Research On Patterns Of EEG During Earlier Post-resuscitation And Their Relationship With Neurological Outcome In Cardiac Arrest Models Of Rats

Cardiac arrest(CA), also called sudden cardiac death, is the leading cause of death in global worldwide especially in developed countries. According to statistics, both about 330000 persons in the Unite Stats and Canada, about 350000 persons in Europe experience CA annually. And each year, about 544000 persons suffer from CA in China.In spite of the development in cardiopulmonary resuscitation(CPR), deep reorganization in more effective interventions, including strategy of artificial ventilation, quality of chest compressions and time for defibrillation, makes more and more patients return spontaneous circulation. The rate of restoration of spontaneous circulation(ROSC) achieves 20% to 50% in a significant improvement in the Western countries, and 5% to 15% in China. However, only 11% of ROSC patients survive to hospital discharge. For those patients who do survive to discharge, only 8.3% have a good neurological outcome, and most of them remain sever neurological deficit.The systemic ischemia/hypoxia injury in CA and sequentially reperfusion damage, termed post-cardiac arrest syndrome(PCAS), account for low rate of discharge and poor neurological recovery. Post-cardiac arrest brain injury, as one of the four elements of PCAS, constitutes a leading cause of morbidity and mortality among patients who are successfully resuscitated from CA. Base in a study of CA patients who survival to the intensive care unit admission, 60~70% of patients died of the resulting anoxic ischemia brain injury and neurologic deficit. Therefore, after ROSC, carrying out the advanced life support(ALS) and post-resuscitation treatment with the aim of cerebral resuscitation plays a vital role of the final survival in the CA patients. It is worth noting that, however, the pathogenesis of PCAS is complex and multifactorial, any single cerebral resuscitation strategy may not gain optimal neuoroprotective and resuscitation effect. A combined cerebral resuscitation strategy is anticipant. Therefore, how to assess the extent of brain injury and neurological recovery during cerebral resuscitation is important to evaluate the curative effect, readjust the cerebral resuscitation strategy and prove the survival quality of CA patients.The electroencephalogram(EEG), which reflects part of the function of cortical neurons, very sensitive to ischemia and easy to bedside monitored, has become a common method in neurological function assessment and prognosis for ROSC patients. The previous studies had shown that continuous EEG patterns within 12 hours after CA predicted good outcome, while an isoelectric or low-voltage EEG after 24 hours and burst suppression or electrographic status epilepticus between post-resuscitation 24 to 72 hours after predicted poor outcome in patients treated with hypothermia. Besides, the quantitative EEG patterns, including time to normal trace(TTNT), burst suppression ratio(BSR), bispectral index(BIS) and approximate entropy, are relative to neurological recovery and have the potential in neurological prognosis at the early post-resuscitation period.Although the clinical studies had improved that quantitative EEG patterns can be used in neurological prognosis at the intermediate phase after resuscitation(post-resuscitation 6 to 72 hours), the patterns of EEG during earlier post-resuscitation(post-resuscitation 20 minutes to 6 hours) and their relationship with neurological outcome are still unclear.(1) There is less known in the relationship between difference causes of CA and the recovery of EEG activity at early post-resuscitation period. There are different causes resulting in CA, making different extent of post-cardiac arrest brain injury. Asphyxia and ventricular fibrillation(VF) are the two most common causes of CA, accounting for 23% and 30% of CA respectively. Contrary to the VF caused CA(VFCA) leading to sudden and complete cessation of blood flow, asphyxial CA(ACA) is characterized by progressive and global hypoxia with incomplete ischemia resulting in systemic hypoxia and ischemia. Meanwhile, during CPR, sever hypoxia and acidosis may deteriorate the reperfusion injury in brain. It is reasonable to assume that the cause of CA, cardiac or asphyxia in origin, may play a key pathophysiologic role in neurologic prognosis. However, since most of CA arises out of hospital and exceed 50% of out-of-hospital CA(OHCA) are without witness, estimation of the exact cause of the collapse can often be very challenging. Thus few studies have been conducted on the relationship between different causes of CA and post-resuscitation EEG recovery in clinical setting. Therefore, the accurate effect of etiologies on early EEG after ROSC is unknown.(2) There is less known in the relationship between therapeutic hypothermia(TH) and the recovery of EEG activity at early post-resuscitation period after VFCA. TH is the only one has been proved having effective neuroprotective strategy in clinical. However, there are many pending issues, including how to determine the optimal objective temperature and duration of hypothermia, how to improve the efficacy and reduce complications, and especially how to estimate the efficacy at the early post-resuscitation period, needed to be further studied. On one hand, the beneficial role of TH after VFCA has been proven, but it is still questionable whether TH should be implemented routinely after ACA. On the other hand, hypothermia as well as sedative and neuromuscular blocking agents used during hypothermia affect the neurological prognosis indexes and their predictive effects. Therefore it is necessary to study the relationship between TH and the early recovery of EEG activity after CA, along with the predictive value of EEG patterns with TH. Although, based on the ACA model in rats, the change regulation of information quantity(IQ) along with temperature has been studied, and proved sensitive to temperature that useful for neurologic prognosis. However, the relationship between TH and the recovery of EEG activity at early post-resuscitation period after VFCA is unknown.In this project, using the ACA and VFCA rat model, representing cardiac and respiratory etiologies respectively, combined with histopathological outcome and biomarker, the relationship between difference causes of CA and the recovery of EEG activity at early post-resuscitation period was been studies. Second, based on VFCA rat model, the relationship between TH and the recovery of EEG activity at early post-resuscitation period was been study.The main research context and results shown as followed.(1) Although brain injuries occurred in both VFCA and ACA models, compared with VFCA, ACA caused more severe brain injuries with more severe functional neurologic deficit and histopathologic neuronal damage. ACA shown malignant recovery of early post-resuscitation EEG activity with prolonged isoelectric period, low burst frequency, and prolonged restoration of continuous background EEG activity. The results indicated that quantitative EEG characteristics, i.e. improved burst frequency at first hour after ROSC, correlated with better neurologic recovery and mild morphologic brain injuries suitable for ACA and VFCA models used in this paper.(2) TH improved the recovery of earlier post-resuscitation EEG by shortening the isoelectric period, increasing the burst frequency, accelerating the restoration of continuous background EEG activity, and enhancing the irregularity of brain rhythm in a rat model of CA. The results indicated that quantitative EEG characteristics of earlier post-resuscitation EEG activity, including improved burst frequency during hypothermia and preserved SE during normothermia, correlated with better neurologic recovery and independently predicted 96 hr survival.In conclusion, the project shows that ACA appears worse functional neurologic deficit and morphologic brain damage compared with VFCA. Early post-resuscitation characters of EEG were associated with the degree of brain damage, as well as neurological outcome and 96 hr survival, regardless of the CA due to asphyxia or due to malignant dysrhythmia. TH greatly improved EEG recovery after resuscitation. Improved burst frequency and preserved SE for animals treated with hypothermia were associated with better neurological outcome and predicted 96 hr survival in this rat model of CA. These results lay the foundation of further research in clinical application of EEG patterns used in evaluation of post-resuscitation brain injury and prediction of neurological prognosis.