The review by Bottiger et al.  highlights several recent studies related to allogenic transfusions for lung transplantation. The authors discuss perioperative factors that increase the risk of bleeding, report the evidence that connects transfusion to worse outcome, and suggest strategies to decrease transfusion. Many studies suggest an association between higher perioperative transfusion totals and primary graft dysfunction which as the authors report is a problem encountered in 15 to 20% of lung transplants, but this association is complicated by multiple variables. Anesthesiologists should appreciate the evidence showing a connection between perioperative transfusion and lung transplantation outcome but also need to be aware of the additional factors involved in this issue.

The severity of primary graft dysfunction (grades 1 to 3) is based on the presence of infiltrates on chest x-ray, decreased ratio of arterial oxygen partial pressure (Pao2) to the fraction of inspired oxygen (Fio2), and the need for extracorporeal life support.  The data from some transplant centers show an increased incidence of chronic lung allograft dysfunction in patients who developed grade 3 primary graft dysfunction within 72 h after transplantation.  The stronger inflammatory cascade seen in worsened primary graft dysfunction may allow more recipient immune cells access to the microvascular areas typically protected by the endothelial-epithelial alveolar membrane causing higher levels of allorecognition and promoting a greater long-term immune response to the allograft.  Likewise, a stronger inflammatory response may cause increased systemic vasodilation and decreased organ perfusion, leading to hypotension and acidosis, which compels perioperative physicians to respond by administering intravenous fluids and lowering the threshold for transfusion.

Ischemia or reperfusion injury is the major cause of primary graft dysfunction and, as mentioned in the review, lung injury in the categories of transfusion-associated lung injury and transfusion-associated circulatory overload are difficult to differentiate from primary graft dysfunction at the cellular level.  In fact, the differences boil down to the precipitating event that causes the disruption of endothelial-epithelial alveolar membrane.  The immunologic or inflammatory cascade that occurs in transfusion-associated lung injury versus the increased pulmonary hydrostatic edema of transfusion-associated circulatory overload. Any factors that can worsen transfusion-associated circulatory overload and transfusion-associated lung injury will worsen primary graft dysfunction. Poor diastolic function is known to worsen transfusion-associated circulatory overload and is one important example of such a factor. For recipients, the severity of the injury or the degree of primary graft dysfunction can be worsened not only by increased transfusion but also by diastolic dysfunction of the recipient’s heart.  Transesophageal echocardiography can measure the degree of diastolic dysfunction and monitor the left ventricular filling pressures in the perioperative period to provide a more nuanced approach to fluid management and guide the administration of inotropes. It is hoped that increased awareness and vigilance regarding this factor will help perioperative physicians make decisions that decrease the incidence or severity of primary graft dysfunction.

Ultimately, the issue may be improved by the development of new techniques that are focused on mitigating ischemia or reperfusion injury. Several studies have examined the use of normothermic ex vivo lung perfusion systems with varying perfusates and show some improvement in primary graft dysfunction at 72 h after transplantation.  Additional preclinical research continues that focuses on new immunosuppression and immunomodulating medications and therapies targeting the complement and cytokine signaling pathways and include gene knockdown therapy via RNA interference to silence the expression of genes involved in ischemia or reperfusion injury.  Improving judgment with regard to perioperative transfusion and blood management techniques is a worthy objective, but decreasing ischemia or reperfusion injury should be our primary goal.