Hyper-oxygenation, oxidative stress, and kidney injury following cardiac surgery

描述（由申请人提供）：在美国，每年有500，000名患者接受心脏手术，25%的患者因急性肾损伤（阿基）而难以恢复。阿基与随后的术后心律失常、伤口感染和败血症相关，并独立预测30天时死亡率增加5倍。主要研究者已经证明，术中F2-异前列烷（活性氧（ROS）诱导的花生四烯酸过氧化产物）浓度可独立预测心脏手术后的阿基，这表明针对手术期间过量ROS产生的治疗可能会减少阿基。尽管经常发生肾缺血，但在心脏手术期间，过度氧合-给予超过使血红蛋白饱和所需的氧气-是普遍的。在体外和实验性缺血后，过度氧合增加ROS的产生。我们的初步研究表明，与过度氧合相比，过度氧合增加了离体血液中的ROS产生，并通过将氧给药限制为使血红蛋白饱和所需的量来维持心脏手术期间的生理氧合是可行且安全的，并且与F2-异前列腺素和阿基降低相关。这些发现与最近在心脏骤停患者中进行的临床研究一致，这些研究表明复苏后的过度氧合会增加认知功能障碍、昏迷和死亡。该项目挑战了手术过程中过量供氧有益的流行文化。该研究小组由心脏手术临床试验、氧化应激和阿基专家组成，将测试以下假设：与过度氧合相比，心脏手术期间的生理性氧合减少术后肾损伤（目的1）、ROS产生和氧化应激（目的2）。该团队将完成一项II期临床试验，在该试验中，他们将招募并随机分配200名心脏手术受试者，（吸入氧气分数（FIO 2）= 0.8-1.0）或生理氧合（达到Hb O2饱和度95-98%和动脉pO 2在80-95 mmHg之间所需的最低FIO 2）在手术过程中，并比较治疗组之间的肾功能和损伤，使用电子顺磁共振的ROS产生，以及通过测量血浆中的F2-异前列烷和异呋喃的全身氧化应激。安全性终点将是与缺氧相关的临床结局。次要终点将是初步和已发表研究中与过量供氧相关的其他临床结局。通过比较氧化应激测量与肾损伤，研究小组还将测试氧化应激是麻醉和手术诱导阿基的机制的假设。这些研究的结果有可能从根本上改变心脏手术患者的术中管理，并增强对手术诱导阿基机制的理解。

DESCRIPTION (provided by applicant): Each year 500,000 patients undergo cardiac surgery in the United States, and acute kidney injury (AKI) complicates recovery in 25% of patients. AKI is associated with subsequent postoperative arrhythmias, wound infections, and sepsis, and independently predicts a 5-fold increase in death at 30 days. The principal investigator has demonstrated that intraoperative concentrations of F2-isoprostanes, products of reactive oxygen species (ROS)-induced arachidonic acid peroxidation, independently predict AKI following cardiac surgery, suggesting that treatments that target excess ROS production during surgery may reduce AKI. Hyper-oxygenation - the administration of oxygen in excess of that required to saturate hemoglobin - is prevalent during cardiac surgery despite frequent renal ischemia. In vitro and following experimental ischemia hyper-oxygenation increases ROS production. Our preliminary studies indicate that hyper-oxygenation increases ROS production in blood ex vivo and maintaining physiologic oxygenation during cardiac surgery by restricting oxygen administration to that required to saturate hemoglobin is feasible and safe and associated with decreased F2-isoprostanes and AKI compared to hyper-oxygenation. These findings are consistent with recent clinical studies in cardiac arrest patients demonstrating that hyper-oxygenation after resuscitation increases cognitive dysfunction, coma, and death. This project challenges the prevailing culture that the administration of excess oxygen during surgery is beneficial. The research team comprised of experts in cardiac surgery clinical trials, oxidative stress, and AKI, will test the hypothesis that physiologic oxygenation during cardiac surgery decreases postoperative kidney injury (Aim 1), ROS production, and oxidative stress (Aim 2) compared to hyper-oxygenation. The team will complete a phase II clinical trial in which they will recruit and randomize 200 cardiac surgery subjects to receive hyper-oxygenation (fraction of inspired oxygen (FIO2) = 0.8-1.0) or physiologic oxygenation (minimum FIO2 required to achieve a Hb O2 saturation of 95-98% and an arterial pO2 between 80-95 mmHg) during surgery and compare kidney function and injury between treatment groups, ROS production using electron paramagnetic resonance, and systemic oxidative stress by measuring F2-isoprostanes and isofurans in plasma. Safety endpoints will be clinical outcomes associated with hypoxia. Secondary endpoints will be other clinical outcomes associated with excess oxygen administration in preliminary and published studies. By comparing oxidative stress measurements to kidney injury the team will also test the hypothesis that oxidative stress is the mechanism by which anesthesia and surgery induce AKI. Results of these studies have the potential to fundamentally alter the intraoperative management of cardiac surgery patients and enhance the understanding of mechanisms of surgery-induced AKI.