Comparison of living-donor lobar lung transplantation and cadaveric lung transplantation for pulmonary hypertension

Abstract

OBJECTIVES

Living-donor lobar lung transplantation (LDLLT) is a life-saving procedure for critically ill patients with various lung diseases, including pulmonary hypertension (PH). However, there are concerns regarding the development of heart failure with pulmonary oedema after LDLLT in which only 1 or 2 lobes are implanted. This study aimed to compare the preoperative conditions and postoperative outcomes of LDLLT with those of cadaveric lung transplantation (CLT) in PH patients.

METHODS

Between 2008 and 2021, 34 lung transplants for PH, including 12 LDLLTs (5 single and 7 bilateral) and 22 bilateral CLTs, were performed. Preoperative variables and postoperative outcomes were retrospectively compared between the 2 procedures.

RESULTS

Based on the preoperative variables of less ambulatory ability (41.7% vs 100%, P < 0.001), a higher proportion of World Health Organization class 4 (83.3% vs 18.2%, P < 0.001) and higher mean pulmonary artery pressure (74.4 vs 57.3 mmHg, P = 0.040), LDLLT patients were more debilitated than CLT patients. Nevertheless, hospital death was similar between the 2 groups (8.3% vs 9.1%, P > 0.99, respectively). Furthermore, the 5-year overall survival rate was similar between the 2 groups (90.0% vs 76.3%, P = 0.489).

CONCLUSIONS

Although LDLLT patients with PH had worse preoperative conditions and received smaller grafts than CLT patients, LDLLT patients demonstrated similar perioperative outcomes and prognoses as CLT patients. LDLLT is a viable treatment option for patients with PH.

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INTRODUCTION

Lung transplantation (LTx) has been performed as the final option for saving the lives of patients with end-stage pulmonary diseases with satisfactory outcomes, and the number of LTx procedures performed has been gradually increasing [1]. However, in countries where severe donor shortage has been a major issue, especially in Japan, living-donor lobar lung transplants (LDLLTs) have played an important role in LTx [2]. The graft size differs greatly between LDLLTs and cadaveric lung transplants (CLTs). In standard bilateral LDLLT, the right or left lower lobe is donated from living donors; 2 lobes are implanted after bilateral pneumonectomy. Therefore, the graft size in LDLLT is usually smaller than that in CLT, and the 2 lobes are often too small for adult recipients. Conversely, since the 2 lobes are sometimes too large for paediatric recipients, a single LDLLT can be a treatment option for them [3, 4].

Currently, bilateral CLT is widely accepted as the standard LTx for various types of pulmonary hypertension (PH) patients, including idiopathic pulmonary arterial hypertension (IPAH) [5, 6]. Conversely, successful case reports of single LDLLT for paediatric recipients with IPAH [7, 8] and favourable outcomes of LDLLT for PH recipients [9] have been reported in Japan; however, there have been no reports directly comparing the postoperative outcomes of LDLLT for PH recipients with those of CLT. As mentioned above, the graft size in LDLLT is smaller than that in CLT. Therefore, it remains unclear whether heart failure with pulmonary oedema develops more frequently after LDLLT than after CLT and whether the postoperative outcomes of LDLLT for PH recipients differ from those of CLT. Herein, we retrospectively reviewed LDLLT and CLT performed in PH recipients and compared the preoperative conditions and postoperative outcomes of PH recipients undergoing LDLLT with those of CLT.

PATIENTS AND METHODS

Ethical statement

This study was approved by the Institutional Review Board (R2389). The requirement for informed consent was waived because of the retrospective nature of the study.

Between 2008 and 2021, 279 lung transplants (110 LDLLTs and 169 CLTs) were performed at our institution. LDLLT was considered for rapidly deteriorating patients who could not wait for CLT. In this study, 34 patients with PH other than secondary PH with pulmonary diseases were enrolled (12 LDLLTs and 22 CLTs). The preoperative conditions and postoperative outcomes, including prognoses, were compared between the 12 LDLLT recipients and 22 CLT recipients.

The observation period was defined as the date of LDLLT/CLT until the last follow-up, or until death. The observation period of chronic lung allograft dysfunction (CLAD)-free survival was defined as the interval between the date of LDLLT/CLT and the last follow-up, CLAD or death. CLAD was diagnosed based on the definition in a consensus report published in 2019 [10]. The follow-up was censored at the end of February 2022.

The immunosuppressive agents mainly used were calcineurin inhibitors (cyclosporine or tacrolimus), mycophenolate mofetil, azathioprine and prednisolone, as reported previously [11, 12]. In the chronic phase, the target trough level of tacrolimus was 8–12 ng/ml and the doses of mycophenolate mofetil and prednisolone were 500–1500 mg daily and 0.2 mg/kg every other day, respectively.

Size matching in living-donor lobar lung transplant and cadaveric lung transplant

As reported elsewhere [13, 14], LDLLT is usually accepted when forced vital capacity (FVC) size matching exceeds 45% in our institution; however, for PH recipients, we consider that FVC size matching should be >50% [4, 9]. FVC size matching was calculated by comparing the total graft FVC estimated from the measured donor FVC and the recipient’s predicted FVC. In cases where FVC size matching is <45%, we consider performing right-to-left inverted LDLLT [15, 16] or LDLLT with the native upper lobe-sparing technique [17, 18].

For CLT, size matching was evaluated as the ratio of the predicted FVC of the graft to that of the recipient. When downsizing lobectomy was performed, the predicted FVC of the graft was calculated based on the number of segments implanted and the predicted FVC of the donor. For example, the predicted FVC of the graft was estimated to be 14/19 of the predicted FVC of the donor when downsizing right lower lobectomy was performed.

Statistical analyses

Descriptive statistics were obtained using EZR software, a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [19, 20]. Continuous variables are presented as mean with range, and categorical variables are expressed as percentages. The Mann–Whitney U-test and Fisher’s exact test were used for between-group analysis. Survival analyses for overall survival (OS) and CLAD-free survival were performed using the Kaplan–Meier method, and the groups were compared using a log-rank test. Statistical significance was defined as P < 0.05.

RESULTS

Recipient characteristics and preoperative conditions

The average age of LDLLT recipients was significantly lower than that of CLT recipients (16.5 vs 30.7 years, P = 0.012, Table 1), but there was no difference in sex distribution. Body mass index tended to be lower in the LDLLT group than in the CLT group (15.7 vs 18.1, P = 0.052). The proportion of ambulatory LDLLT recipients was significantly lower than that of CLT recipients (41.7% vs 100%, P < 0.001), a higher proportion of World Health Organization class 4 was observed in LDLLT recipients than in CLT recipients (83.3% vs 18.2%, P < 0.001) and mean pulmonary artery pressure (mPAP) was significantly higher in LDLLT patients than in CLT patients (74.4 vs 57.3 mmHg, P = 0.040), indicating that the preoperative condition of LDLLT recipients was worse than that of CLT recipients.

All CLT recipients underwent bilateral CLTs, while 5 of the 12 LDLLT recipients underwent single LDLLTs. Upper lobe-sparing technique was used in 2 LDLLT recipients. Downsizing lobectomies were performed in 5 CLT recipients. As predicted, the size matching of LDLLTs was significantly lower than that of CLTs (mean, 64.5% vs 96.6%; P < 0.001). In bilateral LTx (both LDLLT and CLT), lung transplants were performed using the clamshell approach, and central cannulation was used for intraoperative extracorporeal circulation in both intraoperative extracorporeal membrane oxygenation and conventional cardiopulmonary bypass. In unilateral LDLLT, central cannulation was also selected for PH recipients who were enrolled in this study. Regarding intraoperative extracorporeal circulation, cardiopulmonary bypass was used for 18 recipients, while veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was used for 16 recipients.

As additional procedures, closure of the atrial septal defect for 3 LDLLT recipients and 3 CLT recipients, plication of the main pulmonary artery for 1 LDLLT and 1 CLT recipient and pulmonary artery reconstruction using the aorta of the donor for 2 CLT recipients were performed. As expected, a shorter total ischaemic time was observed in LDLLT than in CLT (mean, 157 vs 557 min; P < 0.001). Moreover, the operation time and extracorporeal time in LDLLT were significantly shorter than those in CLT, which seemed to be affected by the fact that 5 of 12 LDLLTs were single LDLLTs (mean, 482 vs 610 min; P = 0.023, and 245 vs 325 min; P = 0.014, respectively).

Perioperative outcomes

The frequency of grade 3 primary graft dysfunction (PGD) within 72 h was relatively high in both LDLLT and CLT, but there was no significant difference between the 2 groups (66.7% in LDLLT and 77.3% in CLT, P = 0.687, Table 2). Grade 3 PGD occurred at 72 h in 4 out of 12 LDLLT recipients (33.3%), while it was observed in 9 out of 22 CLT recipients (40.9%). There was no significant difference in the proportion of cases between the 2 groups (P = 0.727). Postoperative VA-ECMO support was required in 5 LDLLT recipients (41.7%) and 5 CLT recipients (22.7%), which was not significantly different (P = 0.271). The proportion of delayed chest closure in the LDLLT group was also not significantly different from that in the CLT group (41.7% vs 18.2%, P = 0.224). Furthermore, there were no significant differences in the length of intensive care unit between LDLLT and CLT recipients (median, 20 vs 18.5 days; P = 0.503). Hospital death was observed in 1 LDLLT recipient (8.3%) who received a single LDLLT and 2 CLT recipients (9.1%), which was comparable between LDLLT and CLT recipients (P > 0.99).

Regarding postoperative complications, reoperation was performed in 10 recipients. Due to postoperative bleeding, re-thoracotomy was required in 9 patients, and in 1 LDLLT recipient, pulmonary venoplasty was performed to repair stenosis after pulmonary venous anastomosis. Acute kidney injury was observed in 4 recipients, and 2 of these patients required renal replacement therapy. Other representative complications observed included gastrointestinal bleeding (n = 3), pneumothorax (n = 3), posterior reversible encephalopathy syndrome (n = 1), cerebral haemorrhage (n = 1) and diffuse brain damage (n = 1).

In this study, 19 living donors donated their lobes to 12 recipients. There was no mortality among living donors; however, there were 5 morbidities greater than grade 3 according to the Clavien–Dindo classification in 4 donors, which included pleural effusion (n = 4) and pneumothorax (n = 1).

Prognoses

There was no significant difference in the OS between the LDLLT and CLT groups (P = 0.489, Fig. 1A). In LDLLT, both the 1- and 5-year OS rates were 90.9% [95% confidence interval (CI): 50.8–98.7%], while the 1- and 5-year OS rates in CLT were 90.9% (95% CI: 68.3–97.6%) and 76.3% (95% CI: 47.0–90.7%), respectively. Similarly, CLAD-free survival in the LDLLT group was not significantly different from that in the CLT group (P = 0.728, Fig. 1B). In LDLLT, 1- and 5-year CLAD-free survival were 80.8% (95% CI: 42.3–94.9%) and 57.7% (95% CI: 22.1–81.9%), respectively, and those in CLT were 86.1% (95% CI: 62.9–95.3%) and 63.8% (95% CI: 34.9–82.5%), respectively.

Changes of pulmonary arterial pressure

In 27 recipients, consisting of 8 LDLLT recipients and 19 CLT recipients, who underwent both preoperative and postoperative right heart catheterization, the changes in mPAP were examined. The average mPAP in LDLLT was decreased from 74.4 mmHg (range, 50–121 mmHg) to 20.3 mmHg (range, 12–31 mmHg) postoperatively (Fig. 2A). Similarly, the average mPAP in the CLT also decreased from 57.3 mmHg (range, 42–84 mmHg) to 15.5 mmHg (range, 9–25 mmHg) postoperatively (Fig. 2B).

DISCUSSION

In this study, several important findings were observed. First, despite the fact that the preoperative conditions in LDLLT recipients were worse than those in CLT recipients and the size matching in LDLLT was smaller than that in CLT, both the perioperative outcomes and prognoses in LDLLT were comparable with those in CLT. Conversely, since the frequency of PGD grade 3 was high and postoperative VA-ECMO support was required in >20% of both LDLLT and CLT cases, careful postoperative management was important for obtaining favourable outcomes.

As the eligibility criteria for LDLLT in our institution, LDLLT is potentially accepted when FVC size matching is ≥45%, whereas it is desired that FVC size matching is ≥50% for recipients with IPAH [4, 9]. It has been reported that the occurrence of PGD and the rate of perioperative death are generally higher in PH recipients than in recipients with pulmonary diseases other than PH [6, 21], and left heart failure rather than residual PH is considered one of the main causes of PGD [6]. Regarding these points, it is naturally concerning that the smaller graft size and less vascular bed in LDLLT than in CLT, as also observed in this study, may have influenced the perioperative outcomes or the occurrence rate of PGD. Moreover, since recipients who cannot wait for CLT receive LDLLT, it was also observed in this study that the preoperative conditions of LDLLT recipients were worse than those of CLT recipients. Nonetheless, this study indicated that the perioperative outcomes of LDLLT were comparable with those of CLT, which was quite notable. Although the graft size in LDLLT is smaller than that in CLT, the lung grafts in LDLLT have better quality than those in CLT because lung grafts with no injury, namely ‘perfect’ lung grafts, are implanted in recipients, which might have influenced these results [8]. On the other hand, careful postoperative management is necessary since PGD grade 3 occurred in more than half of the recipients and postoperative VA-ECMO support was required in >20% of recipients. Our strategy of postoperative mechanical ventilation usually involves pressure control ventilation. The target tidal volume was set based on the recipient’s body weight. To treat postoperative pulmonary oedema, the positive end-expiratory pressure is sometimes set higher. Regarding haemodynamic and fluid management, fluid balance was kept on the dry side, and correction of hypotension was mainly performed using catecholamines. Fluid balance was estimated using central venous pressure, and in some severe cases, the left atrial pressure was used. Recently, we adopted a new strategy to resume and taper epoprostenol after LTx for recipients who were administered preoperatively [22], aiming to achieve better postoperative outcomes by improving perioperative management.

In addition to perioperative outcomes, there were no significant differences in mid-term and long-term prognoses between LDLLT and CLT recipients, and the 5-year OS in both LDLLT and CLT was favourable, as it was >75%. The prognoses of IPAH recipients surviving >1 year after CLT were reported to be relatively better than those of recipients with pulmonary diseases other than IPAH [23], and the results of this study were compatible.

CLAD usually occurs unilaterally in LDLLT; therefore, the other graft could compensate for pulmonary functions when graft dysfunction is observed in the unilateral graft, which is considered as one of the great advantages of LDLLT [24]. On the other hand, since this study included some paediatric recipients undergoing a single LDLLT, the new onset of CLAD and the requirement of retransplantation due to CLAD would possibly be observed in the future. Therefore, careful follow-up is warranted.

Among recipients receiving both preoperative and postoperative right heart catheterization, postoperative mPAP was remarkably reduced in both LDLLT and CLT groups. Despite the difference in graft size between LDLLT and CLT, the decrease in mPAP was equally observed, which indicates that LDLLT is an appropriate treatment option for rapidly deteriorating recipients with PH who cannot wait for CLT. In addition, some paediatric patients who underwent single LDLLT were included in this study. For paediatric recipients in whom severe donor shortage is expected, single LDLLT can be an important treatment option, considering both functional and anatomical size matching.

Limitations

This study had some limitations. First, this was a retrospective, non-randomized, single-centre study. In addition, the number of recipients included in this study was relatively small. However, this study is novel in that it investigated whether LDLLT is a useful option for PH patients, since there have been no reports directly comparing the postoperative outcomes of LDLLT for PH recipients with those of CLT.

CONCLUSION

Although LDLLT recipients with PH had worse preoperative conditions than CLT recipients with PH, LDLLT recipients demonstrated favourable prognoses similar to those of CLT recipients. LDLLT is a viable treatment option for patients with PH.

Presented at the 30th ESTS Meeting, Hague, Netherlands, 21 June 2022.

ACKNOWLEDGMENTS

The authors are grateful to the anaesthesiologists, cardiac surgeons, pulmonologists, perfusionists, lung transplant coordinators and laboratory technologists from Kyoto University Hospital for their support with the LTx program. The authors also would like to thank Honyaku Center Inc. for English language editing.

Funding

This study was funded by Health Labor Sciences Research Grant in Japan (20FC1027).

Conflict of interest: none declared.

DATA AVAILABILITY

The data underlying this article will be shared on reasonable request to the corresponding author.

Author contributions

Hidenao Kayawake: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Writing—original draft; Writing—review & editing. Satona Tanaka: Writing—review & editing. Yoshito Yamada: Writing—review & editing. Shiro Baba: Writing—review & editing. Hideyuki Kinoshita: Writing—review & editing. Kazuhiro Yamazaki: Writing—review & editing. Tadashi Ikeda: Writing—review & editing. Kenji Minatoya: Writing—review & editing. Yojiro Yutaka: Writing—review & editing. Masatsugu Hamaji: Writing—review & editing. Akihiro Ohsumi: Writing—review & editing. Daisuke Nakajima: Writing—review & editing. Hiroshi Date: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Supervision; Validation; Writing—review & editing.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Michael Eberlein, Tomislav Kopjar and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• CI

  Confidence interval

 
• CLAD

  Chronic lung allograft dysfunction

 
• CLTs

  Cadaveric lung transplants

 
• FVC

  Forced vital capacity

 
• IPAH

  Idiopathic pulmonary arterial hypertension

 
• LDLLTs

  Living-donor lobar lung transplants

 
• LTx

  Lung transplantation

 
• mPAP

  Mean pulmonary artery pressure

 
• OS

  Overall survival

 
• PA

  Pulmonary artery

 
• PGD

  Primary graft dysfunction

 
• PH

  Pulmonary hypertension

 
• VA-ECMO

  Veno-arterial extracorporeal membrane oxygenation