REDUCTION IN REPERFUSION-INDUCED MYOCARDIAL NECROSIS IN DOGS BY RHEOTHRX INJECTION (POLOXAMER-188-NF), A HEMORHEOLOGICAL AGENT THAT ALTERS NEUTROPHIL FUNCTION

Background Reperfusion after prolonged coronary artery occlusion may b e followed by additional myocardial necrosis persisting for hours to d ays. Potential mechanisms include neutrophil-mediated injury and compr omised flow within the microcirculation of the reperfused myocardium. Poloxamer 188 is a nonionic surfactant with beneficial hemorheological and neutrophil-inhibitory properties. The purpose of the present stud y was to determine if poloxamer 188 is capable of reducing the myocard ial injury associated with sustained reperfusion and to examine the ef fect of treatment duration. Methods and Results Three groups of closed -chest dogs underwent 90 minutes of left anterior descending coronary artery occlusion (angioplasty balloon) and 72 hours of reperfusion. Po loxamer 188, formulated as RheothRx Injection (Burroughs Wellcome Co), was given as a 75 mg/kg IV bolus 15 minutes before reperfusion follow ed by a 150 mg.kg(-1).h(-1) continuous TV infusion for 4 hours (n=13) or 48 hours (n=13); control dogs (n=12) received saline for 48 hours. The 48-hour infusion of poloxamer 188 resulted in a 42% reduction in i nfarct size (as a percent of the area at risk) compared with the contr ol group (25.0+/-4.2% versus 43.3+/-4.3%, P<.01), whereas the 4-hour g roup demonstrated a 25% reduction in infarct size compared with the co ntrol group (32.4+/-4.3%, P=.08). ANCOVA demonstrated that the 48-hour infusion of poloxamer 188 reduced myocardial infarct size independent of differences in collateral blood flow (P=.002 versus control). A tr end toward infarct size reduction was observed in the 4-hour infusion group (P=.098 versus control by ANCOVA). Plasma creatine phosphokinase concentration was lower in both poloxamer 188-treated groups (P<.05 v ersus control). Global left ventricular ejection fraction at 72 hours of reperfusion was improved in the 48-hour infusion group compared wit h the control group (43+/-3.1% versus 33+/-2.0%, P<.05), whereas eject ion fraction in the 4-hour group was 37+/-1.3% (P=NS versus control). Regional ventricular function was also significantly better in the 48- hour infusion group compared with the control group. In vitro studies demonstrated that at concentrations comparable to those achieved in vi vo, poloxamer 188 inhibited neutrophil chemotaxis. This finding may re present a beneficial mechanism of action. Conclusions A 48-hour infusi on of poloxamer 188 reduced myocardial infarct size and improved left ventricular function in this dog model of 90 minutes of coronary arter y occlusion and 72 hours of reperfusion. The finding that the 4-hour i nfusion of poloxamer 188 did not result in similar benefits suggests t hat additional reperfusion injury occurred between 4 and 48 hours.