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The decision to perform a single-lung transplant (SLT) when the contralateral donor lung is rejected is a challenging scenario. The introduction of ex vivo lung perfusion (EVLP) has improved donor lung assessment, and we hypothesize that it has improved SLT outcomes in this setting.
Methods
A retrospective single-center review of all SLTs performed between 2000 and 2017 was performed in which the years 2000 to 2008 were considered the “pre-EVLP era” and 2009 to 2017 the “EVLP era.” Recipients of SLT lungs when the contralateral lung was declined were classified into 3 groups: (1) Pre-EVLP era, (2a) EVLP era but EVLP not used, and (2b) EVLP era and EVLP used. The outcomes of interest were survival, time-to-extubation, and intensive care unit and hospital stay.
Results
Among 1692 transplants between 2000 and 2017, 244 (14%) were SLT. SLT rate was similar between eras (pre-EVLP 16% vs EVLP 15%), but more SLTs were performed where the contralateral lung was declined in the EVLP era (pre-EVLP 32% vs EVLP 45%, P = .04). Lungs evaluated on EVLP had lower procurement partial pressure of oxygen and were more often from donation after cardiac death donors. Recipients were generally also sicker, with a greater proportion of rapidly deteriorating recipients. Despite this, outcomes were similar between eras with a trend towards lower 30-day mortality in the EVLP era.
Conclusions
The availability of EVLP allowed for better evaluation of marginal single lungs when the contralateral was declined. This has led to increased use rates with preserved outcomes despite use of more extended criteria organs.
The availability of ex vivo lung perfusion for the evaluation of single donor lungs when the contralateral lung is declined for transplant increases the safe use of these lungs.
A common scenario when donor lungs are assessed for transplant is that one lung is seemingly better than the other. Owing to the concern that injuries will affect lungs bilaterally, both lungs are often declined for transplant. We show that the availability of ex vivo lung perfusion for the evaluation of the better lung results in increased use of these single lungs for transplant.
When evaluating donor lungs for transplantation, it is not unusual to find that one lung is worse than the other. The conservative approach in this situation would be to simply decline both lungs for transplantation, as it would be unusual that one lung would escape injury when the other is unusable. However, given the current organ shortages, use of the better lung for transplant can be tempting when the potential recipient can safely receive a single lung. When considering the use of a single donor lung in this scenario, the putative mechanism of injury is important, ie, contralateral lung injury due to physical damage (contusion) should be lower risk than that due to aspiration.
However, determining the exact mechanism of injury during donor assessment is imprecise and confounded by the potential for multiple injuries, ie, contusion with subclinical aspiration. Thus, it remains unclear whether these lungs can be routinely used safely.
Overall, the major limitation to the safe use of single lungs when the contralateral lung is injured is the imprecise assessment of the single lung, leading to uncertainty. Even though selective blood gas analyses can be performed, the overall effect of contralateral lung injury/inflammation to the less-affected lung cannot be fully established at the time of organ retrieval. Since 2009, we have used ex vivo lung perfusion (EVLP) in our clinical practice to evaluate high-risk donor lung blocks, which has led to a safe overall increase in lung transplant volumes.
We therefore hypothesized that EVLP assessment of single lungs in this scenario would also allow for a safe increase in the use of single lungs. In this study, we reviewed our experience with single-lung transplantation (SLT) when the contralateral lung was declined in the EVLP and non-EVLP eras of the Program.
Methods
Data were retrospectively extracted from the prospectively collected database of the Toronto Lung Transplant Program. The study was approved by the University Health Network Research Ethics Board (18-6346) on February 2, 2019. A waiver for informed consent was provided, given the nature of the study.
To account for the introduction of clinical EVLP to our program in 2008, we considered the years 2000 to 2008 the “pre-EVLP era” and 2009 to 2017 the “EVLP era.” When one lung was declined at the donor site and the other transplanted, these were classified as group 1 for the pre-EVLP era and group 2 the EVLP era. We further split group 2 into group 2a when one lung was declined at the donor site and the other transplanted directly and group 2b when one lung was declined but the transplanted lung deemed acceptable only after evaluation with EVLP.
Single lungs placed on EVLP were evaluated using a combination of radiographs and the trend of serial physiological parameters as per Yeung and colleagues.
When a double lung block was placed on EVLP, one lung may demonstrate obvious deterioration during perfusion. In general, at around 3 hours of EVLP, the transplant team would evaluate the lungs by physical examination, radiographs, and volume of perfusate loss to decide whether one lung could be potentially transplantable. If so, the pulmonary artery, bronchus, and pulmonary veins to the injured lung would be clamped or tied off and the single lung perfused at a single-lung flowrate for an additional 2 hours. A final evaluation by radiographs and physiological parameters would be made at that time to determine suitability for transplant (Video 1).
The primary outcome was 30-day mortality. Secondary outcomes include time-to-extubation, intensive care unit length of stay (LOS), hospital LOS, in-hospital mortality, 90-day mortality, and 1-year mortality.
Univariable analysis was performed by comparing proportions using the χ2 or Fisher exact tests depending on group sizes. Differences in means were assessed by analysis of variance. Univariable and multivariable analyses were performed using Cox regression to further assess covariates affecting survival between the groups. The covariates used in the multivariate analysis were selected from univariate analysis with P value < .1.
Any patients with missing data were included in the initial univariable analysis of outcomes but excluded from the multivariable model; however, there was minimal missing data (Table E1).
Results
A total of 1692 transplants were performed between 2000 and 2017, of which 244 (14%) were SLT. The proportion of SLT was similar between eras (66/524 [16%] pre-EVLP era vs 178/1168 [15%] EVLP era), but more SLTs were performed when the contralateral lung was declined in the EVLP era (21/66 SLTs [32%] pre-EVLP era vs 80/178 [45%] EVLP era, P = .04).
There were 21 (9%) in group 1, 33 (14%) in group 2a, and 47 (19%) in group 2b. Of the 47 in group 2b, 28 (60%) were started on EVLP as a double lung block with one lung ultimately declined and 19 (40%) as a single lung with the contralateral lung declined at the donor site. During this time period, an additional 20 single lungs were perfused but declined after EVLP and 8 double lungs were perfused, a lung clamped, but ultimately neither lung was transplanted.
Donor and recipient data are shown in Table 1. There was a significantly greater rate of donation after cardiac death donors in group 2b (groups 1, 2a, 2b: 4.8%, 6.1%, 25.5% P = .02, respectively), lower mean procurement donor arterial oxygen tension/inspired oxygen fraction ratios (409 mm Hg, 375, 305, P = .003), and fewer female donors in (47.6%, 45.5%, 21.3% P = .03). Donors were younger in group 1 versus group 2 (33.3 years vs 43.7 years, P = .02). Other donor factors were equivalent across groups. For recipient factors, there was a trend toward a greater proportion of sicker “Status 3” recipients (which our program considers rapidly deteriorating) in group 2 (9.5% vs 26.6% P = .05). Other recipient factors were equivalent across groups.
Table 1Recipient and donor demographics and pretransplant data by group
Variable
Group 1 (n = 21)
Group 2a (n = 33)
Group 2b (n = 47)
P value
Donor data
Age Mean, y (SD)
33.3 (16.2)
44.5 (20.2)
43.2 (15.4)
.05
Female, n (%)
10 (47.6)
15 (45.5)
10(21.3)
.03
Smokers, n (%)
10 (47.6)
17 (51.5)
32 (68.1)
.18
Last P/F ratio, mm Hg, mean (SD)
409 (86)
375 (129)
305 (101)
.003
DCD, n (%)
1 (4.8)
2 (6.1)
12 (25.5)
.02
Recipient data
Age, y, mean (SD)
58.8 (9.6)
59.9 (7.8)
59.4 (10.2)
.90
Female, n (%)
10 (47.6)
13 (39.4)
15 (31.9)
.45
Mean BMI, kg/m2, mean (SD)
25.2 (3.6)
26.4 (3.2)
25.8 (3.6)
.55
Status 3, n (%)
2 (9.5)
8 (24.2)
13 (27.7)
.14
Recipient disease
.50
ILD
11
23
33
Emphysema
9
10
13
Retransplant
1
1
Lobar lung transplant, n (%)
0 (0)
1 (3.0)
1 (2.1)
1.00
Pre-Tx ECLS, n (%)
0 (0)
0 (0)
1 (2.1)
1.00
Retransplant, n (%)
1 (4.8)
0 (0)
1 (2.1)
1.00
SD, Standard deviation; DCD, donation after cardiac death; BMI, body mass index; ILD, interstitial lung disease; Tx, transplantation; ECLS, extracorporeal life support.
Posttransplant outcomes were similar between the 3 groups (Table 2, Figure 1). There was a trend toward lower 30-day mortality in group 2 (group 1 vs group 2; 9.5%, 0%, P = .05). 1-year mortality was equivalent (P = .51). We found no significant differences in primary graft dysfunction grade 3 at 72 hours, time-to-extubation, intensive care unit LOS, and hospital LOS. Kaplan–Meier survival curves are shown in Figure 1.
Table 2Early posttransplant outcomes by group
Variable
Group 1 (n = 21)
Group 2a (n = 33)
Group 2b (n = 47)
P value
30-d mortality,n (%)
2 (9.5)
0 (0)
0 (0)
.02
90-d mortality,n (%)
3 (14.3)
2 (6.1)
2 (4.3)
.31
1-y mortality,n (%)
5 (23.8)
5 (15.2)
6 (12.8)
.51
PGD grade 3 at 72 h
3 (14.2)
4 (12.1)
10 (21.2)
.53
Time to extubation, h, median (IQR)
34 (18-114)
24 (24-96)
38 (24-96)
.16
ICU LOS, d, median (IQR)
4.0 (2-15)
3 (1-11)
4.0 (2-8)
.10
Hospital LOS, d, median (IQR)
22 (17-54)
20 (16-38)
22 (19-44)
.37
Post-Tx ECLS, n (%)
1 (4.8)
0 (0)
3 (6.4)
.42
PGD, Primary graft dysfunction; IQR, interquartile range; ICU, intensive care unit; LOS, length of stay; Tx, transplantation; ECLS, extracorporeal life support.
Figure 1Kaplan–Meier survival curves demonstrate similar survival across groups. P value represents log-rank test. Shaded areas correspond to 95% confidence intervals. EVLP, Ex vivo lung perfusion.
A Cox proportional hazards model was generated to analyze mortality across these groups. Group was not found to be a factor associated with survival in both univariable and multivariable models. Donor age was found to be statistically significant on univariable analysis, and diagnosis of interstitial lung disease and extracorporeal life support bridge-to-transplant were factors closest to being associated with survival by P value (.07, .06, respectively, Table 3). We then generated a multivariable model using near-significant factors identified in the univariable model to assess the effect of group on survival and group was not found to be a significant associated factor to survival (Table 4).
Table 3Univariable Cox proportional hazards analysis of mortality in the 4 groups
Characteristic
Univariable model
HR
95% CI
P value
Group
Group 1
(1.00)
Group 2a
0.564
0.163-1.949
.37
Group 2b
0.487
0.149-1.597
.24
Status
Status 1
(1.00)
Status 2
2.648
0.562-12.472
.22
Status 3
3.573
0.693-18.419
.13
Lobar transplant
No
(1.00)
Yes
0.00
0-Inf
1.0
Recipient sex
Female
(1.00)
Male
1.872
0.604-5.804
.28
Recipient primary disease
Non-ILD
(1.00)
ILD
3.962
0.9-17.437
.07
Postoperative ECLS
No
(1.00)
Yes
1.679
0.222-12.721
.62
Recipient BMI
0.893
0.785-1.017
.09
Recipient age at transplant
0.834
0.685-1.016
.07
Donor type
DBD
(1.00)
DCD
0.360
0.048-2.726
.32
ECLS bridge-to-transplant
No
(1.00)
Yes
7.138
0.934-54.6
.06
Donor smoking
No
(1.00)
Yes
0.894
0.333-2.402
.82
Donor sex
Male
(1.00)
Female
0.850
0.295-2.445
.76
Donor P/F ratio
1.353
0.818-2.238
.24
Donor age
0.811
0.691-0.953
.01
HR, Hazard ratio; CI, confidence interval; ILD, interstitial lung disease; ECLS, extracorporeal life support; BMI, body mass index; DBD, donation after brain death; DCD, donation after cardiac death; P/F, arterial oxygen tension/inspired oxygen fraction ratio.
SLT is a valuable option for many patients and presents the opportunity for gaining maximal societal benefit from the scarce pool of donor organs, which remains a priority for transplantation in general.
Does splitting the lung block into two single lung grafts equate to doubling the societal benefit from bilateral lung donors? Comparisons between two single versus one bilateral lung transplant. UK Cardiothoracic Transplant Audit Steering Group.
Right single lung transplantation or double lung transplantation compared with left single lung transplantation in chronic obstructive pulmonary disease.
Accepting a single lung for transplant when the contralateral lung is deemed unsuitable could be an avenue for expanding the number of available lungs for transplant, but these are potentially greater-risk organs since the injurious process affecting one of the lungs may also have affected the quality of the apparently better contralateral organ. EVLP has allowed for the safer use of greater-risk donor lungs by further testing lung function under controlled conditions.
We therefore hypothesized that EVLP has similarly allowed for the safer use of this unique population of single lungs. In this retrospective analysis, we compared outcomes following the transplantation of a single lung when the contralateral lung is declined in the EVLP era to the pre-EVLP era.
Our data indicate that survival and other outcome measures were not significantly different between the EVLP and non-EVLP eras (Figure 2). It is reassuring that clinical judgment by our experienced program has led to safe outcomes for these recipients in any era. However, despite equivalent outcomes, our data indicate that EVLP availability has liberalized our use of these donors. The overall use of SLT when the contralateral lung was declined increased in the EVLP era from 32% to 45%, suggesting more confidence in using these types of lungs by our clinicians when EVLP was available to further assess the quality of the lungs. This allowed for more extended-criteria single lungs to be safely used in the EVLP era, with older donors, donors with lower procurement arterial oxygen tension/inspired oxygen fraction ratios, and greater percentages of donation after cardiac death organs. Recipients were also sicker, with a greater proportion of Status 3 “rapidly deteriorating” recipients of single lungs when the contralateral was declined.
Figure 2Differences in use, last donor arterial oxygen tension/inspired oxygen fraction ratio, and donation after cardiac death rate between the non-EVLP and EVLP era and the hazard ratio for survival with 95% confidence interval. EVLP, Ex vivo lung perfusion, P/F, arterial oxygen tension/inspired oxygen fraction ratio.
We further explored the effect of EVLP availability on donor decision-making and found that EVLP is not obligatory when an experienced lung transplant clinician deems a lung safe to use. Forty percent of the single lungs when the other lung was declined were transplanted without using EVLP in the EVLP era, and the patient characteristics and outcomes between the non-EVLP era and this group were similar. However, if there was any clinical concern, these lungs could be further evaluated on EVLP instead of being declined, leading to the increase in use. Indeed, the single lungs evaluated on EVLP more likely met extended criteria.
Another effect of having EVLP available is the ability to salvage a single lung when a questionable double lung block is placed on EVLP. The majority of the lungs evaluated on EVLP started as a double lung block evaluation and, following EVLP, only a single was transplanted. In this situation, when it became obvious that only one lung was viable during EVLP due to accumulation of edema in the lung, our practice has been to clamp the airway and pulmonary artery of the poorer lung. This allows for perfusion and additional evaluation of the better lung only and reduces the theoretical risk of the poorer lung injuring the better lung by release of harmful cytokines and other mediators into the perfusate. If the recipient is a double-lung only recipient, we will call in a backup single-lung eligible recipient.
The limitations of the present study reside in its single-center retrospective nature and long study period. Although we have chosen the most recent 8-year period before EVLP as our comparison group, there have undoubtedly been evolution in protocols since that era. Furthermore, the number of subjects included in group 1 are low. Indeed, whereas there was a trend toward better survival in group 2 patients at 30 days, we lacked the power to demonstrate this definitively. It was also very difficult to account for the heterogeneity of reasons for declining a contralateral lung for transplantation. While we attempted to capture the reason for declining the contralateral lung, most of the time it was unclear. This is in line with clinical experience where a lung may be heavy after flush, but no definitive diagnosis can be made. Thus, we are not sure that even a prospective analysis could resolve this issue.
In summary, the availability of EVLP has added a new dimension for evaluation of these organs, allowing more rigorous testing and increasing our confidence with using single lungs with a rejected contralateral lung. As our experience with this donor pool has expanded, we have been able to identify which donor lungs require further assessment on EVLP and which will be safe to proceed directly to transplant with good outcomes. We believe these data can empower other transplant programs to explore using single lungs for transplant even when the contralateral lung is deemed unsuitable.
Conflict of Interest Statement
S.K., T.W., and M.C. are founders and shareholders of Perfusix Canada and are consultants for Lung Bioengineering, Inc, Silverspring, MD, and Traferox Technologies Inc, Toronto, Ontario, Canada. All other authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Does splitting the lung block into two single lung grafts equate to doubling the societal benefit from bilateral lung donors? Comparisons between two single versus one bilateral lung transplant. UK Cardiothoracic Transplant Audit Steering Group.
Right single lung transplantation or double lung transplantation compared with left single lung transplantation in chronic obstructive pulmonary disease.
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