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.

Public Health Relevance

Kidney injury affects 25% of the 500,000 patients who undergo cardiac surgery each year. Excess oxygen exposure during surgery may contribute to this kidney injury. This study will test the hypothesis that maintaining normal oxygen delivery during surgery reduces oxidative stress and kidney injury compared to administering excess oxygen.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
6R01GM112871-02
Application #
9253963
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2015-08-01
Project End
2020-07-31
Budget Start
2016-04-30
Budget End
2016-07-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Cummings, Jared J; Shaw, Andrew D; Shi, Jing et al. (2018) Intraoperative prediction of cardiac surgery-associated acute kidney injury using urinary biomarkers of cell cycle arrest. J Thorac Cardiovasc Surg :
Hubers, Scott A; Wilson, Jessica R; Yu, Chang et al. (2018) DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition. Hypertension 72:712-719
Lopez, Marcos G; Pandharipande, Pratik; Morse, Jennifer et al. (2017) Intraoperative cerebral oxygenation, oxidative injury, and delirium following cardiac surgery. Free Radic Biol Med 103:192-198
Price, Catherine C; Garvan, Cynthia; Hizel, Loren P et al. (2017) Delayed Recall and Working Memory MMSE Domains Predict Delirium following Cardiac Surgery. J Alzheimers Dis 59:1027-1035
Lopez, Marcos G; Pretorius, Mias; Shotwell, Matthew S et al. (2017) The Risk of Oxygen during Cardiac Surgery (ROCS) trial: study protocol for a randomized clinical trial. Trials 18:295
Smith, Loren E; Smith, Derek K; Blume, Jeffrey D et al. (2017) High-Density Lipoprotein Cholesterol Concentration and Acute Kidney Injury After Cardiac Surgery. J Am Heart Assoc 6:
O'Neal, Jason B; Billings 4th, Frederic T; Liu, Xulei et al. (2017) Effect of Preoperative Beta-Blocker Use on Outcomes Following Cardiac Surgery. Am J Cardiol 120:1293-1297
O'Neal, Jason B; Billings 4th, Frederic T; Liu, Xulei et al. (2017) Risk factors for delirium after cardiac surgery: a historical cohort study outlining the influence of cardiopulmonary bypass. Can J Anaesth 64:1129-1137
Shuey, Megan M; Billings 4th, Frederic T; Wei, Shouzou et al. (2017) Association of gain-of-function EPHX2 polymorphism Lys55Arg with acute kidney injury following cardiac surgery. PLoS One 12:e0175292
Smith, Loren E; Smith, Derek K; Blume, Jeffrey D et al. (2017) Latent variable modeling improves AKI risk factor identification and AKI prediction compared to traditional methods. BMC Nephrol 18:55

Showing the most recent 10 out of 14 publications