Acetaminophen for Oxidative Stress After Cardiopulmonary Bypass
Condition: Congenital Heart Disease; Cardiopulmonary Bypass
MeSH terms: Heart Diseases; Heart Defects, Congenital
Study type: Interventional

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.
    

Intervention name(s): Acetaminophen
Intervention type(s): Other
Intervention description(s): 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.
Other intervention name(s): Tylenol
Intervention MeSH terms: Acetaminophen
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: ventricular septal defect; atrioventricular septal defect; oxidative stress; cardiopulmonary bypass; acetaminophen; hemolysis; acute kidney injury; Congenital heart disease undergoing cardiopulmonary bypass