Prediction Of Neurodevelopmental Outcome Research Articles

Perioperative Near-Infrared Spectroscopy Monitoring in Neonates With Congenital Heart Disease: Relationship of Cerebral Tissue Oxygenation Index Variability With Neurodevelopmental Outcome.

To evaluate the value of perioperative cerebral near-infrared spectroscopy monitoring using variability analysis in the prediction of neurodevelopmental outcomes in neonates undergoing surgery for congenital heart disease. Retrospective cohort study. Urban, academic, tertiary-care children's hospital. Neonates undergoing surgery with cardiopulmonary bypass for congenital heart disease. Perioperative monitoring of continuous cerebral tissue oxygenation index by near-infrared spectroscopy and subsequent neurodevelopmental testing at 6, 15, and 21 months of age. We developed a new measure, cerebral tissue oxygenation index variability, using the root mean of successive squared differences of averaged 1-minute cerebral tissue oxygenation index values for both the intraoperative and first 24-hours postoperative phases of monitoring. There were 62 neonates who underwent cerebral tissue oxygenation index monitoring during surgery for congenital heart disease and 44 underwent subsequent neurodevelopmental testing (12 did not survive until testing and six were lost to follow-up). Among the 44 monitored patients who underwent neurodevelopmental testing, 20 (45%) had abnormal neurodevelopmental indices. Patients with abnormal neurodevelopmental indices had lower postoperative cerebral tissue oxygenation index variability when compared with patients with normal indices (p = 0.01). Adjusting for class of congenital heart disease and duration of deep hypothermic circulatory arrest, lower postoperative cerebral tissue oxygenation index variability was associated with poor neurodevelopmental outcome (p = 0.02). We found reduced postoperative cerebral tissue oxygenation index variability in neonatal survivors of congenital heart disease surgery with poor neurodevelopmental outcomes. We hypothesize that reduced cerebral tissue oxygenation index variability may be a surrogate for impaired cerebral metabolic autoregulation in the immediate postoperative period. Further research is needed to investigate clinical implications of this finding and opportunities for using this measure to drive therapeutic interventions.

Neurodevelopmental Assessment in Preterm Neonates at Early Ages: Screening of at-risk Infants for Long Term Sequlae

Background: Preterm infants are at risk for long term neurodevelopmental impairements. Neurodevelopmental assessment at early months of infancy has been proposed as a valuable tool for prediction of neurodevelopmental outcomes in this population.Objective: The present study attempted to find the neurodevelopmental impairments in preterm infants and thus to identify the at risk infants for follow up and subsequent therapeutic intervention.Methodology: This prospective cross-sectional observational study was conducted in Dhaka Shishu (Children) Hospital from October 2011 to March, 2012. A total 103 preterm neonates who met the inclusion criteria underwent rapid neurodevelopmental assessment (RNDA) at neonatal period and again at their 3 months of age to find the at risk infants for long term neurodevelopmental impairments.Results: Among the enrolled 103 preterm infants during RNDA at neonatal period, abnormal domains found in primitive reflexes 41(39.7%), gross motor 42(40.7%), fine motor 32(31%), vision 40(38.7%), hearing 32 (31%), speech 40(38.7%), cognition 3(2.8%), behavior 3 (2.8%) and 3(2.8%) had seizure. Again in RNDA at 3 months of age, the no. of preterm infants having abnormal developmental domains are: gross motor 49(47.5%), fine motor 19(18.3), vision 9(8.6%), hearing 16(15.4%), speech 15 (14.5%), cognition 6(5.7%), speech 15 (14.5%), cognition 6(5.7%), behavior 11(10.6%) and 3 (2.9%) had seizure.Conclusion: The identification of neurodevelopmental impairments in early months of preterm infants should offer a valuable complement to tools for identification of at risk infants for long term sequlae (in neurodevelopmental impairment).Bangladesh J Child Health 2016; VOL 40 (1) :5-11

Prognostic Accuracy of Electroencephalograms in Preterm Infants: A Systematic Review.

Brain injury is common in preterm infants, and predictors of neurodevelopmental outcome are relevant. To assess the prognostic test accuracy of the background activity of the EEG recorded as amplitude-integrated EEG (aEEG) or conventional EEG early in life in preterm infants for predicting neurodevelopmental outcome. The Cochrane Library, PubMed, Embase, and the Cumulative Index to Nursing and Allied Health Literature. We included observational studies that had obtained an aEEG or EEG within 7 days of life in preterm infants and reported neurodevelopmental outcomes 1 to 10 years later. Two reviewers independently performed data extraction with regard to participants, prognostic testing, and outcomes. Thirteen observational studies with a total of 1181 infants were included. A meta-analysis was performed based on 3 studies (267 infants). Any aEEG background abnormality was a predictor of abnormal outcome. For prediction of a developmental quotient <70 points, cerebral palsy, or death, the pooled sensitivity was 0.83 (95% confidence interval, 0.69-0.92) and specificity 0.83 (95% confidence interval, 0.77-0.87). All studies were at high risk of bias. Heterogeneity was evident among the studies with regard to the investigated aEEG and EEG variables, neurodevelopmental outcomes, and cutoff values. aEEG or EEG recorded within the first 7 days of life in preterm infants may have potential as a predictor for later neurodevelopmental outcome. We need high-quality studies to confirm these findings. Meanwhile, the prognostic value of aEEG and EEG should be used only as a scientific tool.

Comparison of two common aEEG classifications for the prediction of neurodevelopmental outcome in preterm infants

Neurodevelopmental outcome after prematurity is crucial. The aim was to compare two amplitude-integrated EEG (aEEG) classifications (Hellström-Westas (HW), Burdjalov) for outcome prediction. We recruited 65 infants ≤32 weeks gestational age with aEEG recordings within the first 72 h of life and Bayley testing at 24 months corrected age or death. Statistical analyses were performed for each 24 h section to determine whether very immature/depressed or mature/developed patterns predict survival/neurological outcome and to find predictors for mental development index (MDI) and psychomotor development index (PDI) at 24 months corrected age. On day 2, deceased infants showed no cycling in 80% (HW, p = 0.0140) and 100% (Burdjalov, p = 0.0041). The Burdjalov total score significantly differed between groups on day 2 (p = 0.0284) and the adapted Burdjalov total score on day 2 (p = 0.0183) and day 3 (p = 0.0472). Cycling on day 3 (HW; p = 0.0059) and background on day 3 (HW; p = 0.0212) are independent predictors for MDI (p = 0.0016) whereas no independent predictor for PDI was found (multiple regression analyses).Conclusion: Cycling in both classifications is a valuable tool to assess chance of survival. The classification by HW is also associated with long-term mental outcome.What is Known:•Neurodevelopmental outcome after preterm birth remains one of the major concerns in neonatology.•aEEG is used to measure brain activity and brain maturation in preterm infants.What is New:•The two common aEEG classifications and scoring systems described by Hellström-Westas and Burdjalov are valuable tools to predict neurodevelopmental outcome when performed within the first 72 h of life.•Both aEEG classifications are useful to predict chance of survival. The classification by Hellström-Westas can also predict long-term outcome at corrected age of 2 years.

Fifty years of brain imaging in neonatal encephalopathy following perinatal asphyxia.

In the past brain imaging of term infants with hypoxic-ischemic encephalopathy (HIE) was performed with cranial ultrasound (cUS) and computed tomography (CT). Both techniques have several disadvantages sensitivity and specificity is limited compared with magnetic resonance imaging (MRI) and CT makes use of radiation. At present MRI including diffusion weighted MRI during the first week of life, has become the method of choice for imaging infants with HIE. In addition to imaging, blood vessels and blood flow can be visualized using MR angiography, MR venography, and arterial spin labeling. Since the use of these techniques additional lesions in infants with HIE, such as arterial ischemic stroke, sinovenous thrombosis, and subdural hemorrhages can be diagnosed, and the incidence appears to be higher than shown previously. Phosphorus magnetic resonance spectroscopy (MRS) has led to the concept of secondary energy failure in infants with HIE, but has not been widely used. Proton MRS of the basal ganglia and thalamus is one of the best predictors of neurodevelopmental outcome. cUS should still be used for screening infants admitted to a NICU with neonatal encephalopathy. In the future magnetic resonance techniques will be increasingly used as early biomarkers of neurodevelopmental outcome in trials of neuroprotective strategies.

Assessment of general movements and heart rate variability in prediction of neurodevelopmental outcome in preterm infants

BackgroundAdverse neurologic outcome in preterm infants could be associated with abnormal heart rate (HR) characteristics as well as with abnormal general movements (GMs) in the 1st month of life. AimsTo demonstrate to what extent GMs assessment can predict neurological outcome in preterm infants in our clinical setting; and to assess the clinical usefulness of time-domain indices of heart rate variability (HRV) in improving predictive value of poor repertoire (PR) GMs in writhing period. Study designQualitative assessment of GMs at 1 and 3 months corrected age; 24h electrocardiography (ECG) recordings and analyzing HRV at 1 month corrected age. SubjectsSeventy nine premature infants at risk of neurodevelopmental impairments were included prospectively. Outcome measuresNeurodevelopmental outcome was assessed at the age of 2 years corrected. Children were classified as having normal neurodevelopmental status, minor neurologic dysfunction (MND), or cerebral palsy (CP). ResultsWe found that GMs in writhing period (1 month corrected age) predicted CP at 2 years with sensitivity of 100%, and specificity of 72.1%. Our results demonstrated the excellent predictive value of cramped synchronized (CS) GMs, but not of PR pattern. Analyzing separately a group of infants with PR GMs we found significantly lower values of HRV parameters in infants who later developed CP or MND vs. infants with PR GMs who had normal outcome. ConclusionsThe quality of GMs was predictive for neurodevelopmental outcome at 2 years. Prediction of PR GMs was significantly enhanced with analyzing HRV parameters.

A New IVH Scoring System Based on Laterality Enhances Prediction of Neurodevelopmental Outcomes at 3 Years Age in Premature Infants.

Objective To compare the new intraventricular hemorrhage (IVH) Abdi score to the Papile grading system of IVH for prediction of composite outcome of death or neurodevelopmental impairment (NDI). Methods In a cohort study, all preterm infants with IVH who were born ≤1,250 g and/or ≤ 28 weeks of gestation at birth were prospectively followed up in our neonatal follow-up clinic. All cranial ultrasounds of the included infants were reviewed by neuroradiologists who were blinded to the clinical data and neurodevelopmental outcomes. Cranial ultrasounds were graded according to the Papile scoring system and by calculation of the Abdi score. Results A total of 183 preterm infants met inclusion and exclusion criteria. Of these, 80 (44%) had the composite primary outcome of death or NDI (51 died, 29 survived with NDI). The area under receiver operating characteristic curve for predicting death or NDI was 0.87 (95% confidence interval [CI]: 0.81-0.93) for Abdi score and 0.85 (95% CI: 0.79-0.91) for Papile grading (p = 0.04). Abdi scores had higher specificity than Papile grade II at Abdi score 5 (63.9 vs. 39.2%; p < 0.001) and Abdi score 6 (73.2 vs. 39.2%; p < 0.001). Conclusion Abdi scores seem to be more specific than Papile grading system in predicting death or NDI by 3 years' corrected age.

Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy had favourable outcomes at a referral hospital in a middle-income country.

This South African study documented the survival and neurodevelopmental outcomes of infants with hypoxic-ischaemic encephalopathy (HIE) after introducing cooling to a neonatal intensive care unit and identified early markers for neurodevelopmental outcome. We retrospectively reviewed infants that received cooling according to the Total Body Hypothermia trial protocol from 2008 to 2011. Infants were screened with the Bayley Scales of Infant and Toddler Development, Third Edition, at one year of age and underwent neurological and hearing assessments. Data on 99 infants with HIE showed that 45% of cases were moderate, 23% severe and 32% mild. An abnormal amplitude integrated electro-encephalogram (aEEG) background was documented in 45 cases within 24 hours. Magnetic resonance imaging (MRI) scans were consistent with HIE in all but one case. We reviewed 50 traceable survivors at one year. Development was significantly impaired in nine and 41 were normal or mildly impaired. A severely abnormal aEEG background, severe HIE and an abnormal MRI were associated with death and severe impairment. A good suck, mild HIE, primiparity and normal MRI were associated with good outcomes. Most infants with HIE survived without major impairment. Previously described predictors of neurodevelopmental outcome were good surrogate markers in this population.

Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome

ObjectivesDespite improved survival in children with hypoplastic left heart syndrome (HLHS), significant concern persists regarding their neurodevelopmental (ND) outcomes. Previous studies have identified patient factors, such as prematurity and genetic syndromes, to be associated with worse ND outcomes. However, no consistent relationships have been identified among modifiable management factors, including cardiopulmonary bypass strategies, and ND outcomes after cardiac surgery in infancy. Studies in immature animals, including primates, have demonstrated neurodegeneration and apoptosis in the brain after certain levels and extended durations of anesthetic exposure. Retrospective human studies have also suggested relationships between adverse ND effects and anesthetic exposure. MethodsCumulative minimum alveolar concentration hours (MAC-hrs) of exposure to volatile anesthetic agents (VAA) (desflurane, halothane, isoflurane, and sevoflurane) were collected from an anesthetic database and medical record review for 96 patients with HLHS or variants. ND testing was performed between ages 4 and 5 years, including full-scale IQ, verbal IQ, performance IQ, and processing speed. Four generalized linear modes were hypothesized a priori and tested using a Gaussian (normal) distribution with an identity link. ResultsCumulative VAA exposure ranged from 0 to 35.3 MAC-hrs (median 7.5 hours). Using specified covariates identified previously as significant predictors of ND outcomes, statistically significant relationships were identified between total MAC-hrs exposure and worse full-scale IQ and verbal IQ scores (P's < .05) alone and after adjusting for relevant covariates. ConclusionsIncreased cumulative MAC-hrs exposure to VAA is associated with worse ND outcomes in certain domains in children with HLHS and variants.

Prediction of Neurodevelopmental Outcome of Preterm Babies Using Risk Stratification Score.

To study the incidence of major neurodevelopmental disability (NDD) at 1y age (corrected for prematurity) in a cohort of preterm Indian babies (≤33wk) and to predict NDD based on perinatal risk factors. This prospective cohort study was conducted at a referral neonatal intensive care unit (NICU) with a developmental follow up clinic in private sector in Kerala, India. The study was conducted for 4.5 y - January 2005 to July 2009. All preterm babies ≤33wk at birth, discharged from the NICU were included. Pre-defined perinatal and neonatal risk factors known to affect neurodevelopmental outcome were recorded prospectively, in a structured form. Babies were followed to 1y of age, corrected for prematurity and classified as normal or as having major neurodevelopmental disability (NDD). Major NDD was defined as cerebral palsy or Development Assessment Scale for Indian Infants (DASII) motor /mental score <70 or blindness in one or both eyes or hearing impairment needing hearing aids. The incidence of major NDD at 1y age (corrected for prematurity) among the 225 preterm babies was 6.2%. A clinical score was devised by combining 5 risk factors, gestation ≤28wk, need for extensive resuscitation at birth, symptomatic hypoglycemia, invasive ventilation for >7d and abnormal neurosonogram. Scores of 1 to 5 were associated with 4, 6, 10, 25, 100% risk of major NDD respectively (p < 0.01). The authors could stratify 87.5% of the babies into low risk (score of 1 or 2) for NDD and 12.5% into high risk (score 3 or 4 or 5) for major NDD. Majority of the preterm babies at lower risk of NDD need less intensive follow up, while those at higher risk (12.5%) should be guided to more frequent structured follow up and early intervention program.

Earlier diagnosis of neurodevelopmental disability can only help infants in neonatal intensive care units.

This commentary is on the original article by Einspieler et al. on pages 361–368 of this issue. Parents of infants in neonatal intensive care units (NICUs) are understandably concerned with their infant's development. As survival has markedly improved over the last two decades, the focus of health professionals has shifted to decreasing morbidity and improving neurodevelopmental outcomes. However, predicting development is challenging at an early age. Whilst traditional neurological assessments provide a profile of the neurological status of the infant, they often require prolonged handling that can be poorly tolerated by infants in the NICU and are less valuable in the accurate prediction of neurodevelopmental outcomes when performed before term age.1 The General Movements Trust has, for many decades, been a leader in attempting to predict outcome in an objective way. We know that the general movement assessment (GMA) is a validated non-invasive method to observe infants' spontaneous movements and is clinically feasible to use in a wide variety of infant populations: from extremely preterm infants to term infants recovering from major surgical procedures.2 The GMA, traditionally implemented in Europe, is gaining momentum in other countries, including Australia, with increasing numbers of certification courses run on a regular basis by the General Movements Trust. Repeated studies have shown the GMA to be predictive of later neurological outcome, particularly cerebral palsy (CP),3 with sensitivity and specificity rates that surpass those of traditional neurological assessment or magnetic resonance imaging.1 This data from Einspieler et al.4 adds to this knowledge by applying an important concept, namely optimality. The majority of studies that report on the GMA, use the global assessment categories when describing the quality of general movements; however, this study investigates and describes writhing general movements in more detail. Through further analysis and scoring of components such as amplitude, speed, and spatial range, a semi-quantification of the quality of movement can be achieved. By applying this to a large number of infants across varying preterm and term ages, the authors have been able to provide a rich description of movement characteristics within each global general movement category in the writhing period. This has particular significance for less experienced clinicians and could be used both as a complement to formal training, and in the clinical setting to improve reliability in GMA interpretation. Previous studies on the use of optimality scoring by this group and others have not been able to enhance the prediction of long-term outcome from that of the global GMA scores.5 However, the optimality score may have potential as a method to evaluate subtle change following early therapeutic interventions. Whilst more research is needed to investigate the effectiveness of early neonatal interventions such as providing an enriched environment or supporting infants through painful procedures, the use of assessments that allow the evaluation of these interventions is a step in the right direction. For parents, the GMA provides a chance for early intervention in infants considered ‘at risk’, rather than waiting for milestones to go unmet, or a formal label to be given. For conditions such as CP this is vital, as it allows the commencement of intensive early intervention, with promising research underway into goal and activity-based learning occurring within an enriched environment.6 Assessment tools with good predictive ability are of utmost importance within the clinical setting to identify infants at risk of poor neurodevelopmental outcomes and who may benefit from neuroregenerative therapies and targeted early intervention at the time of maximal neuroplasticity. The GMA is one such extremely promising tool. More studies are needed to investigate the application of detailed GMA using the optimality score across a wide range of infant populations and to determine the benefit in enhancing prediction of outcome. Important steps in the field of neonatology now are for more clinicians to complete the standardized training and certification process for the GMA, as a complement to existing neonatal assessment methods, and for the GMA to be routinely incorporated into infant follow-up.

Multimodal predictor of neurodevelopmental outcome in newborns with hypoxic-ischaemic encephalopathy

Automated multimodal prediction of outcome in newborns with hypoxic-ischaemic encephalopathy is investigated in this work. Routine clinical measures and 1h EEG and ECG recordings 24h after birth were obtained from 38 newborns with different grades of HIE. Each newborn was reassessed at 24 months to establish their neurodevelopmental outcome. A set of multimodal features is extracted from the clinical, heart rate and EEG measures and is fed into a support vector machine classifier. The performance is reported with the statistically most unbiased leave-one-patient-out performance assessment routine. A subset of informative features, whose rankings are consistent across all patients, is identified. The best performance is obtained using a subset of 9 EEG, 2h and 1 clinical feature, leading to an area under the ROC curve of 87% and accuracy of 84% which compares favourably to the EEG-based clinical outcome prediction, previously reported on the same data. The work presents a promising step towards the use of multimodal data in building an objective decision support tool for clinical prediction of neurodevelopmental outcome in newborns with hypoxic-ischaemic encephalopathy.

Cortical burst dynamics predict clinical outcome early in extremely preterm infants.

Intermittent bursts of electrical activity are a ubiquitous signature of very early brain activity. Previous studies have largely focused on assessing the amplitudes of these transient cortical bursts or the intervals between them. Recent advances in basic neuroscience have identified the presence of scale-free 'avalanche' processes in bursting patterns of cortical activity in other clinical contexts. Here, we hypothesize that cortical bursts in human preterm infants also exhibit scale-free properties, providing new insights into the nature, temporal evolution, and prognostic value of spontaneous brain activity in the days immediately following preterm birth. We examined electroencephalographic recordings from 43 extremely preterm infants (gestational age 22-28 weeks) and demonstrated that their cortical bursts exhibit scale-free properties as early as 12 h after birth. The scaling relationships of cortical bursts correlate significantly with later mental development-particularly within the first 12 h of life. These findings show that early preterm brain activity is characterized by scale-free dynamics which carry developmental significance, hence offering novel means for rapid and early clinical prediction of neurodevelopmental outcomes.

OP78 – 2871: Correlation between NIRS and aEEG in hypothermia treated newborns with hypoxic-ischemic encephalopathy

Objective Hypoxic-ischemic encephalopathy (HIE) still is a major cause of neonatal mortality and morbidity. The amplitude-integrated electroencephalogram (aEEG) is reliable for prediction of outcome in asphyxiated neonates. Near-infrared spectroscopy (NIRS) offers the possibility to continuously monitor cerebral oxygen saturation. Only few data have been published on the combined use of NIRS and aEEG in neonates cooled for HIE. The aim of this study was to investigate the correlation between continuous aEEG and NIRS during the first days of life in HIE. Methods aEEG: Brain function was measured continuously immediately after the hypoxic event, during hypothermia, until the end of rewarming using a Olympic 6000 (Natus©). aEEG tracings were analysed for background patterns, appearance of sleep-wake cycling and the presence of seizure activity. Furthermore, a combined aEEG-score was calculated for the timeperiod before, during and after hypothermia. NIRS: Patients were monitored using NIRS (INVOS System by Covidien©) for the mentioned time period. Changes in regional cerebral oxygen saturation (rcSO2) were measured. Fractional tissue oxygen extraction (FTOE) was calculated for the entire duration of the measurement in order to investigate the balance between oxygen delivery and oxygen supply. Results A significant correlation coefficient (CorrC) was found between SWZ and rcSO2 post cooling (CorrC: 0.78) as well as FTOE during (CorrC: 0.69) and post cooling (CorrC: 0.95). Furthermore, a significant CorrC was found between the total aEEG score and rcSO2 post cooling (CorrC: 0.58) as well as FTOE during (CorrC: 0.61) and post cooling (CorrC: 0.79). Conclusion Our data show a significant correlation between continuous aEEG monitoring, which is a valuable and reliable method for prediction of neurodevelopmental outcome in neonates with HIE, and NIRS measurements. Therefore, we suggest that NIRS can serve as an additional prognostic tool in HIE.

Antenatal and Postnatal Assessment of Neurobehavior: Which One should be used?

ABSTRACT It is obvious that this environment is quite different from one man is experiencing after birth, but, although different, intrauterine environment is ideal at that stage of human development. There is a question of the environmental discontinuity between intrauterine conditions characterized by existence of microgravity (baby astronaut hypothesis), and extrauterine life with gravity as developmental condition sine qua non. The human brain is one of the organs which is very sensitive to environmental changes affecting its growth and development. The brain of very tiny prematurely born babies is unable to follow the genetically determined growth pattern in extrauterine environment, even when postnatal nutrition and nurturing of the babies according to our best knowledge are appropriate. Is this fact of any significance to make distinction between normal and abnormal neurodevelopment pre- and postnatally is still unclear? Kurjak antenatal neurodevelopmental test (KANET) using four-dimensional ultrasound (4D US) has been introduced using ten parameters and after attempt of standardization only eight parameters remained for neurodevelopmental assessment of low- and high-risk fetuses. We believe that at present level of knowledge, KANET test could be considered as a good test for the detection of fetuses with high neurological risk, without the possibility to define reliable long-term neurodevelopmental outcome. This is also hardly possible based on postnatal neurological assessment with 27 different postnatal tests. They were primarily neurobehavioral or neuromotor assessments that were suitable for use with preterm infants, and were discriminative, predictive or evaluative. There was a high willingness of clinician to find postnatal neurodevelopmental test which could be predictive for short- term and long-term outcome of low and high-risk infants. Although, there are many tests available for prenatal and postnatal assessment of neurodevelopment, none of them is reliable in the prediction of neurodevelopmental outcome in low-risk population, while many could be used with fairly acceptable predictivity in high-risk population. Although, many studies have been conducted in order to solve this problem, still there is a space for improvement. In postnatal period we are dealing with infant in front of the clinician with direct observation, while pretnatally we are dealing with quite different environment and less mature brain. How to cite this article Stanojevic M. Antenatal and Postnatal Assessment of Neurobehavior: Which One should be used? Donald School J Ultrasound Obstet Gynecol 2015;9(1):67-74.

Serial Plasma Metabolites Following Hypoxic-Ischemic Encephalopathy in a Nonhuman Primate Model

Biomarkers that indicate the severity of hypoxic-ischemic brain injury and response to treatment and that predict neurodevelopmental outcomes are urgently needed to improve the care of affected neonates. We hypothesize that sequentially obtained plasma metabolomes will provide indicators of brain injury and repair, allowing for the prediction of neurodevelopmental outcomes. A total of 33 Macaca nemestrina underwent 0, 15 or 18 min of in utero umbilical cord occlusion (UCO) to induce hypoxic-ischemic encephalopathy and were then delivered by hysterotomy, resuscitated and stabilized. Serial blood samples were obtained at baseline (cord blood) and at 0.1, 24, 48, and 72 h of age. Treatment groups included nonasphyxiated controls (n = 7), untreated UCO (n = 11), UCO + hypothermia (HT; n = 6), and UCO + HT + erythropoietin (n = 9). Metabolites were extracted and analyzed using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry and quantified by PARAFAC (parallel factor analysis). Using nontargeted discovery-based methods, we identified 63 metabolites as potential biomarkers. The changes in metabolite concentrations were characterized and compared between treatment groups. Further comparison determined that 8 metabolites (arachidonic acid, butanoic acid, citric acid, fumaric acid, lactate, malate, propanoic acid, and succinic acid) correlated with early and/or long-term neurodevelopmental outcomes. The combined outcomes of death or cerebral palsy correlated with citric acid, fumaric acid, lactate, and propanoic acid. This change in circulating metabolome after UCO may reflect cellular metabolism and biochemical changes in response to the severity of brain injury and have potential to predict neurodevelopmental outcomes.

Prediction of Neurodevelopmental Outcome in Hypoxic Ischemic Encephalopathy at 12 Months: Correlation of Brain MRI and EEG

Purpose: The aims of this study were to estimate the neurodevelopmental outcome of hypoxic-ischemic encephalopathy (HIE) at 12 months, and determine the usefulness of brain magnetic resonance imaging (MRI) and electroencephalography (EEG) to predict neurodevelopmental outcome in term infants with HIE at 12 months. Methods: This study was conducted retrospectively on term infants with HIE from January 2009 to June 2013. Based on neurodevelopmental outcome at 12 months, infants were categorized into 2 groups. Brain MRI and EEG findings were stratified into 4 categories as normal, mild, moderate and severe groups. Results: Total 42 term infants were enrolled. Fifty seven point one percent (24/42) of total infants had favorable neurodevelopmental outcome at 12 months (favorable outcome, n=24). Thirty eight point one percent (16/42) of total infants had significant neurodevelopmental deficit at 12 months of age, and 4.8% (2/42) had mortality within 12 months (poor outcome, n=18). In brain MRI and EEG findings, there were significant correlations with neurodevelopmental outcome. Brain MRI showed sensitivity of 88.9%, specificity of 70.8%, positive predictive value of 69.6% and negative predictive value of 89.5%, while EEG showed sensitivity of 70.6%, specificity of 82.6%, positive predictive value of 75%, and negative predictive value of 79.2%. In the multivari­ ate analysis, moderate­to­severe findings in brain MRI were the strongest risk factor (odds­ratio, 11.24; 95% confidence interval, 1.36­92.89; P=0.025). Conclusion: Forty two point nine percent of total infants had poor neurodevelopmental outcome at 12 months. Brain MRI and EEG findings were correlated with neurodevelopmental outcome of term infants with HIE at 12 months.

PS-042a Docosahexaenoic Acid (dha) Is Neuroprotective After Newborn Asphyxia Proton-magnetic-resonance-spectroscopy (h±-mrs) On Hypoxic Brain Tissue In Piglets

Background Hypothermia is an established treatment for perinatal asphyxia. Post treatment hypothermia MRI supplemented with H±-MRS is used in clinics as the best predictor for neurodevelopmental outcome. DHA is an omega-3 fatty acid thought to modify apoptosis, inflammation and reduce lipid peroxidation in face of hypoxia. We have previously shown neuroprotective effects of DHA. The current study combines DHA and hypothermia. Methods 54 newborn pigs (age 12–36 h) were randomised to undergo hypoxia (N=48) or not (Control, N=6). Hypoxia was achieved on fully anaesthetised, intubated piglets through FiO2 0.08 until bloodgases reached Base Excess -20 mmol/L or middle arterial blood pressure below 20 mmHg. Piglets were then block randomised to one of four groups: (1) Hypoxia, (2) Hypoxia + Hypothermia, (3) Hypoxia + DHA or (4) Hypoxia +DHA +Hypothermia. Piglets were mechanically ventilated 9,5 h post end hypoxia and then euthanized. Hippocampal brain tissue was immediately snap frozen in liquid nitrogen. H±-MRS measuring lactate (Lac) and glutamate (Glu) in relation to n-acetylaspartate (NAA) was conducted on frozen tissue. Piglets with autolysis of the brain and outliers over 2 standard deviations were removed from the analysis. ![Abstract PS-042a Figure 1][1] Abstract PS-042a Figure 1 Results The only Lac/NAA ratio significantly different than control, is the hypoxia group (p = 0.016). Intervention groups show no significant changes vs controls. Group 1 vs group 3 shows a borderline significance (p = 0.073). Conclusion Hypoxia significantly increases the Lac/NAA biomarker and intervention groups are at a pre-hypoxic control level. The pattern consists through the Glutamate group. DHA may be beneficial in neuroprotection after asphyxia. [1]: pending:yes

PS-155 Comparison Of Clinical And Electrophysiological Signs Of Encephalopathy In Neonates With Perinatal Asphyxia Qualifying For Hypothermia

Background and aims Early prediction of neurodevelopmental outcome following hypoxic-ischaemic encephalopathy remains a challenge. The aim of this retrospective study was to evaluate the aEEG background patterns and Thompson score on admission in asphyxiated neonates receiving hypothermia regarding outcome and neonatal variables. Methods After excluding congenital malformations and muscle paralysis, 89 neonates (January 2008 to June 2012) were included (GA: 39.7 ± 1.8 wks; BW: 3504 ± 640 g). On admission the Thompson score and aEEG were recorded. aEEG was scored as Continuous Normal Voltage (CNV), Discontinuous Normal Voltage (DNV), Burst-Suppression (BS), Continuous Low Voltage (CLV) or Flat Trace (FT). The combination of one or more of the following event (s): death, cerebral palsy, and Griffiths DQ less than 85 at 18 months were considered an adverse outcome. ANOVA, correlation, and binary logistic regression analyses were performed. Results Thompson scores (in mean ± sd) were associated with aEEG pattern (CNV: 8.3 ± 1.7; DNV: 8.9 ± 1.9; BS: 11.6 ± 3.6; CLV: 12.0 ± 2.1; FT: 13.1 ± 3.2; p Conclusions Both Thompson scores and aEEG are associated with outcome in neonates receiving hypothermia for perinatal asphyxia and with 1 min Apgar scores. Further studies are needed to identify which method is preferable for selection of neonates for hypothermia.

Neurodevelopmental Outcomes After Infant Cardiac Surgery With Circulatory Arrest and Intermittent Perfusion

Optimal perfusion strategies for neuroprotection during infant cardiac surgery remain undefined. Despite encouraging experimental data, neurodevelopmental (ND) outcomes after cardiac surgery in neonates and infants using deep hypothermic circulatory arrest (DHCA) with a period of intermittent perfusion have not been reported, and it is not known whether DHCA can be extended while preserving ND outcomes. Cross-sectional ND evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition was conducted at 24 months of age. Retrospective clinical data were extracted from the electronic medical record. Forty patients underwent cardiac surgery during the first year of life using a period of uninterrupted DHCA (24 patients) or DHCA interrupted by a period of intermittent perfusion (16 patients). Total duration of DHCA ranged from 5 to 74 minutes and did not predict ND scores. Despite a longer exposure to DHCA in the intermittent perfusion group (55 minutes [1,3 interquartile [IQ] 45.3 to 65.5] versus 38 minutes [1,3 IQ 32 to 40.8]), no differences in ND scores were detected. Significant comorbidities, duration of intensive care unit and hospital stay, as well as multiple procedures with DHCA were independent predictors of ND outcomes at 24 months of age. Despite extended duration of total DHCA, the use of a period of intermittent perfusion to limit uninterrupted DHCA periods to less than 45 minutes could lead to ND outcomes similar to those of patients exposed to brief periods of DHCA. Deep hypothermic circulatory arrest with intermittent perfusion may facilitate implementation of prospective studies to identify the optimal cerebral perfusion strategy.