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Expanding the lung donor pool

advancements and emerging pathways

Reeb, Jeremie; Keshavjee, Shaf; Cypel, Marcelo

Current Opinion in Organ Transplantation: October 2015 - Volume 20 - Issue 5 - p 498–505
doi: 10.1097/MOT.0000000000000233
LUNG TRANSPLANTATION: Edited by Stephanie G. Norfolk
Free

Purpose of review The number of patients listed for lung transplantation largely exceeds the number of available transplantable organs because of a shortage of organ donors and a low utilization rate of lungs from those donors who are available. In recent years, novel strategies have been developed to increase the donor lung pool: improved donor management, the use of lungs from donations after cardiac death (DCD), the use of lobar lung living-donors (LLLD) and the use of ex-vivo lung perfusion (EVLP) to assess and repair injured donor lungs.

Recent findings An adapted donor management strategy could expand the donor pool up to 20%. DCD lung transplant is an increasing part of the donor pool expansion. Outcomes after controlled DCD seem to be similar to donation after brain death. LLLD transplantation has excellent results for small and critically ill patients. EVLP treatment allows for a significant increase in the rate of suitable lungs and represents an optimal platform for lung reconditioning and specific lung therapies.

Summary A significant increase in the number of available lungs for transplantation is expected in the future because of the wider use of lungs from controlled or uncontrolled DCD and LLLD lungs, and with organ-specific EVLP treatment strategies.

Division of Thoracic Surgery, Toronto Lung Transplant Program, University of Toronto

Toronto Lung Transplant Program, Latner Thoracic Surgery Research Laboratories, Toronto, Ontario, Canada

Correspondence to Marcelo Cypel, MD, MSc, Division of Thoracic Surgery, Toronto Lung Transplant Program, University of Toronto, 200 Elizabeth St Rm 9N969, Toronto, ON M5G 2C4, Canada. Tel: +1 416 340 4800; fax: +1 416 340 3478; e-mail: marcelo.cypel@uhn.ca

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INTRODUCTION

Lung transplantation (LTx) is an effective, life-saving therapy for patients with end-stage lung disease. The number of listed patients has been constantly increasing; however, the number of lung donors remains mostly stable. The main limiting factor for LTx success is a shortage of suitable donors. This deficit comprises two components: an overall low number of multiorgan brain death donors, and a low rate (15–20%) of suitable lungs amongst those donors [1]. Most potential lung grafts are declined at the time of allocation because of lung injuries that occur as a result of brain death and ICU-related complications. Because of the severe early- and long-term complications associated with primary graft dysfunction (PGD), the majority of lung transplant programs adopt a conservative strategy in the selection of donor lungs, resulting in a wait-list mortality as high as 30–40% [2–5]. Four approaches are currently being used to increase the number of suitable lung donors: first, improvement in donor lung preservation and optimization in the ICU; second, use of lungs from donation after controlled or uncontrolled cardiac death (cDCD, uDCD) donors; third, use of lobar lung living donors (LLLD); and fourth, normothermic ex-vivo lung perfusion (EVLP). EVLP allows an increased use of donor lungs through two major processes: first, a more complete assessment of questionable lungs prior to transplant; and second, the treatment and the repair of injured lungs toward clinical acceptability.

Box 1

Box 1

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DONOR MANAGEMENT

Donor lung preservation and optimization refer to a global care strategy that preserves or improves the lung quality of potential donors. Thus, the aim is to increase the number of lung allografts available without an increase in early-, mid- and long-term negative outcomes after LTx.

In 2013, Munshi et al.[6] published different donor-management recommendations based on previous research and clinical studies (Table 1). Those guidelines have recently been confirmed by a multicenter study which compared lung donation and PGD rates before and after implementation of a specific lung donor management protocol. This protocol included the following: an apnea test performed with a ventilator on continuous positive pressure mode; 6–8 ml/kg tidal volume; positive end-expiratory pressure 8–10 cmH2O; recruitment maneuvers once per hour and after any disconnection from the ventilator; bronchoscopy with bilateral bronchoalveolar lavage immediately after brain death; and semilateral decubitus position and recruitment maneuvers if the ratio between the arterial oxygen pressure and the inspiration oxygen fraction (PaO2/FiO2) was less than 300 mmHg. Hemodynamics were closely monitored (extra-vascular lung water level <10 ml/kg, CVP <8 mmHg). Lung donation rate (27% vs. 13%) and the number of lungs retrieved (20% vs. 10%) doubled with the implementation of this protocol. PaO2/FiO2 increased from the beginning of the protocol (338 mmHg) to the operating room (399 mmHg). Thirty-three percent of lungs accepted within the protocol period had an initial PaO2/FiO2 less than 300 mmHg. No differences were observed in terms of the presence of severe PGD or 30-day survival rate. Thirty-day survival rates were similar between recipients who received lungs from donors with a constant PaO2/FiO2 more than 300 mmHg (84%) and those transplanted with lungs presenting with an initial PaO2/FiO2 less than 300 mmHg (93%). In the same donors, the retrieval rate for other organs was similar between the two time periods [7▪▪].

Table 1

Table 1

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DONATION AFTER CARDIAC DEATH

Two types of cadaveric donors are currently used: donation following brain death (DBD); and donation following cardiac death (DCD). Among DCD donors, two subclasses can be distinguished depending on the Maastricht classification: cDCD (Maastricht category 3 and 4) and uDCD (Maastricht categories 1 and 2) donors [8]. The concept of using lungs from DCD donors remains controversial because of concerns over the development of specific lung injuries (hypotension, hypoxemia, warm ischemia, aspiration) during the interval between agony and organ retrieval.

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Donation after controlled cardiac death

cDCD is the most common DCD type and is now used in most countries worldwide. In these cases, life-sustaining medical therapies for a potential donor are withdrawn. After cardiac arrest occurs, the recovery team flushes the organs in a usual fashion.

cDCD represents an important increase in the rate of multiorgan donors: 24% from 2006 to 2008 [9]. Nevertheless, the utilization rates of lungs used from cDCD remain heterogeneous (1.9% in the USA vs. approaching DBD rates in some European countries, Australia and Canada in 2012) [10].

Recently, Krutsinger et al. published the first meta-analysis studying DCD lung donors. Six studies were selected for the final meta-analysis. Pooled results of 1-year survival showed no difference in mortality between recipients of cDCD vs. DBD donors (relative risk 0.88, 95% confidence interval (CI) 0.59–1.31; P = 0.52). Pooled analysis was also used to study the prevalence of grade-3 PGD (PGD3) within 72 h after transplant and acute cellular rejection (ACR); no differences were found between the two groups: in cDCD cases, relative risks for PGD3 and ACR were 1.09 (95% CI 0.68–1.73; P = 0.70) and 0.71 (95% CI 0.48–1.05; P = 0.09), respectively. No significant differences were found between recipients of cDCD and DBD donors with respect to lengths of hospital stay (LOS), airway complications rate and incidence of bronchiolitis obliterans syndrome (BOS) [11▪▪].

A separate review published in 2014 highlighted results of the ISHLT DCD registry, comparing the outcomes of 224 DCD vs. 2744 DBD recipients. The authors concluded that the 1-year survival rate of recipients with lungs from cDCD donors was similar to those found in DBD donor allograft recipients [12]. The observed 30-day mortality was 3% in both groups and the 1-year survival rate was 89% in the DCD group, which was similar to survival rates of recipients with DBD donor lungs within the same institutions [12,13].

More recently, a retrospective study using propensity score matching to compare long-term outcomes after LTx using cDCD was performed. Even though DCD recipients had a slightly lower PaO2/FiO2 within 24-h post-LTx (DBD 358 ± 100 vs. DCD 317 ± 106; P = 0.032), there were no differences in subsequent PGD rates, duration of mechanical ventilation, ICU and hospital LOS, ACR and airway complications rates. Nevertheless, the incidence of BOS was higher in the cDCD group compared with the DBD group (23.5 vs. 11.7%; P = 0.049). The estimated BOS-free survival rate was shorter in the cDCD group compared with the DBD group (P = 0.028). One-, 3- and 7-year survival rates did not differ between the two groups [14▪].

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Donation after uncontrolled cardiac death

The clinical experience using lungs from uDCD donors is mainly reported in studies performed by Spanish centers [15–17]. Potential donors are transported in hospital while undergoing cardiopulmonary resuscitation maneuvers. Once the death is certified, lungs are cooled in situ through two chest tubes and after an IV heparin bolus. Resuscitation maneuvers are halted and mechanical ventilation is suspended [15].

The larger cohort in these studies included 29 (18 double LTx and 11 single LTx) recipients from 29 Maastricht category-2 donors. Grade-3, grade-2- and grade-1 PGD rates were 38%, 17% and 17%, respectively. Overall hospital mortality rate was 17%, with a significant association between mortality and both ischemic time and incidence of PGD. At 1 year after LTx, survival rate, conditional survival rate in patients who survived more than 3 months, and incidence of BOS were 68%, 86% and 11%, respectively. At 5-year follow-up, results were 51%, 65% and 45%, respectively [16]. In comparison, in their meta-analysis, Krutsinger et al. reported 1-year survival, 5-year survival and 5-year incidence of BOS in cDCD donors. These ranged from 68% to 94%, 71% to 90% and 28% to 35%, respectively [11▪▪]. Recent publications on uDCD have reported successful small cohort studies or case reports with short follow-up periods [18–20].

With EVLP technology being integrated into routine practice in lung transplant centers, uDCD activities and prospective studies are expected to increase worldwide.

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LIVING DONOR

Living-donor lobar-LTx (LLTx) has been developed in an effort to increase the supply of donor lungs for small and critically ill patients awaiting LTx. In this procedure, a single right lobe and/or left lobe from a healthy donor is implanted in the recipient in place of whole right and/or left lungs, respectively. A first review, published by Date in 2011, concluded that living-donor LLTx could be performed safely in recipients, with similar survival rates as cadaveric lung transplant recipients [21].

Most studies have reported the absence of operative and functional morbidities induced by lobectomy in donors [21,22,23▪▪]. Chen et al. have published two clinical studies focused on LLLDs. In their first publication, 43 donors were identified. The mean duration of the drainage period was 4.0 ± 1.9 days. Three donors had a chest tube inserted for more than 1 week. A thoracocentesis was performed in one donor, and two donors were treated using a chest tube reinsertion. All donors survived and were discharged at home without significant issue [24]. Recently, a second article studied multidimensional outcomes before, and 1 year after, donor lobectomies. Thirty-three donors were included and none experienced life-threatening complications or death. Five donors had, however, postoperative concerns requiring hospital readmission. All donors were discharged without any specific limitations in daily life at 1 year after donation. Nevertheless, 1 year after lobectomies, LLLD reported a significantly worsening in quality of life (QOL); modified dyspnea scale in these donors deteriorated after surgery, and a psychological study showed a higher anxiety level after donation. Moreover, in cases of recipient death, there were significant decreases in QOL and sleep quality [25].

Concerning recipient outcomes, Date published a comparison between 42 living-donor LLTx (76.2% bilateral LTx) and 37 LTx (40.5% bilateral LTx) using cadaveric donors. Recipients of lungs from the living-donor LLTx group were more often on steroids (64.3 vs. 29.7%) and required less ambulatory treatment (42.9 vs. 86.5%). The living-donor LLTx group presented a significantly higher PaO2/FiO2 immediately after reperfusion (434 ± 121 vs. 303 ± 117 mmHg; P < 0.0001) but had a longer duration of mechanical ventilation (15.6 ± 16.2 vs. 8.5 ± 8.1 days; P = 0.025). Thirty-day and hospital mortality rates, and 1- and 3-year survival rates, did not differ between the two groups [23▪▪].

Another specific issue regarding living-donor LLTx recipients is the development toward a unilateral chronic lung allograft dysfunction which may be successfully halted by treatment or may progress to the other lung metachronously [26].

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Downsized cadaveric donor lungs

Downsized cadaveric donor lungs are primarily used not to strictly expand the donor pool but to decrease the waiting time of small or critically ill patients. Reliable procedures for downsizing donor lungs are lobar-LTx, split-LTx or peripheral/wedge resection. Previous studies have shown that cadaveric-donor LLTx resulted in equivalent survival rates compared with those of whole-LTx [27–30]. Recently, the Vienna group published the largest cohort of cadaveric-donor LLTx to date, and concluded that 1- and 5-year survival rates were inferior in cadaveric-donor LLTx cases compared with other forms of LTx (84.5 vs. 65.1%, and 69.9 vs. 54.9%, respectively; P < 0.001) [31▪]. Nevertheless, cadaveric-donor LLTx recipients were more frequently listed as ‘high urgent’ and more often required a bridging therapy prior to LTx. As previously documented, cadaveric-donor LLTx was associated with a higher incidence of PGD3 and required more postoperative ECMO support [30–32]. No difference was observed in the survival analysis conditional on hospital discharge [31▪].

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EX-VIVO LUNG PERFUSION

Rationale for ex-vivo lung perfusion

The current clinical practice for donor lung preservation is primarily cold static preservation. In this technique, lungs are stored at 4°C which reduces cell metabolism, O2 requirement and nutrient consumption.

In contrast, normothermic EVLP allows for the preservation of metabolic function and lung homeostasis. EVLP-treated donor lungs can remain in a functional physiological state for several hours. During this period, lungs can be assessed, reconditioned and repaired by different mechanisms: dehydration of lung tissue; removal of harmful and toxic waste products; recruitment of atelectatic areas resulting in better ventilation/perfusion matching and improved microcirculation [33].

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Ex-vivo lung perfusion protocols

The Toronto, Lund and Organ Care System (Transmedics, Andover, MA) protocols are currently employed in LTx centers worldwide. Each protocol differs from one another through six main criteria: composition of perfusate; addition or absence of red blood cells; flow characteristics during EVLP; left atrium management; ventilatory settings and initial timing of EVLP treatment (Table 2). The Toronto protocol specificities and rationale are described in Table 3[34–46].

Table 2

Table 2

Table 3

Table 3

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Ex-vivo lung perfusion for lung reconditioning

The Toronto group performed the first clinical trial and currently has the largest clinical experience with EVLP – almost 200 clinical intent EVLP cases have been performed to date [47,48]. In 2012, the team reported their clinical experience with an initial 50 donor lungs that met criteria for EVLP and were subsequently transplanted. All lungs were sourced from DCD donors or initially unsuitable DBD donors, and EVLP duration was 4–6 h. During this time, bronchoscopies and radiographic images were performed at 1 and 3 h. During each hour, PaO2/FiO2, pulmonary artery pressure, lung compliance and peak airway pressure were assessed. Stable readings or improvements in these parameters, alongside a delta PaO2/FiO2 more than 350 mmHg, qualified these lungs for transplantation. PGD3, extracorporeal life support, bronchial complications, duration of mechanical ventilation, ICU and hospital LOS, as well as 30-day, 1-year and 3-year mortality rates were similar in the EVLP group compared with a control LTx group whose donor lungs were not treated with EVLP [47,48]. The Toronto group also published the functional outcomes and QOL of the first 63 patients receiving lungs treated with EVLP and compared these findings to those of 340 conventional donor lung recipients contemporarily transplanted. Five-year survival rates in the EVLP group were 71% vs. 57% in the control group (P > 0.05). Absence of chronic lung allograft dysfunction, highest forced expiratory volume in 1 s predicted, change in 6-min walk distance and the number of ACR episodes were similar between the two groups (P > 0.05). QOL was significantly improved in both groups compared with the time period before LTx. There were no differences in QOL improvement between EVLP and conventional lung groups [49▪▪]. These early- and mid-term results were confirmed worldwide in recent studies: PGD3, ICU and hospital LOS, 30-days and 1-year survival rates are not negatively affected by the use of EVLP [50–54]. Normothermic EVLP results in an increase of viable lungs in the donor pool by at least 20–30% [6,50,53].

An emerging clinical interest of EVLP is the assessment of lung allografts from DCD donors. cDCD donor lungs may experience relatively heightened injury and deterioration as a result of the withdrawal of life-sustaining therapies. The utilization rates of these lungs have traditionally been poor. Through assessment and treatment prior to transplant, EVLP could increase the safety and utilization of extended-criteria cDCD donor lungs. Specifically, EVLP provides the opportunity to thoroughly evaluate these lungs and confirm good lung function prior to initiating LTx. In 2015, the Toronto group reported their DCD LTx experience. First, they compared 55 cDCD LTx to 570 date-matched DBD LTx, and then compared 27 DCD LTx managed without EVLP (DCD-no EVLP group) to 28 DCD LTx associated with EVLP (DCD-EVLP group). There were no differences between DCD and DBD recipients in the duration of mechanical ventilation, ICU and hospital LOS, and 1-, 3- and 5-year survival rates. Compared with DCD-no EVLP, DCD-EVLP recipients had a shorter hospital LOS (23 [16–42] vs. 18 [14▪,22] days; P = 0.047). Although survival curves were comparable, the 3-year survival rate was notably higher in the DCD-EVLP than the DCD-no EVLP group (71% vs. 51%; P = 0.68) [55▪▪]. In a similar study, the Madrid group used EVLP in eight uDCD donor lungs, resulting in four bilateral LTx. Importantly, no recipients experienced PGD3 [56].

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Ex-vivo lung perfusion for specific donor lung repair

EVLP can be an ideal platform for delivering specific therapies to injured donor lungs. Injuries (including edema [57,58], inflammation [59,60], infection [60–62], aspiration [63,64], pulmonary embolism [65,66] and injury related to DCD-[67]) and EVLP-specific treatments are listed in Table 4. Together, these preliminary results provide great promise for the continued development of injured donor lung rehabilitation and donor pool expansion strategies.

Table 4

Table 4

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CONCLUSION

Optimal donor management is the first and most important step in expanding the donor lung pool. Specific therapies in the ICU allow for a significant increase in the donor lung pool without affecting retrieval rates of other organs or the outcomes of lung recipients.

LTx using DCD donor lungs is now a clinical reality. Outcomes from the use of cDCD donor lungs are similar to those of DBD donor lungs. uDCD represents a significant potential additional lung allograft source. It is established that LTx from uCDC is feasible, but retrieval and assessment protocols should be optimized in order to decrease PGD incidence.

Living-donor LLTx is an emergent alternative strategy to expand the donor lung pool for critically ill children and small adult patients. Recipient outcomes are similar to those of cadaveric patients. Nevertheless, the specific issue related to the living donor makes the utilization of this technique a challenge.

Lung preservation and reconditioning using EVLP technology is now well established and outcomes are, at the very least, similar to that of cold static preservation. With the emergence of EVLP technology in the use of DCD lungs, clinicians can now better assess acutely injured lungs. Indeed, this technology represents an ex-vivo arsenal platform able to provide specific therapies for targeted injuries. It is hoped that better knowledge across all of these fields will soon enable clinicians to expand and use the full potential of the donor organ pool.

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Acknowledgements

None.

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Financial support and sponsorship

S.K. and M.C. are co-founders of Perfusix Inc. and XOR Labs Toronto.

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Conflicts of interest

The authors confirm that this paper has not been published in its current form or a substantially similar form. This article has not been accepted for publication elsewhere, and it is not under consideration by another publication.

There are no conflicts of interest.

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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
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This paper is published by the group with the highest level of clinical experience with ex vivo lung perfusion. It is the only paper specifically describing the impact of the ex vivo lung perfusion after cardiocirculatory death donation.

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Keywords:

donation after controlled or uncontrolled cardiac death; donor management; ex-vivo lung perfusion; living donor

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