Donation after cardiac death lung transplantation outcomes Christopher H. Wigfield and Robert B. Love

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1 Donation after cardiac death lung transplantation outcomes Christopher H. Wigfield and Robert B. Love Department of Cardiothoracic Surgery, Loyola University, Chicago, Illinois, USA Correspondence to C.H. Wigfield, MD, FRCS, Loyola University Medical Center, 2160 S 1st Ave, EMS Bldg 110, 6254, Maywood, IL 60153, USA cwigfield@lumc.edu Current Opinion in Organ Transplantation 2011, 16: Purpose of review Lung transplantation is now a well established treatment option for several end-stage respiratory diseases. Survival after lung transplantation has significantly improved over the last decade. The primary limitation to increased utilization of lung transplantation remains donor scarcity. Suitable allografts have been procured from donors after determination of neurologic death and from donors after determination of cardiac death (DDCD or DCD). Historically, the first human lung transplantation performed, utilized an allograft procured after cardiovascular death, also referred to as nonheart-beating donor.the experience at University of Wisconsin in 1993 reintroduced DCD lung transplantation with the first successful clinical case. Recent findings A potential additional lung allograft source, DCD lung transplantation has been established with very acceptable outcomes observed by several centers. We provide the relevant background for the rationale of donor allograft expansion to include DCD lungs from controlled (Maastricht category III donors). Summary This review considers the available evidence for DCD lung transplantation and compares reported primary graft dysfunction rates and current survival data available. Keywords donation after cardiac death, lung transplantation, outcomes Curr Opin Organ Transplant 16: ß 2011 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction Lung transplantation remains the only treatment option for selected end-stage respiratory diseases [1,2 ]. Outcomes after lung transplantation have significantly improved, but donor shortage remains the primary limitation to increased utilization. Donation after cardiac death (DCD) lung transplantation was re-introduced to provide an additional source of lungs to alleviate this shortage of suitable allografts [3 5]. A paradigm shift in the late 1960s resulted in the neurological definition of death in many countries [6]. This resulted in procurement of allografts for transplantation predominantly from verified brain death donors with maintained peripheral organ perfusion. However, only one in five brain death donors yield suitable allografts for lung transplantation and brain stem death has detrimental effects on lung quality due to pulmonary vascular and inflammatory sequelae [7]. The severe shortage of suitable lungs has resulted in excess deaths of candidates on waiting lists and has considerable impact on clinical deconditioning of candidates prior to lung transplantation. DCD provides a readily available, alternative source of lungs for transplantation. The total amount of solid organs transplanted from DCD donors may have plateaued recently, but nonetheless presents a meaningful addition to the lung transplant donor pool. Defined as allografts available from donors after complete cessation of cardiovascular function, these donors require a modified protocol to achieve procurement of viable lungs. Ethical propriety and legislative considerations were provided by several national bodies and in the USA resulted in specific Joint Commission guidelines and Institute of Medicine statements [8]. Despite this, there is evidence of underutilization of this donor source for lung transplantation and currently only a handful centers in Northern America, Europe, and Australia have implemented protocols resulting in active DCD lung transplantation programs. A recent analysis of United Network Organ Sharing (UNOS) DCD procurement data trends confirms that there has only been a modest increase in DCD lung transplant activity over the past 10 years. The current DCD contribution to all lung transplants performed is approximately 2% in the USA (Fig. 1) [9,10 ]. Extrapolation of the UNOS organ procurement organization (OPO) offers received; however, suggest that ß 2011 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /MOT.0b013e32834a99ac

2 Donation after cardiac death lung transplantation outcomes Wigfield and Love 463 approximately 100 suitable DCD lung donors are feasible per annum. In Australia, the percentage of DCD lungs transplanted in 2010 may have provided a more marked expansion of the national donor pool [11 ]. This has been achieved exclusively with Maastricht category III donors, that is, controlled DCD lungs procured (Table 1, see below). A very reasonable risk assessment can be completed for such donors. Despite logistic challenges, a high proportion of such DCD assessments could provide lung allografts, especially when local organ procurement protocols are established and progression to cardiovascular death of donors occurs within 60 min of withdrawal of support. As for all procurement efforts, effective communication is essential and some additional procedural skill can be safely adapted by experienced lung transplant surgeons. An appropriate informed consent process for potential recipients should be in place and address the fact that long-term outcomes are pending. The worldwide experience includes only a very small group of DCD recipients, transplanted prior to 2005 [12,13]. The decline of available brain death donors due to road traffic safety measures has led OPOs to consider categories III and IV as potentially safe options. The viability of DCD lung retrieval has been well established, both experimentally and clinically [14,15]. Safe ischemia times have been proposed in retrospective cohort evaluations [16,17]. The combined effect of transient warm in situ ischemia during withdrawal of support and subsequent cardiovascular arrest and the added mandatory Key points Donation after cardiac death (DCD) lung transplantation results are comparable with conventional brain death donor lung transplant recipient outcomes. Primary graft dysfunction rates observed are somewhat variable, but have been lower than expected for extended criteria donor lung transplantation in some cohorts. A more complete 3-year survival analysis is currently not available due to the re-introduction of DCD reintroduced 1993 (see reference [4]). Longterm outcome data are required, especially for the incidence of bronchiolitis obliterans syndrome in these recipients. cold ischemic period after flush perfusion have not proven to be a clinically significant obstacle. The utilization of DCD lungs from uncontrolled (Maastricht categories I or II, see Table 2) remains more controversial. The potentially vast expansion of national lung donor pools is associated with considerable nonquantifiable risks. These are currently deemed unacceptable for most procurement services and the majority of lung transplant centers. The legislative prerequisite for presumed consent for these donors is in effect only in a few countries. A cohort of category II DCD lung allograft recipients was utilized in Spain. Recipients in this series developed a disproportionately high incidence of primary graft dysfunction Figure 1 Analysis of United Network Organ Sharing donation after cardiac death donor data (with permission) UNOS DCD donors DCD lung donors DCD donors Lung DCD Total DCD donors Linear (lung DCD) Year [10] United Network for Organ Sharing Scientific Registry Data:

3 464 Lung transplantation Table 1 Summary of currently available outcome data for donation after cardiac death lung transplantation Cohort Years Maastricht Category (MC) n PGD (n) ISHLT GRADE s >2 Survival % at 1 year Survival % at 3 years BOS (n) at 3 years UW/Loyola [27 ] 9-09 MC III % St Louis [35] MC III 13 4/ Cleveland [36] 04-7 MC III 31 $ V 4 Australia [11 ] MC III 32 3/ NA 9 Newcastle [37 ] MC III 25 4/ Groningen [38,39 ] MC III # 95 pending pending Toronto [40] MC III 31 P Spain [41,42] MC I 9/17; 53% Information presented based on personal communication with representative physicians of each lung transplant program for updates on previously published cohorts (see references and acknowledgments). N/A, data not available; s, ISHLT criteria for primary graft dysfunction (PGD) [43]; #, data at 72 h after LTx; P, includes ex-vivo lung perfusion (EVLP) optimized donation after cardiac death (DCD) lungs in this cohort; V, survival at 24 months; $, cohort, three patients required extracorporeal membrane oxygenation (ECMO) to survive. (PGD) with an associated higher early mortality rate when compared with conventional brain death donor lung recipients (see Table 1) [18,19]. Due to a lack of additional outcome data, detailed discussion of this cohort is currently not warranted and updates on the existing cohorts are required. The assessment of controlled DCD lung donors and the required protocols for successful procurements are reviewed elsewhere [20]. The clinical context and additional procedural issues relevant to DCD lung transplantation are considered prior to reporting up to date outcome data available for controlled DCD lung transplantation. Primary markers considered for early outcomes are PGD, graded according to ISHLT criteria [21], and 1-year and 3-year survival rates are documented for mid-term outcome. Bronchiolitis obliterans syndrome (BOS) data are presented wherever available, but have to be seen in context of small groups and early follow-up for most of these patients. Donation after cardiac death lung transplantation in context Efforts to reduce the lung transplant waiting list mortality are mostly dependent on identifying suitable donors to provide allografts in time. Several OPOs have reported up to 30% of accepted candidates for lungs may not progress to transplantation. Brain death donors do not suffice to meet the increasing demand for lung transplantation. UNOS registry data confirm the persistent shortage and disparity of lungs when compared with other solid organs procured from DDND offers (Fig. 2). A slight increase in overall lung transplantation has been achieved with considerable liberalization (extended criteria donor; ECD) of the donor criteria for brain dead donors. A more frequent acceptance of marginal donor lungs has been a consequence. Pulmonary allograft parameters or systemic donor criteria associated with such offers are often far from ideal. These ECD lungs have nonetheless provided reasonable outcomes. Several investigators have more recently observed higher associated risks and PGD may be more frequent and overall outcomes of ECD from DDND have been less satisfactory in some series [22]. The potential for DCD has improved prospects for candidates of other solid organ transplants. Excellent results have been achieved in renal transplantation utilizing established DCD protocols. Established DCD donor procurement protocols for controlled donors, therefore, provide a unique opportunity to increase the rate of lung transplantation and reduce lung waiting list mortality. A clinical ISHLT registry for DCD lung transplantation has been established Table 2 Potential utility of donation after cardiac death category donor lungs for transplantation with associated risk stratification DCD donor Maastricht category Donor assessment and declaration of death Availability potential Associated risk profiles LTx I Donor declared dead on arrival Potentially vast supply source Virtually no donor risk profile assessment possible II Donor death declared after Significant increase of donor pool Very limited donor risk evaluation unsuccessful resuscitation III Awaiting cardiovascular death, after withdrawal of support Estimated app. 30% donor expansion Good risk assessment, logistic concerns, donor progression issues IV Cardiorespiratory arrest after verified brain death Less frequent occurrence Additive BD-related and DCD procurement factors present DCD, donation after cardiac death. DCD Maastricht criteria modified from [19].

4 Donation after cardiac death lung transplantation outcomes Wigfield and Love 465 Figure 2 Disparity between total brain death donor offers and resulting lung procurements Donors Lung BD Total BD Source: Data UNOS BD donors Year recently, but is not yet available for analyses. There is currently a paucity of clinical information. Most reports available are from single center retrospective reviews with typical study limitations for small cohorts. Several case series published results in accordance with the first cohort of 24 consecutive DCD lung allografts transplanted and provided excellent early outcomes. The evaluation of DCD donor data and procurement for DCD lung programs has been documented elsewhere [23]. Early experience with DCD lung transplantation has been confounded in some series by selection of highrisk profile candidates. The recipients in the first series reported may not have otherwise survived the waiting time associated with standard allograft availability. The worldwide experience, however, was probably less than 100 cases prior to Donation after cardiac death lung donors Several countries have implemented accreditation standards for DCD (e.g., Joint Commission in the USA) [24]. DCD lung donor offers are usually referred and assessed according to UNOS or other international transplant procurement organization guidelines. Procedures are performed in strict adherence to established local OPO protocols. Recognition of the defined handsoff time stipulated and co-operation with a multiorgan procurement venture with considerable procedural pressures are the key to compliance and successful outcomes. Due to the unpredictability of DCD offers occurring, the consent for DCD lung transplantation has to be completed a priori. The recipient consenting process should reflect the uncertainty regarding long-term graft function, although early experience with DCD lungs transplanted has been very reassuring in most series. Potential candidates have to receive informed consent regarding potential risks while waiting for a transplant. Assessment for contraindications for DCD lung donation includes the following criteria for all declared donors with acceptance of failure to progress in time after support withdrawal. Composite scores have been suggested to predict the likeliness of DCDD occurring. A detailed DCD lung procurement protocol has been published elsewhere and a brief synopsis is provided here only [25 ]. A bronchoscopy should be performed for all procurements to assess allograft adequacy and provide cultures of airway secretions. Endotracheal re-intubation is frequently required after completion of hands-off period subsequent to verified asystole. Administration of antegrade flush solution determines the end of relative warm ischemia time (WIT). This generally has been kept to a mean of less than 40 min in most series. Further procurement adjustments are required for uncontrolled Maastricht DCD Category II Donors. The modified Madrid Criteria have been published by Gamez et al. [26] for potential organ preservation in individuals suffering witnessed sudden cardiac arrest. Outcomes after donation after cardiac death lung transplantation: primary graft dysfunction and survival Several DCD lung transplant cohorts have now been reported with retrospective data. Generally, early and mid-term outcomes have been comparable with lung transplantation from brain dead donors. Most reports published to date, however, summarize the findings of small case series. Most early adopters have now publicly advocated its widened application. The results reported from University Wisconsin and Loyola University Medical Center provided early clinical evidence of the feasibility of DCD lung transplantation with only 12.3% severe PGD (ISHLT Grade 2 or greater) and good mid-term graft function was documented. Both, early oxygenation parameters and up to 60-month forced expiratory volume per 1 second (FEV 1 ), follow-up were essentially equal to conventional lung transplantation from brain dead donors [27 ]. This was achieved despite significantly higher recipient risks and lung allocation scores (LASs). It is noteworthy that only two patients in this early cohort had clinically severe PGD (ISHLT PGD grade 3).

5 466 Lung transplantation Similarly, this has been the experience in several other international centers with increasing utilization of DCD lung transplantation. The initial reports of the Australian experience included a PGD rate of 13%. A recent review of additional DCD lungs transplanted there has shown a decreased incidence with only three of 32 recipients with severe PGD in this cohort. This has not been replicated by all DCD programs; however, early DCD transplants (prior to 2007) may have had more frequent need for extracorporeal membrane oxygenation support with reasonable survival outcomes. A higher reperfusion associated injury rate and PGD was observed with uncontrolled DCD lung transplantation in a Spanish cohort. An early report of nine of 17 (53%) recipients developing severe PGD (29% Grade 3) was reported, although apparently no deaths were directly attributed to PGD. A recent preliminary report describes the feasibility of ex-vivo allograft assessment and subsequent transplantation of human Maastricht Category I DCD donor lungs with no observed immediate reperfusion injury. This may prove to be a risk-reduced strategy to expand the donor pool wherein the required legislation allows, but this has to be confirmed in an appropriate case series [28 ]. The overall observed reduction in severe reperfusion related PGD in controlled DCD (Maastricht category III) lung recipients likewise requires evaluation with multicenter registry data. If confirmed, this potentially constitutes a beneficial clinical aspect of DCD lung transplantation. A very intriguing finding is an apparent recent reduction of PGD rate seen in the Toronto series of DCD lung recipients. The evolution of ex-vivo lung perfusion (EVLP) and application to controlled DCD donor lungs provided a notable reduction of PGD in their experience with DCD lungs (personal communication, Dr Keshafjee, Toronto) [29 ]. This presents an opportunity to further expand the acceptance criteria for donor lungs combined with novel approaches for pulmonary viability assessment [30]. This may positively impact the overall rate of lung utilization and avoid transplantation of lungs not responsive to EVLP. Survival after donation after cardiac death lung transplantation A UNOS data analysis of the early era of controlled DCD lung transplantation ( 87-07) provided an unadjusted survival rate of 94% at 12 months and 87% at 24 months, respectively. The outcomes are remarkable in view of the sporadic utilization of DCD lungs for two decades. The expanded use of DCD lung transplantation including bilateral lung transplantation was supported [31]. Prior to this analysis, only case reports had been published [32 34]. The more recently observed early and mid-term survival for several controlled DCD lung transplant programs has been summarized in Table 1 [18,26,27,35,36,37, 38,39,40,41]. Previously published experience has been updated with data from personal communication to provide a more accurate impression of outcomes observed. The survival data provided have been restricted to 1-year and 3-year survival to provide a comparative overview. Less than 200 recipients have been followed in these case series. The survival reported for 1 year ranges from 72 to 100% and 3-year survival from 47 to 80%. Essentially, these outcomes are comparable with most observed standard criteria donors (SCD) and ECD lung transplant recipient outcomes. Selection bias, a wide range of co-morbidities, and higher LASs are likely confounders not allowing for direct comparison with ISHLT registry data. There is currently no stratification according to recipient diagnosis or age at the time of transplantation. A prospective DCD transplant database is needed for meaningful outcome evaluation. To establish standards and allow for comparison with conventional donor lung recipients, an ISHLT DCD registry has been implemented. Bronchiolitis obliterans syndrome after donation after cardiac death lung transplantation BOS has been recognized as a limiting factor for longterm allograft function after SCD and ECD lung transplantation. The incidence of BOS at 3 and 5 years after DCD lung transplantation has only been reported in two reviews. The cohort reported from University of Wisconsin had a 76.6% freedom from BOS at 3 years. No statistically significant difference was seen when compared with the incidence of BOS in patients receiving lungs from brain death donors in that program (P ¼ 0.59) [11 ]. Early indications from other cohort analysis appear to have somewhat higher rates at 3 years. Wherever possible, actual cases reported with clinically established BOS have been added in Table 1. There is currently insufficient statistical power due to the small number of DCD lung recipients surviving 5 years or more to provide a meaningful comparison with the ISHLT registry for DDND lung transplant incidence of BOS. The ISHLT DCD lung transplant registry will hopefully generate this information and is critical for continued advocacy of DCD lung transplantation. Discussion The rationale for increased utilization of available DCD lungs has been apparent for some time [42,43]. The disparity between acceptable brain death donors

6 Donation after cardiac death lung transplantation outcomes Wigfield and Love 467 identified and numerous candidates waiting for lung transplantation continues worldwide. The scientific evidence available and experimental animal models indicate that lungs may possibly be less vulnerable to the combined ischemic times than previously thought [44]. Adapted protocols are required and strict adherence to local procurement standards for DCD donors is mandatory. Ethical propriety has been confirmed and clinical guidelines have been in place in many regions. A National Conference on Donation after Cardiac Death provided consensus and DCD transplantation has been adopted as an ethically acceptable practice of end-oflifecare, capable of increasing the number of deceaseddonor organs available for successful transplantation [45,46]. The outcomes previously published as well as the updated experience reported here from centers adapting DCD lung transplantation early, have been promising. PGD greater than ISHLT grade 2 may have been observed less frequently than would be expected for ECD from brain death donors. The lack of prospective data evaluation, however, leaves some uncertainty. Skepticism regarding detrimental pulmonary consequences of circulatory arrest has not been borne out in reality. When care is taken to avoid excessive atelectatic collapse and achieve adequate flush perfusion, DCD lungs have proven viable and adequate for transplantation. A possibly unique tolerance for transient lack of perfusion is conspicuous in DCD lungs [47]. This is likely to be at least partially due to absence of detrimental effects of brain death induced lung injury [48]. Thrombotic complications have not been reported, even in cohorts without routine systemic administration of heparin. The usual brief internal cardiac massage to distribute a bolus dose of heparin into the pulmonary vascular bed has been advocated. Optimized flush solution distribution clearly relies on swift re-expansion of lungs with re-ventilation after withdrawal of life support in DCD donors. More subtle early pathophysiologic effects of circulatory arrest on lung parenchyma have not been studied in human donors. These topics should include apoptosis induction, alveolar-capillary integrity, cytokine gradients and alveolar sequestration of neutrophils, alterations in innate immune regulation, and class II MHC upregulation. The actual incidence of acute cellular rejection and the development of BOS need to be established. A DCD registry provided by the International Society for Heart and Lung Transplantation has now commenced tracking outcomes after DCD lung transplantation. At our center, we initially resorted to DCD allografts predominantly in recipients with high risk of mortality on the waiting list, when even ECD lungs would be unlikely to be found in time for transplantation. Much remains to be learned about the best practice of DCD Lung transplantation. How to optimize such donor lungs, especially when they fall into the ECD category, and how to increase the number of DCD transplants performed are the primary concerns [49]. EVLP and functional assessment prior to transplantation of DCD lung allografts will likely prove to be a valuable strategy. This has proven to be a valid approach in the Toronto Lung Transplant Program and is likely to improve outcomes in DCD lung transplantation. Borderline or clearly nonviable DCD lungs may be ruled out during EVLP assessment. Once clinically standardized, this process should facilitate DCD procurement considerably. Conclusion With increasing experience and validation of the clinical applications including ex-vivo assessment, DCD donation is likely to be an increasing source of allografts for lung transplantation. It may provide a realistic alternative for many patients waiting for lung transplantation. Continued public and professional education as well as clinical and basic science research specifically related to DCD lung transplantation is required. The ISHLT DCD lung transplantation registry will provide a means for data analysis far superior to individual cohort analysis and should be seen as an essential contribution in the assessment of outcomes in this field. Acknowledgements The authors would like to thank the following representatives and lung transplant programs for sharing their updated DCD lung transplantation outcomes as included in Table 2: Tanveer Butt and John Dark, Newcastle University; Marcelo Cypel and Shaf Keshafjee, Toronto, Alec Patterson Washington University, St Louis and David Mason, Cleveland Clinic. Michiel Erasmus, Groningen. The authors would like to thank UNOS for permission to analyze the donor data from the registry and Erin Mahoney for preparation of the graphics. Conflicts of interest There are no conflicts of interest. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Arcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med 1991; 340: Hertz M, Aurora P, Christie JD, et al. ISHLT registry report J Heart Lung Transplant 2010; 29: Introduction to the 2010 annual reports.

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