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While controlled donation after circulatory determination of death (cDCDD) donors could increase the supply of donor lungs within the United States, the yield of lungs from cDCDD donors remain low compared to donation after neurologic determination of death (DNDD) donors. To explore the reason for low lung yield from cDCDD donors, Scientific Registry of Transplant Recipient data were used to assess the impact of donor lung quality on cDCDD lung utilization by fitting a logistic regression model. The relationship between center volume and cDCDD use was assessed and distance between center and donor hospital was calculated by cDCDD status. Recipient survival was compared using a multivariable Cox regression model. Lung utilization was 2.1% for cDCDD donors and 21.4% for DNDD donors. Being a cDCDD donor decreased lung donation (adjusted OR 0.101, CI 0.085–0.120). A minority of centers have performed cDCDD transplant with higher volume centers generally performing more cDCDD transplants. There was no difference in center to donor distance or recipient survival (adjusted HR 1.03, CI 0.78–1.37) between cDCDD and DNDD transplants. cDCDD lungs are underutilized compared to DNDD lungs after adjusting for lung quality. Increasing transplant center expertise and commitment to cDCDD lung procurement is needed to improve utilization.
Lung transplantation, a life-sustaining procedure for individuals with end-stage lung disease, is limited by the low rate of lung utilization in deceased donors. While donor lung utilization rates have improved with an increase in the rate of lungs transplanted per donor from 0.25 in 2000 to 0.37 in 2012, there is a disparity between the number of lung transplant candidates and the deficit of donor lungs.(1) This disparity, in conjunction with increasingly ill lung transplant candidates, has contributed to a rising waiting list mortality from 13.5 per 100 waitlist years in 2004 to 15.4 per 100 waitlist years from 2010–2012.(1, 2)
Expanding the number of donor lung organs through the use of controlled donation after circulatory determination of death (cDCDD) donors has the potential to improve this disparity while preserving long-term recipient outcomes.(3–6) Multiple U.S. (7–12) and international (13–20) studies have demonstrated comparable to favorable survival in cDCDD lung recipients compared to donation after neurological determination of death (DNDD) lung recipients. Additionally, the use of cDCDD for organ transplantation is deemed ethical and is endorsed by multiple professional organizations.(6, 21–23) In 2006, the Institute of Medicine recommended that initiatives to increase cDCDD rates be implemented.(6) Despite similar recipient outcomes and these recommended initiatives, the yield of lungs from cDCDD donors in the United States remains low.(3)
A population-based cohort study estimated that universal identification and referral of all cDCDD donors could increase the lung organ supply by up to 22.7% for optimal donor lungs and by 50% for suboptimal donor lungs.(24) Successful utilization of this theoretical donor pool requires collaboration amongst intensive care unit (ICU) and end-of-life caregivers, organ procurement organizations (OPOs), and transplant physicians. Previous studies have assessed perceived barriers to cDCDD amongst ICU and end-of-life caregivers.(25–27) While important, addressing these barriers is of limited benefit without also identifying and addressing the barriers to OPOs and/or lung transplant programs’ utilization of available cDCDD lung organs.
Studies evaluating the quality and utilization of available cDCDD donors for lung transplant within the U.S. are lacking. The overall quality of cDCDD lungs and whether lung quality impacts utilization is particularly relevant as differences in end-of-life care and management within the U.S., as compared to other countries, may affect the quality of cDCDD lungs. The aims of this study are the following: (1) to describe the donor factors, including cDCDD status, that are associated with lung utilization and to compare cDCDD and DNDD lung utilization when adjusted for lung quality, (2) to assess lung transplant center and OPO factors associated with cDCDD lung use, (3) to calculate whether distance from transplant center to donor hospital differs between utilized cDCDD and DNDD lungs, and (4) to provide an updated analysis of outcomes between cDCDD and DNDD recipients within the post lung allocation score era.
Understanding of the above is essential to identifying and addressing the barriers that contribute to the low rate of cDCDD lungs utilization within the U.S., as compared to other regions of the world.
Using Scientific Registry of Transplant Recipients (SRTR) standard analysis files, we identified all eligible organ donors and all lung transplant recipients between January 1, 2006 and March 3, 2014. Donors were identified as either cDCDD or DNDD and those without a specified donor type were excluded. Descriptive variables were generated from the existing SRTR data fields and compared between cDCDD and DNDD donors and recipients. Categorical variables were displayed as number (%) and continuous variables were displayed as median (25th, 75th percentiles). This study used data from the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the U.S., submitted by the members of the Organ Procurement and Transplantation Network (OPTN). The Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors. This study received an exemption from the Stanford University Institutional Review Board as it uses de-identified data.
To compare cDCDD and DNDD lung utilization, the primary donor outcome assessed was whether a lung from an eligible donor was transplanted. Secondary outcomes included cDCDD utilization over time, the relationship between OPO and lung transplant center volume and cDCDD transplantation, and the median distance from transplant center to donor hospital for utilized cDCDD and DNDD lungs. To compare outcomes between cDCDD and DNDD recipients, the primary outcome was time to death. Recipients who were not observed to have the outcome of interest were right-censored at the time we received the SRTR database (March 3, 2014). Secondary recipient outcomes analyzed were hospital length of stay (LOS) and duration of ventilator support.
A multivariable logistic regression was fit to assess the donor factors associated with the primary outcome of lung utilization. Donor type (cDCDD versus DNDD), along with age in years, cigarette use history greater than 20 pack-years, and PaO2 on 100% FiO2 were a priori included in the model. Sex, race, body mass index (BMI), diabetes mellitus, heavy alcohol use, history of cocaine use, history of other drug abuse, high risk donor status, cause of death, chest x-ray (normal, abnormal, or none), blood infection, and lung infection were all considered for inclusion. We identified variables that were most important for inclusion in the model by constructing random forests.(28, 29) A forest was grown using 500 trees with 4 variables sampled at each split in a tree. The variable importance measure was used to rank the variables in relation to their importance in predicting lung donation for transplantation and variables selected were chosen by visually inspecting a plot of variable importance. An identical secondary analysis was performed using a subgroup of patients from 2010–2014. The R package ‘randomForest’, version 4.6–7, was used to construct the random forest.(30)
We evaluated the relationship of cDCDD status on travel distance between the transplant center and the donor hospital. Geodesic distance was calculated according to the law of cosines in the ‘geosphere’ R package by using SRTR provided transplant center and donor hospital latitude and longitude global positioning system (GPS) degree coordinates.(31) We used a Mann-Whitney test to assess whether the distance between donor hospital and transplant center differed by cDCDD status. The frequency of donors and transplant centers residing in the same OPO or UNOS region were calculated and compared by cDCDD status.
Kaplan-Meier curves were plotted to display recipient survival by cDCDD status. Recipient survival was analyzed using a multivariable Cox proportional hazards regression model. Models included an indicator of cDCDD status to evaluate the association between donor type (cDCDD versus DNDD) and recipient survival. Models were a priori adjusted for donor characteristics including age, sex, race, BMI, PaO2 on 100% FiO2, diabetes mellitus, smoking history, public health service (PHS) increased risk donor status, chest radiograph, and presence of lung or blood infection. Models were also a priori adjusted for transplant center volume and recipient characteristics including age, sex, primary diagnosis, cytomegalovirus match status, procedure type (single, bilateral, re-transplant), pre-transplant medical status (hospitalized in ICU, hospitalized not in ICU, not hospitalized), and lung allocation score (LAS) at time of transplant. The proportional hazards assumption was assessed by visual examination of martingale residual plots and Kaplan-Meier plots. An identical analysis was performed for a sub group of recipients from 2010–2014. Hospital length of stay and post-transplant ventilator support were compared by cDCDD status using a two-tailed Mann-Whitney test and a Fisher’s exact test, respectively.
We used multiple imputations by chained equations with predictive mean matching to avoid omitting patients with missing data and to protect against biases due to excluding missing observations in all regression models. Multiple imputation was performed separately for the donor lung utilization model and recipient outcome model. From each dataset, five separate data sets were created with imputed values and the models were fit on each of the five data sets. The estimates from each data set were pooled to obtain a final estimate with a standard error estimate that accounts for the additional uncertainty due to the unobserved entries being imputed. All statistical analyses were performed with R 3.1.0.(32) Multiple imputations were implemented using the R package ‘mice’, version 2.21.(33) All model estimates are shown with 95% confidence intervals and all tests were conducted at the 0.05 significance level.
We evaluated 65,973 eligible donors (7,690 cDCDD and 58,283 DNDD) of which 12,657 donated lungs (162 cDCDD, 12,495 DNDD) to 13,563 recipients (169 cDCDD, 13,394 DNDD) as shown in Figure 1. Ten donors missing cDCDD status were excluded. The overall donor lung utilization rate was 2.1% for cDCDD donors and 21.4% for DNDD donors. Similar to DNDD utilization, the rate of cDCDD lung utilization slightly increased over time as shown in Figure 2. Eligible cDCDD and DNDD donor characteristics are displayed in Table 1. cDCDD donors were more likely to be white (85% versus 64%) and less likely to be black (7% versus 18%) or Hispanic (6% versus 14%). cDCDD donors were less likely to have a PaO2 ≥ 300 and had an overall lower median PaO2 on 100% oxygen. The median time from withdrawal of life-sustaining treatment (WLST) to death for all eligible cDCDD donors was 18 minutes (IQR 12–25 minutes). The median time from WLST to cannulation for all eligible cDCDD donors was 25 minutes (IQR 23–33 minutes).
cDCDD status significantly decreased lung utilization (adjusted [adj.] OR 0.101, CI 0.085–0.120), along with older age (adj. OR 0.981 per year, CI 0.980–0.983), greater than 20 pack-years smoking history (adj. OR 0.353, CI 0.328–0.379), and abnormal chest radiograph (adj. OR 0.384, CI 0.364–0.404) or absence of chest radiograph (adj. OR 0.518, CI 0.391–0.685). Increasing PaO2 on 100% FiO2 (adj. OR 1.083 per 10 additional mmHg, CI 1.081–1.085) was associated with higher lung utilization (Table 2). Within a 2010–2014 subgroup analysis, cDCDD donor type remained the most significant negative predictor of lung utilization (adj. OR 0.086, CI 0.069–0.108).
Fifty-seven of 58 U.S. organ procurement organizations (OPOs) have assisted in the procurement of any type of cDCDD organ. When limited to cDCDD lungs, 35 OPOs have assisted in procurement of at least one cDCDD lung. Of 84 identified U.S. lung transplant centers, 26 (31%) have performed at least one cDCDD lung transplant. Higher total lung transplant volume is correlated with higher cDCDD lung transplant volume for both OPOs (R2 0.337, p value <0.001) and lung transplant centers (R2 0.253, p value <0.001) as shown in Figure 3.
The median geodesic distance between donor hospital and transplant center was similar by cDCDD status (p value 0.506) with a distance of 236 kilometers (IQR 23–723 kilometers) for cDCDD transplants and 261 kilometers (IQR 40–623 kilometers) for DNDD transplants. High cDCDD volume transplant centers, defined as those who performed at least 10 cDCDD transplants during the study period, had a greater donor travel distance but no significant difference (p value 0.652) between cDCDD (427 kilometers, IQR 131–768 kilometers) and DNDD transplants (417 kilometers, IQR 92–711 kilometers). The transplant center and donor resided in the same OPO in 41.4% of cDCDD and 51.8% of DNDD transplants. Similarly, the transplant center and donor resided in the same United Network for Organ Sharing (UNOS) region in 55.0% of cDCDD and 68.3% of DNDD transplants.
The characteristics of transplanted cDCDD and DNDD lung donors and recipients are described in Table 3. cDCDD lung donors were older (37.5 versus 31.0) but less likely to have a significant smoking history (> 20 pack years) or be categorized as a PHS increased risk donor than DNDD lung donors. cDCDD lung transplant recipients were more likely to have cystic fibrosis (18% versus 13%) and be hospitalized (26% versus 19%), including in an intensive care unit (14% versus 10%), prior to transplant. Use of pre-transplant extracorporeal membrane oxygenation (ECMO) (7% versus 2%) and mechanical ventilation (10% versus 8%) were greater in cDCDD lung recipients than DNDD recipients. Median LAS at listing (36.3 versus 37.0) and transplant (39.6 versus 39.9) were similar for cDCDD and DNDD lung recipients.
Kaplan-Meier curves for unadjusted recipient survival are shown in Figure 4. There was no difference in adjusted survival (adj. HR 1.03, CI 0.78–1.37) between cDCDD and DNDD lung recipients. The median hospital length of stay was longer in cDCDD lung recipients (18 versus 16 days, p-value 0.001). There was a non-statistically significant trend towards increased ventilator support beyond 48 hours (16% versus 15%) and beyond 120 hours (26% versus 18%) in cDCDD lung recipients compared to DNDD recipients (p-value 0.092). Within a 2010–2014 subgroup of lung transplant recipients, there was no significant difference in adjusted survival (adj. HR 1.29, CI 0.76–2.20) by cDCDD status.
Amongst currently eligible U.S. donors, the odds of a cDCDD lung being transplanted are one-tenth the odds of a DNDD lung after adjusting for organ quality. While Australia, Canada and Eurotransplant (not including Germany as DCDD use is not legal in Germany) report greater than 20% utilization of cDCDD lungs(16), the utilization of cDCDD lungs remains poor within the U.S. at 2.1% with the majority of transplant centers having never participated in the transplantation of a cDCDD lung. The low likelihood of cDCDD lung utilization compared to DNDD, even after adjusting for organ quality, suggests that barriers unique to cDCDD lungs are responsible for underutilization.
The barriers for the underutilization of cDCDD lungs are multifactorial and may include concerns about lung quality and recipient outcomes, logistical and financial challenges of cDCDD procurement, and lack of cDCDD experience by lung transplant programs. The absence of established cDCDD procurement protocols for donor hospitals, OPOs, and transplant centers were previously recognized as barriers to cDCDD utilization.(22) In response, the Joint Commission stipulated that all U.S. acute care hospitals maintain protocols for the recovery of cDCDD organs.(34) Similarly, the Centers for Medicare and Medicaid Services and the Organ Procurement and Transplantation Network (OPTN) required all OPOs and transplant centers to have established protocols for the evaluation, management, and recovery of cDCDD donors.(35, 36)
Lung transplant centers may utilize cDCDD lungs less than DNDD lungs for several reasons including less experience with cDCDD procurement, uncertainty surrounding the likelihood of a donor’s progression to circulatory death, and cDCDD aversion due to a center contributing the significant financial and time resources required of a procurement run with the heightened possibility of an aborted run due to prolonged warm ischemia time. We found that higher lung transplant center volume correlated with greater cDCDD utilization. This finding may reflect greater overall expertise, greater willingness to accept risk, greater financial resources, or a larger available surgical procurement team, such as surgical transplant fellows, within larger centers. The formation of a national cDCDD collaborative of all lung transplant centers within Australia significantly increased cDCDD lung utilization to over 30%.(16) Similar development of consensus nationwide protocols and mentored training on cDCDD evaluation and procurement within U.S. lung transplant centers may standardize and improve the ability of all centers to utilize cDCDD lungs.
Uncertainty surrounding a donor’s progression to death remains a barrier for transplant centers evaluating a cDCDD donor. While multiple clinical prediction models for the likelihood of donor expiration within 60 minutes have been developed, they remain inaccurate in approximately 20% of individuals.(37–39) Accordingly, aborted cDCDD procurement or “dry-run” rates of 40% have been reported by a U.S. lung transplant center.(11) Nationwide rates of cDCDD procurement aborts are unknown, as they are not captured in registry data. In data supplied by seven OPOs (see acknowledgments), we found an overall cDCDD procurement abort rate of 28.4% (387 of 1365) and a procurement abort rate of 37% (10 of 27) for cDCDD lungs. Three of these cDCDD lung attempts were aborted secondary to prolonged ischemia time or failure to progress to death.
The heightened possibility of an aborted procurement in cDCDD donors and its resulting resource strain on lung transplant centers is a significant barrier to cDCDD utilization. In contrast to other countries, surgical reimbursement within the U.S. health system is tied to performance of procedures and an aborted procurement consumes significant surgeon time and impacts reimbursement. At our institution, aborted lung procurements cost an average of $18,116.73 per donor, without accounting for the time of our procurement team and surgeon. Registry capture of aborted cDCDD procurements secondary to prolonged ischemia time is needed. Additionally, the use of ex-vivo lung perfusion (EVLP) has been used to evaluate cDCDD lungs, including those with prolonged warm ischemia time, and has shown favorable results.(40) Accordingly, use of EVLP possibly in conjunction with the use of a local procurement recovery team could minimize the financial strain of aborted runs and increase cDCDD lung utilization.
The ethical and policy considerations surrounding cDCDD, including authorization, ante mortem interventions, determination of death, and end-of-life care, have been discussed previously in detail and provide a framework for cDCDD protocols.(21) The legal and ethical concerns relevant to transplant center involvement in cDCDD organ procurement should be alleviated in the setting of adherence to carefully established protocols based upon this ethical framework. Previous legal suits against a transplant procurement surgeon, donor hospital, and OPO allegedly resulted from deviation in such established protocols.(41)
We calculated hypothetical numbers of lung donors based upon increasing the odds of cDCDD lung utilization. If the odds of cDCDD lung utilization increased to one-half the odds of DNDD utilization, the number of donated cDCDD lungs would increase to approximately 112 per year (923 per 8.25 years) from the observed 19.64 per year (162 per 8.25 years). If the odds of cDCDD lung utilization were equal to DNDD lung utilization the number of donated cDCDD lungs would increase to approximately 200 per year (1649 per 8.25 years), which falls short of the 303 reported U.S. lung candidate waiting list deaths in 2012.(1) Importantly, these calculations assume that the rate of lung donation in DNDD donors and the total number of cDCDD donors remain unchanged. Based upon these calculations, equal odds of cDCDD and DNDD utilization would expand the number of all lungs donated by 11.75% (from observed total of 12,657 lung donors to estimated total of 14,144 lung donors). It is likely that the increase in donors may be even greater given advances in the understanding of acceptable donor lungs and in the technology to assess donor lungs. This is not as robust as seen in other international experiences, such as the Australian cDCDD experience, which saw an expansion by 28%.(16) This difference may be secondary to national variations in DNDD use along with variations in cDCDD acceptance and distinctions in end-of-life management that affect the absolute number of eligible cDCDD donors. Therefore, in conjunction with efforts to increase cDCDD utilization, continued efforts at increasing awareness and education of cDCDD within society and amongst health care providers is needed to also increase eligible cDCDD donors.
Similar to previous findings, there was no difference in survival between cDCDD and DNDD lung recipients. There was an increase in hospital length of stay and a trend towards prolonged ventilator duration. In a prior U.S. lung transplant registry analysis of 36 cDCDD recipients, there was a trend towards increased hospital length of stay in cDCDD recipients (17 days versus 15 days, p-value 0.7).(8) A multi-center International Society of Heart and Lung Transplantation DCDD registry analysis similarly demonstrated a longer median hospital length of stay in DCDD lung recipients (18 days versus 16 days, p-value 0.002).(18) We hypothesize that the increased length of stay seen in U.S. cDCDD lung recipients is secondary to the increased pre-transplant illness severity of these cDCDD recipients as discussed below. Importantly, previous international data of cDCDD donors have shown no significant increase in primary graft dysfunction (PGD),(15, 16, 18) and the majority of U.S. single-center data show no significant PGD difference.(9, 11, 12)
Prior U.S. registry data showed a significant difference in LAS between cDCDD and DNDD lung recipients (32 versus 40) suggesting that transplant centers may preferentially select cDCDD donors for less ill candidates. Conversely, LAS scores are now similar between cDCDD and DNDD lung recipients with cDCDD recipients more likely to be hospitalized and in the ICU prior to transplant. Additionally, there is greater use of pre-transplant mechanical ventilation and/or ECMO support in cDCDD lung recipients than DNDD recipients. These findings suggest a shift in cDCDD lung use for more ill candidates and may explain the longer hospital length of stay within this group.
There are several limitations to our study, which are inherent to the use of registry databases such as the SRTR. The SRTR data used in our analysis contains donor demographic and clinical variables, which are regularly used in risk-adjusted models of expected donor yield and outcomes for OPOs and transplant centers.(42–44) Despite the precedent for its use in donor quality assessment, the presence of missing donor data and absence of information on aborted procurements remain a limitation within this registry data. Multiple imputation techniques were used to reduce potential bias associated with missing data, but cannot account for every important missing clinical variables. For example, there was a substantial amount of eligible donors who were missing bronchoscopy data, which prevented the inclusion of bronchoscopy findings within our models. As bronchoscopy in a cDCDD donor is correlated with and sometimes dependent on pursuing procurement of a cDCDD donor, it is difficult to distinguish whether cDCDD aversion or other factors contributed to the absence of this variable. Second, there is no national information on the frequency of or reason for aborted cDCDD procurements. Further study into the nationwide impact of aborted runs on cDCDD utilization and the testing of strategies to reduce aborted runs are needed. Third, important cDCDD clinical management information, such as the use of EVLP and post-transplant recipient outcomes such as PGD and chronic lung allograft dysfunction are not readily available within SRTR data and deserve attention in future studies.
Within the current U.S. donor pool, the odds of lungs from cDCDD donors being utilized for transplant are one-tenth the odds of DNDD lungs being utilized when adjusting for donor organ quality. There remains no difference in survival between cDCDD and DNDD lung transplant recipients. Increasing lung transplant center expertise and commitment to cDCDD procurement along with minimizing the impact of aborted runs through the use of technologies such as EVLP are needed to improve U.S. cDCDD lung utilization.
We appreciate the generous provision of information on the rate of aborted cDCDD procurement attempts by the following OPOs: Donor Network West, Sierra Donor Network, New England Organ Bank, Donor Alliance, Intermountain Donor Services, LifeGift Organ Donation Center, and The Center for Organ Recovery and Education and their donors and donor families. We appreciate the assistance of Kim Standridge, Director of Business and Transplant Outreach Operations at Stanford Health Care, in providing information on the cost of aborted lung procurements. This work was conducted with support from a KL2 Mentored Career Development Award of the Stanford Clinical and Translational Science Award to Spectrum NIH KL2 TR 001083 (J.J.M), HL095686 (M.R.N), and the Ranzetta Family Foundation.
The SRTR data reported here have been supplied by the Minneapolis Medical Research Foundation (MMRF) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the SRTR or the U.S. Government.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.