The Pathophysiology and Therapy of Pulseless Electrical Activity

描述（申请人提供）：美国每年至少有50万心脏骤停受害者。在大多数患者中，初始节律不是室颤（VF）或室性心动过速（VT），而是无脉性电活动 (PEA)或者心搏停止VT/VF停搏的存活率平均约为20%。然而，PEA和心搏停止的存活率要低得多，平均只有5%左右。因此，迫切需要改进复苏策略，因为存活率每增加1%将导致大约5000名额外的存活者。这一关键需求在PEA骤停中最为明显，因为对这些骤停的病理生理学或最佳治疗知之甚少，尤其是与VT/VF骤停相比时。除颤是VT/VF停搏的决定性治疗，但不适用于PEA停搏。我们提出了一种新的假设，即大多数PEA逮捕是由于急性缺血和/或缺氧的基底，其中有慢性缺血和/或缺氧的心室肌失败。这与大多数VT/VF停搏形成对比，其中急性缺血在更健康的基质中引起VT/VF。我们进一步假设，这种慢性缺血和/或缺氧诱导预处理，防止或延迟VF的发生，导致PEA停搏。因此，我们推测，PEA停搏的治疗必须针对逆转这种严重的缺血和/或缺氧，以及减轻再灌注损伤。即使可能存在预处理，这种预处理也可能不一致。此外，心脏代谢状态已经严重受损，这将使PEA停搏中任何程度的再灌注损伤比VT/VF停搏中更有害。因此，治疗应针对在复苏过程中产生大量血流，包括使用血管扩张剂，以逆转可能存在的严重缺血。增加血流的方法应包括使用改进的外部加压装置，这可能对治疗院外骤停特别有用;以及使用体外系统，这可能对院内骤停特别有用。控制性再灌注，包括后处理，在再灌注开始时可能是必要的，以减少再灌注损伤。额外的保存策略也可能是有用的，包括术中低温。最后，我们假设这些策略中的每一种都将对PEA心脏骤停的结局产生增量和附加的改善。该项目的目标是提高我们对PEA心脏骤停的病理生理学的理解，开发用于在复苏期间增加血流的改进方法，并且还开发用于减轻PEA骤停中存在的深度缺血和/或缺氧的影响的协同改进策略。这些研究应该提供有关PEA心脏骤停的病理生理学的新信息和见解，并可能导致PEA心脏骤停目前令人沮丧的结局的实质性改善。

DESCRIPTION (provided by applicant): There are at least 500,000 victims of cardiac arrest each year in the United States. In the majority of these patients, the initial rhythm is not ventricular fibrillation (VF) or ventricular tachycardia (VT), but is pulseless electrical activity (PEA) or asystole. The survival rates for VT/VF arrests average around 20%. The survival rates for PEA and asystolic arrests are much lower, however, and average only around 5%. There is a critical need, therefore, for improved resuscitation strategies, since each 1% increase in survival rate would result in approximately 5000 additional survivors. This critical need is most apparent with PEA arrests, since little is known about the pathophysiology or the optimal treatment of these arrests, especially when compared to VT/VF arrests. Defibrillation is the definitive treatment for VT/VF arrest, but is not indicated in PEA arrest. We present the novel hypothesis that most PEA arrests are due to failure of ventricular muscle from acute ischemia and/or hypoxia in a substrate where there has been chronic ischemia and/or hypoxia. This contrasts with most VT/VF arrests where acute ischemia causes VT/VF in a healthier substrate. We further hypothesize that this chronic ischemia and/or hypoxia induces preconditioning, which prevents or delays the occurrence of VF, resulting in PEA arrest. We hypothesize, therefore, that therapy for PEA arrests must be directed at reversing this profound ischemia and/or hypoxia, as well as mitigating reperfusion injury. Even though there may be preconditioning, such preconditioning may not be uniform. In addition, the already severe compromise of the metabolic status of the heart would make any degree of reperfusion injury more detrimental in PEA arrests than in VT/VF arrests. Therapy should, therefore, be directed at generating substantial blood flow during resuscitation, including the use of vasodilators, to reverse the profound ischemia that may be present. Methods for augmenting blood flow should include the use of improved external compression devices, which may be particularly useful for treating out-of-hospital arrests; and the use of extracorporeal systems, which may be particularly useful for in-hospital arrests. Controlled reperfusion, including post conditioning, may be necessary at the beginning of reperfusion to reduce reperfusion injury. Additional preservation strategies may also be useful, including intra-arrest hypothermia. Finally, we hypothesize that each of these strategies will have incremental and additive improvement in outcomes from PEA cardiac arrest. The goals of this project are to improve our understanding of the pathophysiology of PEA cardiac arrest, develop improved methods for augmenting blood flow during resuscitation, and also develop synergistic, improved strategies for mitigating the effects of the profound ischemia and/or hypoxia present in PEA arrest. These studies should provide new information and insights about the pathophysiology of PEA cardiac arrests, and may lead to substantial improvements in the now dismal outcomes from PEA cardiac arrests.