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: 9113044
• 负责人: Frederic Tremaine Billings
• 金额: $ 34.24万
• 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/9113044
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Anesthesia procedures; Arachidonic Acids; Arrhythmia; Blood; Brain; Brain Injuries; Cardiac Output; Cardiac Surgery procedures; Cell Culture Techniques; Cessation of life; Clinical; Clinical Research; Clinical Trials; Coma; Consumption; Creatinine; Delirium; Dialysis procedure; Electron Spin Resonance Spectroscopy; F2-Isoprostanes; Generations; Heart Arrest; Hemoglobin; Hospitalization; Hyperoxia; Hypoxia; Impaired cognition; In Vitro; Incidence; Injury; Injury to Kidney; Intervention Studies; Ischemia; Kidney; LCN2 gene; Length; Measurement; Measures; Mechanical ventilation; Mediation; Monitor; Muscle; Operative Surgical Procedures; Outcome; Oxidative Stress; Oxygen; Oxygen Consumption; Oxygen Therapy Care; Patients; Perfusion; Phase II Clinical Trials; Physiological; Pilot Projects; Plasma; Postoperative Period; Principal Investigator; Production; Publishing; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Recovery; Recruitment Activity; Renal Replacement Therapy; Renal function; Reperfusion Therapy; Research; Resuscitation; Safety; Sampling; Sepsis; Serum; Testing; Tissue Inhibitor of Metalloproteinases; Tissues; United States; Urine; Venous; Whole Blood; Wound Infection; insulin-like growth factor binding protein-related protein 1; oxidative damage; peroxidation; prevent; public health relevance; renal ischemia; tissue oxygenation; treatment as usual; treatment group; Acute Renal Failure with Renal Papillary Necrosis; Affect; Anesthesia procedures; Arachidonic Acids; Arrhythmia; Blood; Brain; Brain Injuries; Cardiac Output; Cardiac Surgery procedures; Cell Culture Techniques; Cessation of life; Clinical; Clinical Research; Clinical Trials; Coma; Consumption; Creatinine; Delirium; Dialysis procedure; Electron Spin Resonance Spectroscopy; F2-Isoprostanes; Generations; Heart Arrest; Hemoglobin; Hospitalization; Hyperoxia; Hypoxia; Impaired cognition; In Vitro; Incidence; Injury; Injury to Kidney; Intervention Studies; Ischemia; Kidney; LCN2 gene; Length; Measurement; Measures; Mechanical ventilation; Mediation; Monitor; Muscle; Operative Surgical Procedures; Outcome; Oxidative Stress; Oxygen; Oxygen Consumption; Oxygen Therapy Care; Patients; Perfusion; Phase II Clinical Trials; Physiological; Pilot Projects; Plasma; Postoperative Period; Principal Investigator; Production; Publishing; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Recovery; Recruitment Activity; Renal Replacement Therapy; Renal function; Reperfusion Therapy; Research; Resuscitation; Safety; Sampling; Sepsis; Serum; Testing; Tissue Inhibitor of Metalloproteinases; Tissues; United States; Urine; Venous; Whole Blood; Wound Infection; insulin-like growth factor binding protein-related protein 1; oxidative damage; peroxidation; prevent; public health relevance; renal ischemia; tissue oxygenation; treatment as usual; treatment group

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）：每年有500,000名患者在美国接受心脏手术，急性肾脏损伤（AKI）使25％的患者的康复复杂化。 AKI与随后的术后心律不齐，伤口感染和败血症有关，并独立预测30天后的死亡增加了5倍。首席研究者表明，术中F2-异前体（活性氧（ROS）诱导的花生四烯酸过氧化的产物，在心脏手术后独立预测AKI，这表明靶向多余的ROS产生的治疗方法可能会减少AKI。高充氧 - 氧气超过饱和血红蛋白所需的氧气 - 尽管经常出现肾脏缺血，但在心脏手术期间很普遍。体外和随后实验性缺血高充氧会增加ROS的产生。我们的初步研究表明，高充氧在心脏手术期间增加血液中的ROS产生，并通过将氧气限制为饱和血红蛋白所需的心脏手术期间的生理氧合，并且与高氧相比，饱和血红蛋白是可行且安全的，并且与F2-异丙烷和AKI的降低相关。这些发现与心脏骤停患者的近期临床研究一致，该研究表明复苏后的高充氧增加了认知功能障碍，昏迷和死亡。该项目挑战了普遍的文化，即手术期间过量氧气是有益的。由心脏手术临床试验，氧化应激和AKI的专家组成的研究小组将检验以下假设：与高氧相比，心脏手术期间的生理氧合减少了术后肾脏损伤（AIM 1），ROS 1），ROS 1），ROS 1），ROS 1），AIM 2）。该团队将完成一项II期临床试验，在该试验中，他们将招募和随机对200名心脏手术受试者进行过度氧化（启发氧的比例（FIO2）= 0.8-1.0）或生理氧合（需要达到95-98％和均型PO2中的HB O2饱和度所需的最小FIO2），并在80-98％的效果和80-95 MM之间进行均匀的效果。通过测量血浆中的F2-异丙烷和异呋喃，使用电子顺磁共振和全身氧化应激产生组。安全终点将是与缺氧相关的临床结果。次要终点将是与初步和已发表研究中过量氧相关的其他临床结果。通过将氧化应激测量与肾脏损伤进行比较，团队还将检验以下假设：氧化应激是麻醉和手术诱导AKI的机制。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治疗，并增强对手术诱发的AKI机制的理解。