Attenuation of Lung Reperfusion Injury by Modified Ventilation and Reperfusion Techniques R. Ramesh Singh, MD, Victor E. Laubach, PhD, Peter I. Ellman, MD, T. Brett Reece, MD, Eric Unger, Irving L. Kron, MD, and Curtis G. Tribble, MD Background: High ventilation and perfusion pressures after lung transplantation may have deleterious effects. We hypothesized that using combined protective approaches for ventilation and perfusion would be optimal for reducing injury and improving function after ischemia–reperfusion. Methods: Using an isolated, blood-perfused, rabbit lung model, lungs underwent 120 minutes of reperfusion either immediately (Sham) or after 18 hours of cold ischemia (IR). Groups Sham-P and IR-P underwent protective ventilation and reperfusion, and Groups Sham-C and IR-C underwent conventional ventilation and reperfusion. Protective ventilation involved gradually increasing the flow rate during 5 minutes to 1.8 liters/min, and conventional ventilation entailed immediate initiation of flow at 1.8 liters/min. Protective reperfusion involved gradually increasing perfusion during 5 minutes to 60 ml/min, and conventional reperfusion entailed immediate perfusion at 60 ml/min. Two other groups underwent either protective ventilation with conventional perfusion or vice versa. Airway pressure, pulmonary artery pressure, and arterial blood gases were measured throughout reperfusion. Wet/dry weight, highest oxygenation index, and bronchoalveolar lavage (BAL) protein were also measured. Results: Protective ventilation and perfusion after ischemia (IR-P) resulted in significant improvements in lung function as measured by increased PO 2 and decreased PCO 2 , airway pressure, and highest oxygenation index compared with conventional reperfusion (IR-C). Injury was significantly reduced in IR-P lungs as measured by reduced edema (wet/dry weight) and vascular leakage (BAL protein). In most cases, IR-P lungs performed better, with less injury than protective ventilation or perfusion alone. Conclusions: This protective approach of ventilation and perfusion after ischemia may improve lung function after transplantation, a simple method that could easily be applied clinically. J Heart Lung Transplant 2006;25:1467–73. Copyright © 2006 by the International Society for Heart and Lung Transplantation. Lungs are the most vulnerable solid organs to be transplanted, and even when strict donor selection criteria are used, less than 25% of lungs from multi- organ donors are suitable for transplantation. 1 Despite advancements in organ preservation and perioperative care, reperfusion injury remains a significant cause of early mortality after transplantation. 2–6 In recent years, our understanding of reperfusion injury has increased considerably. It has been shown that cardiac reperfu- sion injury can be avoided by controlling the composi- tion of the initial reperfusate as well as pressure. 7 DeCampos et al 8 demonstrated that rapid initiation of reperfusion leads to pulmonary edema and dysfunction. Progressive reintroduction of blood flow during a 10- minute period was shown to reduce injury and improve function of transplanted lungs, 9 –11 presumably because increased shear stress induces endothelial damage. Although mechanical ventilation is essential for pa- tients undergoing lung transplantation, several studies have shown that mechanical ventilation can produce lung injury de novo. 12 The effect of different modes of ventilation in the early period after transplantation has not been explored clinically. Using a rat lung transplant model, de Perrot et al 13 demonstrated that ventilation with high tidal volumes and low positive end-expiratory pressure significantly worsened lung function after reperfusion. Our laboratory has shown that hyperoxic ventilation exacerbates lung reperfusion injury, suggest- ing that the lowest possible tension of inspired oxygen should be used during reperfusion. 14 From the University of Virginia Health System, Department of Sur- gery, Charlottesville, Virginia. Submitted May 8, 2006; revised August 24, 2006; accepted Septem- ber 8, 2006. This research was funded by NIH RO1 HL56093 (ILK). Reprint requests: Victor E. Laubach, PhD, University of Virginia Health System, Department of Surgery, PO Box 801359, Charlottes- ville, VA 22908. Telephone: 434-924-2927. Fax: 434-924-1218. E-mail: laubach@virginia.edu Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2006.09.001 1467 ORGAN PRESERVATION