Isolated single-lung perfusion

A study of the optimal perfusate and other pharmacokinetic factors

Benny Weksler, Bruce Ng, Jeffrey T. Lenert, Michael E. Burt

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background.: 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. Methods.: 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 μg/mL or 320 μg/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. Results.: 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. 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 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.

Original languageEnglish (US)
Pages (from-to)624-629
Number of pages6
JournalThe Annals of thoracic surgery
Volume60
Issue number3
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Doxorubicin
Pharmacokinetics
Perfusion
Lung
Hydroxyethyl Starch Derivatives
Pulmonary Edema
Dextrans
Albumins
Potassium
Experimental Sarcomas
Body Surface Area
Linear Models
Analysis of Variance
Body Weight
Regression Analysis

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Pulmonary and Respiratory Medicine
  • Surgery

Cite this

Isolated single-lung perfusion : A study of the optimal perfusate and other pharmacokinetic factors. / Weksler, Benny; Ng, Bruce; Lenert, Jeffrey T.; Burt, Michael E.

In: The Annals of thoracic surgery, Vol. 60, No. 3, 01.01.1995, p. 624-629.

Research output: Contribution to journalArticle

Weksler, Benny ; Ng, Bruce ; Lenert, Jeffrey T. ; Burt, Michael E. / Isolated single-lung perfusion : A study of the optimal perfusate and other pharmacokinetic factors. In: The Annals of thoracic surgery. 1995 ; Vol. 60, No. 3. pp. 624-629.
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abstract = "Background.: 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. Methods.: 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 μg/mL or 320 μg/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. Results.: 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. 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 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.",
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N2 - Background.: 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. Methods.: 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 μg/mL or 320 μg/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. Results.: 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. 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 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.

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