Heart beat variability analysis in perinatal brain injury and infection

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Engenharia Clínica e Instrumentação Médica) Universidade de Lisboa, Faculdade de Ciências, 2018Todos os anos, mais de 95 mil recém-nascidos são admitidos nas Unidades de Cuidados Intensivos Neonatais (UCIN) do Reino Unido, devido principalmente a partos prematuros ou outras complicações que pudessem ter ocorrido, como é o caso da encefalopatia hipóxico-isquémica (EHI), que assume 3% de todas as admissões nas unidades referidas. EHI é o termo que define uma complicação inesperada durante o parto, que resulta em lesões neurológicas a longo prazo e até em morte neonatal, devido à privação de oxigénio e fluxo sanguíneo ao recém-nascido durante o nascimento. Estima-se que tenha uma incidência de um a seis casos por 1000 nascimentos. Nos países desenvolvidos, a hipotermia é utilizada como método preventivo-terapêutico para esta condição. No entanto, existem dois grandes obstáculos para a obtenção da neuroprotecção pretendida e totalmente benéfica, na prática clínica. Em primeiro lugar, esta técnica é eficaz se for iniciada dentro de seis horas após o parto. Visto que o estado clínico da encefalopatia neonatal evolui nos dias posteriores ao nascimento, a sua deteção precoce é um grande desafio. Tal situação pode levar a diversos erros nas UCIN, tal como indivíduos sujeitos à terapia de hipotermia desnecessariamente, ou ainda mais grave, casos em que recém-nascidos foram inicialmente considerados como saudáveis, não tendo sido submetidos à terapia referida, apresentarem sinais de EHI após seis horas de vida. A segunda questão prende-se com o facto de a neuroprotecção poder ser perdida se o bebé estiver stressado durante o tratamento. Para além disso, não existe nenhuma ferramenta válida para a avaliação da dor dos recém-nascidos submetidos a esta terapia. Os obstáculos frisados anteriormente demonstram duas necessidades ainda não correspondidas: a carência de um método não invasivo e largamente adaptável a diferentes cenários para uma correta identificação de recém-nascidos com maior probabilidade de HIE, dentro de uma margem de seis horas após o parto, mas também um método preciso de stress em tempo real, não invasivo, que possa orientar tanto pessoal médico, como pais, de modo a oferecer um tratamento mais responsável, célere e individualizado. Deste modo, a análise do ritmo cardíaco demostra um enorme potencial para ser um biomarcador de encefalopatia neonatal, bem como um medidor de stress, através da eletrocardiografia (ECG), visto que é um importante indicador de homeostase, mas também de possíveis condições que podem afetar o sistema nervoso autónomo e, consequentemente, o equilíbrio do corpo humano. É extremamente difícil a obtenção de um parâmetro fisiológico, sem a presença de artefactos, especialmente no caso de recém-nascidos admitidos nas UCIN. Tanto no caso da aquisição de ECGs, como de outros parâmetros, existe uma maior probabilidade de o sinal ser corrompido por artefactos, visto que são longas aquisições, normalmente dias, onde o bebé é submetido a diversas examinações médicas, está rodeado de equipamentos eletrónicos, entre outros. Artefactos são definidos como uma distorção do sinal, podendo ser causados por diversas fontes, fisiológicas ou não. A sua presença nos dados adquiridos influencia e dissimula as informações corretas e reais, podendo mesmo levar a diagnósticos e opções terapêuticas erradas e perigosas para o paciente. Apesar de existirem diversos algoritmos de identificação de artefactos adequados para o sinal cardíaco adulto, são poucos os que funcionam corretamente para o de recém-nascido. Para além disso, é necessário bastante tempo tanto para o staff clínico, como para os investigadores, para o processo de visualização e identificação de artefactos no eletrocardiograma manualmente. Deste modo, o projeto desenvolvido na presente dissertação propõe um novo algoritmo de identificação e marcação de artefactos no sinal cardíaco de recém-nascidos. Para tal, foi criado um modelo híbrido de um método que tem em consideração todas as relações matemáticas de batimento para batimento cardíaco, com outro que tem como objetivo a remoção de spikes no mesmo sinal. O algoritmo final para além de cumprir com o objetivo descrito acima, é também adaptável a diferentes tipos de artefactos presentes no sinal, permitindo ao utilizador, de uma forma bastante intuitiva, escolher o tipo de parâmetros e passos a aplicar, podendo ser facilmente utilizado por profissionais de diferentes áreas. Deste modo, este algoritmo é uma mais-valia quando aplicado no processamento de sinal pretendido, evitando assim uma avaliação visual demorada de todo o sinal. Para obter a melhor performance possível, durante o desenvolvimento do algoritmo foram sempre considerados os resultados de validação, tais como exatidão, sensibilidade, entre outros. Para tal, foram analisados e comparados eletrocardiogramas de 4 recém-nascidos saudáveis e 4 recém-nascidos com encefalopatia. Todos possuíam aproximadamente 5 horas de sinal cardíaco adquirido após o nascimento, com diferentes níveis de presença de artefactos. O algoritmo final, obteve uma taxa de sensibilidade de 96.2% (±2.4%) e uma taxa de exatidão de 92.6% (±3.2%). Como se pode verificar pelos valores obtidos, o algoritmo obteve percentagens altas nos vários parâmetros de classificação, o que significa uma deteção correta. A taxa de exatidão apresenta um valor mais baixo, comparativamente ao parâmetro da sensibilidade, pois em diversas situações, normalmente perto de artefactos, os batimentos normais são considerados como artefactos, pelo algoritmo. Contudo, essa taxa não é alarmante, tendo sido considerada uma taxa reduzida, pelo pessoal médico. Após o processamento do sinal cardíaco dos grupos mencionados acima, um estudo comparativo, utilizando parâmetros da variabilidade do ritmo cardíaco, foi realizado. Diferenças significativas foram encontradas entre os dois grupos, onde o saudável assumiu sempre valores maiores. SDNN e baixa frequência foram os parâmetros que traduziram uma diferença maior entre os dois grupos, com um p-value <0.01. De modo a corresponder ao segundo obstáculo referido nesta dissertação, outro objetivo desta tese foi a criação de um algoritmo que pudesse identificar e diferenciar uma situação de stress nesta faixa etária, com recurso ao ritmo cardíaco. Um estudo multidimensional foi aplicado aos diferentes métodos de entropia utilizados nesta tese (approximate entropy, sample entropy, multiscales entopy e fuzzy entropy) de modo a estudar como os diferentes métodos de entropia interagem entre si e quais são os resultados dessa relação, especialmente na distinção de estados normais e stressantes. Para tal, a utilização de clusters foi essencial. Dado que para todos os ECGs de bebés saudáveis analisados neste projeto foram registados todas as possíveis situações de stress, como é o caso de choro, examinações médicas, mudança de posição, entre outros, foram escolhidos 10 minutos do sinal do ritmo cardíaco adquirido, antes da situação, para análise. Infelizmente, associado a um evento stressante, na maioria dos casos encontra-se uma percentagem bastante alta do sinal corrompida por artefactos. No entanto, em alguns casos foi possível observar uma clara distinção de grupos de clusters, indicando que naquele período de tempo, houve uma mudança de estado. Foi também realizado um estudo intensivo de diversos métodos de entropia aplicados ao grupo de sujeitos apresentados nesta dissertação, onde foi provado que o método mais adequado a nível de diferenciação é a Fuzzy Entropy (p=0.0078). Ainda é possível sugerir alguns aspetos e apontar algumas limitações, no âmbito de poderem ser ultrapassadas no futuro. Em primeiro lugar, é necessária a aquisição de mais eletrocardiogramas, quer de recém-nascidos saudáveis, quer com encefalopatia hipóxico-isquémica, de modo a aumentar o tamanho da amostra e, deste modo diminuir os valores do desvio-padrão em todos os parâmetros calculados. Relativamente ao estudo do stress, seria interessante, com uma amostra maior, a definição de clusters, de modo a ter uma identificação precisa de situações stressantes. Para além disso, a transformação do software atualmente escrito em MATLAB para GUI (interface gráfica do utilizador), a fim de tornar mais acessível a sua utilização por profissionais de diversas áreas.In Neonatal Intensive Care Unit (NICU), the heart rate (HR) offers significant insight into the autonomic function of sick newborns, especially with hypoxic ischemic encephalopathy condition (HIE). However, the intensity of clinical care and monitoring contributes to the electrocardiogram (ECG) to be often noisy and contaminated with artefacts from various sources. These artefacts, defined as any distortion of the signal caused by diverse sources, being physiological or non-physiological features, interfere with the characterization and subsequent evaluation of the heart rate, leading to grave consequences, both in diagnostic and therapeutic decisions. Besides, its manual inspection in the ECG trace is highly time-consuming, which is not feasible in clinical monitoring, especially in NICU. In this dissertation, it is proposed an algorithm capable of automatically detect and mark artefacts in neonatal ECG data, mainly dealing with mathematical aspects of the heart rate, starting from the raw signal. Also, it is proposed an adjacent algorithm, using complexity science applied to HR data, with the objective of identifying stress scenarios. Periods of 10-minute ECG were considered from 8 newborns (4 healthy and 4 HIE) to the identification of stress situations, whereas for the artefacts removal algorithm small portions varying in time length according to the amount of noise present in the originally 5 hours long samples were utilised. In this report it is also present several comparisons utilising heart rate parameters between healthy and HIE groups. Fuzzy Entropy was considered the best method to differentiate both groups (p=0.00078). In this report, substantial differences in heart rate variability were found between healthy and HIE groups, especially in SDNN and low frequency (p<0.01), confirming results of previous literature. For the final artefact removal algorithm, it is illustrated significant differences between raw and post-processed ECG signals. This method had a Recall rate of 96.2% (±2.4%) and a Precision Rate of 92.6% (±3.2%), demonstrating high efficiency in ECG noise removal. Regarding stress measures, associated with a stressful event, in most cases there is a high percentage of the signal corrupted by artefacts. However, in some cases it was possible to see a clear distinction between groups of clusters, indicating that in that period, there was a change of state. Not all the time segments from subjects demonstrated differences in stress stages, indicating that there is still room for improvement in the method developed

Biomarkers of intrauterine hypoxia and perinatal asphyxia, and gestational age as predictors of neonatal outcome

Fetal life occurs in a relatively hypoxic environment. During normal pregnancy, several compensatory mechanisms secure fetal oxygenation and wellbeing. In complicated pregnancies, however, intrauterine hypoxia predisposes the fetus to growth restriction, stillbirth, neurodevelopmental sequelae such as cognitive dysfunction and cerebral palsy (CP), and adverse long-term health impacts. Impairment of respiratory gas exchange—during either pregnancy or delivery—leads to tissue hypoxia, and, if prolonged, to metabolic acidosis and asphyxia. Worldwide, such asphyxia, diagnosed at birth, annually accounts for a million neonatal deaths. Furthermore, neonatal hypoxic ischemic encephalopathy (HIE) originating from perinatal asphyxia may lead to a variety of neurodevelopmental impairments. Therapeutic neuroprotective interventions such as hypothermia have significantly improved the prognosis of severe neonatal encephalopathy. Increased risk for intrauterine fetal hypoxia and perinatal asphyxia occur in various circumstances and pregnancy complications—such as intrauterine growth restriction (IUGR), which affects up to 10% of pregnancies. Timing the delivery in preterm pregnancy with severe IUGR is challenging, owing to balancing between risks related to prematurity and to fetal hypoxia. Another obstetric challenge concerns timing of delivery as well: Neonatal outcomes vary by gestational age also among term pregnancies. In pregnancies beyond 41 gestational weeks, the risk for perinatal morbidity and mortality increases, probably due to the relative insufficiency of the aging placenta. Numerous methods such as fetal Doppler assessments and computerized cardiotocography help in monitoring placental function and fetal wellbeing. These methods, however, are not unequivocally efficient in predicting adverse neonatal outcomes in IUGR or in prolonged pregnancies. Furthermore, the time window for neuroprotective treatment in birth asphyxia is narrow, and additional methods for identifying those neonates who would benefit from neuroprotective actions are essential. We thus searched for biomarkers identifying those fetuses at risk for hypoxia-caused complications, and for predicting outcome after birth asphyxia. Erythropoietin (EPO) is a biomarker of chronic hypoxia, with high levels of EPO associating with increased risk for adverse outcome. S100B is a biomarker of brain- cell damage, and its levels rise in early phases of acute asphyxia. Copeptin, a by-product of arginine vasopressin (AVP) production, is a potential biomarker of birth asphyxia and HIE. Additionally, we aimed to evaluate the association of gestational age with perinatal asphyctic complications and long-term neurologic morbidity. The biomarker studies (I-III) were conducted in the University Hospital of Helsinki, Finland. Data on maternal pregnancy and delivery characteristics, and short-term neonatal outcomes such as Apgar score, originated from hospital charts. The study populations comprised 66 pregnancies complicated by preterm IUGR, 93 low-risk term and prolonged pregnancies, and 140 term neonates with birth asphyxia. Amniotic fluid samples for EPO evaluations we obtained by amniocentesis, at cesarean section, or vaginally at amniotomy. Umbilical serum plasma samples for EPO, copeptin, and S100B assessments we collected at birth. Biomarker levels in amniotic fluid and umbilical plasma samples we measured by immunoassays. Normal amniotic fluid EPO levels we defined as < 3 IU/L, with abnormal levels exceeding 27 IU/L. We considered as normal umbilical plasma EPO levels below 40 IU/L. The register-based cohort study on asphyxia and neurologic morbidity (IV) comprised 1 138 109 women with singleton pregnancies and their newborns between 1989 and 2008 in Finland. The Finnish Medical Birth Register (MBR), maintained by the National Institute for Health and Welfare (THL), provided data for this study. Statistical analyses we performed with the Statistical Package for Social Sciences (SPSS, Chicago, IL, USA), GraphPad Prism 6 and SAS version 9.3 (SAS Institute, Inc, Cary, NC, USA). All tests were two-sided, with probability (p) values of < 0.05 as statistically significant. In IUGR pregnancies, abnormal amniotic fluid EPO levels were associated with decreased umbilical artery pH and base excess (BE) values, abnormal biophysical profile, and reversed end-diastolic flow in the umbilical artery. Most importantly, such abnormal EPO levels were associated with composite adverse neonatal outcomes defined as intraventricular hemorrhage, periventricular leukomalacia, cerebral infarction, or necrotizing enterocolitis (p < 0.001). In low-risk term and postterm pregnancies, EPO levels in amniotic fluid and in umbilical serum correlated with gestational age. Furthermore, EPO levels in amniotic fluid correlated with the levels in umbilical serum, even after vaginal delivery. Among low-risk pregnancies, however, EPO levels correlated with neither umbilical artery pH or BE, nor with other adverse pregnancy outcomes. In our study on biomarkers in birth asphyxia, only copeptin correlated with arterial pH. Its correlation with umbilical artery BE was significantly stronger than were the correlations of S100B or of EPO. Copeptin levels, significantly higher among neonates with birth asphyxia, we demonstrated to increase as a function of labor duration. In the cohort study, multivariate analysis demonstrated an increased risk for low (< 4) one- and five-minute Apgar score, CP, intellectual disability, sensorineural defects, and perinatal mortality among early-term births. Postterm birth resulted in increased risk for low one- and five-minute Apgar scores (< 4), low umbilical artery pH ≤ 7.10, and intellectual disability, whereas risks for CP, epilepsy, sensorineural defects, and perinatal mortality showed no increase. In conclusion, among preterm IUGR pregnancies, high amniotic fluid EPO levels were associated with decreased umbilical artery pH and BE, and with adverse neonatal outcomes. In selected risk-pregnancies, determining amniotic fluid EPO may thus be a useful additional tool in fetal surveillance and in optimizing delivery timing. In term pregnancies, EPO levels correlated with gestational age, probably explained by advancing gestation resulting in weakening placental function and relative hypoxemia. Among low-risk populations, however, EPO was not related to adverse delivery outcomes, and thus may not prove clinically useful in such populations. Furthermore, in cases of acute birth asphyxia, S100B and EPO as biomarkers may not prove valid. In contrast, copeptin has potential for routine use as a biomarker for acute birth asphyxia and neonatal distress. Future studies should determine the correlation of biomarker levels at birth with severity of HIE and with long-term neurological outcome following birth asphyxia. Concerning gestational age at birth, we found an increased risk for low Apgar score, increased neurologic morbidity, and perinatal mortality among early-term neonates. Among postterm births, the risk for birth asphyxia was increased. The long-term neurologic health impacts of postterm birth, however, were less important than previously expected, meaning that further studies on the optimal management of pregnancies beyond 41 gestational weeks are essential.Raskauden aikana sikiö elää verrattain vähähappisessa ympäristössä. Normaalin raskauden aikana lukuisat kompensaatiomekanismit varmistavat sikiön riittävän hapensaannin ja hyvinvoinnin. Sen sijaan komplisoituneissa raskauksissa sikiön kroonisen hapenpuutteen riski on suurentunut lisäten sikiökuoleman, kasvuhidastuman, neurologisten kehityshäiriöiden ja pitkäaikaisten terveysongelmien todennäköisyyttä. Näissä raskauksissa optimaalisen synnytysajankohdan määrittely on usein haastavaa, koska tällöin on huomioitava kohdunsisäisen hapenpuutteen, ennenaikaisen synnytyksen, sekä obstetristen toimenpiteiden aiheuttamat mahdolliset haitat. Sikiön hengityskaasujen vaihdon ongelmat raskauden tai synnytyksen aikana johtavat kudosten hapenpuutteeseen ja hiilidioksidin kertymiseen eli asfyksiaan, mikä pitkittyessään väistämättä johtaa aineenvaihdunnalliseen happamuuteen. Maailmanlaajuisesti perinataalinen asfyksia aiheuttaa vuosittain jopa miljoonan vastasyntyneen kuoleman. Asfyksian aiheuttama hypoksis-iskeeminen enkefalopatia voi myös johtaa pysyvään vammautumiseen ja vakaviin neurologisiin kehityshäiriöihin. Keskushermoston suojaamiseen tähtäävät hoitotoimenpiteet - kuten vastasyntyneen viilennyshoito - ovat olennaisesti parantaneet vastasyntyneen vaikean enkefalopatian ennustetta. Sikiön hyvinvoinnin ja istukan toiminnan seurannassa käytetään lukuisia menetelmiä, kuten sikiön sydänäänten monitorointia ja Doppler-ultraäänitutkimuksia. Käytössä olevilla menetelmillä ei kuitenkaan aina pystytä yksiselitteisesti ennustamaan vastasyntyneen epäsuotuisaa lopputulemaa riskiraskauksissa. Vastasyntyneen asfyksiadiagnoosin asetuksen ja keskushermostoa suojaavien hoitojen käynnistämisen aikaikkuna on kapea, eikä kaikkia intensiivistä tehohoitoa tarvitsevia vastasyntyneitä löydetä nykymenetelmien avulla ajoissa. Uusia menetelmiä kaivataan sekä hapenpuutteen riskissä olevien sikiöiden, että intensiivisestä tehohoidosta hyötyvien vastasyntyneiden tunnistamiseen ja ennusteen arviointiin. Erytropoietiini (EPO) on punasolujen muodostumista lisäävä hormoni, jota käytetään myös hapenpuutteen merkkiaineena. Napaplasman ja lapsiveden kohonneet EPO-pitoisuudet liittyvät vastasyntyneen huonoon lopputulemaan. S100B-proteiini on aivokudoksen soluvaurion merkkiaine, jonka pitoisuudet nousevat myös asfyksiaan liittyvien vaurioiden ilmaantuessa. Vasopressiini on elimistön nestetasapainoa ylläpitävä hormoni, jonka eritys lisääntyy monentyyppisissä stressitilanteissa. Kopeptiini on vasopressiini-erityksen sivutuote, jota pidetään potentiaalisena perinataalisen asfyksian ja hypoksis-iskeemisen aivovaurion merkkiaineena. Tutkimuksessamme selvitimme näiden valikoitujen biomerkkiaineiden käyttöä hapenpuutteen riskissä olevien sikiöiden tunnistamisessa, sekä näiden merkkiaineiden käytettävyyttä perinataalisen asfyksian diagnostiikassa ja vastasyntyneen ennusteen arvioinnissa. Lisäksi selvitimme raskauden keston vaikutuksia perinataalisen asfyksian ja pitkäaikaisen neurologisen sairastavuuden esiintyvyyteen täysiaikaisissa ja yliaikaisissa raskauksissa. Sikiön kasvuhidastumaa ennenaikaisissa raskauksissa käsittelevässä tutkimuksessamme (n=66) totesimme kohonneiden lapsiveden EPO-pitoisuuksien liittyvän napavaltimon vakava-asteisiin virtausmuutoksiin, sekä vastasyntyneen alentuneisiin napavaltimon pH- ja BE-arvoihin. Lisäksi kohonneet EPO-pitoisuudet liittyivät vastasyntyneen vakavaan sairastavuuteen, mukaan lukien vaikea-asteiset aivokammioverenvuodot, aivoinfarktit, periventrikulaarinen leukomalasia, sekä nekrotisoiva enterokoliitti (p < 0.001). Matalan riskin täysiaikaisissa ja lasketun ajan ohittaneissa raskauksissa (≥41 raskausviikkoa) (n=93) EPO-pitoisuudet korreloivat raskauden keston kanssa. Näissä raskauksissa emme todenneet yhteyttä lapsiveden EPO-pitoisuuden ja vastasyntyneen huonon lopputuleman välillä. Asfyktisilla vastasyntyneillä (n=140) totesimme selvästi korkeammat kopeptiinipitoisuudet kuin hyväkuntoisilla vastasyntyneillä. Kopeptiinipitoisuudet myös nousivat synnytyksen keston myötä. Rekisteritutkimuksemme asfyksiasta ja neurologisesta sairastavuudesta kattoi 1 138 109 raskautta vuosina 1989 – 2008. Totesimme varhaiseen täysiaikaiseen syntymään (raskausviikoilla 37+0-38+6) liittyvän matalien Apgarin pisteiden, CP-vamman, älyllisen kehitysvammaisuuden, aistitoimintojen vammojen, sekä perinataalikuolleisuuden suurentuneen riskin. Yliaikainen raskaus (≥42 raskausviikkoa) lisäsi matalan syntymä-pH:n, matalien Apgarin pisteiden, sekä älyllisen kehitysvammaisuuden riskiä, mutta ei liittynyt yleiseen neurologiseen sairastavuuteen eikä lisännyt perinataalikuolleisuutta. Johtopäätöksenä totesimme, että tietyissä riskiraskauksissa lapsiveden EPO-pitoisuuden määrittäminen saattaa olla hyödyllinen lisämenetelmä sikiön voinnin ja synnytyksen ajankohdan arvioinnissa. Toisaalta matalan riskin raskauksissa EPO-pitoisuuden määrityksestä ei vaikuttaisi olevan hyötyä edes lasketun ajan ylittämisen jälkeen. Kopeptiini vaikuttaa erittäin lupaavalta vastasyntyneen asfyksian ja hypoksis-iskeemisen enkefalopatian biomerkkiaineelta, joskin kopeptiinin käytettävyys pitkäaikaisennusteen arvioinnissa edellyttää jatkotutkimuksia. Kohorttitutkimuksessamme totesimme varhaiseen täysiaikaisuuteen liittyvän suurentuneen riskin vastasyntyneen sairastavuuteen ja kuolleisuuteen, sekä pitkäaikaiseen neurologiseen sairastavuuteen. Löydös tukee nykyistä hoitosuositusta synnytyksen ajoittamisesta mahdollisuuksien mukaan lasketun ajan tuntumaan. Toisaalta laajassa kotimaisessa kohortissamme yliaikaisuuden vaikutukset lapsen pitkäaikaiseen neurologiseen terveyteen olivat oletettua vähäisemmät

Dynamic classifiers for neonatal brain monitoring

Brain injury due to lack of oxygen or impaired blood flow around the time of birth, may cause long term neurological dysfunction or death in severe cases. The treatments need to be initiated as soon as possible and tailored according to the nature of the injury to achieve best outcomes. The Electroencephalogram (EEG) currently provides the best insight into neurological activities. However, its interpretation presents formidable challenge for the neurophsiologists. Moreover, such expertise is not widely available particularly around the clock in a typical busy Neonatal Intensive Care Unit (NICU). Therefore, an automated computerized system for detecting and grading the severity of brain injuries could be of great help for medical staff to diagnose and then initiate on-time treatments. In this study, automated systems for detection of neonatal seizures and grading the severity of Hypoxic-Ischemic Encephalopathy (HIE) using EEG and Heart Rate (HR) signals are presented. It is well known that there is a lot of contextual and temporal information present in the EEG and HR signals if examined at longer time scale. The systems developed in the past, exploited this information either at very early stage of the system without any intelligent block or at very later stage where presence of such information is much reduced. This work has particularly focused on the development of a system that can incorporate the contextual information at the middle (classifier) level. This is achieved by using dynamic classifiers that are able to process the sequences of feature vectors rather than only one feature vector at a time

Long-term outcome after hypothermia-treated hypoxic-ischaemic encephalopathy

Hypoxic-ischaemic encephalopathy (HIE) is a major cause of acquired brain injury in newborn infants. It is a potentially life-threatening condition that leaves survivors at substantial risk of life-long debilitating sequelae including cerebral palsy, epilepsy, intellectual disability, sensory disruption, behavioural issues, executive difficulties and autism spectrum disorder. More subtle cognitive impairments are common among survivors free of major neuromotor disability. Therapeutic hypothermia (TH) reduces the risk of death and disability in nearterm/term new-born infants with moderate and severe HIE. Outcomes in adolescence and adulthood following HIE treated with TH are not yet known. The majority of infants with HIE also suffer multi-organ dysfunction resulting from the hypoxic-ischaemic insult. The kidneys are particularly sensitive to hypoxia-ischaemia, with up to 72% of asphyxiated infants suffering acute kidney injury (AKI) prior to the advent of TH. Evidence point to AKI being independently associated with increased neonatal morbidity and mortality. To date, very little is known about long-term renal consequences following neonatal AKI in asphyxiated infants treated with TH. The overall aim of this thesis was to contribute to the improved treatment and care of infants with HIE by means of increased knowledge about the predictive value of early aEEG, neonatal AKI, and long-term outcomes in the era of TH. In a small population-based cohort, the predictive value of early amplitude-integrated EEG (aEEG) was demonstrated to be altered in infants treated with TH due to HIE. Poor outcome at the age of 1 year was only seen among infants with a persisting abnormal aEEG background pattern at and beyond 24 hours of age. In a population-based, prospective, longitudinal study including all children treated with TH between 2007 and 2009 in Stockholm, Sweden, we assessed neuromotor, neurologic, cognitive and behavioural outcomes at 6-8 and 10-12 years of age. Seventeen per cent of survivors developed CP. Survivors free of major neuromotor impairment had cognitive abilities within normal range. Repeated assessment in early adolescence revealed new deficits in 26% of children with previously favourable outcome. The proportion of children with executive difficulties in this patient population appears to be higher than in the general population. Outcomes in children with a history of moderate HIE remain heterogenous also in the era of TH. In a population-based cohort of all children treated with TH between 2007 and 2009 in Stockholm, Sweden, 45% suffered neonatal AKI. Severe AKI necessitating kidney support therapy was rare. Among infants with AKI, 20% fulfilled only the urinary output criterion of the neonatal modified KDIGO (Kidney Disease Improving Global Outcomes) definition. Mortality was higher among infants with AKI. At 10-12 years of age, 21% of children had decreased glomerular filtration rate (GFR) estimated from creatinine with the Schwartz-Lyon equation. A more in-depth assessment of renal functions in the above-mentioned population-based cohort demonstrated that renal sequelae (defined as decreased GFR, albuminuria, hypertension or normal high blood pressure, reduced renal volume on magnetic resonance imaging, or elevated Fibroblast Growth Factor 23) were rare at 10-12 years of age following perinatal asphyxia and TH. The Schwarz-Lyon equation appears to underestimate GFR in this patient population

Study of the Term Neonatal Brain Injury with combined Diffuse Optical Tomography and Electroencephalography

This thesis describes the application of combined diffuse optical tomography (DOT) and electroencephalography (EEG) in the investigation of neonatal term brain injury. With hypoxic ischaemic encephalopathy (HIE) and perinatal stroke being the most frequent contributors to brain injury in the term neonatal population, the first part of the thesis focuses on the description and ongoing requirement for their further investigation. In continuation to that, the characteristics and unique properties of both DOT and EEG are described and explored. The combination of these two modalities was utilised in elucidating the relationship between neuronal activity and cerebral haemodynamics both in physiological processes as well as in disease, by the infant’s cot side. This work differs to previous studies using near-infrared technologies and EEG, as a denser whole head array was used, offering the potential of 3-dimensional image reconstruction of the cortical haemodynamic events in relation to electro-cortical activity. These methods were applied in the study of critically ill infants presenting with seizures in the first few days of life. The relevant results are presented in three separate chapters of the thesis. Distinct neurophysiological phenomena such as seizures and burst suppression were detected and studied in association to underlying HIE. On the grounds of a pre-existing pilot study of our research group, distinct prolonged de-oxygenated cortical areas were identified following electrical seizure activity. Further exploration of infants with seizures provided limited supporting evidence. The investigation of burst suppression in HIE led to the first ever identification of repeated, waveform, cortical haemodynamic events in response to bursts of electrical activity with some spatial correlation to regions of brain injury. Further analysis of the low frequencies within the diffuse optical signal in cases of perinatal stroke, showed a consistent interhemispheric difference between the healthy and stroke-affected brain regions. The limitations, prospects and conclusions are presented in the final chapter. The use of simultaneous DOT and EEG offers a unique neuro-monitoring and neuro-investigating tool in the neonatal intensive care environment, which is safe, portable, and cost-effective, Ongoing research is required for the exploration and development of the methodology and its potential diagnostic properties