Lung transplantation long-term survival is worse in patients who have undergone previous cardiac surgery

Abstract

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OBJECTIVES

Approximately 10% of lung transplant recipients have had previous cardiothoracic surgery. We sought to determine if previous surgery affects outcomes after lung transplant at a national level.

METHODS

The United Network for Organ Sharing database was analysed from 2005 to 2019 to include adult patients who underwent lung transplant who had previous cardiac surgery and previous thoracic surgery. T-test and chi-squared analysis were used to compare perioperative outcomes. Long-term survival comparison was performed using the Kaplan–Meier method in an unadjusted and propensity-matched analysis.

RESULTS

Out of 24 784 lung transplants, 691 (2.7%) had previous cardiac surgery and 1321 (6.5%) had previous thoracic surgery. Operative mortality was worse in previous cardiac surgery [42 (6.1%)] versus no previous cardiac surgery [740 (3.1%), P < 0.001] and in previous thoracic surgery [65 (4.9%)] versus no previous thoracic surgery [717 (3.1%), P < 0.001]. The previous thoracic surgery group had more primary graft failure and treated rejection during the first-year post-transplant. There was no difference in stroke, dialysis, intubation and extracorporeal membrane oxygenation at 72 h. Long-term survival was significantly worse for lung transplant patients who had undergone previous cardiac surgery (median 3.8 vs 6.3 years, P < 0.001) due to an increase in cardiovascular deaths (P = 0.008) and malignancy (P = 0.043). However, there was no difference in previous thoracic surgery (median 6.6 vs 6.1 years, P = 0.337).

CONCLUSIONS

Previous cardiac surgery prior to lung transplant results in worse survival related to cardiovascular death and malignancies. Previous thoracic surgery worsens perioperative outcomes but does not affect long-term survival.

INTRODUCTION

Orthotopic lung transplant is an effective therapy for end-stage lung disease. The number of lung transplants performed every year appears to be on the rise. In 2019, there was a 7.3% increase from the previous year to 2714 lung transplants [1]. With advancements in lung therapy, organ preservation and innovation such as ex vivo lung perfusion, the number of lung transplants will continue to increase and our definition of who is a suitable candidate for transplant will evolve.

Prior to lung transplantation, patients face the need to undergo non-cardiac thoracic surgery (PTS) for a variety of reasons. Most commonly, diagnosis of the aetiology of lung failure may require surgical tissue sampling by video-assisted thoracic surgery or thoracotomy. The disease process itself may necessitate interventions such as pleurodesis for recurrent pneumothorax or lung volume reduction for advanced emphysema. The formation of adhesions and scar can make explantation of the lung difficult and may extend operative times. A previous report has encountered the greatest number of complications on pleurodesis patients [2] while another study found increased length of intensive care unit stay [3].

Another high-risk PTS group is those with previous lobectomies for lung cancer or benign conditions [4]. Some of these can be mitigated with lung transplantation but postoperative bleeding remains a main concern with a rate of 10–15%. Other series found a worrisome 9% risk of stroke as well [5]. Lung transplant after previous cardiac surgery (PCS) comes with its own set of challenges. Central cannulation can be more difficult or not feasible in an urgent situation. Previous coronary artery bypass grafting (CABG) with a patent left internal mammary artery to left anterior descending artery graft likely presents the most technical challenge when considering bilateral lung transplant. Previous publications have demonstrated that cardiac surgery prior to heart transplantation may have worse outcomes [2, 6–9]. Operative factors such as increased ischaemic time, increased use of blood products and distorted anatomy are potential factors contributing to worse outcomes. Additionally, patients with PCS represent a more medically complex subset of patients. Prior institutional studies have not shown increased risk [3]. Nevertheless, intuitively coronary or valve disease may have an impact in the long-term follow-up not appreciated in small series. We believe that this risk should be studied to help transplant clinicians decision-making in the often-controversial multidisciplinary selection process.

We hypothesized that prior surgery would negatively impact postoperative outcomes at a national level. In our study, we examine the impact of previous cardiac or thoracic surgery on perioperative outcome and long-term survival in contemporary lung transplant patients.

MATERIALS AND METHODS

Ethics statement

This study was approved by the Mayo Clinic institutional review board under Investigating Outcomes of Heart and Lung Transplantation Utilizing the United Network for Organ Sharing (UNOS) Database ID: 21-008555.

This study was a retrospective review of an administrative database. Data were obtained from the UNOS database and analysed from January 2005 to June 2019 to include adult patients who underwent lung transplantation during the current era of lung allocation score. Patients were excluded if they did not undergo transplant or underwent multi-organ transplant or retransplantation.

Patients were then identified as having undergone PCS or non-cardiac PTS prior to the time of lung transplantation. PCS included CABG, valve surgery, a combination of CABG and valve and other open operations, such as congenital cases. It did not include endovascular or minimally invasive surgery. Data was additionally coded manually from the comments entered in the database to avoid missing data as much as possible. Patients with previous surgery were stratified by type of procedure. Minimally invasive or video-assisted thoracic surgery biopsies were not considered a PTS. However, thoracotomy biopsies were included in the PTS group. Cause of death was categorized as related to graft failure, infection, cardiovascular, pulmonary, malignancy or others. Preoperative and postoperative characteristics were compared. The primary outcome of the study was perioperative 30-day mortality and long-term survival after lung transplantation.

Statistical methods

All statistical analyses were completed using SPSS v. 22 (IBM, Armonk, NY, USA) and BlueSky Statistics (BlueSky Statistics LLC, Chicago, IL, USA). Due to the large sample size, T-test and chi-squared analysis were used to compare study group characteristics. P-Values were adjusted using Bonferroni’s method. Log-rank analysis using Kaplan–Meier survival method was used to compare survival between study groups. Propensity score matching analysis in a 1:1 fashion using a multivariable logistic regression model with a calliper of 0.2 and standardized mean differences was then used to compare survival between study groups using the following variables: recipient’s age, sex, body mass index, ethnicity, diabetes history, creatinine, hospitalization status, lung allocation score, ventilator status, use of inhaled nitric oxide (NO), extracorporeal membrane oxygenation (ECMO) status, ischaemic time, days spent on the waiting list, bilateral transplant and diagnosis and donor’s age, sex, body mass index, creatinine, ethnicity, cocaine use, smoking history, diabetes history, hypertension history, myocardial infarction history and use of extended-criteria donor. Values are reported as n (%) or average (standard deviation). A P-value of 0.05 or less was considered statistically significant. Confidence intervals of 95% were used.

RESULTS

A total of 691 (2.7%) patients had PCS, and 1321 (6.5%) patients had PTS. Types of surgery performed for both previous cardiac and thoracic surgeries are shown in Table 1. Most patients (71%) had ischaemic heart disease with a previous CABG or CABG + valve procedure. The other category consisted of mainly congenital procedures but also included sternotomy for trauma, central ECMO, aortic procedures, pulmonary endarterectomy and pericardiectomy. The PTS group was stratified based on laterality, approach and type of surgery. The most common previous surgery was a biopsy by thoracotomy 614 (46%) and 237 (17.9%) minimally invasive or video-assisted biopsies were classified as no-PTS. Laterality was left (N = 260, 19.7%), right (N = 441, 33.4%), bilateral (N = 51, 3.9%) or unknown (N = 569, 43.1%).

The characteristics of donors and recipients are shown in Table 2 and are divided into 2 main groups: PCS and PTS. For the PCS group, those that had surgery were older, had a higher proportion of white males with a diagnosis of idiopathic pulmonary fibrosis and were more likely to have a history of diabetes and smoking. The lung allocation score was slightly higher for this group correlating with a higher proportion hospitalized, on inhaled NO or on ECMO at the time of transplant. For the PTS group, patients who had undergone surgery were more likely to be male, have a diagnosis of idiopathic pulmonary fibrosis, require ventilator therapy at the time of transplant and have a higher lung allocation score. Patients who did not undergo PTS were more likely to have a history of diabetes and smoking. Donor characteristics were similar between groups for both the PCS and PTS groups.

Postoperative outcomes are described in Table 3. Patients with PCS were more likely to require inhaled NO at 72 h (P = 0.008). Patients with no PCS were more frequently treated for rejection within 1 year post-lung transplant (P = 0.007). Outcomes for the PTS group were similarly compared. Those who had surgery were more likely to use inhaled NO at 72 h (P = 0.04) and to have been treated for rejection within 1 year (P = 0.004). Importantly, both PCS and PTS groups had a higher 30-day mortality (P < 0.001).

Survival analysis demonstrated that patients who had undergone PCS had worse post-transplant survival. Five-year survival for patients who underwent lung transplant with PCS was 41.1% compared to 57.1% for patients with no PCS (P < 0.001). Nevertheless, there was no significant difference in post-transplant survival between patients who had undergone PTS (58.4%) with those who had not (56.5%, P = 0.47, Fig. 1). In addition, when survival was compared between the types of procedure performed, patients who had undergone other procedures including mainly congenital operations had significantly better post-transplant surgery than those who had undergone coronary artery bypass grafting (CABG), valve or percutaneous interventions (P = 0.007, figure not shown). Finally, survival outcomes were compared for patients who underwent CABG (n = 465) compared to those who underwent percutaneous coronary interventions (PCI, n = 210), and there was no difference in survival (P = 0.338); however, patients who underwent coronary intervention either with PCI or with CABG had significantly worse survival after lung transplant compared to those who had not (P < 0.001). Furthermore, when we repeated the analysis of survival with the most hostile types of PTS—pleurodesis, lung volume reduction, lobectomy—no statistically significant difference was shown (P = 0.871).

Graft failure was the main cause of higher 30-day mortality in the PCS group. In the PTS, there was a tendency to increased mortality in the several types of death; however, no one reached significance (Table 4). During long-term follow-up, cause of death was most likely cardiovascular or/and malignancy in PCS patients. There was no difference in the PTS group (Table 5).

Propensity matching analysis demonstrated appropriate matching for 666 pairs in the PCS versus no history of surgery group and 1276 pairs in the PTS versus no history of surgery group (Table 6). The matched patients with PCS had significantly worse survival than those with no PCS (P = 0.00044, Fig. 2A). There was no difference in post-transplant survival between the matched patients with PTS compared with no PTS (P = 0.36, Fig. 2B).

DISCUSSION

Lung transplantation remains the best treatment for patients with end-stage lung disease. Patients who qualify for lung transplant are increasingly medically complex, many having had thoracic surgical intervention for the diagnosis and treatment of cardiothoracic disease processes [10]. There is evidence that more patients with previous cardiothoracic surgery are being referred for transplant and that some centres consider this a contraindication for transplantation [3]. Our study sought to determine if previous cardiothoracic surgery affects postoperative outcomes including long-term survival in patients who undergo lung transplant.

Our analysis shows that patients who had undergone PCS had significantly worse survival following lung transplantation. The difference in 30-day mortality was most striking. The patient population who underwent PCS was older with more comorbidities, but with little difference in perioperative outcomes when compared to the patient population without previous cardiac interventions, which may influence survival outcomes. Survival analysis based on the type of cardiac surgery showed the best survival for the ‘other’ group which consisted of patients who were much younger at the time of transplant further reinforcing the idea that co-morbidities present at the time of transplant may contribute to decreased survival. This is also supported by the finding that PCI and previous CABG had equivocal survival which was worse than those with no PCS. However, Cox regression analysis supported the hypothesis that PCS is an independent predictor of decreased survival following lung transplant.

The literature is lacking in breadth and consensus on this topic. In an analysis of the UNOS database, McKellar et al. [2] demonstrated that previous CABG surgery negatively impacted survival after bilateral lung transplantation, which is consistent with our findings. This study concluded that offering single-lung transplant in patients with a history of CABG surgery should be considered in reasonable candidates. However, in a retrospective, single-centre study, Kanaparthi et al. [11] showed no difference in post-transplant survival for patients who had a history of CABG or concomitant CABG when compared to patients who underwent percutaneous coronary interventions or no revascularization. Omara et al. [12] similarly demonstrated no difference in post-transplant survival after cardiothoracic interventions, but patient numbers were low, cardiac and thoracic procedures were combined into 1 group, and only 25 patients had previous cardiac procedures. Some studies suggest that moderate coronary artery disease does not impact post-transplant survival [13–15]. While the UNOS database does not quantify the degree of coronary disease, our analysis suggests that coronary disease is an independent factor associated with decreased survival after lung transplant. Additional analysis of cause of death demonstrated in increased frequency in infection in the non-PCS group. This is counterintuitive to what one would expect as patients with PCS are often more sensitized thus requiring more immunosuppression resulting in increased infection. We speculate that because the PCS group more frequently died from a cardiac cause with a shorter survival time, they did not necessarily have the opportunity to die from long-term immunosuppression and infectious causes. We also found that malignancy was a more common reason for death in the PCS group. While the UNOS database is not specific in the coding of malignancy, it is possible that the higher rate of smoking in the PCS group may have contributed to the higher rate of malignancy as a cause of death. After propensity matching was performed, there was no difference in cause of death between the PCS and no PCS groups, which would support that the smoking history may contribute significantly. Our study shows clearly that cardiac surgery negatively influenced survival, but given these recent studies, appropriate patient selection at experienced centres may mitigate the negative effects.

In contrast, previous thoracic surgical intervention did not negatively impact long-term survival after lung transplantation for all comers or when type of approach was compared. Similar to our findings, Omara et al. [12] found no difference in survival; however, post-transplant outcomes were worse, particularly for those who underwent pleurodesis in a single centre, in a retrospective review by Shigemura et al. [3]. Survival was unaffected but was only analysed out to 3 years after lung transplant. Our analysis did not find any difference in survival based on the type of procedure, despite the hypothesis that a more extensive previous operation would proportionately and negatively impact postoperative outcomes. Likely, the large number of missing descriptive data and small group numbers did not allow for a more granular analysis. We also found that primary graft failure and 30-day mortality were higher in the previous thoracic surgery group despite the lack of difference in survival outcomes. While it is difficult to give a definitive explanation, 1 possibility is that these recipients were matched with better donors and were able to overcome the immediate postoperative outcomes. In addition, it highlights the risk of re-operative surgery both in the setting of cardiac and thoracic surgery. Re-operative surgery can lead to longer operative times, and increased blood loss which may contribute to early mortality and PGD. Overall, the literature is more consistent in demonstrating that PTS does not affect long-term survival after lung transplant [16], although certain circumstances may warrant caution in patient selection.

This study is limited by the use of a retrospective, administrative database. The database was not designed to answer the question proposed in this study and, thus, had frequent incomplete data with regards to previous surgical history possibly biasing results. In addition, the UNOS database does not grade primary graft dysfunction based on the ISHLT classification and the definition of graft failure might have been variably entered by the database coders. Lung transplant recipients as an entire cohort are a heterogenous group, and this should be taken into consideration when drawing conclusions from the study.

This analysis demonstrates that PCS results in significantly worse 5-year survival after lung transplant. PTS does not affect long-term post-transplant survival but does worsen perioperative outcomes. The decision to list for lung transplant for these 2 populations, those who underwent PCS and those who underwent PTS, should be taken with extra caution, particularly in the PCS population but should not be prohibitive to proceeding with transplant, especially in experienced centres.

ACKNOWLEDGEMENTS

The authors thank Brian D. Lahr, MS, for his statistical help.

Funding

There were no funding sources for this project.

Conflict of interest: none declared.

Data Availability Statement

The data underlying this article were provided by United Network for Organ Sharing by permission. Data will be shared on request to the corresponding author with permission of UNOS.

Author contributions

Erin M. Schumer: Conceptualization; Data curation; Formal analysis; Writing—original draft; Writing—review & editing. Sahar A. Saddoughi: Conceptualization; Writing—original draft; Writing—review & editing. Philip J. Spencer: Methodology; Writing—review & editing. Alberto Pochettino: Conceptualization; Methodology; Writing—review & editing. Richard C. Daly: Conceptualization; Methodology; Writing—review & editing. Mauricio A. Villavicencio: Conceptualization; Methodology; Supervision; Writing—review & editing.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Bartosz Kubisa, Luca Luzzi and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.

Presented as a virtual poster at the Society of Thoracic Surgeons Annual Meeting, 29–31 January 2021.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• CABG

  Coronary artery bypass grafting

 
• ECMO

  Extracorporeal membrane oxygenation

 
• NO

  Nitric oxide

 
• PCS

  Previous cardiac surgery

 
• UNOS

  United Network for Organ Sharing