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Ann Thorac Surg 1995;60:624-629
© 1995 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Isolated Single-Lung Perfusion: A Study of the Optimal Perfusate and Other Pharmacokinetic Factors

Thoracic Oncology Laboratory, Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

Accepted for publication April 6, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
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.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Complete surgical resection is the cornerstone of therapy for pulmonary metastases from sarcoma, with 5-year survival rates of 25% to 30% [1–4]. Most recurrences are probably due to micrometastases present at the time of the initial operation [4]. However, adjuvant chemotherapy has not had an impact on survival [5]. Doxorubicin hydrochloride is one of the most active drugs for the treatment of sarcoma [6] but is associated with a high incidence of untoward systemic side effects, limiting optimal dose delivery [7].

Isolated single-lung perfusion has been proposed as a strategy to deliver high-dose chemotherapy while minimizing systemic side effects [8–10]. Initial experiments [8, 11-13] with isolated lung perfusion with doxorubicin used recirculating perfusion with blood as the perfusate and achieved a relatively low lung concentration of doxorubicin. We [10, 14, 15] have developed a rat model of in vivo isolated lung perfusion with doxorubicin using nonrecirculating perfusion with normal saline solution as the perfusate. Advantages of one-pass nonrecirculating perfusion include easy delivery of the drug and easier characterization of the pharmacokinetics of the perfused drug. Although in theory blood is the ideal perfusate for isolated lung perfusion, its use is not practical because of the large volume required in nonrecirculating perfusion circuits. Awad and associates [16] perfused canine pulmonary lobes for extended periods (2 to 3 hours) and found that normal saline solution was the worst perfusate, producing injury to lungs, and that a mixture of dextran and blood was the best, causing the least amount of injury. Still, the mortality was high, greater than 60% in all groups. Although several reports [17–20] have dealt with lung ``flush'' for organ preservation in lung transplantation experiments, few other studies on the ideal nonblood perfusate for isolated single-lung perfusion are available.

In previous work studying the pharmacokinetics of isolated single-lung perfusion with doxorubicin, we [10] have shown that lung tissue concentration of doxorubicin increased linearly with increasing perfusate concentration of the drug. Other factors that may influence the final lung levels of doxorubicin such as total amount of drug delivered, total perfusion time, and rate of perfusion have not been studied. In the present study, we determined the best nonblood perfusate for isolated lung perfusion and the relation of the perfusate concentration, perfusion rate, total perfusion time, and dose of chemotherapy to the final lung concentration of doxorubicin.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
One hundred twenty-five male Fisher 344 rats (Charles River Laboratories, Kingston, NY) were used in two experiments. Animals were treated in accordance with the Animal Welfare Act and the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication no. 85-23, revised 1985). All experiments were approved by the Institutional Animal Care and Use Committee, Memorial Sloan-Kettering Cancer Center. Animals were allowed access to standard laboratory chow (Ralston-Purina, St. Louis, MO) and water ad libitum.

Experimental Design
EXPERIMENT 1.
Animals were randomized into six groups for isolated left lung perfusion with six different perfusates. Five control animals did not undergo any procedure. All perfusion groups had 10 animals. In each group, 5 animals were perfused at room temperature with 80 µg/mL of doxorubicin in the perfusate, and 5 animals were perfused with doxorubicin-free perfusate. The fluids used for perfusion were: normal saline solution (SAL); low-potassium–dextran (LPD); 5% albumin (ALB); 6% hetastarch (Hespan; Du Pont Pharmaceuticals, Wilmington, DE) (HES); 5% buffered albumin solution (BAL); and 6% buffered hetastarch solution (BHE). Animals were perfused for a total of 20 minutes at a rate of 1 mL/min. Rats perfused with doxorubicin were perfused for 10 minutes with doxorubicin followed by 10 minutes' perfusion with doxorubicin-free perfusate.

At the end of the perfusion, the left lung was excised and the animal was sacrificed. The lung was homogenized, an aliquot was dried for 3 days in an oven at 80°C, and then the wet to dry ratio was calculated. Lung doxorubicin level was measured by high-performance liquid chromatography [10].

EXPERIMENT 2.
Sixty animals underwent isolated left lung perfusion at room temperature with BHE as the perfusate. Thirty animals underwent isolated left lung perfusion with 80 µg/mL of doxorubicin, and 30 animals were perfused with 320 µg/mL of doxorubicin in the perfusate. In each group, 15 animals had isolated left lung perfusion at a rate of 0.5 mL/min, and 15 animals were perfused at 1 mL/min. At each rate, 5 animals underwent isolated left lung perfusion with doxorubicin for 2 minutes, 5 animals were perfused for 6 minutes, and 5 animals were perfused for 10 minutes. At the end of the doxorubicin perfusion period, animals were perfused for 5 minutes with doxorubicin-free perfusate to clear the lung of unbound doxorubicin. We [10] have previously shown that 5 minutes of perfusion with doxorubicin-free perfusate is sufficient to accomplish this.

At the end of the perfusion period, the left lung was excised and the animal, sacrificed. Lung tissue doxorubicin concentration was measured by high-performance liquid chromatography. Perfusate doxorubicin concentration was measured before and after perfusion, and results were averaged. Lung extraction ratio (at the end of the full perfusion period) was calculated as the total amount of doxorubicin in the lungs divided by the total amount of doxorubicin perfused.

Isolated Left Lung Perfusion
Isolated left lung perfusion was performed as previously described [14]. Briefly, animals were anesthetized with 50 mg/kg of intraperitoneal sodium pentobarbital, and the left chest was shaved and prepared. The animals were orotracheally intubated with a 16-gauge intravenous catheter [21] and were ventilated with a rodent volume ventilator (rodent ventilator model 683; Harvard Apparatus, South Natick, MA) at 70 strokes/min and a tidal volume of 10 mL/kg. Anesthesia was maintained with 100% oxygen and 0.5% halothane.

A left thoracotomy was performed, and the left lung was mobilized by dissecting the inferior pulmonary ligament. Using a surgical microscope (x16 magnification, OpMi-1; Karl Zeiss, Wotan, Germany), the pulmonary artery and vein were dissected free, and a microvascular clamp was placed proximally on the artery and vein. An arteriotomy was performed, and a PE-10 catheter welded into a PE-50 catheter [22] (Clay-Adams, Parsippany, NJ) was introduced into the pulmonary artery. The pulmonary vein was cannulated with a PE-90 catheter, and the effluent was collected. Perfusion was carried out with a syringe pump (Syringe Infusepump 22; Harvard Apparatus). At the end of the perfusion period, the left lung was excised and the animal, sacrificed.

Perfusate Preparation
Saline, ALB, and HES were obtained commercially. The LPD, BAL, and BHE were prepared sterilely in our laboratory. The composition and chemicals used in the preparation of the different perfusates are shown in Tables 1 and 2. All chemicals were high grade and high purity.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Experiment 1
There was no interaction between the presence of doxorubicin and the type of perfusate used (p = 0.374 by factorial analysis of variance). By the same model, the presence of doxorubicin did not change the final wet to dry ratio (p = 0.126). The wet to dry ratio of the seven different groups is shown in Figure 1. Animals perfused with BHE had the lowest lung wet to dry ratio of all the groups, significantly different from all other groups except the controls (p < 0.05). Animals perfused with SAL had the highest lung wet to dry ratio, also significantly different from all other groups (p < 0.05). There was no difference in the wet to dry ratio of the lungs between groups perfused with or without doxorubicin: with doxorubicin (n = 30), 5.7 (95% CI, 5.3 to 6.1), and without doxorubicin (n = 30), 5.4 (95% CI, 5.1 to 5.7). Animals perfused with buffered solutions (LPD, BAL, BHE) had a lower lung wet to dry ratio compared with animals perfused with nonbuffered perfusates (SAL, ALB, HES) (p < 0.01): buffered perfusate (n = 30), 5.2 (95% CI, 4.9 to 5.5), and nonbuffered perfusate (n = 30), 5.9 (95% CI, 5.5 to 6.2).

View larger version (15K): [in this window] [in a new window]   Fig 1. . Wet to dry ratios. Animals perfused with 6% buffered hetastarch solution (BHE) had the lowest wet to dry ratio among animals undergoing isolated lung perfusion, and it was not different from that of nonperfused controls (CT). Data are shown as the mean ± the standard deviation. (ALB = albumin; BAL = buffered albumin; HES = hetastarch; LPD = low-potassium–dextran; SAL = saline; * = p < 0.05 versus BHE.)

View larger version (16K): [in this window] [in a new window]   Fig 2. . Lung tissue doxorubicin concentrations (dox conc.). Animals perfused with low-potassium–dextran solution (LPD) had the highest tissue level. Data are shown as the mean ± the standard deviation. (ALB = albumin; BAL = buffered albumin; BHE = buffered hetastarch; HES = hetastarch; SAL = saline; * = p < 0.05 versus all other groups.)

View larger version (23K): [in this window] [in a new window]   Fig 3. . Lung concentration of doxorubicin in animals with either 80 µg/mL or 320 µg/mL of doxorubicin in the perfusate given at a rate of either 0.5 mL/min or 1 mL/min for 2, 6, or 10 minutes. Data are shown as the mean ± the standard deviation.

Animals perfused at a rate of 0.5 mL/min had lung and heart concentrations similar to those of animals perfused at 1 mL/min (Table 3). Extraction ratio in animals perfused at 0.5 mL/min was significantly higher than that of rats perfused at 1 mL/min (6.3% [95% CI, 5.3 to 7.2] versus 3.5% [95% CI, 3.2 to 3.8], respectively; p < 0.001).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
The lungs are the most common site of metastases in patients with soft tissue sarcoma; more than 50% of patients have recurrence exclusively in the lung after resection of the primary disease [24]. Most patients (72% to 86%) can be rendered disease free by resection of pulmonary metastases [24, 25], but up to 75% of patients rendered disease free by the initial resection of metastatic pulmonary nodules will show recurrence exclusively in the lungs because of the presence of micrometastatic disease at the time of the initial operation [4, 24]. Adjuvant chemotherapy has not been useful in prolonging survival possibly because of systemic toxicity when used in high doses [5, 7].

Isolated single-lung perfusion is a promising new experimental technique for the treatment of pulmonary metastases that offers the benefits of delivery of very high doses of chemotherapy and minimal systemic toxicity. In our laboratory, we [10, 14, 15] developed a rat model of isolated single-lung perfusion with doxorubicin with low operative mortality and negligible long-term injury to the lungs. We [10] have previously shown that isolated lung perfusion with doxorubicin results in significantly higher final lung doxorubicin levels and significantly lower heart levels of doxorubicin compared with a high intravenous injection of doxorubicin. Studies of experimental pulmonary micrometastases showed complete eradication of experimental sarcoma metastases in rats undergoing isolated single-lung perfusion with doxorubicin [15].

In our previous work, we have used SAL as the perfusate fluid of choice. Although rats tolerated the perfusion well, we were concerned that as we experiment with higher animal species such as dogs, SAL may be an inadequate perfusate fluid. We have observed that when rats are perfused with SAL for longer periods, some pulmonary edema develops (unpublished observations). Awad and colleagues [16] perfused canine lungs for 2 to 3 hours with blood, SAL, dextran, and a mixture of blood and dextran. All animals perfused with SAL died with pulmonary edema and frothy sputum in the endotracheal tube.

Several lung preservation solutions, including Euro-Collins, University of Wisconsin, and LPD, have been looked at in lung transplantation literature [26]. Oka and colleagues [18] demonstrated in an ex vivo canine reperfusion model that LPD was superior to both University of Wisconsin and Euro-Collins solutions when wet to dry ratio and partial pressure of arterial oxygen of pulmonary vein blood were evaluated. Low-potassium–dextran solution was also shown to be less toxic to cultured type II pneumocytes than was Euro-Collins solution [27].

In our experiment, we compared the best experimental preservation solution used in lung transplantation with SAL, ALB, and HES. Because ALB and HES are solutions with a low pH and tissue damage is possible at a low, unphysiologic pH, we constructed albumin and hetastarch solutions buffered with a sodium phosphate buffer (BAL and BHE, respectively). We also added glucose, as there is evidence of improved lung preservation if substrates for cell glycolysis are provided [26]. Although in previous experiments, animals underwent isolated lung perfusion at a rate of 0.5 mL/min [10, 14, 15], in testing different perfusates, we doubled the rate to 1 mL/min so we could stress the lungs further. A higher perfusion rate will induce more pulmonary edema.

In the present study, we demonstrated that buffered solutions (LPD, BAL, BHE) are superior to unbuffered solutions (SAL, ALB, HES) in provoking less pulmonary edema after isolated lung perfusion. Of the buffered solutions, BHE had the lowest degree of pulmonary edema after perfusion. Both BHE (buffered hetastarch) and BAL (buffered albumin) have a high sodium concentration (216 mEq/L), which increases the osmolarity and helps prevent pulmonary edema. In survival experiments at our laboratory, animals undergoing isolated lung perfusion with BHE do not appear to have any untoward effect from the high sodium concentration in these solutions (unpublished observations). This solution has not been tested in pulmonary preservation for lung transplantation experiments, and it would be interesting to look at the preservation of lungs with BHE.

Animals perfused with LPD had higher lung tissue doxorubicin levels. The reason for the superiority of the dextran-based solution is unclear but may involve ``improved microcirculation.'' Dextran may recruit more capillaries, thus allowing a more uniform perfusion and a better uptake of doxorubicin by the lung [26].

When we first studied the effect of perfusate concentration of doxorubicin on the final lung tissue level of the drug, we [10] concluded that there was a linear increase in the final lung concentration of doxorubicin as the perfusate concentration of the drug increased up to 255 µg/mL. In the present study, we further define other factors that affect the final lung doxorubicin level. We studied the following variables: rate of perfusion, duration of perfusion, perfusate concentration, and total dose of doxorubicin per kilogram of animal body weight. We again observed that the measured concentration of doxorubicin in the perfusate was lower than the planned concentration of doxorubicin. This is expected, as doxorubicin binds to tubing and is light sensitive. The final lung concentration was higher in animals receiving 320 µg/mL compared with those receiving 80 µg/mL as we have previously observed [10]. Lung concentrations in the present study after 10 minutes of perfusion were in the same range as in our previous experiments [10]. We again demonstrated that heart concentration after isolated lung perfusion with doxorubicin is very low. Because there was no difference in heart doxorubicin concentration in animals perfused with a high or a low concentration of doxorubicin, it is evident that isolated lung perfusion effectively shields the systemic circulation from doxorubicin and that this will minimize systemic toxicity even in high perfusion doses of chemotherapy.

The rate of perfusion did not affect the final lung concentration of doxorubicin. It is apparent that as the rate of perfusion increased, the ability of the lung to extract doxorubicin (extraction ratio) decreased. The importance of this finding is that even though the lung was exposed to twice as much doxorubicin, it did not change the final lung tissue doxorubicin concentration, a finding suggesting that a lower perfusion rate may be of benefit in exposing the tissues to less doxorubicin and achieving the same final lung concentration. The rate of perfusion also did not affect the heart concentration of doxorubicin (see Table 3). By multilinear analysis, the only two variables that made a significant difference in the final lung concentration were duration of perfusion and perfusate concentration. The dose of doxorubicin, the total amount of doxorubicin administered, and the rate of perfusion were not important in determining the final lung doxorubicin concentration.

If this finding is confirmed in other animal models and eventually in humans, it will have important therapeutic implications. Dose per square meter of body surface area or per kilogram of body weight will not predict the final lung concentration of doxorubicin. The concentration of doxorubicin in the perfusate will be critical in guiding therapy. It is also reasonable to assume that the current doses of doxorubicin in humans will not be useful in predicting response or toxicity and that new guides to therapy will have to be developed for patients undergoing isolated lung perfusion with doxorubicin. It is possible that the kinetics will also be valid for other drugs used in isolated lung perfusion.

In summary, BHE is the best perfusate solution to minimize the lung edema that may occur in isolated lung perfusion. Lung perfusion with doxorubicin in LPD solution offered the highest final lung concentration of doxorubicin but caused more pulmonary edema than BHE. The most important factors determining the final lung concentration of doxorubicin after isolated lung perfusion are length of perfusion and perfusate concentration. The dose of doxorubicin and the rate of perfusion are not important factors in determining final lung concentration. The superiority of BHE and LPD and the reproducibility of the factors affecting perfusion should be studied in another animal species such as the dog. Careful evaluation of all these factors will be necessary in planning for human trials of isolated lung perfusion with doxorubicin.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Burt, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Benny Weksler Michael E. Burt Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weksler, B. Articles by Burt, M. E. Search for Related Content PubMed PubMed Citation Articles by Weksler, B. Articles by Burt, M. E.