There was no observed difference in survival rates when grafts were exposed to 6 or more hours of ischemia (P = .41, log-rank test).
There was no observed difference in survival rates when grafts were exposed to 6 or more hours of ischemia (P = .82, log-rank test).
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Grimm JC, Valero V, Kilic A, et al. Association Between Prolonged Graft Ischemia and Primary Graft Failure or Survival Following Lung Transplantation. JAMA Surg. 2015;150(6):547–553. doi:10.1001/jamasurg.2015.12
The effect of prolonged graft ischemia (≥6 hours) on outcomes following lung transplantation is controversial.
To evaluate the effect of prolonged total graft ischemia times on long-term survival rates and the development of primary graft failure (PGF) following lung transplantation.
Design, Setting, and Participants
In this retrospective study, the United Network for Organ Sharing database was queried for adult patients who underwent lung transplantation from May 1, 2005, through December 31, 2011. Primary stratification by the presence of prolonged graft ischemia was performed. Kaplan-Meier estimates at 1 and 5 years were used to compare survival in the 2 cohorts. A multivariable Cox proportional hazards regression model was constructed to identify predictors of 1- and 5-year mortality. A risk-adjusted predictive model for the development of PGF was formulated in a similar fashion.
Main Outcomes and Measures
The primary outcome of interest was 1- and 5-year survival. Secondary outcomes included PGF and other postoperative events, such as renal failure, biopsy-proven rejection, and stroke.
Of the 10 225 patients who underwent lung transplantation, 3127 (30.6%) had allografts exposed to prolonged ischemia. There was no difference in survival at 1 (83.6% [95% CI, 82.3%-84.9%] vs 84.1% [95% CI, 83.3%-85.0%]; P = .41) or 5 (52.5% [95% CI, 51.0%-54.0%] vs 53.5% [95% CI, 51.3%-55.6%]; P = .82) years between patients who received grafts that were or were not exposed to ischemia that lasted 6 hours or more, respectively. Prolonged graft ischemia did not independently predict 1- or 5-year mortality or the development of PGF (odds ratio, 1.11; 95% CI, 0.88-1.39; P = .37). Furthermore, prolonged ischemia did not independently predict 1-year (hazard ratio, 1.09; 95% CI, 0.97-1.22; P =.15) or 5-year (hazard ratio, 1.05; 95% CI, 0.98-1.14; P =.18) mortality or the development of PGF (odds ratio, 1.11; 95% CI, 0.88-1.39; P =.37).
Conclusions and Relevance
No association was found between prolonged total graft ischemia times and primary graft failure or survival following lung transplantation. Given the scarcity of organs and the paucity of suitable recipients, prolonged ischemia time should not preclude transplantation. It is, therefore, reasonable to consider extending the accepted period of ischemia to more than 6 hours in certain patient populations to improve organ use.
Lung transplantation provides an excellent therapeutic option for patients with end-stage pulmonary disease because it improves patients’ quality of life and duration of survival. Despite measures to reduce waiting times, such as the implementation of the lung allocation score (LAS), a paucity of suitable donors continues to negatively affect graft availability.1 Extending the accepted period of graft ischemia time may augment the supply of this scarce resource by broadening the time frame to execute long-distance organ donor recoveries. Reluctance exists, however, to universally advocate for prolonging the accepted graft ischemia time owing to the perceived increased rate of posttransplant ischemia-reperfusion injuries, which deleteriously affect graft function and can precipitate primary graft failure (PGF).2,3
Previous studies4-6 that investigated the role of graft ischemia time in lung transplantation outcomes have yielded conflicting results but are limited in their scope owing to small sample sizes and recent changes in preservation strategies and surgical technique. We evaluated a large cohort from the United Network for Organ Sharing (UNOS) database to evaluate the significance of prolonged graft ischemia times on long-term survival rates and to determine whether it was an independent predictor of PGF following lung transplantation.
Patients aged 18 years or older who underwent initial or repeated lung transplantation from May 1, 2005, through December 31, 2011, were identified in the UNOS database. Primary stratification by a graft ischemia time of less than 6 hours or 6 or more hours was conducted. Patients who underwent heart-lung transplantation were excluded from analysis. Only the index single-lung transplantation was included for patients who underwent sequential lung transplantation. This study was approved by the Johns Hopkins Institutional Review Board.
Baseline donor and recipient characteristics as well as transplant-related outcomes were compared between the 2 ischemia-time cohorts. Recipient-specific variables included age, sex, LAS, race, body mass index, single or bilateral transplant, etiologic features of end-stage lung disease, diabetes mellitus status, history of previous transplant, mechanical ventilation and extracorporeal membrane oxygenation (ECMO) before transplantation, and intensive care unit (ICU) status at the time of transplant. Donor-related variables included age, body mass index, tobacco use, race, and history of diabetes or hypertension. Transplant outcomes included new-onset dialysis, postoperative stroke, PGF, biopsy-proven rejection, and 30-day and 1-year mortality rates. Continuous variables, reported as mean (SD) or median (interquartile range), were compared using a paired 1-tailed t test (parametric) or Wilcoxon rank sum test (nonparametric) when appropriate. Categorical variables, reported as number (percentage), were analyzed using Pearson χ2 analysis. Findings were considered significant at P < .05.
The primary outcome was 1- and 5-year survival rates, as estimated by the Kaplan-Meier survival model, with the log-rank test providing comparison between the 2 cohorts. Univariate Cox proportional hazards regression modeling was conducted to determine the association of each of the aforementioned recipient and donor variables on 1- and 5-year mortality rates. Covariates associated with an increase in 1- and 5-year mortality rates (P < .20) were then systematically included in a multivariable model. Similarly, a predictive model for the development of PGF was constructed after the significance of each variable was established in univariate analysis. To investigate the effect of prolonged graft ischemia on mortality and PGF, this variable was included in both multivariable models irrespective of its influence at the univariate level (creating a risk-adjusted model for mortality and PGF). The postoperative diagnosis of PGF was made at the institutional level; therefore, the specific criteria that were used as a metric for this outcome are not included in the UNOS database. Stata, version 12.1 (StataCorp) was used for statistical analysis.
A total of 10 225 patients met the criteria for inclusion in this study, and 3127 (30.6% ) were given transplants with grafts that were exposed to 6 or more hours of ischemia. In general, the prolonged-ischemia cohort had a greater incidence of several high-risk characteristics, including history of diabetes and previous transplantation, an LAS of 60 or greater, ICU admission, and treatment with ECMO and/or mechanical ventilation before transplantation. Compared with patients whose grafts had shorter ischemia times, the prolonged-ischemia cohort comprised more patients with cystic fibrosis and fewer with chronic obstructive pulmonary disease or pulmonary fibrosis (Table 1). Graft ischemia of 6 or more hours was also associated with increased incidence of postoperative renal failure and stroke, while the rate of biopsy-proven rejection and PGF were no different between the 2 cohorts (Table 2). In the cohort that comprised patients whose grafts were exposed to 6 or more hours of ischemia, a considerable proportion of patients had a severely prolonged cold time, with 10.4%, 6.3%, and 5.6% of the grafts being ischemic for 8 or more, 10 or more, and 12 or more hours, respectively.
The 1- and 5-year survival rates were not statistically different between the prolonged-ischemia and shorter-ischemia cohorts (P = .41 and P = .82, respectively) (Figure 1 and Figure 2). Although not a primary outcome in this study, the 30-day survival rate was greater among those with a longer graft ischemia time (P = .002).
After univariate analysis, 17 covariates were included in both the 1- and 5-year Cox proportional hazards regression models. Prolonged graft ischemia did not meet the independent criteria for inclusion in either multivariable model. After risk adjustment, graft ischemia of 6 or more hours was not associated with an increase in 1-year (hazard ratio, 1.09; 95% CI, 0.97-1.22; P = .15) or 5-year (hazard ratio, 1.05; 95% CI, 0.98-1.14; P = .18) mortality. The variables that had the strongest associations with mortality at both periods included ICU admission and ECMO cannulation before lung transplantation, single-lung transplantation, previous thoracic transplantation, and donor diabetes status (Table 3 and Table 4).
Owing to the possible influence of prolonged graft ischemia on the development of PGF, a best-fit multivariable predictive model was constructed from 12 covariates. After adjustment, graft ischemia of 6 or more hours (odds ratio, 1.11; 95% CI, 0.88-1.39; P = .37) was not shown to be an independent predictor of PGF. The variables with the strongest predictive power included ICU admission and ECMO cannulation before lung transplantation as well as recipient diabetes status (Table 5). The overall model had good predictive strength (area under the curve, 0.62).
The recent increase in patients listed for lung transplantation has not been met by parallel growth in the number of suitable donors.1 As such, it is paramount that resources be optimally used to satisfy this demand for organs and thus prevent further burgeoning of the waiting list. There has been a reluctance to use grafts exposed to prolonged ischemia owing to the hypothetical risks of post–lung transplantation injury and mortality. This reluctance has the untoward effect of limiting the volume of potential donors and has possibly resulted in a misallocation of organs owing to geographical restrictions. In 2012, the Organ Procurement Organization in which Maryland resides (Organ Procurement Organization Region 2) had 402 donor lungs available for transplantation, while only 253 lung transplantations occurred (62.9%), highlighting the sizeable percentage of grafts that may go unused. Many of these donor organs may represent poor-quality grafts, while some would be transplantable in outside Organ Procurement Organizations if a suitable donor-recipient match and cold graft ischemia time were present.
Several series3-5 have demonstrated that the perceived detrimental sequelae of prolonged graft ischemia might not be well founded. During a 10-year period, Fiser et al4 evaluated 136 patients who underwent lung transplantation and showed no significant increase in the incidence of several key clinical outcomes in transplanted grafts that were exposed to 6 or more hours of cold graft ischemia. They reported a similar rate of graft ischemia and reperfusion injury—a key factor in early mortality following lung transplantation—in patients with prolonged cold graft ischemia.2,4 Like Fiser et al,3 Gammie et al5 and Meyer et al7 showed that protracted graft ischemia did not increase the risk of short- or long-term mortality. There is not, however, a unified consensus on the effect of prolonged graft ischemia on mortality. In contrast to these studies, Thabut et al8 demonstrated that a cutoff of 330 minutes (<6 hours) best discriminated long-term patient survival in both single- and double-lung transplantation. Furthermore, these studies were conducted before implementation of the LAS and the broad use of Perfadex (XVIVO) as a preservation solution; thus, the applicability of these assertions in the current age of lung transplantation is unknown.
Since the implementation of the LAS in 2005, the severity of disease for those undergoing lung transplantation has worsened as manifested by the percentage of patients who are admitted to an ICU before their operation.1 In this critically ill cohort, the consequence of any poorly taken risk is undeniably magnified. Therefore, before universally advocating for the transplantation of grafts with prolonged graft ischemia times, it is crucial to compare the outcomes of recipient candidates that are in relatively similar states of health at the time of transplant. Our study demonstrates that there was actually a tendency to transplant more ischemic grafts into patients with a set of very-high-risk recipient and donor characteristics—namely, an LAS greater than 60, a history of recipient diabetes and ICU admission, ECMO cannulation or mechanical ventilation before transplantation, and a history of donor diabetes and tobacco use. Given the nature of the database, the exact reason for this trend is not clear; however, intuitively, one could infer that, in critically ill patients with no alternative options, a marginal graft (as deemed by an extended period of graft ischemia) would, therefore, be tolerated. Whatever the reason, these data support the assertion that prolonged graft ischemia times do not affect survival in the face of a critically ill patient population.
While it was imperative to show that survival, even in these critically ill patients, was equivalent between the 2 graft ischemia cohorts, we also sought to explore the influence of prolonged ischemia on short- and long-term mortality rates as well as on the development of PGF. In our risk-adjusted analyses, graft ischemia of 6 or more hours did not independently predict either event. The lack of an association between graft ischemia time and subsequent graft failure should not be trivialized because it is a dreaded complication and a leading cause of early death following lung transplantation.9,10 Given that the proposed mechanism by which allograft edema ultimately culminates in PGF involves the formation of reactive oxygen species and the release of locally produced inflammatory cytokines, it would be logical to assume that an association exists.9,11-13 In our analysis, however, graft ischemia of 6 or more hours was not a predictor either before or after controlling for other variables in the model.
Last, we recognize that graft ischemia time serves as an important parameter to consider when presented with a potential graft for transplantation; however, a better understanding of its possible influence (or lack thereof) on postoperative outcomes is important. Elucidating the true upper limit of graft ischemia time in lung transplantation will improve organ use while maintaining PGF and patient survival rates within currently accepted norms. Moreover, while grafts with extreme ischemia of 8, 10, and 12 hours experienced acceptable 1-year survival rates in our study of 80.1%, 81.2%, and 81.3%, respectively, we expect that there is an upper limit to the degree of ischemia that can be safely tolerated before transplantation. This fact is especially true in organs that are preconditioned for ischemia-reperfusion injury, such as those obtained from brain-dead donors. These lung allografts, if exposed to the common hypertensive crisis following brain death, are highly susceptible to inflammation owing to disruption of the capillary-alveolar membrane.14,15 In similar high-risk donor organs, the use of ex vivo lung preservation has resulted in physiologically stable allografts with acceptable posttransplant outcomes.16 While still experimental in many regards, ex vivo lung preservation could further expand the volume of grafts that are deemed marginal owing to prolonged ischemia or donor-specific considerations.
The UNOS database features a robust set of observations that are available for long-term analysis, but its utility in addressing clinical questions has similar limitations to those of any other retrospective study design. While most variables are entered with consistency, it is common to have sets that lack completion. We attempted to be diligent in determining which variables warranted inclusion in our models, with the understanding that omitted variables could have interacted with our outcomes of interest. For example, while the cause of the organ donor’s death is recorded and most grafts in this study were procured following brain death (9980 of 10 225), the time from injury until graft recovery is unknown. This temporal relationship could result in increased injury to the lung allograft and affect the likelihood of developing PGF. The secondary outcome of interest, PGF, is reported as a binary variable in the UNOS database; therefore, it is impossible to determine the International Society for Heart and Lung Transplantation grade (0-3). Thus, the clinical relevance is unknown. Last, the UNOS database does not collect warm ischemic times, and thus the effect of operative length and complexity on outcomes is not accounted for in our analysis. This fact might partially explain the 30-day survival rate difference between the 2 cohorts.
In this study of more than 10 000 lung transplant recipients, graft ischemia times of 6 or more hours resulted in no significant difference in several key clinical parameters. Exposure of grafts to protracted ischemia did not result in diminished survival and, after risk adjustment, was not an independent predictor of short- and long-term mortality or PGF. Accordingly, it is reasonable to advocate for an extension of the accepted graft ischemia time to more than 6 hours in carefully selected candidates to ease the geographical limitations on donor graft procurement and allow for a more appropriate allocation of scarce resources. However, given the limitations of the UNOS data set, further investigation into more detailed factors, such as cold vs warm ischemic time and donor-specific characteristics, could provide additional insight regarding the effect of total graft ischemia on outcomes following lung transplantation.
Accepted for Publication: October 7, 2014.
Corresponding Author: Ashish S. Shah, MD, Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University, 1800 Orleans, Zayed Tower 7107, Baltimore, MD 21287 (firstname.lastname@example.org).
Published Online: April 15, 2015. doi:10.1001/jamasurg.2015.12.
Author Contributions: Dr A. S. Shah had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis.
Study concept and design: Grimm, Valero, A. S. Shah.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Grimm, Valero, Magruder.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Grimm, Valero, Kilic, Magruder, Merlo.
Obtained funding: A. S. Shah.
Administrative, technical, or material support: A. S. Shah.
Study supervision: Merlo, P. D. Shah, A. S. Shah.
Conflict of Interest Disclosures: None reported.
Previous Presentation: This study was presented at the 2014 Annual Meeting of the International Society for Heart and Lung Transplantation; April 11, 2014; San Diego, California.
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