Implementation of an experimental isolated lung perfusion model on surgically resected human lobes

Alexis Slama,Dirk Theegarten,Till Ploenes,Celia Hedderich,Balazs Hegedüs,Clemens Aigner,Paul Stockhammer,Christian Raber,Achim Koch

doi:10.1038/s41598-019-48719-8

Abstract

Isolated lung perfusion (ILP) is an ideal model to study treatment effects on a variety of pathologies. As published research mostly relies on rejected donor lungs or animal organs, this study investigates the use of surgically resected human lobes as an alternative and novel model for personalized experimental research. Ten surgically resected lobes were perfused in acellular and normothermic condition. The indication for surgery was lung cancer. Perfusion and ventilation were adapted to the size of the lobes and both functional and metabolic parameters were assessed during ILP. Patients (age 67.5 y (59–81)|♀n = 3|♂n = 7) underwent anatomic pulmonary lobectomy. Ischemic time between arterial ligation and ILP was 226 minutes (161–525). Median duration of ILP was 135 (87–366) minutes. Gas exchange and mechanical respiratory parameters remained steady during ILP (pulmonary venous pO2 196(151–219) mmHg | peak AWP: 14.5(11–22) cmH2O). Metabolism stayed constant during ILP (Glucose consumption: 1.86 mg/min/LTLC (95%CI: −2.09 to −1.63) | lactate production: 0.005 mmol/min/ LTLC (95%CI: 0.004 to 0.007)). ILP of surgically resected human lobes is a feasible and promising method. By maintaining a near physiological setting, this model may pave the way for future experimental lung research including cancer research, transplantation, physiology, pharmacology and mechanical ventilation.

Highlights

Lung physiology and therapeutic interventions can ideally be studied on isolated lung models
The first “modern” ex-vivo lung perfusion (EVLP) protocol was initially developed to assess gas exchange in donor lungs retrieved from organ donors without cardiocirculatory function[5,6,7]
A new perfusion approach was developed in Toronto[11,12], which led to the first published clinical series of 23 EVLPs of initially rejected donor lungs which were successfully transplanted after re-evaluation[13]

Summary

Introduction

Lung physiology and therapeutic interventions can ideally be studied on isolated lung models. The safety and feasibility of EVLP to increase the donor lung pool available for transplantation by re-evaluating “marginal” donor lungs could be clearly demonstrated Those promising results led to two randomized trials on “standard” lungs[22,23]. In vivo lung perfusion (IVLP) with chemotherapeutic drugs still has to prove its clinical benefit in thoracic oncology, promising future developments of this method can be expected During such procedure, pulmonary circulation is separated unilaterally and reattached to an extracorporeal circuit without removing the lungs from the patient. A porcine experiment (n = 6) showed that IVLP with Steen solution can be performed for total duration of four hours without histological or functional damage to the lung[27] Those observations could be reproduced with the addition of doxorubicin and Ifosfamide[28]. Dose finding for therapeutic IVLP has been carried in toxicity/efficacy experiments on perfused (porcine and human) lungs and in vitro[28,29,30]

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