Acetaminophen for Oxidative Stress After Cardiopulmonary Bypass

Does Preoperative Acetaminophen Reduce Biochemical Markers of Oxidative Stress From Cardiopulmonary Bypass?

The current proposal tests the central hypothesis that acetaminophen will attenuate the oxidative stress response associated with cardiopulmonary bypass (CPB)-induced hemolysis in children undergoing cardiac surgery.

Infants with complex congenital cardiac defects frequently undergo cardiopulmonary bypass (CBP) during surgical repair of their cardiac lesions (1). CBP exposes infants and children to endothelial damage, hyperoxia, hemolysis, and systemic inflammatory response (2-7). The systemic inflammatory response contributes to the organ dysfunction and is initiated by exposure of blood to the artificial surfaces of the extracorporeal circuit resulting in significant hemolysis and activation of complement. Hyperoxia has been shown to cause oxidative stress and the production of free radical molecules, which contributes to the morbidity of CPB. Hemolysis leads to free hemoglobin and the subsequent release of free iron in the plasma, which can catalyze redox reactions and has been shown to be another source of severe oxidant injury in children following bypass (8, 9). Additionally, the release of proinflammatory cytokines, hypothermia, hemorrhage requiring multiple transfusions, and activation of neutrophils leading to an enhancement of the respiratory burst contribute to oxidative injury and worsening inflammation (9). Myoglobin and hemoglobin contain ferrous iron (Fe2+), which normally transports reversibly bound oxygen molecules to tissues. When muscle or red blood cells are damaged, the iron-chelating heme molecules are released into the plasma, and the ferrous iron is oxidized to the ferric (Fe3+) state. In the higher oxidation state, the ferric hemoproteins are able to reduce other molecules, notably hydrogen peroxide and lipid hydroperoxides, producing lipid peroxides and ferryl (Fe4+) hemoproteins. The ferryl hemoproteins can then enter an oxidation-reduction cycle with lipid molecules, causing further lipid peroxide production, leading to a cascade of oxidative damage to cellular membranes (10-12). With increasing oxidative stress, oxygen free radicals attack esterified arachidonate layered within cell membrane lipid bilayers, resulting in the production of multiple lipid peroxidation products called isoprostanes (Iso-P) and isofurans (IsoF) (13-17). Many forms of IsoF and IsoP have been shown to be powerful vasoconstrictors, and have been shown to contribute to the pathogenesis and organ dysfunction associated with rhabdomyolysis, subarachnoid hemorrhage and hemolytic disorders (10, 16, 18-21). F2-isoprostanes are sensitive and specific markers of oxidative stress in vivo. (4) The mechanism/s causing increased oxidative stress during CPB are incompletely understood and the relationship between free hemoglobin and F2-isoprostanes in humans undergoing CPB is unknown. Inhibition of hemoprotein-induced oxidative stress may have important clinical applications in humans. Hemolysis, in addition to contributing to the oxidative stress response, is also associated with acute kidney injury (AKI) in patients undergoing CPB or extracorporeal life support (5-6). In fact, plasma free hemoglobin has been shown to be an independent predictor of AKI in the early postoperative period (5). We have recently demonstrated that acetaminophen, through inhibition of prostaglandin H2-synthases (PGHS), inhibits the oxidation of free arachidonic acid catalyzed by myoglobin and hemoglobin. Moreover, in an animal model of rhabdomyolysis-induced kidney injury, acetaminophen significantly attenuated the decrease in creatinine clearance compared to control (10). The current proposal tests the central hypothesis that acetaminophen will attenuate the oxidative stress response associated with CPB-induced hemolysis in children undergoing cardiac surgery. If acetaminophen attenuates the oxidative stress response associated with CPB-induced hemolysis the potential therapeutic benefit extends to all cardiac surgery patients requiring CPB. Based on the outcome of this pilot study we will design a prospective randomized trial to test the hypothesis that acetaminophen will reduce AKI associated with hemoprotein-induced oxidative stress following CPB.

ventricular septal defect, atrioventricular septal defect, oxidative stress, cardiopulmonary bypass, acetaminophen, hemolysis, acute kidney injury, Congenital heart disease undergoing cardiopulmonary bypass

Subjects will be randomly assigned to treatment using a permuted-block randomization algorithm. Acetaminophen will be given at a standard dose of 15 mg/kg IV every 6 hours for children >=2 years of age, 12.5mg/kg IV every 6 hours for children 29 days to <2 years of age, and 7.5mg/kg IV every 6 hours for neonates up to 28 days old for a total of 4 doses, starting shortly after intubation in the OR and before the start of CPB.

Subjects will be randomly assigned to treatment using a permuted-block randomization algorithm. Acetaminophen will be given at a standard dose of 15 mg/kg IV every 6 hours for children >=2 years of age, 12.5mg/kg IV every 6 hours for children 29 days to <2 years of age, and 7.5mg/kg IV every 6 hours for neonates up to 28 days old for a total of 4 doses, starting shortly after intubation in the OR and before the start of CPB.

Acetaminophen will be given at a standard dose of 15 mg/kg IV every 6 hours for children >=2 years of age, 12.5mg/kg IV every 6 hours for children 29 days to <2 years of age, and 7.5mg/kg IV every 6 hours for neonates up to 28 days old for a total of 4 doses, starting shortly after intubation in the OR and before the start of CPB.

Test the hypothesis that acetaminophen attenuates the oxidative stress response, as measured by F2-isoprostanes, in children undergoing cardiopulmonary bypass. The primary outcome is the oxidative stress response as measured by F2-isoprostane

Because free hemoglobin (hemolysis) has been associated with acute kidney injury (AKI) we will assess renal function as a secondary outcome in the immediate postoperative period. To assess renal function we will collect already available data including urine output, blood urea nitrogen, Creatinine and daily fluid ins and outs. Other potential confounders of AKI including cardiopulmonary bypass (CPB) time, daily use vasopressors and re-exploration for bleeding will be collected. In addition we will also measure urine neutrophil gelatinase-associated lipocalin (NGAL) as an early marker for AKI.

Patients will be eligible for enrollment based on the following inclusion criteria: 1) Infants or children (newborn to 17years of age) undergoing cardiopulmonary bypass for biventricular surgical correction of their congenital heart lesions. Patients will not be eligible for this study based on the following exclusion criteria: Patients scheduled for single ventricle palliation will be excluded, in an effort to standardize the time of repair, time on CPB, and surgical procedure. Patients with severe neurological abnormalities at baseline. Patients with major non-cardiac congenital malformations, developmental disorders or serious chronic disorders. Benign congenital malformations (such as club foot, ear tags, etc.) will not exclude the subject from the study. Non-English speaking patients, or parent/legal guardians. Patients less than 3 kg, to limit risk of excessive blood loss from lab draws. Previous adverse reaction to acetaminophen History of acute or chronic kidney disease History of chronic liver disease Emergency surgery

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