, cerebral blood flow (CBF), and oxygen saturation (SO2) were derived from a single MRI sequence during a respiratory challenge in healthy volunteers. These changes were compared to SO2 obtained by a single probe SRS NIRS setup. In addition, concentration changes in oxygenated (O2Hb), deoxygenated (HHb), and total haemoglobin (tHb), obtained by NIRS, were compared to the parameters obtained by MRI. NIRS SO2 correlated with end-tidal CO2 (0.83, p<0.0001), the BOLD signal (0.82, p<0.0001), CBF (0.85, p<0.0001), and also MRI SO2 (0.82, p<0.0001). The BOLD signal correlated with NIRS HHb (−0.76, p<0.0001), O2Hb (0.41, p=0.001), and tHb (r=0.32, p=0.01). Good correlations show that changes in cerebral physiology, following a respiratory challenge, go hand in hand with changes in the BOLD signal, CBF, O2Hb, HHb, NIRS SO2, and MRI SO2. Out of all NIRS derived parameters, the SO2 showed the best correlation with the BOLD signal. •A setup to simultaneously quantify oxygen saturation with MRI and NIRS is presented.•Healthy adults were subjected to two episodes of hypercapnia breathing.•NIRS oxygen saturation had a good correlation with fMRI/BOLD oxygen saturation.•NIRS oxygen saturation had the best correlation with the fMRI BOLD signal.•Deoxygenated haemoglobin had the second best correlation with the fMRI BOLD signal.

Background: Neonatal encephalopathy induced by perinatal asphyxia is a serious condition associated with high mortality and morbidity. Inflammation after the insult is thought to contribute to brain injury. This inflammatory response to hypoxia-ischemia (HI) may not only occur in the brain but also in peripheral organs. The aim of the present study was to investigate the effect of neonatal HI on the inflammatory response in the liver in comparison to inflammation in the brain. Methods: HI was induced in P7 Wistar rats by unilateral carotid artery occlusion and hypoxia. Cytokine and chemokine mRNA levels were determined in the brain and liver by quantitative PCR. Polarization of brain macrophages to the M1/M2-like phenotype and infiltration of neutrophils were characterized by immunohistochemistry. Results: 3 h after HI, an upregulation of the proinflammatory cytokines TNF-α and IL-1β and anti-inflammatory IL-10 was observed in the ipsilateral hemisphere of the brain compared to mRNA levels in sham-operated animals. Additionally, cerebral CINC-1 and MCP-1 mRNA expressions were increased. We also observed increased numbers of macrophages/microglia of the M1-like phenotype as well as a small increase in granulocyte influx in the ipsilateral hemisphere. Conversely, in the liver 3 h after HI, a downregulation of TNF-α, IL-1β, and MCP-1 and a trend towards an upregulation of IL-10 were observed compared to mRNA levels of sham-operated animals. However, hepatic CINC-1 expression was increased compared to levels in sham-operated animals. Following systemic hypoxia only, no significant changes in the expression of TNF-α, CINC-1 or MCP-1 were observed in the liver compared to sham-operated littermates, except for an upregulation in hepatic IL-1β expression 3 h after hypoxia. Twenty-four hours after insult, cerebral ipsilateral TNF-α, MCP-1 and CINC-1 mRNA expression was still increased, together with an increase in TGF-β expression. Moreover, an increase in macrophages/microglia of the M1-like phenotype was observed together with the appearance of macrophages/microglia of the M2-like phenotype around the cerebral lesion as well as an increase in granulocyte influx in comparison to 3 h after HI. In the liver, 24 h after HI, cytokine and chemokine responses were similar to mRNA levels in sham-operated animals except for a decrease in IL-10 and MCP-1. Conclusion: We describe for the first time that brain damage following neonatal HI induces an early downregulation of the proinflammatory response in the liver. HI induces an early proinflammatory response in the brain with a concomitant increase in influx of neutrophils and polarization of macrophages/microglia to the M1-like phenotype starting at 3 h and increasing up to 24 h after HI. The inflammatory state of the brain changes after 24 h, with an increase in the anti-inflammatory cytokine TGF-β together with the appearance of macrophages/microglia of the M2-like phenotype. The downregulation of proinflammatory cytokines in the liver is not due to systemic hypoxia only, but is induced by the cerebral damage.

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.

Objective: To investigate whether postnatal allopurinol would reduce free radical induced reperfusion/reoxygenation injury of the brain in severely asphyxiated neonates. Method: In an interim analysis of a randomised, double blind, placebo controlled study, 32 severely asphyxiated infants were given allopurinol or a vehicle within four hours of birth. Results: The analysis showed an unaltered (high) mortality and morbidity in the infants treated with allopurinol. Conclusion: Allopurinol treatment started postnatally was too late to reduce the early reperfusion induced free radical surge. Allopurinol administration to the fetus with (imminent) hypoxia via the mother during labour may be more effective in reducing free radical induced post-asphyxial brain damage.

Background:In preterm infants with respiratory distress syndrome (RDS) nasal continuous positive airway pressure (nCPAP) with the “InSurE” procedure (intubation, surfactant, extubation) is increasingly used. However, its effect on cerebral oxygenation and brain function is not known.Objective:To evaluate the effects of the “InSurE” procedure in infants with RDS on regional cerebral oxygen saturation (rScO2) and relative cerebral fractional tissue oxygen extraction (cFTOE) using near infrared spectroscopy and on electrical brain activity using amplitude-integrated electroencephalography (aEEG).Methods:Sixteen infants with RDS, treated with the “InSurE” procedure, and 16 matched controls with nCPAP, were monitored for mean arterial blood pressure (MABP), arterial oxygen saturation (SaO2), rScO2, cFTOE and aEEG. Ten-minute periods were selected and averaged at 120 and 20 minutes before, during the procedure and at 30 minutes, 1, 2, 6, 12 and 24 h after the start of the “InSurE” procedure. aEEG was analysed by quantitative and qualitative (Burdjalov score) methods.Results:MABP was not different between groups on all time points. rScO2 and cFTOE were comparable between groups, but there was a trend towards lower rScO2 and higher cFTOE 30 minutes after opioid administration in the “InSurE” infants compared with controls (62% (SD 11) vs 68% (SD 10) and 0.30 (SD 0.10 ) vs 0.28 (SD 0.11), respectively). aEEG amplitudes and Burdjalov scores were significantly lower in “InSurE” infants from 30 minutes after opioid administration up to 24 h after the start of the procedure (p<0.05).Conclusion:In the present study, the “InSurE” procedure did not induce perturbation of cerebral oxygen delivery and extraction, whereas electrical brain activity decreased for a prolonged period of time.

Objective Perinatal hypoxia-induced free radical formation is an important cause of hypoxic-ischaemic encephalopathy and subsequent neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced brain damage. We investigated placental transfer and safety of allopurinol after maternal allopurinol treatment during labour to evaluate its potential role as a neuroprotective agent in suspected fetal hypoxia. Design We used data from a randomised, double-blind multicentre trial comparing maternal allopurinol versus placebo in case of imminent fetal hypoxia (NCT00189007). Patients We studied 58 women in labour at term, with suspected fetal hypoxia prompting immediate delivery, in the intervention arm of the study. Setting Delivery rooms of 11 Dutch hospitals. Intervention 500 mg allopurinol, intravenously to the mother, immediately prior to delivery. Main outcome measures Drug disposition (maternal plasma concentrations, cord blood concentrations) and drug safety (maternal and fetal adverse events). Results Within 5 min after the end of maternal allopurinol infusion, target plasma concentrations of allopurinol of ≥2 mg/L were present in cord blood. Of all analysed cord blood samples, 95% (52/55) had a target allopurinol plasma concentration at the moment of delivery. No adverse events were observed in the neonates. Two mothers had a red and/or painful arm during infusion. Conclusions A dose of 500 mg intravenous allopurinol rapidly crosses the placenta and provides target concentrations in 95% of the fetuses at the moment of delivery, which makes it potentially useful as a neuroprotective agent in perinatology with very little side effects. Trial registration The study is registered in the Dutch Trial Register (NTR1383) and the Clinical Trials protocol registration system (NCT00189007).

Background Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods This study on the effects of AL lopurinol in addition to hypothermia treatment for hypoxic-ischemic B rain I njury on N eurocognitive O utcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration NCT03162653, www.ClinicalTrials.gov , May 22, 2017.

BackgroundLidocaine is used as an add-on anti-epileptic drug (AED) in neonates when seizures persist despite treatment with first line anticonvulsants. Although lidocaine has shown to be an effective anticonvulsant, cardiac toxicity associated with plasma concentrations >9 mg/L have limited its wide scale use.1 Previous studies from our group have proposed a dosing regimen for effective and safe lidocaine use in term and preterm neonates with plasma concentrations not exceeding 9 mg/L.2,3 AimThe present study evaluated lidocaine use as anticonvulsant in neonates and prospectively validated the new dosing regimen.MethodsData were collected at the neonatal intensive care unit of the University Medical Centre Utrecht. Neonates refractory to at least one AED received lidocaine according to clinical protocol. Lidocaine was administered as a 2 mg/kg loading dose in 10 minutes followed by a three stage maintenance phase with tapering lidocaine doses. Lidocaine plasma concentrations were measured from blood samples taken at the end of the first stage (highest lidocaine dose) and during the second or third stage (tapered lidocaine dose). Efficacy was determined as abolishment of seizures during lidocaine therapy and no recurrence within 24 h after cessation.ResultsLidocaine data were available from 75 neonates (gestational age 36.2 weeks [range 25.0–42.4, < 36.0 38.7%], birth weight 2771 g [range 675–4875], male 64.0%, mortality 45.3%). 23 patients (30.7%) received the new dosing regimen, 52 patients (60.7%) the old regimen. Highest measured plasma concentration with the new regimen was 9.15 mg/L and 16.8 mg/L with the old regimen. Efficacy with the new regimen was 56.5% and 53.8% for the old regimen. No cardiac toxicity was observed in either group.ConclusionsThe new lidocaine dosing regimen leads to safe and effective lidocaine plasma concentrations and has similar efficacy compared to the previous dosing regimen.ReferencesWeeke LC, Toet MC, Van Rooij LGM, Groenendaal F, Boylan GB, Pressler RM, et al. Lidocaine response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and preterm infants 2015;233–42.Van den Broek MPH, Rademaker CMA, van Straaten HLM, Huitema ADR, Toet MC, de Vries LS, et al. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed 2013;98(4):F341–5.Van Den Broek MPH, Huitema a. DR, Van Hasselt JGC, Groenendaal F, Toet MC, Egberts TCG, et al. Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures. Clin Pharmacokinet 2011;50(7):461–9.Disclosure(s)Nothing to disclose

Part of asphyxia-related brain damage occurs upon reoxygenation. Renewed availability of oxygen activate biochemical pathways and neuronal cell death. Important pathways are: 1) Calcium-induced formation of neurotransmitters; 2) formation of (pro-) radicals; 3) activation of inflammation; 4) induction of apoptosis; 5) depletion of growth factors. Four important sources of free radicals are: 1) Nitric oxide (NO)-related formation of peroxynitrite. It is reported that selective iNOS/eNOS inhibitor 2-iminobiotin induced neuroprotection after asfyxia in animal models. 2) Pro-radicals, such as non proteinbound-iron (NPBI), lead to formation of hydroxyl free radicals. NPBI chelation with deferoxamine, which has also a stabilising effect on HIF1-alpha and stimulates trophic factors, showed encouraging results in experimental models. 3) Formation of superoxide radical by metabolisation by xanthine-oxidase (XO) can be blocked by XO-inhibitors such as allopurinol. 4) Metabolisation of arachidonic acid to prostaglandin leading to superoxide can be blocked by cyclo-oxygenase inhibitors. Since XO-derived superoxide occurs upon reoxygenation after asphyxia, a trial with allopurinol to the mother with signs of perinatal fetal hypoxia has been started. Activation of inflammatory factors after asphyxia is recognised to be related to post-aphyxial brain damage.Rather than monotherapy directed to one pathway, a combination of drugs intervening in various pathways in relation with the time-profile of these pathways, might achieve optimal reduction of reperfusion injury.

Background and aimThe waveform amplitude produced by pulse oximeters can be expressed as an index of pulsatile vs. non-pulsatile signal. This perfusion index (PI) has been shown to correlate with cardiac output, stroke volume, and superior vena cava flow. The aim was to gather PI reference data in preterm infants and to explore if the PI is associated with common clinical parameters.Patients/methodsThe PI was recorded in 312 neonates <32 weeks GA during the first 72 h of life. Mixed-effects modelling was applied with PI as the dependent variable and the individual patient as a random factor. Subsequently the association with clinical parameters (i.e. GA, birth weight, IVH, PDA, inotropes) was explored.ResultsMean GA was 28.5 weeks (SD ± 2.1). A quadratic model (0–24 h) combined with a linear model (24–72 h) provided the best fit. The lowest PI was reached 12–18 h after birth, thereafter gradually increasing until 72 h postnatal age. For the first 24 h PI was associated with gender (coefficient 0.05, p = 0.04), inotrope administration (-0.123, p < 0.0001), pulse pressure (0.014, p < 0.0001), SaO2 (-0.015, p < 0.0001), MABP (-0.013, p < 0.0001), and GA (0.014, p = 0.0168). After the first day, only associations with, inotrope administration (-0.17, p < 0.0001), pulse pressure (0.007, p < 0.0001), MABP (-0.014, p < 0.0001), and SaO2 (-0.01, p < 0.0001) remained. No association was found with, IVH, PDA, fluid boluses, or birth weight.ConclusionsThe evolution of PI values over time probably reflects transitional physiology. The associations with pulspressure, MABP, and inotrope administration suggest that the PI might have an application in blood pressure management.