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.

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.

Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome.

We have previously shown that mild hypothermia applied after hypoxia-ischemia in newborn piglets and rats reduces brain injury evaluated 3-7 d after the insult. The aim of the present study was to assess the neuroprotective efficacy of hypothermia with respect to short- (neuropathology) and long-term (neuropathology and sensorimotor function) outcome after hypoxia-ischemia in 7-d-old rats. One hundred fourteen animals from 13 litters survived either 1 or 6 wk after a hypoxic-ischemic insult. The animals were randomized to either 1) normothermic recovery for the whole 1- or 6-wk period or 2) cooling to a rectal temperature of 32.0 degrees C for the first 6 h followed by normothermic recovery with the dam. Hypothermia offered a uniform protection of 27, 35, 28, and 25% in cerebral cortex, hippocampus, basal ganglia, and thalamus, respectively, in the 1-wk survivors (n = 32). The corresponding values for the 6-wk survivors (n = 61) were 22, 28, 37, and 35%. There was a significant correlation between sensorimotor performance and infarct volume (r = 0.66; p < 0.001). However, the sensorimotor function was not significantly improved by hypothermia if all animals were included, but in female pups the total functional score was higher in the hypothermia group (150 +/- 35 versus 100 +/- 34, p < 0.0007) which corresponded to a marked (51%) reduction of the neuropathology score in this subgroup. This is the first neonatal study to show a long-term histopathologic protection of the brain after posthypoxic hypothermia.

Free radicals are formed in the brain of fetal sheep during reperfusion after cerebral ischemia.

Free radical production in the brain of acutely anesthetized, exteriorized lamb fetuses (n = 11, gestational age = 135 d) was measured using spin trap methodology. Communications between the vertebral and carotid circulations were tied, producing a two-vessel supply to the brain. Flow probes and occlusion slings were placed around each carotid. The spin trap 2-ethyl-3-hydroxy-2,4,4-trimethyloxazolidine (OXANOH) was infused intermittently into one carotid at a constant rate, and blood samples were taken at intervals from the sagittal sinus. These samples were analyzed for the stable radical OXANO. using electron spin resonance spectrometry. Six animals were subjected to 30 min of complete cerebral ischemia, and five fetuses served as sham-operated control animals. During postischemic reperfusion radical formation increased 2-fold during the first 20 min. However, the elevation of OXANO. in the venous effluent from the brain did not start until the transient hyperemia had passed. It is thus concluded that the increase of OXANO. observed is caused by an augmentation of free radical production during reperfusion. Because the spin trap agent was infused directly into the arterial supply and recovered directly from the venous effluent of the brain, the site of production could be the brain tissue, the endothelial cells of the cerebral circulation, and activated leukocytes. This is the first demonstration of increased radical production from the fetal brain. It is noteworthy that it takes place despite oxygen tension of the reperfusing blood of only 3-3.5 kPa.

Formation of free radicals in hypoxic ischemic brain damage in the neonatal rat, assessed by an endogenous spin trap and lipid peroxidation.

The formation of free radicals and lipid peroxidation in the brain after hypoxic ischemia was investigated. Seven-day-old rats were subjected to unilateral (left) carotid artery ligation followed by 70 min of hypoxia with 8% oxygen at 36 degrees C. The animals were randomized into six groups as follows: control animals (no anesthesia, ligation or hypoxia) and animals decapitated at 0, 15, 30, 60 and 180 min into the reoxygenation period. Lipid peroxidation was quantified in brain homogenates using the thiobarbituric acid assay (TBA). The TBA-malondialdehyde (MDA) complex was measured with HPLC. The semi-dehydroascorbate radical was measured using electron spin resonance (ESR) spectroscopy. The semi-dehydroascorbate radical levels increased more than 3-fold in the left HI hemisphere compared to the left control hemisphere 15 min posthypoxic ischemia. The amount of MDA was significantly increased in the hypoxic ischemic (HI) hemisphere ipsilateral to the carotid ligation compared with contralateral hypoxic hemisphere. The MDA level in the left HI hemisphere was also significantly elevated at 0, 15, 30 and 60 min, but not at 180 min into the reoxygenation period. Reoxygenation after hypoxic ischemia thus induced formation of semi-dehydroascorbate radicals and lipid peroxidation.

Impact of reoxygenation with oxygen and air on the extent of the brain damage after hypoxia-ischaemia in neonatal rats.

Brain damage after hypoxia-ischaemia develops partly during the state of reoxygenation. The generation of free oxygen radicals is considered to be one possible mechanism. In order to evaluate the role of hyperoxygenation, a comparison was made between reoxygenation with pure oxygen and with air after hypoxia-ischaemia in a rat model of unilateral cerebral hemisphere damage. Brain damage was induced in 7-day-old rats. The animals were treated during reoxygenation with either 100% oxygen for 0.5 h or air. The extent of the brain damage was determined at 3 weeks of age by weighing the left and right hemispheres separately. No significant difference in weight deficit of the hemispheres was seen in the oxygen-treated group (15.5%, median) compared to the air-treated group (25.0%). Reoxygenation with pure oxygen after hypoxia-ischaemia in neonatal rats does not cause increased brain damage compared with reoxygenation with room air.

Effects of the 21-amino steroid tirilazad mesylate (U-74006F) on brain damage and edema after perinatal hypoxia-ischemia in the rat.

Using 7-d-old rat pups, the neuroprotective efficacy of the lipid peroxidation inhibitor tirilazad mesylate (U-74006F) was tested in a model of perinatal hypoxic-ischemic (HI) brain damage. The experimental protocol was divided into five parts: 1) pre- plus post-HI treatment or 2) only post-HI treatment with tirilazad (7.5 mg/kg intraperitoneally) or vehicle with evaluation of hemispheric weight deficit 14 d after the insult; 3) post-HI treatment with tirilazad or vehicle with histopathologic evaluation 14 d after the insult; 4) pre- plus post-HI treatment; or 5) posthypoxic treatment with tirilazad or vehicle with evaluation of brain edema 20 h after the insult. In the pre- plus post-HI treatment group, the mean left hemispheric weight deficit was 20.7% +/- 17.8 (mean +/- SD) in tirilazad-treated rats and 27.5% +/- 20.4 in vehicle-treated rats (p = 0.032). Corresponding values for the post-HI treated animals were 19.6% +/- 16.0 and 28.6% +/- 15.4 (p = 0.043). Histopathologic injury assessed as pathology score on a scale of 0-5 was less extensive in tirilazad-treated animals compared with controls (p = 0.038). There was a significant increase in water content in the HI hemisphere compared with the contralateral (hypoxic) hemispheres in tirilazad- and vehicle-treated animals. This increase of water content in the HI hemispheres did not differ between tirilazad- and vehicle-treated animals. The lipid peroxidation inhibitor tirilazad administered after perinatal HI reduced brain damage by 30%, but no effect was found on early postinsult edema.

The stress of being restrained reduces brain damage after a hypoxic-ischaemic insult in the 7-day-old rat.

Experimental animals and patients are immobilized to allow continuous monitoring of physiological parameters. Restraint stress affects brain neurotransmitter levels and induces expression of immediate early genes. Whether immobilization stress affects outcomes in newborn animals which have suffered a hypoxic-ischaemic insult is unknown. Twenty 7-day-old rats subjected to unilateral carotid ligation followed by 2 h hypoxia were randomly assigned to carry a rectal probe or to move freely. The 10 restrained animals showed 50% reduction in damage in all brain regions (p < 0.0.3). Plasma lactate levels, a marker of stress, were three times higher in animals carrying a rectal probe (p < 0.0.02) than those moving freely. We conclude that the stress of being restrained reduced damage after a hypoxic-ischaemic insult in the immature rat.

Posthypoxic cooling of neonatal rats provides protection against brain injury.

AIM: To determine whether moderate hypothermia, applied after a hypoxic-ischaemic insult in neonatal rats, reduces cerebral damage. METHOD: Unilateral hypoxic-ischaemic brain damage was induced in 7 day old rats by left carotid ligation, followed by 120 minutes of normothermic exposure to 8% O2, followed by random selection to three hours of hypothermia (rectal temperature, mean (SD), 32.5 (0.4) degrees C) or normothermia (38.3 (0.4) degrees C). One hundred and one animals were used for brain temperature or blood chemistry studies and 24 for survival studies (7 days) with neuropathology, including cell counting as outcome measures. RESULTS: Thirty sections from each brain were histologically examined with respect to distribution and pattern of damage and given a score from 0 to 4. Animals treated with hypothermia had significantly less damage than normothermic animals (score 0.5 (0.3) vs 1.8 (0.5)). CONCLUSIONS: Posthypoxic hypothermia reduces brain damage in awake, unrestrained 7 day old rats.

Scavengers of free oxygen radicals in combination with magnesium ameliorate perinatal hypoxic-ischemic brain damage in the rat.

The effect of oxygen radical scavengers in combination with magnesium administered after a hypoxic-ischemic insult was evaluated in a model of perinatal brain damage. A mixture of scavengers of oxygen-derived free radicals (L-methionine, 0.2 g; mannitol, 0.5 g) and magnesium sulfate (0.3 g) per kg body weight was given to 34 1-wk-old rat pups immediately after a session of unilateral carotid artery ligation and 2 h of hypoxia (8% O2 in N2). Thirty-four littermates served as controls; they received a placebo. At 3 wk of age, there was a significantly smaller reduction of hemisphere weight ipsilateral to the ligation in the treated animals compared with the controls (0.7 versus 8.8% of contralateral hemisphere weight median values, p < 0.01). The difference was especially marked for the most severe degrees of brain damage. Only one of the 34 treated animals, compared with 13 of 34 control animals, had a reduction of ipsilateral hemisphere weight > 25%. The protection offered by the mixture used was larger than in previously published studies using this model and treatment after the hypoxic exposure with only one protective agent. It is concluded that a combination of oxygen radical scavengers and magnesium administered in the phase of resuscitation mitigates perinatal postasphyxial brain damage in the rat. An additive protective effect of different therapeutic strategies on the brain damage may be present in this situation.

Intra- and extracellular changes of amino acids in the cerebral cortex of the neonatal rat during hypoxic-ischemia.

Excitatory amino acids (EAAs) have been implicated to play a part in the development of hypoxic-ischemic brain injury in the neonate. The aim of the present study was to follow changes of intra- and extracellular (microdialysis) amino acids in the cerebral cortex in a model where cortical hypoxic-ischemic damage is produced consistently. Hypoxic-ischemia (unilateral ligation of the carotid artery + 2 h of exposure to 7.8% oxygen) caused a depletion of tissue ATP, phosphocreatine and glucose with a concomittant accumulation of AMP and lactic acid in cortical tissue. These changes were accompanied by a decrease of tissue aspartate and glutamine whereas the contents of gamma-aminobutyric acid (GABA), phenylalanine, leucine, isoleucine, valine and alanine increased. In the extracellular fluid GABA, glutamate, aspartate, taurine, glycine and alanine all increased multi-fold during hypoxic-ischemia. Aspartate and glutamate returned to near initial levels 2 h after the end of the insult, whereas the elevation of glycine persisted during recovery. In conclusion, the high extracellular levels of EAAs and glycine may exert injurious effects during and after hypoxic-ischemia.