Single Lung Transplant Remains a Viable Option for Patients With Severe Secondary Pulmonary Hypertension : Transplantation

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Original Clinical Science—General

Single Lung Transplant Remains a Viable Option for Patients With Severe Secondary Pulmonary Hypertension

Sunagawa, Gengo MD1; Kehara, Hiromu MD, PhD1; Mangukia, Chirantan MD1; Brann, Stacey MD1; Leotta, Eros MD1; Yanagida, Roh MD, PhD1; Minakata, Kenji MD, PhD1; Shenoy, Kartik V. MD2; Mamary, Albert James MD2; Marchetti, Nathaniel MD2; Cordova, Francis MD2; Criner, Gerard J. MD2; Toyoda, Yoshiya MD, PhD1; Shigemura, Norihisa MD, PhD1

Author Information
doi: 10.1097/TP.0000000000004191
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Abstract

INTRODUCTION

Severe pulmonary hypertension (PH) secondary to advanced lung disease is considered a complicating factor in the entire field of chest medicine and has led to cautious approaches when caring for patients with severe PH and limited opportunities for lung transplantation.1,2 Conceptually, patients with severe PH should require double lung transplantation, and the utility of this approach is supported by numerous studies,3-7 including a recent report using national registry data.7

Over the past 10 y, we have observed an outstanding and steady increase in patients >70 y of age with multiple comorbidities referred to our high-volume center as potential candidates for lung transplant. Demographic analysis of waiting list registrations, performed for the Scientific Registry of Transplant Recipients Annual Report, demonstrated that we have approximately 3 times more patients older than 70 on our waitlist proportional to our yearly lung transplant volume than on all waitlist registrations in the United States (31.8% versus 12.0%) and twice as many as compared with our Organ Procurement and Transplantation Network region as a whole (31.8% versus 16.2%).8

In aging populations, many patients have multiple diseases characterized by acceleration of the aging process, including cardiovascular diseases, metabolic diseases, and chronic kidney diseases.3,9,10 When performing lung transplant in this elderly patient cohort, we think it is important to minimize their surgical burden to potentially reduce postoperative mortality and morbidity and promote faster recovery. Accordingly, we prioritize single lung transplantation as the first surgical option for patients over 70 y of age with multiple comorbidities. This approach of prioritizing single lung transplant has been applied even in patients with severe PH. The aim of this study was to evaluate the outcomes of this unique approach to patients with severe secondary PH (SPH).

MATERIALS AND METHODS

This study (protocol #28951) was approved by the Temple University Institutional Review Board and was exempt from the requirement for informed consent. We reviewed the records of all patients who underwent single lung transplant at our institution between January 2017 and December 2019. The patients diagnosed primary PH were excluded because all of them received double lung transplantation. The study period was selected because we could confirm standardized patient selection (for both recipients and donors) and management, preoperatively, intraoperatively, and postoperatively, from January 2017 to the present. We then divided the patients into 3 groups for analysis based on the degree of SPH they exhibited. The severe PH group was defined by mean pulmonary artery pressure (mPAP) >40 mm Hg. The mild PH group was defined by mPAP >25 mm Hg and ≤40 mm Hg. Patients without PH transplanted over the same time period comprised the control group. The PAPs used for data analysis were obtained by Swan-Ganz catheterization at the time of transplantation. We prioritized the lung with lower blood flow for the decision of the laterality, if the differences in blood flow between the right and left are not significant, approximately <40%. Preoperative, intraoperative, and postoperative characteristics and survival were compared between the 3 patient groups.

Statistical Analysis

Data are presented as mean ± SEM (median), unless noted. Survival curves were generated using the Kaplan-Meier method, and log-rank analysis was used to determine significance. Measured clinical data were compared using ANOVA and χ2 analysis. A P value <0.05 was considered significant.

RESULTS

Recipient and Donor Characteristics

Queries of our institutional database identified 318 patients who had undergone a single lung transplant during the 3-y study period. All patients met widely accepted criteria for lung transplantation based on their primary lung disease and were believed to be suitable candidates for a lung transplant. Of the 318 recipients of a single lung transplant, 59 patients (18.5%) had severe PH, 217 (68.2%) had mild PH, and 42 (13.2%) did not exhibit PH. The median mPAP in the patients with severe PH was 44 mm Hg (range: 40–60 mm Hg), median mPAP in patients with mild SPH was 31 mm Hg (range: 25–39 mm Hg), and median mPAP in patients without PH was 22 mm Hg (range: 17–24 mm Hg).

The only significantly different preoperative characteristics between the patients with severe PH, the patients with mild PH, and the patients without PH were body mass index (28.5 versus 27.8 versus 25.7, respectively; P < 0.01) and pulmonary vascular resistance (4.23 versus 3.08 versus 2.58, P < 0.01; Table 1). There were 2 patients who were on veno-venous (VV) extracorporeal membrane oxygenation (ECMO) in the mild PH group preoperatively. The donors of the lungs shared similar characteristics between the recipient groups when the distribution of donor age, sex, body mass index, and the rate of donation after circulatory determination of death were examined (Table 1).

TABLE 1. - Demographics and preoperative characteristics of single lung transplant recipients and lung donors
No PH, n = 42 Mild PH, n = 217 Severe PH, n = 59 P
Recipient demographics
 Age, mean ± SD, y 66.9 ± 6.3 65.4 ± 7.5 66.9 ± 6.6 0.55
 Sex, n (%) 0.64
  Male 28 (66.7) 137 (63.1) 41 (69.5)
  Female 14 (33.3) 80 (36.9) 18 (30.5)
 BMI, mean ± SD, kg/m2 25.7 ± 4.4 27.8 ± 4.4 28.5 ± 4.5 <0.01
 BMI, range, kg/m2 16.6–34.7 15.9–38.9 18–37
 Height, cm 166.9 166.9 167.4 0.92
 Creatinine, mg/dL 0.84 0.86 0.92 0.14
 Ejection fraction, % 60.4 59.4 60.9 0.21
 Coronary artery disease, % 23.8 16.1 22 0.35
 Cardiac index, L/min/m2 2.57 2.52 2.42 0.31
 Mean PAP (time of listing), mean ± SD, mm Hg 20.9 ± 5.1 23.3 ± 7.1 26.9 ± 7.4 <0.0001
 Right atrial pressure, mean ± SD, mm Hg 5.0 ± 2.8 4.9 ± 3.4 4.6 ± 3.6 0.797
 Pulmonary vascular resistance 2.58 3.08 4.23 <0.01
 PCWP, mm Hg 9.1 9.3 9.4 0.97
 Lung allocation score 41.5 41.9 45.5 0.21
 Time on waitlist, d 165.4 168.7 136.7 0.66
 Diagnosis, n (%) 0.14
  COPD 15 (35.7) 73 (33.6) 12 (20.3)
  Pulmonary fibrosis 18 (42.9) 112 (51.6) 30 (50.8)
  Interstitial lung disease 3 (7.1) 15 (6.9) 5 (8.5)
  CPFE 5 (11) 13 (6) 11 (18.6)
 Predicted TLC, L 5.9 5.9 6.0 0.809
 Pulmonary function
  FVC, % predicted 53.5 54.7 60.8 0.05
  FEV1, % predicted 42.4 44.5 51 0.08
  6MWD, ft 816 796 702 0.14
Donor demographics
 Age, mean ± SD, y 38.8 ± 14.2 36.4 ± 13.7 36.1 ± 14.0 0.54
 Sex, n (%) 0.51
  Male 28 (66.7) 136 (62.7) 33 (55.9)
  Female 14 (33.3) 81 (37.3) 26 (44.1)
 BMI, kg/m2 28 27.8 26.7 0.23
 Height, cm 173.0 172.8 172.6 0.981
 Predicted TLC, L 6.4 6.4 6.3 0.824
 Donor after circulatory death, n (%) 1 (2.4) 12 (5.5) 4 (6.8) 0.61
6MWD, 6-min walking distance; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CPFE, combined pulmonary fibrosis and emphysema; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; TLC, total lung capacity.

Perioperative and Postoperative Data With Survival

Perioperative and postoperative data are summarized in Table 2. The severe PH group was more likely to have single lung transplant of the left lung (62.7% versus 38.1% or 48.9%; P = 0.043). The use of mechanical circulatory support (MCS), including cardiopulmonary bypass (CPB) and ECMO, during the lung transplant surgery was significantly higher in the severe PH group than in the mild PH or no PH groups (37.3% versus 10.3% versus 4.8%, respectively; P < 0.001). One patient in the severe PH group and 3 patients (including 2 patients who were on VV ECMO preoperatively) in the mild PH group came out the operating room with VV ECMO all due to primary graft dysfunction (PGD). In terms of posttransplant intubated period, one fourth of the patients were still intubated at 72 h, but there was no statistical difference among the groups. Hospital stays appeared to be longer in patients with severe PH, but this difference did not reach statistical significance when the 3 groups were compared. Similarly, the need for hemodialysis or reintubation and the incidence of PGD requiring ECMO support did not differ significantly between the groups.

TABLE 2. - Perioperative and postoperative characteristics of single lung transplant recipients
No PH, n = 42 Mild PH, n = 217 Severe PH, n = 59 P
Operative data
 Transplant laterality, n (%) 0.04
  Left 16 (38.1) 106 (48.9) 37 (62.7)
  Right 26 (61.9) 111 (51.1) 22 (37.3)
 V/Q scan, % P = 0.01 between no PH and severe PH, otherwise NS
  Left 51.5 47.4 44.3
  Right 48.5 52.6 55.7
 MCS, n (%) 2 (4.8) 22 (10.3) 22 (37.3) <0.01
  CPB 0 9 12
  VA ECMO 2 9 10
  VV ECMO 0 4 0
 Cold ischemic time, mean ± SD, min 265 ± 75 278 ± 71 284 ± 68 0.43
 Warm ischemic time, mean ± SD, min 56 ± 16 58 ± 16 59 ± 19 0.68
Postoperative data
 Hemodialysis, n (%) 0 3 (1.4) 2 (3.4) 0.37
 Intubated at 72 h, n (%) 6 (14.3) 32 (14.8) 15 (25.4) 0.13
 Intubated at 120 h, n (%) 3 (7.1) 23 (10.6) 6 (10.2) 0.79
 Reintubation, n (%) 6 (14.3) 13 (6) 5 (8.5) 0.17
 Tracheostomy, n (%) 3 (7.1) 19 (8.8) 7 (11.9) 0.69
 PGD requiring ECMO, n (%) 0 12 (5.5) 2 (3.4) 0.25
 Hospital length of stay, median (range), d 16 (11–21) 14 (11–20) 14 (11–27) 0.38
 ICU stay, d 6.75 9.68 8.17 0.79
 30-d mortality, n (%) 0 2 (0.9) 0 NA
 90-d mortality, n (%) 0 9 (4.1) 0 NA
 1-y survival, n (%) 39 (92.9) 194 (89.4) 55 (93.2) 0.58
 3-y survival, n (%) 27 (65.4) 163 (75.1) 47 (79) 0.37
CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; MCS, mechanical circulatory support; NA, not available; NS, not significant; PGD, primary graft dysfunction; PH, pulmonary hypertension; VA, veno-arterial; V/Q, ventilation-perfusion; VV, veno-venous.

Of the 59 patients with severe PH, 2 patients required hemodialysis after single lung transplant. Both transplants were performed without MCS. In contrast, no patients with severe PH supported intraoperatively with either ECMO (10 patients) or CPB (12 patients) required hemodialysis after transplant. Patients with severe PH had a 3.4% incidence of severe PGD that required ECMO support, and all recovered and were successfully weaned off ECMO within a week postoperatively.

In the patients with severe PH, overall survival after single lung transplant was 93.2% at 1 y posttransplant, 87.1% at 2 y posttransplant, and 79.0% at 3 y posttransplant. Survival after single lung transplant of the patients with severe PH was not significantly different than that of single lung recipients with mild PH (89.4% at 1 y, 78.3% at 2 y, and 75.1% at 3 y) or no PH (92.9% at 1 y, 85.2% at 2 y, and 65.4% at 3 y; P = 0.873; Figure 1).

F1
FIGURE 1.:
Kaplan-Meier survival curves after single lung transplantation. PH, pulmonary hypertension.

DISCUSSION

This retrospective study demonstrated that single lung transplant in patients with severe SPH yields at least equivalent posttransplant outcomes as compared with single lung transplant in patients with mild or no PH. Anecdotally, the incidence of acute renal insufficiency after single lung transplant was higher in the lung transplant recipients with severe PH than in recipients with mild or no PH, but MCS was not used intraoperatively in either patient with severe PH who developed postoperative renal insufficiency in this cohort.

The Reemerging Role of Single Lung Transplantation in the Current Era

Although single lung transplant in patients with severe SPH is not typically considered an appropriate option in the current era, there were multiple studies and reports in early 2000 that attempted to demonstrate that single lung transplant could play a role in patients with SPH (Table 3)4,6; however, because most reports have advocated the superiority of double lung transplant regardless of the underlying pulmonary etiology (Table 3),3,7,11 single lung transplant and its potential benefits, such as reducing postoperative mortality and morbidity and promoting faster recovery for certain lung transplant recipients, appear to be currently underutilized.

TABLE 3. - Studies of lung transplantation in patients with secondary pulmonary hypertension
Year Author PH definition mPAP, mm Hg No. of transplant recipients Age of transplant recipients, y Survival Comments
2019 Nasir et al 7 >40 SLT = 4825 SLT: 61–62 SLT: 1 y, 77.7%; 2 y, 64%; 3 y, 54.8% DLT may be superior to SLT in patients with mPAP >40 mm Hg.
DLT = 7567 DLT: 55–56 DLT: 1 y, 82.4%; 2 y, 73.5%; 3 y, 66.7%
2018 Villavicencio et al 3 <25 SLT = 4734 SLT: 60.7 SLT: 1 y, 78%; 2 y, 65%; 3 y, 57% DLT showed better survival in patients younger than 70 y.
25–30 SLT for patients with mPAP >30 mm Hg should be discouraged.
30–40 DLT = 4457 DLT: 55.7 DLT: 1 y, 87%; 2 y, 80%; 3 y, 76%
>40
2005 Whelan et al 4 >35 SLT = 636 SLT: 55 Risk analysis for 90-d mortality DLT has a greater risk of early mortality than SLT.
DLT = 194 DLT: 50.4 Increasing PAP is a risk factor for death after SLT.
2005 Fitton et al 6 30–40 SLT = 51 Total: 48.4 SLT: 1 y, 82%; 2 y, 82%; 4 y, 82% Survival is equivalent between SLT and DLT.
>40 DLT = 36 DLT: 1 y, 87%; 2 y, 62%; 4 y, 62%
1998 Gammie et al 5 >30 SLT = 21 SLT = 36 SLT: 1 mo, 81%; 1 y, 67% Survival is equivalent between SLT and DLT.
DLT = 37 DLT = 38 DLT: 1 mo, 84%; 1 y, 67%
DLT, double lung transplant; mPAP, mean pulmonary arterial pressure; PH, pulmonary hypertension; SLT, single lung transplant.

Although most lung transplants in the United States are double lung transplants, the national shortage of transplantable donated lungs remains unresolved, limiting opportunities for survival of patients with end-stage lung diseases.12 The Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipient 2019 Annual Data Report demonstrated that waitlist mortality rates in lung transplantation increase with increasing age and were highest for candidates age 65 or older. The mortality rates were also highest for candidates with a diagnosis of restrictive lung disease, which would be the classification of most of the patients with severe SPH in this study.13 In addition, because of the prevailing dogma that double lung transplant is needed for severe PH, many patients, particularly patients older than 70 y of age, continue to be declined for a lung transplant because of their severe PH. Some are referred to us as a high-volume transplant center. With this background, single lung transplant in patients with severe SPH should be considered a viable option. It is worth revisiting and pursuing in the current era if outcomes are supported by the data. This study provides support for single lung transplant in patients with severe SPH as long as appropriate intraoperative MCS is provided.

Intraoperative Management With MCS in Patients With Severe PH

In our center’s experience, posttransplant survival in patients with severe PH was satisfactory. These results are encouraging given that most of the patients who received a single lung transplant in this study were septuagenarians who currently tend to be declined for lung transplant by most transplant centers because of their advanced age as well as having less survival advantage; however, it should also be noted that our data suggest a higher incidence of acute renal insufficiency requiring hemodialysis after single lung transplant in patients with severe PH. The incidence of 3.3% (2/59) that we observed does not appear to be higher than that reported by others, however.14,15 Nonetheless, given the impact of acute renal insufficiency on the long-term survival after lung transplant, this necessitates further consideration. Of note, single lung transplant was performed without ECMO or CPB as intraoperative MCS in both patients who developed acute renal insufficiency despite the existence of severe PH, whereas transplant utilizing MCS did not result in adverse renal consequences necessitating hemodialysis. We speculate that, during the lung transplant procedure in patients with severe PH, MCS plays a preemptive role in stabilizing hemodynamics and better preserving organ function, in particular in the kidneys, which is in line with previous data.16

We previously reported the immediate effects of the double lung transplant procedure on right ventricular (RV) morphology and cardiac function in the context of severe PH.17 The impact of RV morphology on transplant outcomes is different in patients with primary PH and patients with SPH. We believe that intraoperative transesophageal echocardiogram (TEE) assessment of RV function is the key to successfully complete these complex procedures as a result of our extended experience with patients with severe SPH. Further studies are currently ongoing to assess the upper limits of SPH and its association with preoperative, intraoperative and postoperative RV morphology to support single lung transplant as a viable and safe option.

Postoperative Management With or Without Preemptive Intervention in Elderly Patients

A recent report by Hoetzenecker and colleagues in Vienna advocated the use of extended prophylactic ECMO into the early postoperative period to prevent severe PGD.18 Currently, we do not use extended prophylactic ECMO in our single lung transplant recipients with severe PH. Although some patients experienced PGD that required ECMO, this complication was not observed more frequently in the patients with severe PH than in patients with mild or no PH, and all of the patients with PGD recovered and were successfully weaned off ECMO within a week postoperatively.

Among elderly patients, peripheral arterial disease is also very common,19 and it is important to avoid any procedure-associated complications and promote patient ambulation and recovery to optimize transplant outcomes. Theoretically, single lung transplant is a less invasive procedure than double lung transplant and should lead to early recovery with fewer surgical complications. This easier surgical recovery may contribute to circumventing coexisting morbidities, including cardiovascular disease, metabolic syndrome, obesity, and chronic kidney disease, as we recently reported.20 The outcomes data from single lung transplant recipients with severe SPH in this study support the use of single lung transplant in patients with age-related comorbidities.

Study Limitations

The primary limitations of this study are its retrospective nature and the sample size. In addition, as a result of prioritizing a study period during which we could confirm standardized patient selection (for both recipients and donors) and management, all the data were collected from patients who received a single lung transplant relatively recently, and we could not evaluate 5-y survival. Concerns about sample size can be tempered by the fact that we were able to assess 59 patients with severe PH in our study, and it compares well with a recent report using a national database that examined 199 patients.7 With regards to RV function, the precise assessment of RV function is the key to making the right judgment to successfully perform single lung transplantation for those with severe PH. Although we highly value the intraoperative TEE assessment of RV function through real time images routinely, the recorded TEE data set was so limited in this study, so the further studies are ongoing to prospectively collect the TEE data and assess the upper limits of PAP in the cases with SPH and its association with preoperative, intraoperative, and postoperative RV morphology.

Summary

In conclusion, our experience demonstrated that single lung transplantation in patients with severe PH secondary to advanced lung diseases remains a viable option and can be safely performed without increasing operative mortality or postoperative morbidity. The proactive use of intraoperative MCS may play a crucial role promoting acceptable outcomes in patients with severe SPH who undergo single lung transplant.

ACKNOWLEDGMENTS

We thank Shannon Wyszomierski for editing a draft of the manuscript.

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