Weksler B, Ng B, Lenert J T, Burt M E
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Ann Thorac Surg. 1995 Sep;60(3):624-9. doi: 10.1016/0003-4975(95)00401-6.
Isolated single-lung perfusion with doxorubicin hydrochloride was shown to be effective in clearing experimental sarcoma lung metastases in the rat. The best perfusate to be used for isolated lung perfusion and factors affecting the final lung concentration of doxorubicin are the subject of the present study.
In experiment 1, 60 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 doxorubicin concentration were determined. In experiment 2, 60 animals underwent isolated left lung perfusion with either 80 micrograms/mL or 320 micrograms/mL of doxorubicin. Animals were perfused at either 0.5 mL/min or 1 mL/min and for 2, 6, or 10 minutes. At the end of the perfusion period, the left lung doxorubicin concentration was measured. Statistical analysis included analysis of variance, the Duncan test for multiple comparisons, and multiple linear regression analysis. Significance was defined as a p value of less than 0.05.
In experiment 1, perfusion with 6% buffered hetastarch resulted in the lowest lung wet to dry ratio, significantly different from all groups except the controls. Perfusion with low-potassium-dextran solution led to the highest final lung concentration of doxorubicin. In experiment 2, a model to predict final lung doxorubicin concentration was constructed: Log (final lung concentration) = 1.9 + 0.0071.P + 0.186.T, where P is the measured perfusate concentration of doxorubicin, and T is the time of perfusion in minutes. The R2 was 0.91 and p, less than 0.001. The dose of doxorubicin per kilogram of animal body weight, the dose of doxorubicin per square meter of body surface area, the total amount of doxorubicin delivered, and the rate of perfusion did not meet the criteria to enter the equation.
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 determining the final lung concentration of doxorubicin. In lung perfusion experiments, the dose of chemotherapy is not as important as the perfusate concentration and the duration of the perfusion. Animals should be perfused at a lower rate so the lungs are exposed to less doxorubicin without changing the final lung concentration.
盐酸多柔比星的单肺灌注已被证明在清除大鼠实验性肉瘤肺转移方面有效。本研究的主题是用于单肺灌注的最佳灌注液以及影响多柔比星最终肺内浓度的因素。
在实验1中，60只动物被随机分为6组（每组n = 10），用六种不同的灌注液进行左肺灌注：生理盐水、低钾右旋糖酐、5%白蛋白、6%羟乙基淀粉、5%缓冲白蛋白和6%缓冲羟乙基淀粉。5只动物作为阴性对照。灌注后，测定肺湿干比和肺内多柔比星的最终浓度。在实验2中，60只动物用80微克/毫升或320微克/毫升的多柔比星进行左肺灌注。动物以0.5毫升/分钟或1毫升/分钟的速度灌注2、6或10分钟。在灌注期结束时，测量左肺多柔比星浓度。统计分析包括方差分析、用于多重比较的邓肯检验和多重线性回归分析。显著性定义为p值小于0.05。
在实验1中，用6%缓冲羟乙基淀粉灌注导致最低的肺湿干比，与除对照组外的所有组有显著差异。用低钾右旋糖酐溶液灌注导致多柔比星在肺内的最终浓度最高。在实验2中，构建了一个预测肺内多柔比星最终浓度的模型：Log（最终肺内浓度）= 1.9 + 0.0071.P + 0.186.T，其中P是测量的灌注液中多柔比星的浓度，T是灌注时间（分钟）。R2为0.91，p < 0.001。每千克动物体重的多柔比星剂量、每平方米体表面积的多柔比星剂量、输送的多柔比星总量以及灌注速率均不符合纳入方程的标准。
单肺灌注实验应使用6%缓冲羟乙基淀粉作为灌注液。灌注液中多柔比星的浓度和灌注持续时间是决定多柔比星最终肺内浓度的唯一因素。在肺灌注实验中，化疗剂量不如灌注液浓度和灌注持续时间重要。动物应以较低的速率进行灌注，以便在不改变最终肺内浓度的情况下，肺接触到的多柔比星更少。
