Prognostic capacity of automated quantification of suppression time in the EEG of post-asphyctic full-term neonates.

AIM: To evaluate the prognostic capacity of a new method for automatic quantification of the length of suppression time in the electroencephalogram (EEG) of a group of asphyxiated newborn infants. METHODS: Twenty-one full-term newborn infants who had been resuscitated for severe birth asphyxia were studied. Eight channel continuous EEG was recorded for prolonged time periods during the first days of life. Artefact detection or rejection was not applied to the signals. The signals were fed through a pretrained classifier and then segmented into burst and suppression periods. Total suppression length per hour was calculated. All surviving patients were followed with structured neurodevelopmental assessments to at least 18 months of age. RESULTS: The patients who developed neurodevelopmental disability or died had significant suppression periods in their EEG during the first days of life while the patients who had a normal follow-up had no or negligible amount of suppression. CONCLUSIONS: This new method for automatic quantification of suppression periods in the raw, neonatal EEG discriminates infants with good from those with poor outcome.

Does indomethacin for closure of patent ductus arteriosus affect cerebral function?

OBJECTIVE: To study whether indomethacin used in conventional dose for closure of patent ductus arteriosus affects cerebral function measured by electroencephalograms (EEG) evaluated by quantitative measures. STUDY DESIGN: Seven premature neonates with haemodynamically significant persistent ductus arteriosus were recruited. EEG were recorded before, during and after an intravenous infusion of 0.2 mg/kg indomethacin over 10 min. The EEG was analysed by two methods with different degrees of complexity for the amount of low-activity periods (LAP, "suppressions") as an indicator of affection of cerebral function. RESULTS: Neither of the two methods identified any change in the amount of LAPs in the EEG as compared to before the indomethacin infusion. CONCLUSION: Indomethacin in conventional dose for closure of patent ductus arteriosus does not affect cerebral function as evaluated by quantitative EEG.

Cerebellar white matter injury following systemic endotoxemia in preterm fetal sheep.

Injury to the cerebellum and brainstem is becoming increasingly recognized in prematurely born infants. The role of infection/inflammation in mediating damage to those structures in the preterm brain is largely unknown. Preterm fetal sheep (70% gestation) received either saline-vehicle (control group; n=11) or Escherichia coli lipopolysaccharide (100 ng intravenous [i.v.]; lipopolysaccharide [LPS] group; n=9), and were allowed to recover for 3 days before sacrifice. A diffuse pattern of cerebellar white matter damage was observed in all animals exposed to LPS, while focal cerebellar white matter lesions were observed in three out of nine animals, and an intragyral white matter hemorrhage in one animal. Cerebellar white matter injury was associated with a statistically significant loss of oligodendrocyte transcription factor-2-positive oligodendrocytes and increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cell counts. Ionized calcium binding adapter molecule 1 (Iba1)-positive cells which had the morphology of activated microglia were commonly observed in areas of injury. There was no obvious injury to the cerebellar cortex or to cerebellar Purkinje cells, and no obvious injury in any region of the brainstem. These data provide support for a role of infection/inflammation in selective white matter injury in the immature cerebellum, and demonstrate a differential vulnerability of the brainstem and cerebellar white matter to injury at this time.

Classification of burst and suppression in the neonatal electroencephalogram.

Fisher's linear discriminant (FLD), a feed-forward artificial neural network (ANN) and a support vector machine (SVM) were compared with respect to their ability to distinguish bursts from suppressions in electroencephalograms (EEG) displaying a burst-suppression pattern. Five features extracted from the EEG were used as inputs. The study was based on EEG signals from six full-term infants who had suffered from perinatal asphyxia, and the methods have been trained with reference data classified by an experienced electroencephalographer. The results are summarized as the area under the curve (AUC), derived from receiver operating characteristic (ROC) curves for the three methods. Based on this, the SVM performs slightly better than the others. Testing the three methods with combinations of increasing numbers of the five features shows that the SVM handles the increasing amount of information better than the other methods.

Comparing a supervised and an unsupervised classification method for burst detection in neonatal EEG.

Hidden Markov Models (HMM) and Support Vector Machines (SVM) using unsupervised and supervised training, respectively, were compared with respect to their ability to correctly classify burst and suppression in neonatal EEG. Each classifier was fed five feature signals extracted from EEG signals from six full term infants who had suffered from perinatal asphyxia. Visual inspection of the EEG by an experienced electroencephalographer was used as the gold standard when training the SVM, and for evaluating the performance of both methods. The results are presented as receiver operating characteristic (ROC) curves and quantified by the area under the curve (AUC). Our study show that the SVM and the HMM exhibit similar performance, despite their fundamental differences.

Comparison of three methods for classifying burst and suppression in the EEG of post asphyctic newborns.

Fisher's linear discriminant, a feed-forward neural network (NN) and a support vector machine (SVM) are compared with respect to their ability to distinguish bursts from suppression in burst-suppression electroencephalogram (EEG) signals using five features inherent in the EEG as input. The study is based on EEG signals from six full term infants who have suffered from perinatal asphyxia, and the methods have been trained with reference data classified by an experienced electroencephalographer. The results are summarized as area under the curve (AUC) values derived from receiver operating characteristic (ROC) curves for the three methods, and show that the SVM is slightly better than the others, at the cost of a higher computational complexity.

Spectral distance for ARMA models applied to electroencephalogram for early detection of hypoxia.

A novel measure of spectral distance is presented, which is inspired by the prediction residual parameter presented by Itakura in 1975, but derived from frequency domain data and extended to include autoregressive moving average (ARMA) models. This new algorithm is applied to electroencephalogram (EEG) data from newborn piglets exposed to hypoxia for the purpose of early detection of hypoxia. The performance is evaluated using parameters relevant for potential clinical use, and is found to outperform the Itakura distance, which has proved to be useful for this application. Additionally, we compare the performance with various algorithms previously used for the detection of hypoxia from EEG. Our results based on EEG from newborn piglets show that some detector statistics divert significantly from a reference period less than 2 min after the start of general hypoxia. Among these successful detectors, the proposed spectral distance is the only spectral-based parameter. It therefore appears that spectral changes due to hypoxia are best described by use of an ARMA- model-based spectral estimate, but the drawback of the presented method is high computational effort.

Detection of bursts in the EEG of post asphyctic newborns.

Eight features inherent in the electroencephalogram (EEG) have been extracted and evaluated with respect to their ability to distinguish bursts from suppression in burst-suppression EEG. The study is based on EEG from six full term infants who had suffered from lack of oxygen during birth. The features were used as input in a neural network, which was trained on reference data segmented by an experienced electroencephalographer. The performance was then evaluated on validation data for each feature separately and in combinations. The results show that there are significant variations in the type of activity found in burst-suppression EEG from different subjects, and that while one or a few features seem to be sufficient for most patients in this group, some cases require specific combinations of features for good detection to be possible.

Infraslow EEG activity in burst periods from post asphyctic full term neonates.

OBJECTIVE: To investigate whether very low EEG frequency activity can be recorded from post asphyctic full term neonates using EEG equipment where the high pass filter level was lowered to 0.05 Hz. METHODS: The time constant of the amplifier hardware was set to 3.2 s in order to enable recordings that equal to a high pass filter cut off at 0.05 Hz. Burst episodes were selected from the EEGs of 5 post asphyctic full term neonates. The episodes were analysed visually using different montages and subjected to power spectrum analysis. Powers in two bands were estimated; 0-1 and 1-4 Hz, designated very low- and low-frequency activity, respectively (VLFA, LFA). RESULTS: In all infants, VLFA coinciding with the burst episodes could be detected. The duration of the VLFA was about the same as that of the burst episode i.e. around 4s. The activity was most prominent over the posterior regions. In this small material, a large amount of VLFA neonatally seemed to possibly be related to a more favourable prognosis. CONCLUSIONS: VLFA can be recorded from post asphyctic full term neonates using EEG equipment with lowered cut off frequency for the high pass filter. SIGNIFICANCE: VLFA normally disregarded due to filtering, is present in the EEG of sick neonates and may carry important clinical information.

Spectral analysis of burst periods in EEG from healthy and post-asphyctic full-term neonates.

OBJECTIVE: To investigate whether the periodic EEG patterns seen in healthy and sick full term neonates (trace alternant and burst suppression, respectively) have different frequency characteristics. METHODS: Burst episodes were selected from the EEGs of 9 healthy and 9 post-asphyctic full-term neonates and subjected to power spectrum analysis. Powers in two bands were estimated; 0-4 and 4-30 Hz, designated low- and high-frequency activity, respectively (LFA, HFA). The spectral edge frequency (SEF) was also assessed. RESULTS: In bursts, the LFA power was lower in periods of burst suppression as compared to those of trace alternant. The parameter that best discriminated between the groups was the relative amount of low- and high-frequency activity. The SEF parameter had a low sensitivity to the group differences. In healthy neonates, the LFA power was higher over the posterior right as compared to the posterior left region. CONCLUSIONS: Spectral power of low frequencies differs significantly between the burst episodes of healthy and sick neonates. SIGNIFICANCE: These results can be used when monitoring cerebral function in neonates.

On evaluation of spectrum estimators for EEG.

In the search for how neonatal EEG is affected by asphyxia it is of importance to find reliable estimates of EEG power spectra. Several spectral estimation methods do exist, but since the true spectra are unknown it is hard to tell how well the estimators perform. Therefore a model to generate simulated EEG with known spectrum is proposed and the model is used to evaluate performance of several parametric and Fourier based spectral estimators.

Brain electrical impedance at various frequencies: the effect of hypoxia.

Non-invasive multi-frequency measurements of transcephalic impedance, both reactance and resistance, can efficiently detect cell swelling of brain tissue and can be used for early detection of threatening brain damage. We have performed experiments on piglets to monitor transcephalic impedance during hypoxia. The obtained results have confirmed the hypothesis that changes in the size of cells modify the tissue impedance. During tissue inflammation after induced hypoxia, cerebral tissue exhibits changes in both reactance and resistance. Those changes are remarkably high, up to 71% over the baseline, and easy to measure especially at certain frequencies. A better understanding of the electrical behaviour of cerebral tissue during cell swelling would lead us to develop effective non-invasive clinical tools and methods for early diagnosis of cerebral edema and brain damage prevention.

Association between serum oncofetal antigens CA 19-9 and CA 125 and clinical status in patients with cystic fibrosis.

UNLABELLED: In cystic fibrosis (CF), mucus plugging in the airways and in the gastrointestinal tract leads to severe morbidity and mortality. The mucin-associated antigens CA 19-9 and CA 125 are markers of gastrointestinal malignancy, and CA 19-9 has also been reported in association with pulmonary function in CF. AIM: To test whether these antigens might serve as markers for the severity of pulmonary and gastrointestinal disease in CF. METHODS: In 99 patients, aged 1 to 48 y, serum levels of CA 19-9 and CA 125 were measured by RIA and ELISA and related to clinical data. RESULTS: Patients with severe mutations had significantly increased serum levels of CA 125, indicating an association with a more severe CF phenotype. This was further supported by the association with lung function, chronic pulmonary colonization of Pseudomonas aeruginosa and pancreatic insufficiency. CA 19-9 was also shown to be associated with lung function and Ps. aeruginosa colonization. No gastrointestinal malignancy was found in our patients despite very high values of CA 19-9 in some patients. During a 5-y follow-up, the very high serum levels of CA 19-9 decreased along with improved general condition of the patients. CONCLUSION: Increased serum levels of CA 125 in CF patients were associated with severe cystic fibrosis transmembrane conductance regulator mutations and a severe phenotype. Both antigens were associated with pseudomonas colonization and lung function and CA 125 also with pancreatic insufficiency. The estimates of CA 19-9 are hampered by the influence of the Lewis histo-blood group system on the synthesis of CA 19-9.

Follow-up into young adulthood after cardiopulmonary resuscitation in term and near-term newborn infants. I. Educational achievements and social adjustment.

AIM: Long-term sequelae after perinatal asphyxia have generally been assessed at preschool or school age. The aim of the study was to confirm the hypothesis that there could be impairment of cognitive and memory functions that does not become apparent until education and adult life impose special demands. METHODS: Seventy-one term or near-term newborns in need of cardiopulmonary resuscitation because of presumed perinatal asphyxia were investigated with evoked EEG potentials during the first week of life and were investigated at a follow-up clinic until 18 mo of age. At that time 12 subjects showed signs of neuro-developmental impairment. The remaining 59 were considered healthy. They were contacted at young adult age and given a questionnaire containing questions about type of education, need for extra support at school, present activity/employment, living conditions, spare-time activities and self-estimation of health. RESULTS: Thirty-five control subjects were approached at the same time. From the group that was resuscitated at birth, 53 questionnaires were returned and 30 from the control group. Although the resuscitated subjects had signs of both encephalopathy and pathologic evoked responses during their neonatal period, the questionnaire revealed that they had coped with school equally as well as their peers, that the rate of entering university studies was the same and that living conditions were similar between the groups. CONCLUSION: These individuals who were resuscitated at birth and who demonstrated various degrees of neonatal encephalopathy suffered either brain injury that could be diagnosed at 18 mo of age or managed as well as their non-resuscitated peers in terms of educational achievement and social adjustment at young adult age.

Follow-up into young adulthood after cardiopulmonary resuscitation in term and near-term newborn infants. II. Neuropsychological consequences.

AIM: Brain injury after neonatal cardiopulmonary resuscitation in the term baby is often described as an all-or-nothing phenomenon, but little is known about possible late cognitive consequences. The aim of this study was therefore to investigate whether children who needed cardiopulmonary resuscitation because of presumed mild and moderate intra-partum asphyxia with no evidence of neurological impairments at 18 mo of age may display neuropsychological impairments later in life. METHODS: A long-term follow-up of young adults was carried out. A blinded comprehensive neuropsychological assessment of the main aspects of cognitive functions was made. The subjects who were resuscitated were divided into two groups according to the clinical course: 20 cases with mild asphyxia and 11 cases with moderate asphyxia, all followed prospectively and compared with 18 healthy controls. The 31 subjects were born at term or near-term and selected randomly from 59 infants born in 1969-1978 at Sahlgren's Hospital, Göteborg. All infants with early neurological impairments were excluded. RESULTS: No major differences could be established between the two clinical groups and normal controls in any aspects of cognitive function or intelligence. All the groups performed within the normal range in all tests. A tendency toward minor deficits in verbal ability in the mild group compared to the controls was found. Only one subject had a clear, defined memory deficit. CONCLUSIONS: Infants who underwent cardiopulmonary resuscitatation at birth without neurological deficits at 18 mo of age did not show any cognitive deficits or neuropsychological impairments in adulthood even though inferior performance on some verbal subtests was observed compared to the control group.

Cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogram for intrapartum fetal monitoring: a Swedish randomised controlled trial.

BACKGROUND: Previous studies indicate that analysis of the ST waveform of the fetal electrocardiogram provides information on the fetal response to hypoxia. We did a multicentre randomised controlled trial to test the hypothesis that intrapartum monitoring with cardiotocography combined with automatic ST-waveform analysis results in an improved perinatal outcome compared with cardiotocography alone. METHODS: At three Swedish labour wards, 4966 women with term fetuses in the cephalic presentation entered the trial during labour after a clinical decision had been made to apply a fetal scalp electrode for internal cardiotocography. They were randomly assigned monitoring with cardiotocography plus ST analysis (CTG+ST group) or cardiotocography only (CTG group). The main outcome measure was rate of umbilical-artery metabolic acidosis (pH <7.05 and base deficit >12 mmol/L). Secondary outcomes included operative delivery for fetal distress. Results were first analysed according to intention to treat, and secondly after exclusion of cases with severe malformations or with inadequate monitoring. FINDINGS: The CTG+ST group showed significantly lower rates of umbilical-artery metabolic acidosis than the cardiotocography group (15 of 2159 [0.7%] vs 31 of 2079 [2%], relative risk 0.47 [95% CI 0.25-0.86], p=0.02) and of operative delivery for fetal distress (193 of 2519 [8%] vs 227 of 2447 [9%], 0.83 [0.69-0.99], p=0.047) when all cases were included according to intention to treat. The differences were more pronounced after exclusion of 291 in the CTG+ST group and 283 in the CTG group with malformations or inadequate recording. INTERPRETATION: Intrapartum monitoring with cardiotocography combined with automatic ST-waveform analysis increases the ability of obstetricians to identify fetal hypoxia and to intervene more appropriately, resulting in an improved perinatal outcome.

Non-nutritive sucking in sick preterm infants.

BACKGROUND: Non-nutritive sucking (NNS) by the newborn infant is a fundamental behaviour and is one of the first coordinated muscular activities in the fetus. AIMS: Our objective is to study the NNS pattern in prematurely born infants, who had various conditions commonly associated with immaturity. METHOD: A specially designed computer-based method that analyses and quantifies components of the NNS pattern was used. SUBJECTS: The pattern of 51 clinically stable prematurely born infants (gestational ages 26-35 weeks) making a total of 206 observations were analysed and findings were compared with those obtained from 58, healthy preterm infants. RESULTS: The rhythmic NNS pattern of alternating sucking and pauses was elicited in all examined infants, the earliest at post-menstrual age (PMA) 26 weeks. The role of PMA, the dominant predictor for several sucking variables seen in the control group, became diminished for the infants with risk factors but changes were otherwise similar. The infants' sucking activity and sucking frequency increased and the variability of the pattern declined with increased PMA and weight. Follow-up of a subgroup of infants revealed fewer sucking bursts per minute, slower sucking frequency and a greater variability of the frequency and amplitudes in those infants who developed sequelae. CONCLUSIONS: It would, thus, appear that the NNS pre-programmed rhythm generator, primarily modulated by maturation in healthy preterm infants, becomes affected by known risk associated events and in infants who later develop sequelae. Quantification of the NNS pattern in preterm infants may be a valuable future component of their evaluation.

Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation.

Posthemorrhagic ventricular dilatation (PHVD) is closely associated with white matter injury and neurologic disability in the preterm infant. An important factor in periventricular white matter damage may be the specific vulnerability of iron-rich immature oligodendroglia to reactive oxygen species toxicity. Non-protein-bound iron (NPBI) is a potent catalyst in the generation of hydroxyl radicals (Fenton reaction). Our objective was to determine whether NPBI is increased in cerebrospinal fluid (CSF) from preterm infants with PHVD compared with preterm control infants. Samples of CSF were obtained from 20 infants with PHVD and 10 control subjects. The level of NPBI was determined by a new spectrophotometric method using bathophenanthroline as a chelator. To evaluate the effect of hemolysis, CSF and blood were mixed in different proportions, spun, frozen and thawed, and then analyzed for NPBI. NPBI was found in 75% (15 of 20) of infants with PHVD and in 0% (0 of 10) of control infants (p = 0.0002). Hemolysis induced in vitro did not result in any significant levels of NPBI. Within the group with PHVD, NPBI concentrations in CSF did not correlate with disability, parenchymal brain lesions, or the need for shunt surgery. NPBI was increased in CSF from preterm infants with PHVD, and the increase could not be explained by hemolysis alone. Free iron may help to explain the association between intraventricular hemorrhage and white matter damage.

Non-nutritive sucking by infants exposed to pethidine in utero.

UNLABELLED: Obstetric analgesia in the form of pethidine (meperidine) to mothers during delivery has adverse effects on some aspects of the behaviour of their newborn infants. The non-nutritive sucking (NNS) pattern of nine healthy full-term infants exposed to pethidine in utero was compared to that of a control group of infants. The pattern was analysed and quantified using an automatic computer-based method. The results are discussed in the context of endogenous and exogenous opiates and their effect on brain-stem rhythm generators. CONCLUSIONS: The typical NNS pattern with alternating sucking activity (bursts) and pauses is preserved in the exposed infants. There is a significantly lower sucking frequency (md 1.74 vs 1.90 Hz, p = 0.030*) and a tendency to a less stable rhythm in pethidine-exposed infants.

Non-nutritive sucking in the healthy pre-term infant.

In the infant, sucking behaviour is one of the first coordinated muscular activities. It is under the control of the brainstem. In utero sucking is observed from 13 weeks' gestation. The healthy full-term newborn infant has a very stable rhythm of alternating bursts of sucking with pauses in between. The non-nutritive sucking (NNS) patterns of 58 low-risk prematurely born infants (gestational ages between 26 and 35 weeks) were studied using a specially designed computer-based method that analyses and quantifies NNS. A total of 183 observations were analysed. The typical NNS pattern with bursts of sucking activity separated by quiescent periods was recorded in all infants studied and was already present before 30 weeks of gestation. A gradual change over time of their NNS was seen. With increased maturation the sucking activity, sucking frequency, amplitude and burst duration all increased, while the variability of the sucking frequency and the duration of the intervals between bursts declined. Post-menstrual age (PMA) was the dominant predictor of this result but gender, state of activity and weight also influenced it to some extent. Girls had more sucking activity and a higher sucking frequency than boys. State of activity affected the stability of the rhythm. The weight of the infant influenced both sucking activity and duration of separate bursts.