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

心脏手术后的高氧合、氧化应激和肾损伤

• 批准号: 9253963
• 负责人: Frederic Tremaine Billings
• 金额: $ 10.78万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253963
• 关键词: Hyper; oxygenation; oxidative; stress; kidney

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.

描述（由申请人提供）：美国每年有 500,000 名患者接受心脏手术，急性肾损伤 (AKI) 使 25% 的患者康复变得复杂。 AKI 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 天时死亡率会增加 5 倍。主要研究人员证明，F2-异前列烷（活性氧 (ROS) 诱导的花生四烯酸过氧化的产物）的术中浓度可独立预测心脏手术后的 AKI，这表明针对手术期间过量 ROS 产生的治疗可能会减少 AKI。尽管经常发生肾缺血，但心脏手术期间，过度氧合（施用的氧气超过血红蛋白饱和所需的氧气）仍然很常见。体外和实验后的缺血过度氧合会增加 ROS 的产生。我们的初步研究表明，与过度氧合相比，过度氧合可增加离体血液中 ROS 的产生，并通过将供氧限制在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，并且与减少 F2-异前列烷和 AKI 相关。这些发现与最近对心脏骤停患者的临床研究一致，表明复苏后的过度氧合会增加认知功能障碍、昏迷和死亡。该项目挑战了手术期间使用过量氧气有益的流行文化。该研究小组由心脏手术临床试验、氧化应激和 AKI 方面的专家组成，将测试以下假设：与高氧相比，心脏手术期间的生理氧合可减少术后肾损伤（目标 1）、ROS 产生和氧化应激（目标 2）。 -氧化。该团队将完成一项 II 期临床试验，其中他们将招募并随机分配 200 名心脏手术受试者，接受高氧合（吸入氧分数 (FIO2) = 0.8-1.0）或生理氧合（达到 Hb O2 所需的最低 FIO2）手术期间饱和度为 95-98%，动脉氧分压在 80-95 mmHg 之间），并比较治疗组之间的肾功能和损伤，使用 ROS 产生电子顺磁共振，通过测量血浆中的 F2-异前列腺素和异呋喃来评估全身氧化应激。安全终点将是与缺氧相关的临床结果。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果。通过将氧化应激测量值与肾损伤进行比较，研究小组还将检验氧化应激是麻醉和手术诱发 AKI 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。