Asphyxic Arrest Research Articles

Abstract T P326: Additive Neuroprotection of a 20-hete Inhibitor with Delayed Therapeutic Hypothermia after Asphyxic Cardiac Arrest in Neonatal Piglets

The arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been found to contribute to neurodegeneration after asphyxic cardiac arrest in neonatal piglets. Current therapy involving hypothermia is only partially effective, in part, because initiation of hypothermia is often delayed. Therefore, an unmet need is to find a neuroprotective drug that can be safely given early after resuscitation and that provides additional protection compared to delayed hypothermia alone. Here, we tested whether administration of the 20-HETE-synthesis inhibitor HET0016 (1 mg/kg) at 5 min after return of spontaneous circulation (ROSC) combined with whole body cooling initiated at 3 h of ROSC enhances the neuroprotection compared to delayed hypothermia alone. Anesthetized piglets (3-4-day-old) were subjected to 45 min ventilation with 10% O2, 7 min of airway occlusion, and CPR. In hypothermic groups, cooling started at 3 h ROSC and rewarming occurred over 4 h starting at 20 h ROSC. The density of viable neurons at 10 days ROSC was significantly increased with delayed hypothermia alone (n=12) compared to normothermic recovery (n=6) in sensorimotor cortex (63±5% to 71±6%; % of sham; ±SD), ventral posterolateral thalamus (41±6% to 57±8%), putamen (23±2% to 61±75%), caudate nucleus (58±5% to 72±6%), and CA3 hippocampus (59±3% to 71±5%). Further significant increases occurred with HET0016+hypothermia (n=12) in cortex (86±6%), thalamus (73±8%), and putamen (70±6%), but values remained less than in the sham group (n=6). Neurologic deficits with combined treatment were less than in the normothermic group through 6 days ROSC. Early treatment with the 20-HETE inhibitor HET0016 enhances the therapeutic benefit of delayed hypothermia in protecting regionally vulnerable neurons from asphyxic arrest.

Higher-order spectral analysis of burst patterns in EEG.

Burst suppression patterns in electroencephalograms (EEG's) have been observed in a variety of situations including recovery of a subject from a traumatic brain injury. They are associated with grave prognostic outcomes in neonates. We study power spectral parameters and bispectral parameters of the EEG at baseline, during early recovery from an asphyxic arrest (EEG burst patterns) and during late recovery after EEG evolves into a more continuous activity. The bicoherence indexes, which indicate the degree of phase coupling between two frequency components of a signal, are significantly higher within the delta-theta band of the EEG bursts than in the baseline or late recovery waveforms. The bispectral parameters show a more detectable trend than the power spectral parameters. In the second part of the study, we looked into the possibility of higher (> 2)--order nonlinearities in the EEG bursts using the diagonal slices of the polyspectrum. The diagonal elements of the polyspectrum reveal the presence of self-frequency and self-phase coupling of orders higher than two in majority of the EEG bursts studied. The bicoherence indexes and the diagonal elements of the polyspectrum strongly indicate the presence of nonlinearities of order two and in many cases higher, in the EEG generator during episodes of bursting. This indication of nonlinearity in EEG signals provides a novel quantitative measure of brain's response to injury.