During cold ischemic storage of the lung allograft, hypoxia can lead to degradation of ATP to hypoxanthine, which generates superoxide through xanthine oxidase during reperfusion and reoxygenation. In addition, ischemia can also lead to generation of oxygen radicals independent of oxygen or the presence of ATP, leading to lipid peroxidation and membrane damage during ischemia, mediated predominantly through NADPH oxidase (1–3). After reperfusion, these oxygen radicals contribute to the inter-related pathophysiologic mechanisms that amplify the development of lung injury, including inflammatory cytokines and chemokines, coagulation products, complement activation, platelet and immune cell activation, and cellular adhesion molecules (4–6). This cascade of events may lead to primary graft dysfunction, which represents a spectrum of injury ranging from mild pulmonary edema to a clinical picture similar to the acute respiratory distress syndrome (7). Although it makes sense that longer ischemic times would predispose to more injury, there has been conflict in the clinical literature to date.

In this issue of the Journal (pp. 786–791), Thabut and colleagues provide an important contribution to understanding the effect of longer ischemic times on early oxygen exchange and mortality after lung transplantation (8). In a large sample of subjects, the authors report significantly increased mortality in both single and bilateral lung transplants when ischemic time climbed above 330 minutes. The observation that this threshold value was consistent in both single and bilateral transplants supports the credibility of the findings. The finding of a minimal difference in Pa_O2/Fi_O2 ratio is of less clear clinical significance, although this may suggest that worse early graft function is the major determinant of the observed mortality differences.

The authors should be commended on their careful statistical methodology, which sets the standard for handling of the ischemic time variable in future studies. In addition, the findings in the current report serve to clarify some of the controversy regarding the effect of ischemic times on clinical outcomes. Previous authors (including our group) found no effect of ischemic time on graft dysfunction (9, 10). However, most of the previous “negative” association studies were performed in the setting of relatively few subjects with ischemic time above 330 minutes. Thus, the observed threshold effect in the current article may help explain some of the apparently conflicting past findings.

The association of prolonged ischemic time with mortality is the most important finding of the paper. What should the research community take from this paper? First, it appears that the major effect of ischemic time is apparent in the first 90 days. The authors conclude that the most likely explanation for this finding is an increased incidence of primary graft dysfunction with longer ischemic times. Although there is a spectrum of injury after lung transplantation, the more severe forms of primary graft dysfunction are associated with an early mortality up to 73% (11), and primary graft dysfunction is the major contributor to early mortality in ISHLT registry report (12). The findings of Thabut and colleagues serve to underscore the importance of primary graft dysfunction and suggest that future research efforts should be aimed at understanding the effect of ischemic time on lung injury. Given its clear clinical impact, future efforts at minimizing the degree of ischemia-reperfusion lung injury could dramatically affect lung transplant outcomes.

In addition to the effects of prolonged ischemic time on short-term outcomes, the authors found persistent longer-term mortality effects, as illustrated in Figure E2 of the online supplement to their article. These findings are consistent with emerging evidence that primary graft dysfunction impacts longer-term outcomes in addition to early mortality (11). The reasons for the observed effect on late outcomes are not well understood, but may be due to the effects of a prolonged ICU course (13), or alternately due to increased episodes of acute rejection triggered by early injury and inflammation in the allograft. The “injury response” hypothesis proposes a link between the inflammation of early ischemia-reperfusion injury and subsequent enhanced alloimmunity leading to acute rejection (14). This hypothesis is supported by the report of Thabut and colleagues showing that ischemic time had a significant effect on longer-term mortality. Future research into understanding the reasons for longer-term mortality deficit after primary graft dysfunction is warranted, and should include investigations of the link between early graft injury and later immune response.

The report of Thabut and colleagues also may have important clinical ramifications. In their study, 153/752 subjects had an ischemic time greater than 6 hours. As the authors point out in their discussion, in regions where ischemic time can be estimated and is often above this threshold, the decision on the match of patient to donor may be impacted by anticipated ischemia-reperfusion injury. Alternately, these findings may be reassuring for other centers where ischemic time is usually below 5 hours. The findings also suggest that transportation of organs over large distances with resultant prolonged ischemic times should not be performed routinely.

Despite the clear strengths of the study, the investigators' findings should be interpreted with some caution, given that all data were collected before 1998, and much has changed in clinical lung transplantation since that time. One important advance has been in the development of newer preservation fluids, with extracellular fluids hypothesized to have less ischemia-reperfusion injury (4, 15). To address this point, the authors evaluated the 277 subjects with extracellular solution, and the 330-minute threshold effect on survival persisted. Nonetheless, there have been other changes in the field since 1998, and confirmation of these findings in other, more modern populations should be performed before modifying clinical practice (16).

In summary, the study of Thabut and colleagues provides an important advance in our understanding of the effects of ischemic time on mortality, and provides a threshold value for future studies. The findings highlight the importance of primary graft dysfunction on both short- and longer-term mortality. These results provide ample grounds for future research aimed both at preventing ischemia-reperfusion lung injury and at understanding the mechanisms of the effects of early lung injury on relevant clinical outcomes.

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