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

描述(申请人提供)：在美国，每年有500,000名患者接受心脏手术，25%的患者急性肾损伤(AKI)合并康复。AKI与随后的术后心律失常、伤口感染和败血症有关，并独立预测30天的死亡率增加5倍。首席研究人员已经证明，术中F2-异前列腺素浓度(ROS诱导的花生四烯酸过氧化产物)可以独立预测心脏手术后AKI，这表明针对术中过量ROS产生的治疗可能会减少AKI。尽管经常出现肾脏缺血，但心脏手术中仍然普遍存在高氧血症--给氧的量超过饱和血红蛋白所需的氧气。在体外和实验性缺血后，高氧可增加ROS的产生。我们的初步研究表明，高氧增加体外血液中ROS的产生，在心脏手术期间通过将氧气供应限制在饱和血红蛋白所需的氧量来维持生理性氧合是可行和安全的，并且与高氧相比F2-异前列腺素和AKI的减少有关。这些发现与最近对心脏骤停患者的临床研究一致，该研究表明，复苏后的高氧血症会增加认知功能障碍、昏迷和死亡。这个项目挑战了流行的文化，即在手术期间管理过量的氧气是有益的。该研究小组由心脏外科临床试验、氧化应激和AKI方面的专家组成，将测试以下假设：与高氧合相比，心脏手术期间生理性氧合可减少术后肾损伤(AIM 1)、ROS产生和氧化应激(AIM 2)。该团队将完成第二阶段临床试验，他们将招募并随机选择200名心脏手术患者，在手术中接受高氧(吸入氧气分数(FiO2)=0.8-1.0)或生理性氧合(达到95-98%的Hb O2饱和度和80-95 mm Hg之间的动脉血氧饱和度所需的最低FiO2)，并比较治疗组之间的肾功能和损伤，使用电子顺磁共振产生ROS，以及通过测量血浆中的F2-异前列腺素和异呋喃来测量全身氧化应激。安全终点将是与缺氧相关的临床结果。在初步和已发表的研究中，次要终点将是与过量给氧有关的其他临床结果。通过将氧化应激测量与肾脏损伤进行比较，该团队还将检验氧化应激是麻醉和手术导致急性肾损伤的机制的假设。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，并增强对手术诱发AKI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.