ISOLATED SINGLE-LUNG PERFUSION - A STUDY OF THE OPTIMAL PERFUSATE ANDOTHER PHARMACOKINETIC FACTORS

Background. Isolated single-lung perfusion with doxorubicin hydrochlor ide was shown to be effective in clearing experimental sarcoma lung me tastases in the rat. The best perfusate to be used for isolated lung p erfusion and factors affecting the final lung concentration of doxorub icin are the subject of the present study. Methods. In experiment 1, 6 0 animals were randomized to undergo isolated left lung perfusion with doxorubicin with six different perfusates (n = 10 per group): saline, low-potassium-dextran, 5% albumin, 6% hetastarch, 5% buffered albumin , and 6% buffered hetastarch. Five animals served as negative controls . After perfusion, the lung wet to dry ratio and final lung doxorubici n concentration were determined. In experiment 2, 60 animals underwent isolated left lung perfusion with either 80 mu g/mL or 320 mu g/mL of doxorubicin. Animals were perfused at either 0.5 mL/min or 1 mL/min a nd for 2, 6, or 10 minutes. At the end of the perfusion period, the le ft lung doxorubicin concentration was measured. Statistical analysis i ncluded analysis of variance, the Duncan test for multiple comparisons , and multiple Linear regression analysis. Significance was defined as a rho value of less than 0.05. Results. In experiment 1, perfusion wi th 6% buffered hetastarch resulted in the lowest lung wet to dry ratio , significantly different from all groups except the controls. Perfusi on with low-potassium-dextran solution led to the highest final lung c oncentration of doxorubicin. In experiment 2, a model to predict final lung doxorubicin concentration was constructed: Log (final lung conce ntration) = 1.9 + 0.0071 . P + 0.186 . T, where P is the measured perf usate concentration of doxorubicin, and T is the time of perfusion in minutes. The R(2) was 0.91 and rho, less than 0.001. The dose of doxor ubicin per kilogram of animal body weight, the dose of doxorubicin per square meter of body surface area, the total amount of doxorubicin de livered, and the rate of perfusion did not meet the criteria to enter the equation. Conclusions. Isolated lung perfusion experiments should use 6% buffered hetastarch as the perfusate. The perfusate doxorubicin concentration and the duration of perfusion are the only factors dete rmining the final lung concentration of doxorubicin. In lung perfusion experiments, the dose of chemotherapy is not as important as the perf usate concentration and the duration of the perfusion. Animals should be perfused at a lower rate so the lungs are exposed to less doxorubic in without changing the final lung concentration.