First, we would like to thank Strauss et al. for their insight regarding the problem of primary graft dysfunction in response to our recent clinical review article. 

This article correctly points out that primary graft dysfunction, or perioperative allograft injury due to ischemia or reperfusion injury, is a significant problem after lung transplantation and is multifactorial. In 2017, the International Society for Heart and Lung Transplantation (Chicago, Illinois) published the clinical definition of primary graft dysfunction, which created a consensus for diagnosis, that can be consistently measured across centers at specific time points, and quantified severity.  We appreciate Strauss et al. highlighting the other contributing factors to primary graft dysfunction, which include the disruption of the endothelial-epithelial alveolar membrane of the new allograft and the direct result of ischemia-reperfusion injury. Primary graft dysfunction is a diagnosis that well characterizes the clinical injury to the new allograft, with ischemia and reperfusion being the most obvious inflammatory insult in the setting of many other potentially injurious risk factors in the perioperative period.

Although there is overlap in the molecular markers of primary graft dysfunction and transfusion-related injury the intent of our review was not to suggest that transfusion is the sole variable influencing primary graft dysfunction. In fact, many studies in this space prove only a retrospective association of transfusion with primary graft dysfunction, which should not presume causation. We intend to encourage the reader to understand who is at high risk for perioperative transfusion and the myriad clinical implications in this niche patient population, investigate recipient optimization processes when possible, and examine transfusion decision-making. The goal of our review was to point out variability in the literature in how we quantify bleeding and define significant transfusion, and the influences on our decisions to transfuse in clinical practice. We present concepts central to pragmatic, judicious blood product use in a unique patient population that has a significant incidence of perioperative complications. However, we understand that reducing unnecessary transfusion is only one potentially modifiable variable of many that contribute to primary graft dysfunction. Unlike ischemia and reperfusion injury, the judicious use of goal-directed transfusion is easily within our capacity as intensivists and anesthesiologists.

The final comment in the letter to the editor suggests that ischemia and reperfusion injury should be best prevented through more investigation of immunosuppression, immunomodulation, and new therapies and technologies (e.g., therapies provided through ex vivo lung perfusion). Developing therapies for the lung donor and recipient to prevent primary graft dysfunction specifically would undoubtedly be an incredible step forward. However, the goal of our review was not to identify all of the treatable risk factors or potential future therapies to prevent the outcome of primary graft dysfunction. A review centered on reducing primary graft dysfunction would require an extensive review of existing literature on molecular targets and developing therapies, and an examination of many perioperative processes, starting in the preclinical period, that influence both the donor and recipient.

Because anesthesiologists and intensivists are key perioperative providers who both make decisions and provide therapies in the perioperative space, we are uniquely qualified to examine processes and optimize outcomes alongside the multidisciplinary team. We encourage the reader to consider their daily clinical practices to identify and reduce risk factors not limited to improving the outcome of primary graft dysfunction, but that might reduce all types of perioperative injury. Topics for additional study should include management and preservation of the donor organ, ventilator management of both the donor and the recipient, anesthetic and pain management, volume management, selection and management of hemodynamics on mechanical circulatory support mode, recipient and donor selection, management of perioperative immunosuppression, infection prevention, and other experimental therapies.

Thank you again for your interest in our clinically focused review and your response to the editor. We agree that primary graft dysfunction and ischemia or reperfusion may be significantly reduced through a more comprehensive examination of perioperative risk factors and the use of specific therapies under development. We hope that our review prompts a careful evaluation of not only transfusion practice, but an in-depth look at each modifiable risk factor for perioperative injury.