Risk of Oxygen During Cardiac Surgery Trial (ROCS)

Risk of Oxygen During Cardiac Surgery (ROCS) Trial

The investigators will recruit and randomize 200 elective cardiac surgery patients to receive physiologic oxygenation (normoxia) or hyper-oxygenation (hyperoxia) during surgery to test the hypothesis that intraoperative physiologic oxygenation decreases the generation of reactive oxygen species, oxidative damage, and postoperative organ injury compared to hyper-oxygenation.

Study Overview

• Status: Completed
• Conditions: Cardiac Surgery
• Intervention / Treatment: Drug: Oxygen - normoxia; Drug: Oxygen - hyperoxia

• Study Type: Interventional
• Enrollment (Actual): 213
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Open-heart cardiac surgery, defined as surgery on the heart or aorta that requires sternotomy or thoracotomy.

Exclusion Criteria:

• Current acute coronary syndrome (defined as ST elevation myocardial infarction or non-ST elevation myocardial infarction (troponin leak within 72 hours of surgery or consent +/- EKG changes consistent with myocardial ischemia)).
• Home supplemental oxygen use.
• Preoperative supplemental oxygen requirement to maintain arterial O2 sat of 92%.
• Right to left intracardiac shunt including atrial septal defect and ventricular septal defect with Cor Pulmonale.
• Carotid stenosis defined as >50% stenosis.
• Cardiac surgery that requires intraoperative circulatory arrest, such as aortic arch replacement.
• Current use of hemo- or peritoneal dialysis.
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normoxia; Oxygen administration to maintain a hemoglobin oxygen saturation of 95-97% or arterial PaO2 80-110 mmHg during surgery.	Drug: Oxygen - normoxia; Titration of FIO2 to maintain normal hemoglobin oxygen saturation (95-97%); Other Names: oxygen
Active Comparator: Hyperoxia; Fraction of inspired oxygen 1.0 during mechanical ventilation and 0.8 during cardiopulmonary bypass during surgery.	Drug: Oxygen - hyperoxia; Administration of 1.0 FIO2 during ventilation and 0.8 or above during cardiopulmonary bypass; Other Names: oxygen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraoperative Systemic Oxidative Damage	quantified by measuring F2-isoprostanes isofurans following separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting	separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)
Acute Kidney Injury	quantified by change in serum creatinine concentration	baseline to postoperative day 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial Injury or Infarction	plasma concentration of creatine kinase, myocardial band	morning of postoperative day 1
Number of People With Stroke	Defined as new deficit on neurologic exam and confirmed with radiologic evidence occurring at any point prior to hospital discharge	from surgery to hospital discharge, average of 6 days following surgery
Respiratory Failure	reintubation	from surgery to hospital discharge, average of 6 days following surgery
Hemolysis	plasma free hemoglobin	separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)
Acute Brain Dysfunction (Delirium)	The number of participants with acute brain dysfunction as assessed by the Confusion Assessment Method for the ICU (CAM-ICU) twice daily while patients are in the ICU or for first 3 postoperative days.	from surgery to hospital discharge, average of 6 days following surgery
Acute Kidney Injury, According to KDIGO Criteria	KDIGO acute kidney injury is defined as an increase in SCr ≥ 0.3 mg/dL (≥ 26.5 lmol/L) within 48 hours of surgery or 1.5 to 1.9 times baseline within 7 days of surgery	up to 7 days following surgery
Vascular Reactivity / Endothelial Function (as Measured by Flow Mediated Dilation)	brachial artery flow mediated dilation assessed when patient arrives in ICU after surgery. brachial artery flow mediated dilation is represented as the percent change in brachial artery diameter following 5 minutes of artery occlusion. The entire assessment takes place at ICU admission.	ICU admission (immediately after arrival in ICU from operating room)
Mitochondrial Function	mitochondrial function in atrial myocardium estimated by quantifying adenylate kinase at the end of surgery and oxygen intervention	up to 2 days following surgery
Number of People With Arrhythmia	defined as any atrial fibrillation following surgery until hospital discharge assessed using continuous telemetry, rhythm strips, and electrocardiograms	from surgery to hospital discharge, average of 6 days following surgery
Postoperative Cognitive Dysfunction	Median change scores at the Short Blessed Scale (SBT) administered one-year following surgery. The SBT is a validated rating scale, administered by the clinician, measuring the cognitive performance. Sum Total (range 0-28) with 0 indicating no cognitive impairment and 28 indicating severe cognitive impairment.	up to 18 months following surgery
Chronic Kidney Disease	eGFR one year following surgery	12 months following surgery
Inflammation	Estimated by quantifying plasma concentration of plasminogen activator inhibitor-1 (PAI-1)	up to 2 days following surgery
Reactive Oxygen Species Production	TMH electron spin probe	end of surgery, defined as immediately after separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)
Oxygenation and Perfusion (Lactate)	arterial lactate measured from arterial blood collected at ICU admission (immediately after arrival in ICU from operating room)	ICU admission (immediately after arrival in ICU from operating room)
Acute Kidney Injury Estimated by Urine Concentration of TIMP-2 IGFBP7	Urinary concentration of [TIMP2]*[IGFBP7] 6 hours after ICU admission	baseline to 2 days following surgery
Acute Kidney Injury Estimated by Urine Concentration of NGAL	Urinary concentration of neutrophil gelatinase-associated lipocalin (NGAL) 6 hours after ICU admission.	baseline to 2 days following surgery
Reactive Oxygen Species Production	CAT1H electron spin probe	end of surgery, defined as immediately after separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)
Oxygenation and Perfusion (SpO2)	hemoglobin O2 saturation summarized using SpO2 data continuously measured and recorded every minute during surgery. We calculated the median SpO2 throughout surgery using all the minute to minute values. For example, if a participant had a 5 hour (300 minutes) long surgery, the participant would have 300 SpO2 measurements. We calculated and report the median of those measurements.	during surgery
Oxygenation and Perfusion (PaO2)	partial pressure of oxygen in arterial blood measured from blood sampled at end of surgery, defined as following separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)	end of surgery, defined as separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)
Oxygenation and Perfusion (Cerebral Oximetry)	brain hemoglobin oxygenation using near-infrared spectroscopy (NIRS). The median percent changes from baseline (baseline measured at beginning of surgery when probes placed on forehead, prior to intervention) throughout surgery was calculated using cerebral oximetry measurements collected every minute throughout surgery. We calculated the difference between baseline and each measurement throughout surgery. For example, if a participant had a 5 hour (300 minutes) long surgery, the participant would have 300 cerebral oximetry measurements. We calculated and report the median of those measurements.	continuously assessed throughout surgery and recorded each minute
Oxygenation and Perfusion (SvO2)	mixed venous O2 saturation, measured from blood sampled from pulmonary artery sampled at end of surgery, defined as following separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)	end of surgery, defined as following separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)
Oxygenation and Perfusion (Cardiac Index)	cardiac output (normalized to body surface area, i.e., cardiac index)	end of surgery, defined as immediately after separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)
Vascular Reactivity / Endothelial Function (Peripheral Artery Tonometry)	reactive hyperemia index measured at ICU admission (immediately after arrival in ICU from operating room). The reactive hyperemia index is a number generated by an endopat machine performing peripheral artery tonometry. The index ranges from approximately 1-3, where higher values indicate better vascular reactivity and endothelial function.	ICU admission (immediately after arrival in ICU from operating room)
Vascular Reactivity / Endothelial Function (Tension Wire Myography, Endothelial Dependent Vasodilation, EC50)	Effective concentration for 50% dilation acetylcholine dose response, tension wire myography from arterioles dissected from epicardial fat	tissue collected during surgery when heart is exposed approximately 2 hours into intervention
Vascular Reactivity / Endothelial Function (Tension Wire Myography, Endothelial Dependent Vasodilation, Emax)	Maximum percentage of arteriole dilation after increasing doses of acetylcholine measured using tension wire myography of arterioles dissected from epicardial fat. The fat sample was collected during surgery when heart is exposed approximately 2 hours into intervention.	tissue collected during surgery when heart is exposed approximately 2 hours into intervention
Vascular Reactivity / Endothelial Function (Tension Wire Myography, Endothelial Independent Vasodilation, EC50)	Effective concentration for 50% dilation sodium nitroprusside dose response, tension wire myography from arterioles dissected from epicardial fat	tissue collected during surgery when heart is exposed approximately 2 hours into intervention
Vascular Reactivity / Endothelial Function (Tension Wire Myography, Endothelial Independent Vasodilation, Emax)	Maximum percentage of arteriole dilation after increasing doses of sodium nitroprusside measured using tension wire myography of arterioles dissected from epicardial fat. The fat sample was collected during surgery when heart is exposed approximately 2 hours into intervention.	tissue collected during surgery when heart is exposed approximately 2 hours into intervention
Vascular Reactivity / Endothelial Function (Tension Wire Myography, sGC Activation Vasodilation, EC50)	Effective concentration for 50% dilation cinaciguat dose response, tension wire myography from arterioles dissected from epicardial fat	tissue collected during surgery when heart is exposed approximately 2 hours into intervention
Vascular Reactivity / Endothelial Function (Tension Wire Myography, sGC Activation Vasodilation, Emax)	Maximum percentage of arteriole dilation after increasing doses of cinaciguat measured using tension wire myography of arterioles dissected from epicardial fat. The fat sample was collected during surgery when heart is exposed approximately 2 hours into intervention.	tissue collected during surgery when heart is exposed approximately 2 hours into intervention
Vascular Reactivity / Endothelial Function (PAI-1)	Plasminogen activator inhibitor 1	end of surgery, defined as immediately after separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)
Vascular Reactivity / Endothelial Function (E-selectin)	E-selectin	end of surgery, defined as immediately after separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Frederic T. Billings, IV, MD, MSc, Vanderbilt University Medical Center

Publications and helpful links

General Publications

• Lopez MG, Pretorius M, Shotwell MS, Deegan R, Eagle SS, Bennett JM, Sileshi B, Liang Y, Gelfand BJ, Kingeter AJ, Siegrist KK, Lombard FW, Richburg TM, Fornero DA, Shaw AD, Hernandez A, Billings FT 4th. The Risk of Oxygen during Cardiac Surgery (ROCS) trial: study protocol for a randomized clinical trial. Trials. 2017 Jun 26;18(1):295. doi: 10.1186/s13063-017-2021-5.

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2016
• Primary Completion (Actual): October 8, 2020
• Study Completion (Actual): January 8, 2021

Study Registration Dates

• First Submitted: January 30, 2015
• First Submitted That Met QC Criteria: February 6, 2015
• First Posted (Estimated): February 12, 2015

Study Record Updates

• Last Update Posted (Actual): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: anesthesia; delirium; myocardial injury; surgery; renal failure; oxygen; oxidative stress; endothelial function; oxidative damage; hyperoxia; arrythmia; mitochondrial function; reactive oxygen species; kidney injury; vascular reactivity
• Other Study ID Numbers: 131128; R01GM112871 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No