Risk of Oxygen During Cardiac Surgery Trial

Phase 2

Completed

Conditions: Cardiac Surgery

Interventions: Drug: Oxygen - hyperoxia
Drug: Oxygen - normoxia

Registration Number: NCT02361944

Lead Sponsor: Vanderbilt University

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 213

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Hyperoxia	Oxygen - hyperoxia	Fraction of inspired oxygen 1.0 during mechanical ventilation and 0.8 during cardiopulmonary bypass during surgery.
Normoxia	Oxygen - normoxia	Oxygen administration to maintain a hemoglobin oxygen saturation of 95-97% or arterial PaO2 80-110 mmHg during surgery.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Vascular Reactivity / Endothelial Function (as Measured by Flow Mediated Dilation)	ICU admission (immediately after arrival in ICU from operating room)	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.
Mitochondrial Function	up to 2 days following surgery	mitochondrial function in atrial myocardium estimated by quantifying adenylate kinase at the end of surgery and oxygen intervention
Number of People With Arrhythmia	from surgery to hospital discharge, average of 6 days following surgery	defined as any atrial fibrillation following surgery until hospital discharge assessed using continuous telemetry, rhythm strips, and electrocardiograms
Myocardial Injury or Infarction	morning of postoperative day 1	plasma concentration of creatine kinase, myocardial band
Number of People With Stroke	from surgery to hospital discharge, average of 6 days following surgery	Defined as new deficit on neurologic exam and confirmed with radiologic evidence occurring at any point prior to hospital discharge
Postoperative Cognitive Dysfunction	up to 18 months following surgery	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.
Reactive Oxygen Species Production	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)	CAT1H electron spin probe
Acute Kidney Injury Estimated by Urine Concentration of NGAL	baseline to 2 days following surgery	Urinary concentration of neutrophil gelatinase-associated lipocalin (NGAL) 6 hours after ICU admission.
Oxygenation and Perfusion (PaO2)	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)	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)
Oxygenation and Perfusion (Cerebral Oximetry)	continuously assessed throughout surgery and recorded each minute	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.
Vascular Reactivity / Endothelial Function (Tension Wire Myography, Endothelial Dependent Vasodilation, EC50)	tissue collected during surgery when heart is exposed approximately 2 hours into intervention	Effective concentration for 50% dilation acetylcholine dose response, tension wire myography from arterioles dissected from epicardial fat
Oxygenation and Perfusion (SpO2)	during surgery	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.
Vascular Reactivity / Endothelial Function (Peripheral Artery Tonometry)	ICU admission (immediately after arrival in ICU from operating room)	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.
Respiratory Failure	from surgery to hospital discharge, average of 6 days following surgery	reintubation
Inflammation	up to 2 days following surgery	Estimated by quantifying plasma concentration of plasminogen activator inhibitor-1 (PAI-1)
Oxygenation and Perfusion (Lactate)	ICU admission (immediately after arrival in ICU from operating room)	arterial lactate measured from arterial blood collected at ICU admission (immediately after arrival in ICU from operating room)
Acute Kidney Injury, According to KDIGO Criteria	up to 7 days following surgery	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
Acute Kidney Injury Estimated by Urine Concentration of TIMP-2 IGFBP7	baseline to 2 days following surgery	Urinary concentration of \[TIMP2\]\*\[IGFBP7\] 6 hours after ICU admission
Oxygenation and Perfusion (SvO2)	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)	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)
Vascular Reactivity / Endothelial Function (Tension Wire Myography, Endothelial Dependent Vasodilation, Emax)	tissue collected during surgery when heart is exposed approximately 2 hours into intervention	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.
Vascular Reactivity / Endothelial Function (Tension Wire Myography, Endothelial Independent Vasodilation, Emax)	tissue collected during surgery when heart is exposed approximately 2 hours into intervention	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.
Chronic Kidney Disease	12 months following surgery	eGFR one year following surgery
Acute Brain Dysfunction (Delirium)	from surgery to hospital discharge, average of 6 days following surgery	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.
Vascular Reactivity / Endothelial Function (Tension Wire Myography, Endothelial Independent Vasodilation, EC50)	tissue collected during surgery when heart is exposed approximately 2 hours into intervention	Effective concentration for 50% dilation sodium nitroprusside dose response, tension wire myography from arterioles dissected from epicardial fat
Vascular Reactivity / Endothelial Function (Tension Wire Myography, sGC Activation Vasodilation, EC50)	tissue collected during surgery when heart is exposed approximately 2 hours into intervention	Effective concentration for 50% dilation cinaciguat dose response, tension wire myography from arterioles dissected from epicardial fat
Hemolysis	separation from cardiopulmonary bypass or completion of off-pump coronary artery bypass grafting (approximately 3-5 hours into surgery and intervention)	plasma free hemoglobin
Oxygenation and Perfusion (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)	cardiac output (normalized to body surface area, i.e., cardiac index)
Vascular Reactivity / Endothelial Function (Tension Wire Myography, sGC Activation Vasodilation, Emax)	tissue collected during surgery when heart is exposed approximately 2 hours into intervention	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.
Vascular Reactivity / Endothelial Function (PAI-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)	Plasminogen activator inhibitor 1
Vascular Reactivity / Endothelial Function (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)	E-selectin