STUDIES OF HYPOXEMIC REOXYGENATION INJURY - WITHOUT AORTIC CLAMPING .4. ROLE OF THE IRON-CATALYZED PATHWAY - DEFEROXAMINE/

This study tests the hypothesis that an iron chelator, deferoxamine, c an reduce oxygen-mediated myocardial injury and avoid myocardial dysfu nction after cardiopulmonary bypass by its action on the iron-catalyze d Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets we re placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five pi glets underwent cardiopulmonary bypass without hypoxemia (cardiopulmon ary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to ab out 25 mm Hg, followed by reoxygenation at oxygen tension about 100 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level, In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenous ly just before reoxygenation and by a bolus injection (5 mg/kg) into t he cardiopulmonary by-pass circuit; nine others were not treated (no t herapy). Myocardial function after cardiopulmonary bypass was evaluate d from end-systolic elastance (conductance catheter) and Starling curv e analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxida nt reserve capacity was determined by measuring malondialdehyde in pos tcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhy droperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidan t or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (con jugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinas e: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass con trol), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus c ontrol), and produced severe postbypass dysfunction (end-systolic elas tance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypas s control), Deferoxamine avoided conjugated diene production and creat ine kinase release and retained normal antioxidant reserve, and functi onal recovery was complete (95% +/- 11%, p < 0.05 versus no treatment) . These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgi cal advantage.