Graft Side-mismatching for Single-lung Transplantation Does Not Affect Outcomes: Role of the Pre-operative Quantitative Lung Perfusion Scan

Graft Side-mismatching for Single-lung Transplantation Does Not Affect Outcomes: Role of the Pre-operative Quantitative Lung Perfusion Scan

CLINICAL LUNG AND HEART/LUNG TRANSPLANTATION Graft Side-mismatching for Single-lung Transplantation Does Not Affect Outcomes: Role of the Pre-operati...

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CLINICAL LUNG AND HEART/LUNG TRANSPLANTATION

Graft Side-mismatching for Single-lung Transplantation Does Not Affect Outcomes: Role of the Pre-operative Quantitative Lung Perfusion Scan Benjamin D. Fox, MRCP,a,b Ilanit Ben Nachum, MD,c Hanna Bernstine, MD, MSc,b,d Anat Amital, MD,a Ilana Bakal, RN,a Nir Peled, MD,a,b David Shitrit, MD,a,b and Mordechai R. Kramer, FCCP, MDa,b Background: There are concerns about which lung to explant during single-lung transplantation (SLT). Traditionally, a quantitative lung perfusion scan (QLPS) is performed, and the better-perfused lung is retained. Occasionally, there is transplantation with graft “side-mismatching,” where the less-wellperfused lung is retained. We performed a retrospective study of patients undergoing SLT at our institution to evaluate the effects of side-mismatching (according to the QLPS) on graft performance and outcome. Methods: We defined graft side-mismatching with a prospectively designed formula using baseline QLPS, and defined patients as either side-matched or side-mismatched. Data on mortality, requirement for cardiopulmonary bypass, relative graft perfusion, lung function and exercise capacity were obtained from institutional databases and patients’ files. Results: In a cohort of 114 patients, we defined 97 as having received a side-matched SLT and 17 as having received a side-mismatched graft. After lung transplantation, forced expiratory volume in 1 second (FEV1) and exercise capacity improved in both groups (p ⬍ 0.001). Patients with mismatched lungs had significantly higher relative graft perfusion post-operatively (p ⫽ 0.0012). There was no significant difference between the two groups (matched vs mismatched) in mortality, physiologic parameters and need for cardiopulmonary bypass. Conclusions: There is no apparent risk to the patient when a side-mismatched lung graft is transplanted. We conclude that side-mismatched lung transplantation appears to be feasible when required. J Heart Lung Transplant 2008;27:272–5. Copyright © 2008 by the International Society for Heart and Lung Transplantation.

Lung transplantation remains the therapeutic modality of choice for end-stage lung disease.1,2 Assessment of patients for lung transplantation includes a thorough clinical, laboratory and radiologic evaluation, as described in the guidelines of the International Society for Heart and Lung Transplantation.1,2 At our institution, evaluation also includes a quantitative lung perfusion scan (described in what follows) and, in most cases, pulmonary artery catheterization.

From the aPulmonary Institute, Rabin Medical Center (Beilinson Campus), Petach Tikva, Israel; bFaculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the cRadiology Institute and dInstitute of Nuclear Medicine, Rabin Medical Center (Beilinson Campus), Petach Tikva, Israel. Submitted September 14, 2007; revised November 29, 2007; accepted December 14, 2007. Reprint requests: Mordechai R. Kramer, MD, Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. Telephone: 972-3-937-7221. Fax 972-3-924-2091. E-mail: [email protected] netvision.net.il. Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2007.12.005

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There is little evidence to support decision-making about which side to transplant when single-lung transplantation (SLT) is considered. The decision is usually based on the quantitative lung perfusion scan (QLPS). In normal subjects, each lung is approximately equally perfused (right lung 55%, left lung 45%). In end-stage lung disease, one lung, or even individual lobes, may have dominant perfusion due to effects of parenchymal disease on vessel density and hypoxic pulmonary vasoconstriction.3 Examples of QLPS are shown in Figure 1. For SLT, the less-well-perfused lung is usually explanted, because the “better” lung is considered more able to ensure adequate gas exchange and cardiovascular stability during the transplantation operation.4 Of note, cardiopulmonary bypass may be associated with primary graft dysfunction and poor outcome.5 In certain situations, the less-well-perfused lung may be retained. Donor factors limiting choice of side include unilateral traumatic or infective processes associated with poor outcome. Recipient factors include previous pleural adhesions/surgery on the preferred side that may make surgery more risky. Alternatively, a graft may become available for a needy recipient that is suitable in

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Figure 1. Examples of quantitative lung perfusion scintigraphy (posterior projections). (a) Relatively normal distribution of perfusion (49% left lung, 51% right lung). (b) Preferential perfusion of the left lung (68% left lung, 32% right lung).

all aspects other than the QLPS scan. Such graft sidemismatch is a relatively minor contraindication to SLT. In this retrospective study, we reviewed case notes to determine the effect of graft side-mismatch on intraoperative, physiologic and mortality outcomes after SLT.

(SPX-4; Varicam, Elscint Haifa, Israel). The posterior view was used for calculations of relative perfusion. Right and left counts were obtained separately from rectangular regions of interest. The percentage counts of each lung relative to the total lung count was called relative perfusion.

METHODS The institutional review board gave permission for this study. Information was collated on all patients followed up after SLT at our institute since 1998. Data were acquired from case notes and institutional database systems holding relevant information. We extracted data on pre-operative and 6-month post-operative QLPS, systolic pulmonary artery pressure (sPAP), forced expiratory volume in 1 second (FEV1), oxygen saturation, peak oxygen extraction during cycle ergometry (VO2peak) and 6-minute walking distance (6MW). Dates of death from all causes were recorded. Patients undergoing retransplantation were not included in the study.

Allocation of Patients to Groups

Lung Scintigraphy Scintigraphy was performed after intravenous administration of 111 MBq (3 mCi) of 99Tc-macro-aggregated albumin (Pulmolite; DuPont, Billerica, MA) with the patient supine. Anterior, posterior, right posterior oblique and left posterior oblique views were obtained, collecting 400,000 counts per view on a gamma-camera equipped with a low-energy, high-resolution collimator

Matched or mismatched grafts were as defined as in Table 1. Use of Cardiopulmonary Bypass Our institutional policy is to avoid cardiopulmonary bypass (CPB) for SLTs except in the case of unacceptable gas exchange or hemodynamic instability during surgery. All decisions to commence CPB were made ad hoc by the transplant team during surgery.

Table 1. Definition of Graft Side-matching According to Percent Perfusion of Right Lung on Baseline Lung Scintigraphy Study Right lung perfusion (%) ⬍45% 46–58% ⬎58%

Preferred side to transplant Right Either Left

Mismatched lung Left Neither Right

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Table 2. Results of Retrospective Review

Total Age Male gender (%) Indication Emphysema Fibrosis Connective tissue disease Other

Matched lung 97 56.1 ⫾ 11.2 57 (58%) 49 39 5 4

(51%) (41%) (4%) (4%)

Mismatched lung 17 57.4 ⫾ 7.0 13 (77%) 6 (35%) 11 (65%) 0 0

Pre-operative variables Perfusion of retained lung (%) Baseline SPAP (mm Hg) Baseline FEV1 (% predicted) Baseline VO2 peak (ml/kg/min) Baseline 6MW (m)

55.8 ⫾ 7.8 42.4 ⫾ 10.9 37.2 ⫾ 16.8 9.0 ⫾ 2.6 327 ⫾ 108

39.8 ⫾ 6.0a 47.2 ⫾ 16.4 35.8 ⫾ 16.4 9.2 ⫾ 3.8 262 ⫾ 16.4

Outcomes Graft ischemic time (min) Required CPB Six-month graft perfusion (%) Six-month FEV1 (% predicted) Six-month VO2 peak (ml/kg/min) Six-month 6MW (ms) Six month SpO2 (%) All-cause mortality at 1 year All-cause mortality at 5 years

180 ⫾ 58 5 (5.2%) 70.6 ⫾ 16.0 57.9 ⫾ 15.6a 11.1 ⫾ 2.4a 404 ⫾ 97a 96 ⫾ 2.4 18/97 28/97

167 ⫾ 26 1 (5.9%) 85.5 ⫾ 3.9b 61.4 ⫾ 14.8a 10.9 ⫾ 1.0a 471 ⫾ 68a 97 ⫾ 3.2 6/17 8/17

Continuous data are shown as mean ⫾ standard deviation. a Significant difference (p ⬍ 0.001) between baseline and 6 months. b Significant difference (p ⬍ 0.001) between the two groups.

Statistical Analysis Data were analyzed using SPSS software, version 14.0 (SPSS, Inc., Chicago, IL), by a professional statistician. Physiologic parameters before and after transplantation were analyzed with repeated-measures analysis of variance (ANOVA), using time as as the within-subjects factor and side-matching/mismatching as the betweensubjects factor. Other continuous parameters were compared by Student’s t-test. Categoric variables were analyzed by Fisher’s exact test. Correlations between continuous parameters were evaluated using Pearson’s r correlation. Mortality was evaluated by the Kaplan– Meier technique with log-rank (Mantel–Cox) comparisons. All tests were 2-tailed with p ⬍ 0.05 considered statistically significant.

Baseline Characteristics Apart from overall number of patients, the baseline characteristics (both demographic and physiologic) were similar in both groups. The one exception was the relative perfusion of the lung retained at transplantation, which was significantly higher in the matched group (p ⬍ 0.001). Effect of Graft Side-mismatch on Graft Function at 6 Months Post-transplantation In both groups, at 6 months post-transplantation there was significant improvement in FEV1, VO2peak and 6MW distance compared with baseline values (p ⬍ 0.001 in all cases; Table 2). We observed a statistically significantly higher relative graft perfusion in the patients with the side-mismatched grafts (p ⫽ 0.0012), and this difference was maintained with time (Figure 2). There was no statistically significant difference between the matched and mismatched groups in any of the following parameters: graft ischemic time (p ⫽ 0.54); requirement for CPB (p ⫽ 1.0); FEV1 (p ⫽ 0.64); oxygen saturation (p ⫽ 0.33); peak oxygen uptake (p ⫽ 0.54); and 6MW distance (p ⫽ 0.73). There was no significant correlation between graft perfusion at 6 months and other measures of graft function (FEV1, SpO2, VO2peak and 6MW). Mortality There was no statistically significant difference in survival between the matched and mismatched recipients (p ⫽ 0.142). Mortality at 1 year was analyzed utilizing a composite end-point of transplant-related death (primary graft dysfunction, acute rejection, chronic rejection and pneumonia) (Table 3). There was no statistically significant difference between the groups (p ⫽ 0.30).

RESULTS Of the 119 SLTs in our database, 114 were eligible for analysis (in 5 patients information on the pre-operative isotope scan was missing). We determined that 17 patients received side-mismatched lungs and 97 received side-matched lungs according to their pre-operative QLPS scan. Results are shown in Table 2.

Figure 2. Graft perfusion over time in side-matched and sidemismatched patients. Open triangles, side-matched lung; closed triangles, side mismatched lung.

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Table 3. Transplant-related Mortality at 1 Year as Defined by Death From Primary Graft Dysfunction, Acute or Chronic Rejection and Pneumonia Transplant-related death Alive/non-transplant–related death

Matched lung Mismatched lung 16 5 81 12

DISCUSSION In this retrospective series of 114 single-lung transplants, we did not demonstrate any deleterious effect of side-mismatching (according to QLPS) on outcome at 6 months or overall mortality. The observation of increased graft perfusion in the mismatched patients is of interest because previous studies showed that lower graft perfusion with QLPS predicts onset of chronic rejection.6 We suggest that this difference reflects the fact that side-mismatched patients retain a poorer quality native lung with a high pulmonary vascular resistance (PVR), and therefore the relative perfusion of the graft is higher. This is supported by a previous study evaluating pulmonary venous flow by transesophageal echo.7 In this study, blood flow through the graft was higher than the native lung, and the relative flow correlated with relative lung perfusion according to QLPS. We are not aware of any studies in which PVR was measured selectively in the native/transplanted lung post-operatively, but PVR does decrease overall after SLT.8 Although QLPS is the accepted technique for evaluating relative lung perfusion, other techniques are available. Magnetic resonance imaging is able to measure blood flow in each lung, and compares favorably with QLPS in terms of accuracy in pre-operative assessment for SLT.4 Further, Boyd and colleagues used transesophageal echocardiography, which is a promising technique that could potentially be extended to pre-operative evaluation of both relative lung perfusion and cardiac function.7 Both of these techniques are free of the radiation burden associated with QLPS. An important finding of our study is the lack of a statistically significant difference in mortality between the matched and mismatched groups, although the percentage mortality in the mismatched group at 1 year seems to be higher. Reassuringly, death from transplantrelated causes (primary graft dysfunction, acute or chronic

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graft rejection or pneumonia) was not higher at 1 year in the side-mismatched group (p ⫽ 0.30; Table 3). The limitations to this study are its retrospective nature, and the relatively small number of patients in the mismatched group. It is possible that the study design was not sufficiently powerful to determine a difference between the two groups. However, the use of objective physiologic end-points should minimize bias in the data. To our knowledge, this series is the first to address the issue of graft side-mismatching on outcomes after SLT. The apparent absence of risk to the patient due to sidemismatching suggests that transplanting the “wrong side” is feasible and should not be considered a contraindication for transplantation. REFERENCES 1. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745–55. 2. Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. J Heart Lung Transplant 1998;17:703–9. 3. Tiel-van Buul MMC, Verzijlbergen JF. Ventilation–perfusion lung scintigraphy. Imag Decis MRI 2004;8:3–14. 4. Silverman JM, Julien PJ, Herfkens RJ, Pelc NJ. Quantitative differential pulmonary perfusion: MR imaging versus radionuclide lung scanning. Radiology 1993;189:699 –701. 5. Prekker ME, Nath DS, Walker AR, et al. Validation of the proposed International Society for Heart and Lung Transplantation grading system for primary graft dysfunction after lung transplantation. J Heart Lung Transplant 2006;25:371– 8. 6. Hardoff R, Steinmetz AP, Krausz Y, et al. The prognostic value of perfusion lung scintigraphy in patients who underwent single-lung transplantation for emphysema and pulmonary fibrosis. J Nucl Med 2000;41:1771– 6. 7. Boyd SY, Sako EY, Trinkle JK, O’Rourke RA, Zabalgoitia M. Calculation of lung flow differential after single-lung transplantation: a transesophageal echocardiographic study. Am J Cardiol 2001;87:1170 –3. 8. Bjortuft O, Simonsen S, Geiran OR, et al. Pulmonary haemodynamics after single-lung transplantation for end-stage pulmonary parenchymal disease. Eur Respir J 1996;9:2007–11.