Acetaminophen for Oxidative Stress After Cardiopulmonary Bypass

Not Applicable

Completed

• Conditions: Congenital Heart Disease; Cardiopulmonary Bypass

• Registration Number: NCT01228305
• Lead Sponsor: Vanderbilt University Medical Center

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2010-10-22
• Study First Submitted QC: 2010-10-25
• Study First Posted: 2010-10-26
• Study Start: 2011-07
• Primary Completion: 2014-01
• Study Completion: 2014-03
• Status Verified: 2017-04
• Last Update Submitted: 2017-04-19
• Last Update Posted: 2017-04-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
oxidative stress response as measured by F2-isoprostane	24 hours after cardiopulmonary bypass	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

Secondary Outcome Measures

Name	Time	Method
renal function	for the first 24 hrs after cardiopulmonary bypass	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.

Trial Locations

Locations (1)

Vanderbilt University; 🇺🇸 Nashville, Tennessee, United States