Single-lung transplantation: does side matter? - CiteSeerX

European Journal of Cardio-thoracic Surgery 40 (2011) e83—e92 www.elsevier.com/locate/ejcts

Single-lung transplantation: does side matter?§,§§ Sokratis Tsagkaropoulos a, Ann Belmans b, Geert M. Verleden c, Willy Coosemans d, Herbert Decaluwe d, Paul De Leyn d, Philippe Nafteux d, Dirk Van Raemdonck d,* b

a Department of Thoracic Surgery, University La Sapienza Rome, Rome, Italy Biostatistics and Statistical Bioinformatics Centre, Katholieke Universiteit Leuven, Leuven, Belgium c Department of Pneumology, University Hospitals Leuven, Leuven, Belgium d Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium

Received 28 June 2010; received in revised form 27 February 2011; accepted 1 March 2011; Available online 14 April 2011

Abstract Objective: Single-lung transplantation (SLTx) is a valid treatment option for patients with non-suppurative end-stage pulmonary disease. This strategy helps to overcome current organ shortage. Side is usually chosen based on pre-transplant quantitative perfusion scan, unless specific recipient considerations or contralateral lung offer dictates opposite side. It remains largely unknown whether outcome differs between left (L) versus right (R) SLTx. Methods: Between July 1991 and July 2009, 142 first SLTx (M/F = 87/55; age = 59 (29—69) years) were performed from 142 deceased donors (M/F = 81/61; age = 40 (14—66) years) with a median follow-up of 32 (0—202) months. Indications for SLTx were emphysema (55.6%), pulmonary fibrosis (36.6%), primary pulmonary hypertension (0.7%), and others (7.0%). Recipients of L-SLTx (n = 72) and R-SLTx (n = 70) were compared for donor and recipient characteristics and for early and late outcome. Results: Donors of L-SLTx were younger (37 (14—65) vs 43 (16—66) years; p = 0.033). R-SLTx recipients had more often emphysema (67.1% vs 44.4%; p = 0.046) and replacement of native lung with 50% perfusion (47.1% vs 23.6%; p = 0.003). The need for bypass, time to extubation, intensive care unit (ICU) and hospital stay, and 30-day mortality did not differ between groups. Overall survival at 1, 3, and 5 years was 78.4%, 60.5%, and 49.4%, respectively, with a median survival of 60 months, with no significant differences between sides. Forced expiratory volume in 1 s (FEV1) improved ( p < 0.01) in both groups to comparable values up to 36 months. Complications overall (44.4% vs 50.0%) or in allograft (25.0% vs 24.3.0%) as well as time to bronchiolitis obliterans syndrome (BOS) (35 months) and 5-year freedom from BOS (68.9% vs 75.0%) were comparable after L-SLTx versus R-SLTx, respectively. There were no differences in all causes of death ( p = 0.766). On multivariate analysis, BOS was a strong negative predictor for survival (hazard ratio (HR) 6.78; p < 0.001), whereas side and mismatch for perfusion were not. Conclusion: The preferred side for SLTx differed between fibrotic versus emphysema recipients. Transplant side does not influence recipient survival, freedom from BOS, complications, or pulmonary function after SLTx. Besides surgical considerations in the recipient, offer of a donor lung opposite to the preferred side should not be a reason to postpone the transplantation until a better-matched donor is found. # 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. Keywords: Lung transplantation; Single lung; Bilateral lung; Lung perfusion scan; Side

1. Introduction Lung transplantation (LTx) is an effective treatment modality for selected patients suffering from any form of end-stage pulmonary disease. Early and late survival rates have improved in recent years [1]. Besides the occasional heart—lung transplantation (HLTx) in patients with Eisenmenger’s syndrome or complex congenital heart disease, two

§ Presented at the 18th European Conference on General Thoracic Surgery, Valladolid, Spain, May 30—June 2, 2010. §§ Funding: Dirk Van Raemdonck is a senior clinical investigator supported by the Fund for Research-Flanders (G.3C04.99). * Corresponding author. Address: Department of Thoracic Surgery, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 34 68 23; fax: +32 16 34 68 24. E-mail address: [email protected] (D. Van Raemdonck).

transplant types mostly used are single-lung transplantation (SLTx) and bilateral-lung transplantation (BLTx). Since the first reports of successful SLTx for pulmonary fibrosis by the Toronto Lung Transplant Group in 1986 [2] and for emphysema by the Paris Group in 1989 [3], indications and LTx type have evolved over the past two decades with, currently, a preference for BLTx because of superior longterm survival compared with SLTx, both in patients with emphysema [4] and pulmonary fibrosis [5]. As a result, the proportion of SLTx compared with BLTx reported to the Registry of the International Society for Heart and Lung Transplantation (ISHLT) has decreased over recent years [1]. SLTx is contraindicated in patients with suppurative lung diseases, such as cystic fibrosis or bronchiectasis, for reasons of infectious risk and imminent death from pulmonary sepsis. The technique is also not recommended in patients with pulmonary vascular disease and associated pulmonary

1010-7940/$ — see front matter # 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejcts.2011.03.011

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S. Tsagkaropoulos et al. / European Journal of Cardio-thoracic Surgery 40 (2011) e83—e92

arterial hypertension because of the increased risk for massive reperfusion edema and dysfunction of the allograft early on. Moreover, severe ventilation—perfusion mismatch may occur once chronic rejection and bronchiolitis obliterans develop in the allograft later on [6]. Most SLTx nowadays are performed in elderly patients with smoking-induced emphysema or pulmonary fibrosis [1]. The latter indication is still believed to be the ideal disease for SLTx because both ventilation and perfusion will be largely directed toward the newly implanted allograft [2]. Recipient factors that may play a role in listing a patient for either SLTx or BLTx are: type of the underlying lung disease, age and general condition, history of previous chest surgical interventions, or specific unilateral problem, such as after previous pneumonectomy [7]. Further, donor factors can be decisive for transplant side in case the quality of the contralateral donor lung precludes its use [8]. Center experience and annual transplant volume may also play a role, as SLTx is a less complex and a more straightforward procedure compared with BLTx. Finally, SLTx is preferred by some teams as a strategy helping to overcome current organ shortage with reduced time and mortality on the waiting list [9]. There is little evidence to support decision making which side to transplant when SLTx is considered. In clinical practice, the side is usually chosen based on findings on pretransplant quantitative lung perfusion scan. In normal subjects, each lung is approximately equally perfused (right (R) lung 55%, left (L) lung 45%). In patients with end-stage parenchymal or vascular lung disease, the distribution may be unequal [10], and the less-perfused lung is then preferentially explanted and replaced, whenever surgically possible. It remains largely unknown whether outcome differs after L-SLTx versus R-SLTx. This review of our lung-transplant cohort aimed to compare the characteristics and the outcome in L versus R single-lung recipients.

2. Patients and methods 2.1. Study design Informed consent for data analysis was obtained from all recipients, according to the Belgian law on patients’ rights regarding data registration. Approval for analyzing recorded data was waived by the institutional ethics committee on human research, given the retrospective nature of the study. All consecutive LTx procedures (n = 493) performed at the University Hospitals Leuven between July 1991 and July 2009 were reviewed using a prospectively gathered database. There were 150 SLTx, 301 BLTx and 42 HLTx performed during the study period. The annual numbers and percentages of single versus bilateral transplant procedures are presented in Table 1. A shift from SLTx to BLTx as procedure of choice was noted over the years. However, the proportion of L-SLTx versus R-SLTx did not change when compared per decade (1991—2000: 27 L vs 26 R; 2001—2009: 48 L vs 49 R). Of these 150 SLTx procedures, eight SLTx procedures were excluded from the study, as no native lung was left in place in the recipient. Four recipients were retransplanted for bronch-

Table 1. Annual number and percentage of single versus bilateral-lung transplants performed at the University Hospitals Leuven between July 1991 and July 2009. SLTx n (L—R) 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Total

1 7 4 9 7 5 6 2 8 4 10 10 15 14 9 19 8 8 4

(1—0) (3—4) (2—2) (5—4) (3—4) (5—0) (4—2) (1—1) (2—6) (1—3) (4—6) (8—2) (5—10) (8—6) (4—5) (6—13) (5—3) (5—3) (3—1)

150 (75—75)

BLTx % 100% 64% 80% 82% 88% 63% 60% 20% 67% 24% 32% 33% 36% 39% 24% 36% 17% 16% 12%

n 0 4 1 2 1 3 4 8 4 13 21 20 27 22 28 34 38 41 30

% 0% 36% 20% 18% 12% 37% 40% 80% 33% 76% 68% 67% 64% 61% 76% 64% 83% 84% 88%

301

SLTx, single-lung transplant; BLTx, bilateral-lung transplant; L: left; R: right.

iolitis obliterans syndrome (BOS), including two contralateral SLTx (n = 2) after first SLTx (n = 2) and two BLTx after first SLTx (n = 2). Two recipients with cystic fibrosis had previously undergone pneumonectomy for septic complications 1 day (n = 1) and 23 years (n = 1) prior to SLTx. 2.2. Recipients and donors Donor and recipient characteristics are listed in Table 2. This study comprises 142 first SLTx recipients with a median age of 59 (29—69) years. Eighty-seven (61.3%) recipients were male. Two paired recipients received one allograft each from one donor (twinning procedure). These donors were counted twice in the analysis. Their median age was 40 (14— 66) years. Eighty-one (57.0%) donors were male. Donor— recipient matching was based on blood group identity (compatibility) and predicted total lung capacity (TLC), but not on age, gender, or cytomegalovirus status. 2.3. Indications Patients considered for SLTx were evaluated according to the ISHLT guidelines [11]. The main indications for SLTx in our recipients were emphysema in 79 (55.6%) patients and pulmonary fibrosis in 52 (36.6%), followed by primary pulmonary hypertension in one patient (0.7%), and miscellaneous in 10 patients (7.0%). 2.4. Side L-SLTx versus R-SLTx was well distributed (n = 72 vs n = 70, respectively). The side of transplantation was chosen preferentially, based on pre-transplant quantitative perfusion scan. A total of 92 recipients (64.8%) were transplanted on the side with the lowest perfusion, whereas the opposite side was dictated for various reasons in 50 patients (35.2%),


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Table 2. Donor and recipient characteristics in left versus right single-lung recipients. Donor

Statistic

L-SLTx

R-SLTx

Total

p-value

Age (years)

N Median Range

72 37 (14; 65)

70 43 (16; 66)

142 40 (14; 66)

0.033

n/N (%) n/N (%)

42/72 (58.3%) 30/72 (41.7%)

39/70 (55.7%) 31/70 (44.3%)

81/142 (57.0%) 61/142 (43.0%)

0.753

n/N (%) n/N (%) n/N (%) n/N (%) N Median Range N Median Range

35/72 (48.6%) 28/72 (38.9%) 7/72 (9.7%) 2/72 (2.8%) 72 47 (18; 204) 72 489 (127; 630)

32/70 (45.7%) 37/70 (52.9%) 1/70 (1.4%) 0/70 (0.0%) 70 35 (11; 240) 70 489 (205; 660)

67/142 (47.2%) 65/142 (45.8%) 8/142 (5.6%) 2/142 (1.4%) 142 44 (11; 240) 142 489 (127; 660)

0.049

Sex Male Female Cause of death Trauma CVA Anoxia Other a Ventilation (h)

PO2/FiO2 (mmHg)

0.092

0.848

Recipient

Statistic

L-SLTx

R-SLTx

Total

p-value

Age (years)

N Median Range

72 59 (29; 67)

70 60 (29; 69)

142 59 (29; 69)

0.233

n/N (%) n/N (%)

48/72 (66.7%) 24/72 (33.3%)

39/70 (55.7%) 31/70 (44.3%)

87/142 (61.3%) 55/142 (38.7%)

0.180

n/N (%) n/N (%) n/N (%) n/N (%) N Median Range

32/72 (44.4%) 33/72 (45.8%) 1/72 (1.4%) 6/72 (8.3%) 72 1.12 (0.78; 1.53)

47/70 (67.1%) 19/70 (27.1%) 0/70 (0.0%) 4/70 (5.7%) 70 1.14 (0.87; 1.55)

79/142 (55.6%) 52/142 (36.6%) 1/142 (0.7%) 10/142 (7.0%) 142 1.13 (0.78; 1.55)

0.046

n/N (%) n/N (%) N Median Range N Median Range

55/72 (76.4%) 17/72 (23.6%) 72 121 (1; 812) 72 29 (0; 171)

37/70 (52.9%) 33/70 (47.1%) 70 141 (1; 1196) 70 33 (0; 202)

92/142 (64.8%) 50/142 (35.2%) 142 127 (1; 1196) 142 32 (0; 202)

Sex Male Female Lung disease Emphysema Fibrosis PPH Otherb D/R predicted TLC

Perfusion to explanted lung 50% of cardiac output to explanted lung) compared with L-SLTx (23.6%); p = 0.003. 3.2. Hospital outcome Early outcome in L- and R-lung recipients is compared in Table 3. One patient with primary pulmonary hypertension needed partial cardiopulmonary bypass to implant the left allograft. The proportion of extracorporeal support needed in other recipients did not differ between L-SLTx (18.1%) and R-SLTx (14.3%). No significant differences were found between groups in time to extubation, length of ICU and hospital stay, and 30day mortality (Table 3). Cardiac arrhythmias after SLTx were equally observed in both groups. 3.3. Late outcome Late outcome between L- and R-lung recipients is compared in Table 3. No differences in bacterial, viral, or fungal infections in the allograft, malignancies, or other complications were seen between groups. Further, no differences in native lung complications (infection, tumor, pneumothorax, and hyperinflation) were observed. Two male patients after L-SLTx needed pneumonectomy of the contralateral, native lung for chronic infection (one emphysema patient after 18 months for invasive aspergillosis and one fibrosis patient after 38 months for lung abscess). At the end of the study, 39 patients had died after R-SLTx versus 38 after L-SLTx. No significant differences in cause of death were noticed between both groups (Table 3). Overall survival after SLTx was 78.4% (70.5—84.3), 60.5% (51.5— 68.4), and 49.4% (40.0—58.1) at 1, 3, and 5 years, respectively. No significant difference in survival was found between both sides (Fig. 2(A)) with a median survival of 63 months in L-lung recipients and 55 months in R-lung recipients. BOS was diagnosed in 20 patients after L-SLTx versus in 19 patients after R-SLTx (NS). The median time to develop BOS was 35 (5—104) months and did not differ between sides (Table 3). Freedom from BOS was 97.1% (96.1—97.8), 83.6% (79.5—86.9), and 72.2% (64.7—78.0) at 1, 3, and 5 years after

[()TD$FIG]


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SLTx, respectively and did not differ between L- versus R-lung recipients (Fig. 2(B)). 3.4. Cox regression and interaction analysis On univariate analysis, female patients had a better overall survival compared with males (hazard ratio (HR) 0.52 (95% confidence interval (CI) 0.31—0.86); p = 0.01). Gender mismatch between donor and recipient (HR 2.10 (95% CI 1.04—4.24); p = 0.04), length of ICU stay (HR 1.06 (95% CI 1.02—1.10); p < 0.01), hospital stay (HR 1.03 (95% CI 1.01— 1.05); p < 0.01), and the presence of BOS (HR 6.44 (95% CI 3.50—11.85); p < 0.0001) were significant negative predictive factors for survival after SLTx. Cardiac arrhythmias ( p = 0.13) and side mismatch for perfusion ( p = 0.08) were not significant predictors of survival. On multivariate analysis, female gender (HR 0.44 (95% CI 0.26—0.74); p = 0.002) and BOS (HR 6.78 (95% CI 3.63—12.65); p < 0.0001) remained the only predictors of survival (Table 4). Subgroup analyses were performed for all variables in the model, and their interaction with transplant side was assessed. Inspection of the forest plot presented in Fig. 3 reveals that no differences between transplant sides were found in any of the subgroups and that none of the interactions were statistically significant. 3.5. Pulmonary function Improvement in FEV1 from pre-transplant value to all post-transplant values was significant ( p < 0.01) up to 36 months, both after L-SLTx and R-SLTx (Fig. 4). An overall test for transplant side including all variables analyzed in the repeated-measures ANOVA yielded a p-value of 0.1827, indicating no difference in FEV1 over time between sides.

4. Discussion

Fig. 1. Donor versus recipient predicted total lung capacity (TLC) for all singlelung transplantation (SLTx), left (L) SLTx, and right (R) SLTx.

In the present study, we failed to find a difference in early and late outcome between recipients of left versus right single-donor lungs. In particular, the need for perioperative bypass, the time to extubation, the length of ICU stay and hospital stay, and 30-day mortality were comparable between both groups. Further, overall survival and freedom from BOS were not different according to the side of SLTx. Post-transplant FEV1 was also not different between groups, indicating that both R- and L-lung transplantation can lead to a comparable improvement in pulmonary function for at least 3 years after SLTx. The proportional imbalance between both diagnostic groups with more emphysema patients having RSLTx and more fibrosis patients undergoing L-SLTx is the reflection of the preferred side at the time our patients were listed for transplantation. In patients with an equal (up to 10% difference) distribution of blood flow between L and R lung, we prefer to transplant the L (larger) donor lung into a fibrotic patient with a small chest cavity, as the liver on the right side may prohibit a downward replacement of the diaphragm. Inversely, we prefer to transplant the R donor lung (smaller volume to oversized) into an emphysematous

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Table 3. Early and late outcome in left versus right single-lung recipients. Patient characteristic Extracorporeal support No Yes Extubation (days)

ICU stay (days)

Hospital stay (days)

30-day mortality No Yes Overall complications No Yes Cardiac arrhythmias No Yes Native lung complication No Yes Type of native lung complication Infection Tumor Pneumothorax Hyperinflation Time to BOS (months)

Cause of death Rejection Infection Tumor AMI CVA Other

Statistic

L-SLTx

R-SLTx

Total

p-value

n/N (%) n/N (%) N Median Range N Median Range N Median Range

59/72 (81.9%) 13/72 (18.1%) 66 3 (1; 22) 72 5 (2; 47) 72 33 (7; 192)

60/70 (85.7%) 10/70 (14.3%) 65 3 (0; 25) 70 7 (1; 90) 70 30 (1; 175)

119/142 (83.8%) 23/142 (16.2%) 131 3 (0; 25) 142 6 (1; 90) 142 31 (1; 192)

0.542

n/N (%) n/N (%)

69/72 (95.8%) 3/72 (4.2%)

67/70 (95.7%) 3/70 (4.3%)

136/142 (95.8%) 6/142 (4.2%)

0.972

n/N (%) n/N (%)

40/72 (55.6%) 30/72 (44.4%)

35/70 (50.0%) 35/70 (50.0%)

75/142 (52.8%) 67/142 (47.2%)

0.507

n/N (%) n/N (%)

66/72 (91.7%) 6/72 (8.3%)

62/70 (88.6%) 8/70 (11.4%)

128/142 (90.1%) 14/142 (9.9%)

0.536

n/N (%) n/N (%)

54/72 (75.0%) 18/72 (25.0%)

53/70 (75.7%) 17/70 (24.3%)

107/142 (75.4%) 35/142 (24.6%)

0.921

n/N (%) n/N (%) n/N (%) n/N (%) N Median Range

10/18 (55.6%) 3/18 (16.7%) 3/18 (16.7%) 2/18 (11.1%) 20 35 (11; 80)

8/17 (47.1%) 5/17 (29.4%) 1/17 (5.9%) 3/17 (17.6%) 19 35 (5; 104)

18/35 (51.4%) 8/35 (22.9%) 4/35 (11.4%) 5/35 (14.3%) 39 35 (5; 104)

0.594

n/N n/N n/N n/N n/N n/N

14/38 (36.8%) 9/38 (23.7%) 1/38 (2.6%) 2/38 (5.3%) 1/38 (2.6%) 11/38 (28.9%)

14/39 (35.9%) 11/39 (28.2%) 3/39 (7.7%) 1/39 (2.6%) 0/39 (0.0%) 10/39 (25.6%)

28/77 (36.4%) 20/77 (26.0%) 4/77 (5.2%) 3/77 (3.9%) 1/77 (1.3%) 21/77 (27.3%)

0.766

(%) (%) (%) (%) (%) (%)

0.229

0.397

0.865

0.704

L-SLTx, left single-lung transplant; R-SLTx, right single-lung transplant; ICU, intensive care unit; BOS, bronchiolitis obliterans syndrome; AMI, acute myocardial infarction; CVA: cerebrovascular accident; continuous data are presented as median (range), categorical data as numbers (percentages).

patient with a large chest cavity. This is to avoid compression by a remaining hyperinflated, emphysematous R native lung in case of L-SLTx, as previously believed [12]. Survival at 1, 3, and 5 years after SLTx in our cohort was 78.4%, 60.5%, and 49.4%, respectively. These results compare favorably with those reported by Cai in 2007, based on United Network for Organ Sharing (UNOS) registry data (76.0% and 41.8% for L-SLTx and 78.3% and 44.8% for R-SLTx at 1 and 5 years) [13]. In a recent review of 1000 adult lung transplants by the University of Washington lung-transplant group at St Louis, survival rates of 82.1%, 68.2%, 47.6%, and 20.1% were reported at 1, 3, 5, and 10 years after SLTx, respectively [14]. On univariate analysis, perfusion-side mismatch was not found to be a clear predictive factor for survival after SLTx (HR = 1.54; p = 0.08). Further analysis yielded no statistically significant interaction between perfusion-side mismatch and transplant side (HR 0.96 vs HR 0.56 for