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Dr. Duarte is Assistant Professor, Division of Pulmonary & Critical Care Medicine, and Dr. Lick is Associate Professor, Division of Cardiothoracic Surgery, University of Texas Medical Branch.
Correspondence to: Alexander G. Duarte, MD, FCCP, Division of Pulmonary & Critical Care Medicine, University of Texas Medical Branch, 301 University Blvd, John Sealy Annex, Galveston, TX 77555-0561; e-mail:aduarte{at}utmb.edu
Immediate effective allograft function is essential for successful lung transplantation. Yet, despite progress in lung preservation and improvements in surgical techniques and perioperative care, primary graft failure (PGF) continues to be a significant cause of early morbidity and mortality.1 The incidence of PGF has been reported to occur in 13 to 35% of lung transplant recipients.2 The clinical spectrum of early graft dysfunction ranges from mild hypoxemia with associated radiographic infiltrates to full-blown ARDS with hemodynamic instability manifesting within 24 h following the transplant procedure. In addition, histopathologic specimens of lung tissue from patients experiencing severe graft dysfunction reveal nonspecific diffuse alveolar damage. Thus, PGF represents a syndrome consisting of elevated pulmonary vascular resistance, pulmonary edema, and hypoxemia. Although a number of expressions have been used to describe this syndrome, the term primary graft failure has evolved to describe post-transplantation ischemia-reperfusion injury.3 Some of the identified risk factors include prolonged graft ischemia time, increasing donor age, recipient diagnosis of pulmonary hypertension, and use of cardiopulmonary bypass.4 5 6 However, another group reported no increase in mortality for patients with prolonged graft ischemia time or recipient diagnosis.7 Thus, the unpredictable nature and increased mortality of PGF have created a need to better understand the mechanism of ischemia-reperfusion lung injury.
Ischemia-reperfusion is the major etiologic factor associated with the development of PGF. This phenomenon involves a complex cascade of interactions between the pulmonary vascular endothelium, fragile type II pneumocytes, "passenger" macrophages, and recipient neutrophils.8 9 Ischemia-reperfusion injury following lung transplantation results in an increased pulmonary vascular permeability related to graft ischemia time, lung preservation, and reperfusion.10 Attention has been directed toward lung preservation and modulating allograft reperfusion in order to diminish the extent and severity of graft dysfunction.11 Despite these efforts, it is not uncommon for situations to arise in which a "healthy-appearing" set of lungs with a short ischemia time fails to function, and conversely, a set of marginal donor lungs with a long ischemia time functions well. Once PGF manifests, a variety of supportive therapies are available, and timely implementation has been described to improve outcome. However, these therapies have not yet been tested in a prospective, controlled, randomized outcomes study. Hence, there is a need for reliable predictors to estimate whether a donor lung will or will not function adequately, and to estimate the likelihood of mortality once PGF ensues in order to attempt to alter the clinical outcome.
In this issue of CHEST, Thabut and colleagues (see page 1876) describe the risk factors and outcomes in a large group of lung transplant recipients experiencing PGF. They define PGF as hypoxemia (ie, PaO2/fraction of inspired oxygen [FIO2] ratio, < 300) and radiographic infiltrates in the allograft within 72 h of the transplant in the absence of atelactasis, rejection, or an infectious complication. Using this operational definition, they reported a 50% incidence of PGF. Moreover, recipients developing PGF had a 29% ICU mortality rate compared to 10.9% for those without PGF. The severity of hypoxemia corresponded with the degree of early hemodynamic failure, and the combination of PGF and severe early hemodynamic failure resulted in a 63% mortality rate. The risk factors associated with an increased risk of ICU mortality were prolonged graft ischemia time, increased recipient age, impaired oxygen transfer, and hemodynamic instability requiring vasopressor administration. Using these risk factors, the authors created a severity score with which to predict the likelihood of mortality in transplant recipients experiencing PGF. In this severity score, severe hypoxemia portends a poor prognosis. When plotted, the relationship between the severity score and the likelihood of death is a sigmoid-shaped curve. An examination of this plot indicates an expected 20% mortality rate for a 61-year-old man who has experienced a graft ischemia time of > 6 h and a has PaO2/FIO2 ratio of < 250. This scoring system is heavily weighted toward the PaO2/FIO2 ratio, so that the same patient with a PaO2/FIO2 ratio of < 100 has a 50% mortality rate. Finally, patients surviving an episode of PGF were noted to have a decreased survival rate at 1 and 2 years compared to transplant recipients not experiencing PGF.
The study by Thabut and colleagues describes a greater incidence of PGF compared with earlier reports,1 2 3 and this is likely due to the inclusion of patients with less severe hypoxemia. Yet, the ICU mortality rate in the PGF group was similar to those in findings from other centers.1 3 In addition, the present report found prolonged ischemia time to be a significant influence on the outcome of patients experiencing PGF. In contrast, another group reported7 that prolonged graft ischemia time (ie, > 6 h) did not increase the risk of graft dysfunction. Others have reported6 that graft ischemia time alone does not increase the risk of early mortality; however, an interaction between ischemia time and donor age increases this prospect. Other reports3 also have indicated that the type of preservation solution used, the recipient diagnosis, the year of transplantation, and the use of cardiopulmonary bypass are not significant risk factors. It would appear that factors other than graft ischemia time are concerned with the development of ischemia-reperfusion injury. Interestingly, a recent report12 examined the relationship between cytokine levels and graft ischemia time. These investigators reported that increased levels of interleukin-8, a proinflammatory cytokine and neutrophil chemotactic factor, correlated with the severity of oxygen impairment. In addition, older donors had diminished levels of interleukin-10, an anti-inflammatory cytokine, and this finding possibly may explain why older donors are more susceptible to ischemia-reperfusion injury and the associated increased mortality rate. However, cytokine levels were not influenced by ischemia time.
The report by Thabut and colleagues highlights the use of a prediction model, and the authors are to be commended for developing an outcome severity score predicting ICU mortality related to PGF. Other investigators13 14 have attempted to predict ICU outcome in solid-organ transplant recipients. One group examined the ICU length of stay in a group of single-lung transplant recipients and demonstrated the immediate postoperative PaO2/FIO2 ratio to be the best predictor and the APACHE (acute physiology and chronic health evaluation) II score to be a poor predictor of prolonged ICU length of stay.14 The strength of the current outcome model is that it uses simple, commonly measured parameters. As pointed out by the authors, a limitation of this model is that it does not allow the accurate prediction of individual patient survival. On the other hand, this model should help to evaluate specific therapies for the treatment of PGF (eg, nitric oxide or surfactant). In addition, the findings of this outcome model should be validated by other centers. Once validated, whether in the present or modified form, it will be useful in prospective studies to determine risk factors, causes, and treatments of PGF. The ultimate utility will be to separate true risk from myth, thereby allowing the careful expansion of the donor pool while simultaneously decreasing the incidence of severe reperfusion injury.
References
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