doi:10.1016/j.athoracsur.2006.04.020 
Copyright © 2006 The Society of Thoracic Surgeons Published by Elsevier Inc.
Original article
Modified Approach of Administering Cytostatics to the Lung: More Efficient Isolated Lung Perfusion
Bart P. van Putte MDa, b, e, 
, 
, Jeroen M.H. Hendriks MD, PhDb, Gunther Guetens PhDc, d, Gert de Boeck PhDc, Ernst A. de Bruijn PharmDc, Paul E.Y. van Schil MD, PhDb and Gert Folkertse
aDepartment of Cardiothoracic Surgery, St. Antonius Hospital, Nieuwegein, the Netherlands
bDepartment of Thoracic and Vascular Surgery, University Hospital Antwerp, Antwerp, Belgium
cLaboratory of Experimental Oncology, Catholic University Leuven, Leuven, Belgium
dLaboratory of Cancer Research and Clinical Oncology, University of Antwerp, Antwerp, Belgium
eDepartment of Pharmacology and Pathophysiology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, the Netherlands
Accepted 5 April 2006.
Available online 22 August 2006.
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Background
Isolated lung perfusion (ILuP) is an experimental technique for the treatment of pulmonary metastases. We hypothesized that part of the drug taken up by the lung during ILuP is washed out during the flush procedure. Therefore, we investigated gemcitabine uptake at different inflow concentrations, and the effect of delayed clamp release after ILuP on lung levels was studied.
Methods
Thirty rats had ILuP during 30 minutes using gemcitabine perfusate levels of 1.3, 2.7, 4.0, 5.3, and 6.7 mg/mL. Another 37 rats underwent ILuP with gemcitabine perfusate levels of 6.7 mg/mL during 6 minutes followed by a 5-minute flush and 30 or 60 minutes of reperfusion, while two other groups had ILuP and delayed clamp release for 30 or 60 minutes followed by a 5-minute flush. All effluent and lung samples were stored for later analysis. Results were evaluated using Friedmann two-way analysis and two-way analysis of variance.
Results
At 6 minutes, steady-state of gemcitabine uptake was achieved for all inflow concentrations and a linear relation (r = 0.933, p < 0.0001) between effluent and lung levels was observed. Delayed clamp release resulted in significantly higher lung levels compared with immediate restoration of blood circulation after ILuP (456% at 30 minutes and 828% at 60 minutes).
Conclusions
Effective gemcitabine lung levels are already achieved after 6 minutes of ILuP with 6.7 mg/mL followed by delayed clamp release during 30 minutes instead of the clinically applied 30 minutes ILuP.
Fig 1. Diagram of the experimental design. (ILuP = isolated lung perfusion.)
Fig 2. Gemcitabine effluent levels (plus standard error) in function of perfusion time for a concentration escalating schedule of the inflowing perfusate. The concentration-escalating schedule of gemcitabine delivered by isolated lung perfusion (ILuP) resulted in a rapid augmentation of the gemcitabine effluent levels between 3 and 6 minutes exposure for all groups. A 43% (for the 1.3 mg/mL group) to 51% (for the 6.7 mg/mL group) uptake into the lung tissue occurred. Each concentration-escalating step resulted in significantly higher lung levels and areas under the curve (p < 0.01) except for 6.7 mg/mL inflow concentration (0.05 < p < 0.01 compared with 5.3 mg/mL). (Boxes = 6.7 mg/mL; triangles = 5.3 mg/mL; circles = 4.0 mg/mL; small diamonds = 2.7 mg/mL; large diamonds = 1.3 mg/mL.).
Fig 3. 1. Gemcitabine lung levels (plus standard error) in function of the inflowing perfusate levels after 30 minutes of isolated lung perfusion. As a function of the initial perfusate concentration, 43% to 51% uptake into the lung tissue occurred.
Fig 4. 1. The upper line shows gemcitabine lung levels (plus standard error) as a function of time during isolated lung perfusion (ILuP [p = 0.024, 6 versus 30 minutes (boxes); upper line]). In the lower curve, a rapid washout after ILuP is demonstrated during a 5-minute flush followed by further diminishing lung levels after restored circulation (circles) until 60 minutes of normal blood circulation. However, delayed clamp release (triangles) after ILuP followed by a 5-minute washout resulted in significantly higher lung levels and areas under the curve up to 60 minutes (456% at 30 minutes, p = 0.002, and 828% at 60 minutes, p = 0.03; middle curve).
Table 1.
Wet-to-Dry Ratios With Standard Error After ILuP During Blood Flow Occlusion and Immediate Restoration of Blood Circulation
ILuP = isolated lung perfusion; NA = not available.
Abstract
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