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Eur J Cardiothorac Surg 2004;26:800-806
© 2004 Elsevier Science NL

Evaluation of isolated lung perfusion as neoadjuvant therapy of lung metastases using a novel in vivo pig model: II. High-dose cisplatin is well tolerated by the native lung tissue

^a Department of Cardiothoracic and Vascular Surgery, Friedrich-Schiller-University Jena, D-07740 Jena, Germany
^b Institute for Clinical Chemistry and Laboratory Diagnostics, Friedrich-Schiller-University, Jena, Germany
^c Institute of Pathology, Kaufbeuren, Germany

Received 31 October 2003; received in revised form 19 April 2004; accepted 27 April 2004.

^* Corresponding author. Tel.: +49-3641-932-2913; fax: +49-3641-932-2902
e-mail: ulrich.franke{at}med.uni-jena.de

Objective: Efficacy of in vivo isolated lung perfusion (ILP) with cisplatin could be shown in different rodent tumor models. Despite the use of this alternative therapeutical strategy in very few patients with lung metastases, there are no systematic studies regarding the tolerance of the native lung tissue in large animal models or humans. Methods: In a novel ILP pig model, groups with two different concentrations of cisplatin (group CP150: 150 mg/m² cisplatin, n=5; group CP300: 300 mg/m² cisplatin, n=5) were compared with a control group (n=5) and a Sham group (n=5) concerning the influence on hemodynamic, ventilatory and gas exchange parameters as well as on structural integrity of the lung. In the additional CP300-HT group the potentially cumulative effect of hyperthermia and high-dose cisplatin perfusion was evaluated (300 mg/m² cisplatin, 41.5 °C, n=5). Following the ILP of the left lung for 40 min, right main bronchus and right pulmonary arteries were clamped and survival as well as lung function parameters were dependent on the previously perfused lung for the 6-h-reperfusion period. Quantification of histological acute lung injury was performed using the score of Chiang. ANOVA, ANOVA with repeated measures and Pearson's correlation estimation were applied for statistical evaluation. Results: All animals survived ILP and the entire reperfusion period. Platinum levels of the perfusate and lung tissue showed a significant correlation with the dose given (P<0.001) but no correlation with the very low plasma levels in all groups (P=0.825). ILP resulted in a slight deterioration of most functional parameters compared to the Sham group. Although there were no differences between the perfusion groups regarding hemodynamic and ventilatory parameters, gas exchange parameters (pO₂/FiO₂-index, pCO₂, AADO₂) demonstrated a trend toward dose-related functional impairment. Histological evaluation confirmed a dose-depending damage of lung tissue (P<0.001, correlation coefficient 0.670). The hyperthermic ILP with high-dose cisplatin led to improved gas exchange parameters and a reduction of morphological lung damage. Conclusions: In vivo ILP with high-dose cisplatin represents a safe procedure in this pig model. Hyperthermic perfusion up to 41.5 °C was beneficial to reduce the acute lung injury. The promising results of this study might be used for initiation of clinical trials as an alternative treatment in patients with a very poor prognosis.

Key Words: Isolated lung perfusion • Lung metastases • Cisplatin • Lung function • Acute lung injury • Hyperthermia