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Ann Thorac Surg 1998;65:1523-1528
© 1998 The Society of Thoracic Surgeons

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Original articles: general thoracic

Cytostatic Lung Perfusion by Use of an Endovascular Blood Flow Occlusion Technique

^a Department of Thoracic and Cardiovascular Surgery, University of Berne, Berne, Switzerland

Accepted for publication January 2, 1998.

Address reprint requests to Dr Furrer, Thoracic and Vascular Surgery Unit, Kantonsspital, CH-7000 Chur, Switzerland
e-mail: (markus.furrer{at}ksc.chur.ch)

	Abstract

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Different modalities of cytostatic lung perfusion were compared regarding plasma and tissue drug concentrations to assess the efficacy of an endovascular blood flow occlusion technique.

Methods. A cytostatic lung perfusion study with doxorubicin hydrochloride was performed on large white pigs (n = 12). Plasma and tissue concentrations of doxorubicin were compared for isolated lung perfusion with open cannulation (ILP), blood flow occlusion perfusion with open cannulation of the pulmonary artery alone (BFO), and intravenous drug administration (IV). In a fourth group, thoracotomy-free BFO perfusion was performed by endovascular balloon catheterization of the pulmonary artery (endovascular BFO). The 3 animals in this group were used to compare the doxorubicin-perfused pulmonary tissue with the contralateral nonperfused lobes after 1 month.

Results. The mean lung tissue doxorubicin concentration at the end of perfusion was 19.8 ± 1.6 µg/g after ILP, 27.6 ± 2.2 µg/g after BFO (p = not significant), and 3.0 ± 0.8 µg/g after IV perfusion (p < 0.01). Whereas doxorubicin was not detectable in the plasma in the ILP group, concentrations ranged from not detectable to 0.44 µg/mL in the BFO group and from 0.31 to 0.84 µg/mL in the IV group (p < 0.05). Mean myocardial tissue concentration was not significantly different after BFO than IV perfusion (1.1 ± 0.5 µg/g and 1.8 ± 0.1 µg/g, respectively). In the endovascular BFO group, balloon-blocked pulmonary artery perfusion was successfully performed in all animals, and after 1 month, lung tissue showed no cytostatic-induced histologic changes.

Conclusions. Compared with ILP, BFO cytostatic lung perfusion produced an insignificantly higher lung-tissue concentration, corresponding to a sixfold to ninefold higher level than after IV perfusion. Plasma drug levels during BFO perfusion were lower than during IV perfusion. Endovascular BFO may be a promising technique for repeated cytostatic lung perfusion.

	Introduction

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Surgical resection of pulmonary metastases from soft tissue sarcoma is the treatment of choice, but the 5-year survival rate does not exceed 25% with surgical intervention alone [1, 2]. Systemic chemotherapy has not been shown to be effective, and the majority of these patients will die of pulmonary recurrence [3–6]. Doxorubicin hydrochloride is efficacious for treating soft tissue sarcoma, but its toxicity limits its systemic use [4].

Isolated lung perfusion (ILP) provides increased drug concentration in the target tissue without risk of systemic toxicity [7–15]. To achieve control of pulmonary artery inflow and pulmonary venous outflow, thoracotomy is necessary for ILP. Alternatively, single-lung perfusion by means of pulmonary artery blood flow occlusion (BFO) during drug administration without control of venous outflow was performed in rats [16]. These studies revealed similar pharmacokinetic advantages compared with intravenous (IV) drug application as those obtained with ILP [16, 17]. Blood flow occlusion of the pulmonary artery during drug administration can also be achieved without thoracotomy using a percutaneously inserted balloon catheter (endovascular BFO). This technique would be simple and safe and could be used repeatedly if necessary [16, 18] provided it is feasible in large animals and delivers sufficient drug concentration to lung tissue without causing systemic toxicity.

This study evaluates the use of endovascular pulmonary artery blood flow occlusion (endovascular BFO) for the treatment of soft tissue sarcoma metastasis in the lung. In a large animal model, plasma, lung, and myocardial tissue concentrations of doxorubicin were compared using three different techniques for drug administration: ILP, perfusion by BFO, and the common IV perfusion. An endovascular BFO perfusion technique was studied in regard to technical feasibility including the evaluation of possible drug- or perfusion-induced intermediate-term lung tissue damage.

	Material and methods

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Experiments were carried out on large white pigs weighing 20 to 25 kg. They were divided equally into the four study groups (ILP, BFO perfusion, IV perfusion, and endovascular BFO perfusion). The 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 85-23, revised 1985). The pigs that were allowed to survive had free access to food and water ad libitum. They were kept at the Animal Hospital of the University of Berne, Berne, Switzerland, in temperature-controlled areas with free access to daylight. Animals were daily observed by one of us (D.M.).

Anesthesia, monitoring, and surgical approach
The animals were premedicated with ketamine hydrochloride, 10 mg/kg intramuscularly, and standard endotracheal intubation (Portex blue line 7.0 or 7.5) was performed. Anesthesia was maintained by oxygen and nitrogen dioxide–halothane administration. Perioperative monitoring consisted of on-line measurements of arterial blood pressure obtained by open cannulation (6F catheter) of the left common carotid artery. A 6F venous catheter for infusions and blood sample collections was introduced through the left external jugular vein. All but the 3 animals in the endovascular BFO group underwent a standard anterolateral left thoracotomy through the fifth intercostal space. After cytostatic lung perfusion and restoration of pulmonary artery circulation, the thoracotomy was closed and the animals were sacrificed.

The 3 animals in the endovascular BFO group were allowed to survive for 1 month and received amoxicillin as antibiotic therapy, 1 g before the operation and 1 g from postoperative day 1 to postoperative day 3.

Open perfusion techniques
Isolated lung perfusion
The left pulmonary artery and the left superior and inferior pulmonary veins were dissected and encircled with tapes. After IV administration of heparin sodium (2 mg/kg), a 16F metal-tipped right-angled cannula was introduced into the left pulmonary artery through a pursestring suture after proximal occlusion of the vessel. Using an angled Satinsky clamp partially placed across the left atrium, venotomies were performed separately in the superior and inferior pulmonary veins. The lung was then perfused by continuous pulmonary artery infusion of 50 mg/m² of doxorubicin (Adriblastin; Farmacia, Milano, Italy) dissolved in 6% buffered hetastarch [15] with a flow rate of 100 mL/min for 15 minutes. The venous effluent was shed, and the left lung was ventilated during perfusion. At the end of perfusion, the perfusate was discarded and the lung washed with 0.5 L of buffered hetastarch solution for 5 minutes to remove unbound doxorubicin before reestablishing blood flow to the left lung. The pulmonary artery cannula was removed, and the artery and the vein were repaired with 7-0 monofilament sutures. Protamine sulfate (corresponding to the dose of heparin) was given after restoration of blood flow.

Pulmonary artery perfusion with blood flow occlusion
Dissection and cannulation of the left pulmonary artery for BFO perfusion was performed in the same manner as in ILP. Heparin, 2 mg/kg, was given before proximal occlusion of the pulmonary artery using a vascular clamp. No effort was made to control the venous outflow. The lung was perfused by continuous pulmonary artery infusion of 50 mg/m² of doxorubicin dissolved in 500 mL of 6% buffered hetastarch for 15 minutes. The left lung was ventilated during perfusion. At the end of perfusion, the pulmonary artery cannula was removed, and repair of the artery and administration of protamine were performed as in the ILP technique.

Intravenous drug admistration
For the animals receiving doxorubicin by IV administration, anesthesia, monitoring, and thoracotomy were performed as in the ILP and BFO groups. Also as in the BFO group, the perfusate comprised doxorubicin, 50 mg/m², dissolved in 500 mL of 6% buffered hetastarch. It was given through a caval catheter for 15 min.

Endovascular pulmonary artery blood flow occlusion perfusion
A right-sided groin dissection was performed to introduce a 6F, 12-mm balloon-tip catheter (Schneider Co, Buelach, Switzerland) through the right femoral vein. The tip of the catheter was placed into the proximal left pulmonary artery under fluoroscopic control. The artery was blocked by balloon inflation, and on-table pulmonary angiography was performed to confirm perfusion of the entire left lung (Fig 1). Doxorubicin, 100 mg/m², dissolved in 500 mL of 6% buffered hetastarch was administered for 15 minutes. After completion of the cytostatic perfusion, pulmonary angiography was repeated to confirm the correct position of the pulmonary artery catheter. After removal of the perfusion catheter, the femoral vein was ligated and the wound in the groin, closed. Animals were extubated and transferred to the animal hospital.

View larger version (109K): [in this window] [in a new window]   Fig 1. Endovascular blood flow occlusion perfusion of the left lung: The tip of the catheter is placed into the proximal left pulmonary artery, and the artery is blocked by balloon inflation. Pulmonary angiography confirms perfusion of the entire left lung.

Pharmacokinetic study
For all types of perfusion, samples from the drug infusions were collected for doxorubicin concentration assessment before perfusion. Blood sampling (from the arterial cannula) was performed at the start of perfusion and 5, 10, 15, 30, 45, and 90 minutes thereafter. For tissue drug level assessment, lung biopsy specimens were harvested from the left lower lobe 5, 15, and 90 minutes after the start of perfusion (ILP only at 15 minutes), and myocardial specimens of the left ventricle were harvested at postmortem examination. Doxorubicin concentration in plasma and perfusate as well as in lung and myocardial tissues was assessed by high-performance liquid chromatography as described in our previous study [19].

Histologic assessment of lung tissue injury
In the endovascular BFO group, the whole lung specimen was examined after 1 month at postmortem examination, and histologic findings in the left and right upper and lower lobes were compared. Histologic examination was conducted in a blinded way by the same pathologist (H.-J.A.). Findings in each specimen were described individually.

Data analysis
Data were analyzed using the Student t test for unrelated samples if appropriate. A bidirectional hypothesis was applied, and significance was accepted at a p value of less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Doxorubicin concentrations
Mean doxorubicin concentration in the perfusate, as determined at the beginning of cytostatic perfusion, was not significantly different in the BFO group compared with the IV group (27.2 ± 0.7 µg/mL and 25.9 ± 0.9 µg/mL, respectively; target concentration, 30 µg/mL) (Table 1). Likewise, for the ILP animals, the measured drug level in the perfusate (7.4 ± 0.4 µg/mL) was somewhat lower than the target concentration of 10 µg/mL for this group.

View larger version (30K): [in this window] [in a new window]   Fig 2. Plasma levels of doxorubicin during and after blood flow occlusion perfusion (x) and intravenous (o) perfusion.

View larger version (26K): [in this window] [in a new window]   Fig 3. Doxorubicin levels in perfusate samples (left scale) and in lung and myocardial (heart) tissue samples (right scale) at 5, 15, and 90 minutes for blood flow occlusion perfusion (x) and intravenous (o) perfusion. The myocardial tissue samples were collected after death.

All animals survived and eating behavior was normal in 2 of the 3 animals. One animal had signs of persistent sepsis, which was due to an infected venous access catheter and which continued even after removal of the catheter after 14 days. Postmortem examination showed an occluded superior vena cava caused by catheter-induced severe thrombophlebitis, which had caused multiple bilateral lung abscesses. In the remaining 2 animals histologic examination of both the perfused and nonperfused lungs revealed bilateral hemorrhagic edema, focal atelectasis, and slightly enlarged alveolar septa with no differences between the perfused lung and the nonperfused lung. The pulmonary artery wall did not reveal any morphologic alterations caused by the occluding balloon.

	Comment

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Doxorubicin-based chemotherapy has proved to be effective in the treatment of metastatic pulmonary sarcoma, but the dose required is associated with cardiotoxicity, thus limiting its systemic use [3, 4]. Regional chemotherapy by infusion of drugs into the pulmonary artery was first tried in the treatment of lung cancer more than 30 years ago [20, 21]. Infusion of cytostatic drugs into the pulmonary artery without blocking the arterial inflow and without retrieving the venous outflow, however, does not avoid systemic toxicity of the agent. Isolated lung perfusion settings provide the benefit of drug administration strictly limited to the target organ, but this technique requires pulmonary artery and vein cannulation by way of a thoracotomy [8–15]. Cytostatic lung perfusion with BFO but without control of the venous effluent would be a simpler and less invasive system, which perhaps could be repeatedly applied using an endovascular balloon catheter [16–18]. Blood flow occlusion perfusion might offer the same important pharmacokinetic advantages as ILP compared with IV doxorubicin injection. The aim of this study was to assess doxorubicin distribution by BFO perfusion and compare it with ILP in an identical setup for both techniques and to develop an endovascular BFO system in a large animal model.

As a first step, plasma, lung, and myocardial tissue doxorubicin concentrations were compared between BFO, ILP, and IV perfusions. The same drug dose was dissolved in the same perfusate for the three types of perfusion and the perfusion lasted for 15 minutes. The perfusate volume in the BFO and IV groups, however, had to be reduced to one third the volume in the ILP group to avoid IV fluid overload of nonisolated perfusion.

The lung tissue doxorubicin level at the end of BFO perfusion was nine times higher than that achieved by IV perfusion. Although the drug concentrations in tissue were even higher after BFO perfusion than after ILP, the difference was not significant. After restoration of pulmonary circulation at 90 minutes, the doxorubicin concentration in the lung tissue decreased after BFO perfusion but remained stable after IV perfusion. This might reflect the washout phenomenon of unbound doxorubicin resulting from reestablishment of the pulmonary circulation after BFO perfusion.

Plasma doxorubicin concentrations were significantly higher in the IV group than in the BFO group at all assessments during the perfusion period. The first-pass effect of regional perfusion with high doxorubicin affinity to lung tissue [12] and with BFO avoiding rapid dilution of the drug might have contributed to this result. Although the myocardial tissue concentration of doxorubicin was higher after IV than BFO perfusion, the difference was not significant; in the ILP group, doxorubicin was not detectable in the plasma during perfusion or in the myocardial tissue at postmortem examination.

The estimated peak blood concentration in patients receiving an IV doxorubicin dose of 50 to 90 mg/m² is about 1.0 µg/mL [22], and this corresponds well to our level of 0.7 to 0.8 µg/mL after administration of 50 mg/m² of doxorubicin in the IV group. The final answer in regard to tumor response by a sixfold to ninefold augmentation of lung tissue drug levels with BFO perfusion versus IV perfusion, as demonstrated in this study, has to be left to clinical trials, even if complete tumor response has been demonstrated in animal models by only a fivefold increase in the lung tissue drug concentration by BFO perfusion [16].

Wang and colleagues [16] performed BFO perfusion using doxorubicin in rats with a perfusion time of only 1 minute but followed by 20 minutes of BFO. This group measured final lung tissue concentrations ranging from 29.7 µg/g to 112.1 µg/g after application of 0.1 mg/kg to 0.5 mg/kg of doxorubicin. In our study, doxorubicin, dissolved in 500 mL of hetastarch, was applied continuously during the entire period of BFO in a dose of 50 mg/m² (corresponding to about 0.6 mg/kg). This resulted in the same high lung tissue doxorubicin levels as reached by ILP (27.6 ± 2.2 µg/g and 19.8 ± 1.6 µg/g, respectively). Baciewicz and associates [12] advocated longer ILP periods of 45 minutes in mongrel dogs, but final tissue drug levels were not higher (20.6 µg/g) when the same perfusate concentration was used. Perfusion periods longer than 15 minutes in ILP or perfusate concentrations higher than 10 µg/ml, as in our BFO group, might not further increase the final lung tissue drug concentration because of the limited doxorubicin uptake by the lung at least in pigs and dogs [12]. In contrast to the limited doxorubicin extraction rates of lung tissue in dogs and pigs, Weksler and coworkers [10, 14] observed in rats that tissue drug levels increased linearly with increased perfusate concentration, reaching a plateau at 255 µg/mL. Therefore, important interspecies differences in tissue uptake of doxorubicin must be taken into consideration if different animal models are compared in this respect.

Another aim of this study was to develop an endovascular BFO technique. Such a modality would obviate a thoracotomy and therefore could be used repeatedly on both lungs if necessary. Thus, the second part of our investigation was directed to test the feasibility of endovascular BFO. Further, the study of long-term sequelae was possible only in this group that did not have a thoracotomy, thus avoiding the well-known inflammatory reaction of pulmonary tissue after thoracotomy and vascular cannulation in pigs.

The introduction of a double-lumen 6F catheter into the femoral vein and the placement of the balloon-tip catheter under fluoroscopic control were successfully performed in all 3 animals within 30 minutes. Complete perfusion of all left lung areas was confirmed by preperfusion and postperfusion angiography. The lung injuries observed 1 month after BFO perfusion consisted of hemorrhagic edema and focal atelectasis. However, the same alterations were observed on the contralateral nonperfused lung and therefore might be attributable to factors other than drug-induced tissue changes. Similar histologic findings were seen not only in lung specimens harvested during all types of lung perfusion, but also in biopsy samples from nonperfused animals in previous studies [19].

In conclusion, our experiments demonstrate that the same doxorubicin levels in lung tissue can be obtained using ILP and BFO perfusion. Compared with IV drug administration, the plasma levels are four times lower and the lung tissue concentrations nine times higher with BFO perfusion. In contrast to ILP, BFO perfusion is technically less demanding and can be used without thoracotomy by percutaneous balloon catheterization. This appears to be a promising approach for repeated treatment of patients with lung metastasis from soft tissue sarcoma.

	Acknowledgments

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Financial support was provided by a grant from the "Schweizerische Krebsliga," Monbijoustr 61, CH-3001 Bern, Switzerland.

We thank Max Lanz and Giula Vucic (technical support), Regula Theurillat (pharmacologic studies), and Dr Gert Prinzen and Helga Bockhoff (methodologic support).

	Footnotes

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
¹ Doctor Michael E. Burt passed away on October 4, 1997.

	References

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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