Textbook Outcome in Lung Transplantation: Planned Venoarterial Extracorporeal Membrane Oxygenation versus Off-pump Support for Patients Without Pulmonary Hypertension

Abstract

BACKGROUND:

Planned venoarterial extracorporeal membrane oxygenation (VA ECMO) is increasingly used during bilateral orthotopic lung transplantation (BOLT) and may be superior to off-pump support for patients without pulmonary hypertension. In this single-institution study, we compared rates of textbook outcome between BOLTs performed with planned VA ECMO or off-pump support for recipients with no or mild pulmonary hypertension.

METHODS:

Patients with no or mild pulmonary hypertension who underwent isolated BOLT between 1/2017 and 2/2021 with planned off-pump or VA ECMO support were included. Textbook outcome was defined as freedom from intraoperative complication, 30-day reintervention, 30-day readmission, post-transplant length of stay >30 days, 90-day mortality, 30-day acute rejection, grade 3 primary graft dysfunction at 48 or 72 hours, post-transplant ECMO, tracheostomy within 7 days, inpatient dialysis, reintubation, and extubation >48 hours post-transplant. Textbook outcome achievement was compared between groups using multivariable logistic regression.

RESULTS:

237 BOLTs were included: 68 planned VA ECMO and 169 planned off-pump. 14 (20.6%) planned VA ECMO and 27 (16.0%) planned off-pump patients achieved textbook outcome. After adjustment for prior BOLT, lung allocation score, ischemic time, and intraoperative transfusions, planned VA ECMO was associated with higher odds of textbook outcome than planned off-pump support (odds ratio 3.89, 95% confidence interval 1.58-9.90, p=0.004).

CONCLUSIONS:

At our institution, planned VA ECMO for isolated BOLT was associated with higher odds of textbook outcome than planned off-pump support among patients without pulmonary hypertension. Further investigation in a multi-institutional cohort is warranted to better elucidate the utility of this strategy.

INTRODUCTION

Lung transplantation (LTx) is increasingly performed as the definitive operative therapy for patients with end-stage lung disease^1,2; however, the optimal mode of intraoperative cardiorespiratory support remains debated. There are no standardized guidelines to inform surgeons’ decisions to perform sequential LTx “off-pump” using single-lung ventilation without mechanical circulatory support (MCS), or on MCS in the form of extracorporeal membrane oxygenation (ECMO) or cardiopulmonary bypass (CPB).³ Accordingly, selection of intraoperative support modality is dictated by institution or surgeon preference and patient factors on a case-by-case basis.^4–7

Compared to off-pump LTx, planned intraoperative MCS encourages hemodynamic stability, ensures adequate gas exchange, facilitates complex technical maneuvers and surgical exposure, and prevents overperfusion of newly implanted or smaller lung allografts.^3,6,8,9 Historically, these advantages have been tempered by need for anticoagulation, risk of systemic inflammation, and pursuant complications including bleeding and primary graft dysfunction (PGD) associated with CPB.^3–6,8 Accordingly, surgical plans that include intraoperative MCS have been employed selectively for higher-risk LTx operations involving patients with severe pulmonary hypertension (PH), planned concomitant cardiac surgery, or lobar LTx that require greater hemodynamic and technical support.^{6–8,10–13} In the modern era, risks associated with intraoperative MCS have been mitigated by increasing use of venoarterial (VA) ECMO during LTx,^{7,9,11,12,14–16} after multiple studies showed fewer perioperative complications and superior post-transplant survival with VA ECMO versus CPB.^7,11,12,15 More recently, some have advocated for planned use of VA ECMO during all LTx operations,¹⁷ offering preliminary evidence to support excellent outcomes.^9,18

However, it is unclear how implementation of routine, planned intraoperative VA ECMO impacts perioperative outcomes in patients who have traditionally undergone LTx without MCS.⁴ Textbook outcome (TO) is a novel composite quality metric that encompasses multiple perioperative endpoints to describe optimal surgical outcomes and assess quality of care for complex surgical procedures.^19,20 In this study of bilateral orthotopic LTx (BOLT) recipients without PH, we compared rates of TO achievement between patients with preoperative surgical plans of intraoperative VA ECMO or off-pump support. We hypothesized that in patients without PH, planned use of VA ECMO during BOLT improves rates of TO achievement.

METHODS

Data sources and study population

We conducted a single-center retrospective cohort study using institutional and United Network for Organ Sharing (UNOS) data. Adult (age≥18) patients who underwent isolated BOLT with planned off-pump or VA ECMO support at Duke University Hospital between January 1, 2017 and February 28, 2021 were included. Follow-up was closed in November 2021. Patients who underwent multiorgan or single LTx, had moderate or severe PH (mean pulmonary artery pressure [mPAP] ≥30 mmHg on most recent pre-transplant right heart catheterization), required concomitant cardiac surgery, or had planned intraoperative support strategies other than off-pump or VA ECMO were excluded (Figure 1). This study was approved by our Institutional Review Board (Pro00093325).

Figure 1.

Flow diagram of study cohort selection.

Study design

Recipients were grouped into planned off-pump and VA ECMO strata based on intraoperative support plans documented at transplant listing. VA ECMO has been our preferred intraoperative support strategy for all patients undergoing isolated BOLT since February 1, 2020.²¹ Recipient, operative, and donor characteristics, rates of TO achievement, and reasons for TO failure were compared between planned support groups.

Planned VA ECMO technique

In patients who underwent BOLT with planned VA ECMO, ECMO was initiated after preliminary hilar dissection and adhesiolysis, but prior to the first pneumonectomy. Since 2/2020, our preferred surgical strategy includes central cannulation with a 29/37 French dual-stage venous cannula in the right atrium (Edwards Lifesciences, Irvine, CA) and an 18-20 French arterial cannula in the ascending aorta (Medtronic, Minneapolis, MN).

Definition of textbook outcome

Our group previously proposed definitions for TO in LTx using institutional and national data.^22,23 In this analysis, TO was defined as freedom from intraoperative complication, 30-day reintervention (surgical, bronchoscopic, radiologic), 30-day intensive care unit and/or hospital readmission, post-transplant length of stay >30 days, 90-day mortality, 30-day biopsy-proven acute rejection, grade 3 PGD at 48 or 72 hours post-transplant, ECMO within 72 hours post-transplant, reintubation or renal replacement therapy during the index hospitalization, tracheostomy within 7 days, and extubation >48 hours post-transplant. Bronchoscopic reintervention was defined as bronchial dilation or stenting beyond routine post-transplant surveillance. PGD was graded using International Society for Heart and Lung Transplantation guidelines.²⁴ Patients who were free of all listed complications were considered to have achieved TO.

Statistical analysis

Recipient, operative, and donor characteristics were compared between planned off-pump and VA ECMO strata using Wilcoxon rank-sum tests for continuous variables and Chi-squared or Fisher’s exact tests for categorical variables. The effect of planned VA ECMO on TO achievement was estimated using multivariable logistic regression. Covariates were selected based on clinical judgement and differences between planned support groups in our descriptive analysis. In addition to planned intraoperative support strategy, the final logistic regression model included history of prior LTx, lung allocation score (LAS), allograft ischemic time, and total intraoperative transfusions.

During BOLT, intraoperative MCS may be urgently escalated (i.e., off-pump to VA ECMO, VA ECMO to CPB) in the event of hemodynamic instability. Such escalations of support imply unexpected complications that may portend compromised post-transplant outcomes. Likewise, redo BOLT is a complex operation that portends worse outcomes than primary BOLT.^25–27 Thus, we performed sensitivity analyses using the multivariable logistic regression model to investigate the effect of planned VA ECMO on TO achievement excluding A) patients who required unanticipated escalations of MCS and B) redo BOLT recipients. A two-sided p-value less than 0.05 was considered statistically significant. All analyses were performed using SAS version 9.4 (Cary, NC) and R version 3.6.2 (Vienna, Austria).

RESULTS

Recipient, operative, and donor characteristics

A total of 237 adult, isolated BOLT recipients with no or mild PH were included. Of those, 68 (28.7%) and 169 (71.3%) were in the planned VA ECMO and planned off-pump strata, respectively. Consistent with our standard practice, 94.6% of BOLTs in our cohort were planned off-pump before February 2020; thereafter, 85.5% were planned VA ECMO (Figure S1). Compared to planned off-pump patients, planned VA ECMO patients were more likely to have undergone prior LTx (13.2% vs 5.3%, p=0.04). Additional recipient characteristics were similar between groups (Table 1).

Table 1.

Recipient characteristics stratified by planned use of venoarterial extracorporeal membrane oxygenation (VA ECMO) support.

Characteristic	Planned Off-pump N = 169	Planned VA ECMO N = 68	Total N = 237	p-value
Age (years)	60 [48, 67]	64 [49, 68]	61 [48, 67]	0.203
Male sex	91 (53.8%)	38 (55.9%)	129 (54.4%)	0.776
Race/ethnicity				0.925
White	146 (86.4%)	60 (88.2%)	206 (86.9%)
Black	19 (11.2%)	7 (10.3%)	26 (11.0%)
Asian	1 (0.6%)	0 (0.0%)	1 (0.4%)
American Indian/Alaska Native	1 (0.6%)	0 (0.0%)	1 (0.4%)
Hispanic	2 (1.2%)	1 (1.5%)	3 (1.3%)
Body mass index (kg/m2)	24.4 [21.1, 26.7]	23.5 [21.1, 27.6]	24.4 [21.1, 26.9]	0.837
Diagnosis group				0.066
A: Obstructive lung disease	41 (24.3%)	12 (17.6%)	53 (22.4%)
B: Pulmonary vascular disease	0 (0.0%)	0 (0.0%)	0 (0.0%)
C: Cystic fibrosis or immunodeficiency	24 (14.2%)	4 (5.9%)	28 (11.8%)
D: Restrictive lung disease	104 (61.5%)	52 (76.5%)	156 (65.8%)
Lung allocation score	41.5 [36.0, 50.4]	44.6 [36.2, 57.3]	42.0 [36.0, 52.2]	0.132
Waitlist time (days)	17 [7, 35]	12 [5, 30]	15 [7, 32]	0.154
History of prior lung transplantation	9 (5.3%)	9 (13.2%)	18 (7.6%)	0.038
Cytomegalovirus positive	99 (58.6%)	38 (55.9%)	137 (57.8%)	0.704
Preoperative mPAP (mmHg) a	23 [20, 26]	24.5 [20, 27]	23 [20, 26]	0.121
Preoperative mPAP category				0.059
No PH (mPAP <25 mmHg)	107 (63.3%)	34 (50.0%)	141 (59.5%)
Mild PH (mPAP 25-29 mmHg)	62 (36.7%)	34 (50.0%)	96 (40.5%)
Preoperative left ventricular ejection fraction b	60 [55, 65]	60 [55, 65]	60 [55, 65]	0.603
Missing	23 (13.6%)	4 (5.9%)	27 (11.4%)
Preoperative right ventricular function				0.240
Normal	130 (76.9%)	50 (73.5%)	180 (75.9%)
Mild dysfunction	36 (21.3%)	14 (20.6%)	50 (21.1%)
Moderate dysfunction	3 (1.8%)	4 (5.9%)	7 (3.0%)
Preoperative ECMO				0.193
None	167 (98.8%)	67 (98.5%)	234 (98.7%)
VV	2 (1.2%)	0 (0.0%)	2 (0.8%)
VAV	0 (0.0%)	1 (1.5%)	1 (0.4%)

Presented as median (interquartile range) for continuous variables and frequency (proportion) for categorical variables.

ECMO, extracorporeal membrane oxygenation. mPAP, mean pulmonary artery pressure. PH, pulmonary hypertension. VA, venoarterial. VAV, venoarteriovenous. VV, venovenous.

^aBy most recent pre-transplant right heart catheterization.

^bBy last pre-transplant transthoracic echocardiogram.

The maximum mode of intraoperative support differed between planned off-pump and planned VA ECMO groups (Figure 2, p<0.001). Thirty-eight (16.0%) patients required unanticipated escalations of intraoperative MCS. Compared to planned off-pump patients, planned VA ECMO patients were less likely to require escalations of intraoperative MCS (4.4% vs 20.7%, p=0.002). Planned VA ECMO patients were also more likely than planned off-pump patients to receive donation after circulatory death (DCD) donor lungs (22.1% vs 11.2%, p=0.03) (Table 2).

Figure 2.

Maximum mode of intraoperative support stratified by planned use of venoarterial extracorporeal membrane oxygenation (VA ECMO).

Table 2.

Operative and donor characteristics stratified by planned use of venoarterial extracorporeal membrane oxygenation support (VA ECMO).

Characteristic	Planned Off-pump N = 169	Planned VA ECMO N = 68	Total N = 237	p-value
Lung allograft ischemic time (minutes)	323 [281, 399]	383 [314, 454]	343 [291, 422]	<0.001
Ex-vivo lung perfusion used	9 (5.3%)	1 (1.5%)	10 (4.2%)	0.289
Unanticipated escalation of intraoperative support	35 (20.7%)	3 (4.4%)	38 (16.0%)	0.002
Cardiovascular injury necessitating cardiac decompression for repaira	2 (5.7%)	1 (33.3%)	3 (7.9%)
Dense adhesions leading to difficult dissection and bleedinga	4 (11.4%)	0 (0.0%)	4 (10.5%)
Elevated pulmonary artery pressuresa	4 (11.4%)	0 (0.0%)	4 (10.5%)
Hemodynamic instabilitya	5 (14.3%)	1 (33.3%)	6 (15.8%)
Hypercarbiaa	2 (5.7%)	0 (0.0%)	2 (5.3%)
Hypoxiaa	12 (34.3%)	0 (0.0%)	12 (31.6%)
Patent foramen ovale closurea	0 (0.0%)	1 (33.3%)	1 (2.6%)
Othera	4 (11.4%)	0 (0.0%)	4 (10.5%)
Unspecifieda	2 (5.7%)	0 (0.0%)	2 (5.3%)
Intraoperative transfusions (units)
Packed red blood cells	1 [0, 2]	2 [0, 3]	1 [0, 3]	0.005
Fresh frozen plasma	0 [0, 0]	0 [0, 1]	0 [0, 0]	0.042
Cryoprecipitate	0 [0, 1]	1 [0, 2]	0 [0, 1]	<0.001
Platelets	0 [0, 0]	0 [0, 1]	0 [0, 0]	0.001
Total	1 [0, 3]	3 [1, 6]	2 [0, 4]	<0.001
Donor age (years)	33 [26, 45]	34 [27, 46]	34 [26, 45]	0.803
Donor male sex	98 (58.0%)	40 (58.8%)	138 (58.2%)	0.906
Donation after circulatory death	19 (11.2%)	15 (22.1%)	34 (14.3%)	0.032
Donor PaO2/FiO2 ratio	450 [394, 502]	445 [389, 489]	449 [437, 497]	0.566
Donor smoking history ≥20 pack-years	16 (9.7%)	3 (4.5%)	19 (8.2%)	0.189
Missing	4 (2.4%)	1 (1.5%)	5 (2.1%)
Donor Epstein-Barr virus seropositive	151 (91.0%)	61 (91.0%)	212 (91.0%)	0.984
Missing	3 (1.8%)	1 (1.5%)	4 (1.7%)
Donor Cytomegalovirus seropositive	105 (62.9%)	44 (64.7%)	149 (63.4%)	0.792
Missing	2 (1.2%)	0 (0.0%)	2 (0.8%)

Presented as median (interquartile range) for continuous variables and frequency (proportion) for categorical variables.

^aAmong patients who required unanticipated escalation of intraoperative support.

Achievement of textbook outcome

Overall, 41 (17.3%) patients achieved TO including 14 (20.6%) planned VA ECMO and 27 (16.0%) planned off-pump patients. On adjusted analysis, planned VA ECMO was independently associated with higher odds of TO achievement than planned off-pump support (adjusted odds ratio [aOR] 3.89, 95% confidence interval [CI] 1.58-9.90, p=0.004) (Table 3).

Table 3.

Association between planned venoarterial extracorporeal membrane oxygenation (VA ECMO) and achievement of textbook outcome (TO).

	Unadjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
Planned VA ECMO (vs off-pump)	1.36 (0.65, 2.76)	0.400	3.89 (1.58, 9.90)	0.004
History of prior lung transplant (yes vs no)	0.26 (0.01, 1.34)	0.201	3.12 (0.13, 31.95)	0.377
Lung allocation score (per point)	0.95 (0.91, 0.99)	0.013	0.95 (0.91, 0.99)	0.016
Lung allograft ischemic time (per 10 minutes)	0.94 (0.90, 0.98)	0.005	0.93 (0.88, 0.98)	0.007
Total intraoperative transfusions (per unit)	0.70 (0.54, 0.85)	0.002	0.68 (0.51, 0.86)	0.004

CI, confidence interval. OR, odds ratio.

Sensitivity analyses

In a sensitivity analysis restricted to patients who did not require unanticipated escalations of intraoperative MCS (N=199), planned VA ECMO remained associated with higher odds of TO achievement than planned off-pump support (aOR 4.40, 95% CI 1.71-11.95, p=0.003) (Table 4A). Among primary BOLT recipients (N=219), planned VA ECMO was also associated with higher odds of TO achievement than planned off-pump support (aOR 4.02, 95% CI 1.57-10.76, p=0.004) (Table 4B).

Table 4.

Sensitivity analyses exploring the association between planned venoarterial extracorporeal membrane oxygenation (VA ECMO) and achievement of textbook outcome (TO).

	Adjusted Odds Ratio (95% Confidence Interval)	p-value
A. Patients who did not require an unanticipated escalation of intraoperative support (N = 199)
Planned VA ECMO (vs off-pump)	4.40 (1.71, 11.95)	0.003
History of prior lung transplant (yes vs no)	3.22 (0.13, 36.94)	0.382
Lung allocation score (per point)	0.94 (0.90, 0.98)	0.010
Lung allograft ischemic time (per 10 minutes)	0.92 (0.86, 0.97)	0.005
Total intraoperative transfusions (per unit)	0.70 (0.51, 0.89)	0.013
B. Patients without prior history of lung transplantation (N = 219)
Planned VA ECMO (vs off-pump)	4.02 (1.57, 10.76)	0.004
Lung allocation score (per point)	0.95 (0.91, 0.99)	0.015
Lung allograft ischemic time (per 10 minutes)	0.92 (0.86, 0.97)	0.004
Total intraoperative transfusions (per unit)	0.68 (0.50, 0.85)	0.004

Reasons for textbook outcome failure

Reasons for TO failure differed between groups and event rates varied widely. Among events that occurred at rates >5%, planned VA ECMO patients were less likely to remain intubated >48 hours post-transplant, less likely to experience acute rejection within 30 days, and more likely to require reintervention within 30 days than planned off-pump patients (Table 5). Although any single complication was sufficient to determine TO failure, most patients experienced multiple complications (planned off-pump: 59.7%; planned VA ECMO: 55.9%) (Figure S2).

Table 5.

Reasons for textbook outcome (TO) failure stratified by planned use of venoarterial extracorporeal membrane oxygenation (VA ECMO) support.

Reasons for TO failure	Planned Off-pump N = 169	Planned VA ECMO N = 68	Total N = 237
Intraoperative complication	6 (3.6%)	3 (4.4%)	9 (3.8%)
Reintervention within 30 days	32 (18.9%)	22 (32.4%)	54 (22.8%)
Surgical	27 (16.0%)	20 (29.4%)	47 (19.8%)
Re-exploration for bleedinga	17 (63.0%)	15 (75.0%)	32 (68.1%)
Re-exploration for infectiona	2 (7.4%)	1 (5.0%)	3 (6.4%)
Pleural effusion evacuationa	4 (14.8%)	2 (10.0%)	6 (12.8%)
Othera	4 (14.8%)	2 (10.0%)	6 (12.8%)
Bronchoscopic	0 (0.0%)	0 (0.0%)	0 (0.0%)
Radiologic	6 (3.6%)	4 (5.9%)	10 (4.2%)
Intensive care unit readmission within 30 days	29 (17.2%)	13 (19.1%)	42 (17.7%)
Hospital readmission within 30 days	50 (29.6%)	13 (19.1%)	63 (26.6%)
Post-transplant length of stay >30 days	56 (33.1%)	30 (44.1%)	86 (36.3%)
Mortality within 90 days	2 (1.2%)	4 (5.9%)	6 (2.5%)
Acute rejection within 30 days	19 (11.2%)	1 (1.5%)	20 (8.4%)
Grade 3 primary graft dysfunction at 48 or 72 hours	28 (16.6%)	8 (11.8%)	36 (15.2%)
ECMO within 72 hours post-transplant	21 (12.4%)	14 (20.6%)	35 (14.8%)
Timing of post-transplant ECMO initiation b
Cannulated in the operating room prior to transfer to the intensive care unit	20 (95.2%)	14 (100%)	34 (97.1%)
Postoperative day 1	0 (0.0%)	0 (0.0%)	0 (0.0%)
Postoperative day 2	0 (0.0%)	0 (0.0%)	0 (0.0%)
Postoperative day 3	1 (4.8%)	0 (0.0%)	1 (2.9%)
Post-transplant ECMO mode
None	146 (86.4%)	54 (79.4%)	200 (84.4%)
VA	2 (1.2%)	0 (0.0%)	2 (0.8%)
VV	21 (12.4%)	14 (20.6%)	35 (14.8%)
Renal replacement therapy during the index hospitalization	16 (9.5%)	6 (8.8%)	22 (9.3%)
Tracheostomy within 7 days	27 (16.0%)	9 (13.2%)	36 (15.2%)
Reintubation during the index hospitalization	38 (22.5%)	14 (20.6%)	52 (21.9%)
Extubation >48 hours post-transplant	104 (61.5%)	27 (39.7%)	131 (55.3%)

ECMO, extracorporeal membrane oxygenation. TO, textbook outcome. VA, venoarterial. VV, venovenous.

^aAmong patients who underwent surgical reintervention within 30 days.

^bAmong patients who required ECMO within 72 hours post-transplant.

DISCUSSION

Sequential BOLT performed off-pump using single-lung ventilation has long represented the standard planned intraoperative support strategy for BOLT recipients without PH at many institutions, including ours.^4,6 However, VA ECMO is increasingly used non-selectively for all patients undergoing BOLT.¹⁸ In this study, we characterized the perioperative recovery profile of patients without PH who underwent BOLT on planned VA ECMO using the composite TO measure. We found that planned VA ECMO was associated with improved odds of TO achievement compared to planned off-pump support. These findings suggest that planned VA ECMO may be superior to planned off-pump support for BOLT recipients without PH and support broader use of VA ECMO as the standard planned intraoperative support strategy during BOLT.

The ideal intraoperative support strategy during BOLT should encourage recipient hemodynamic stability and facilitate protective allograft handling to minimize the risk of PGD.^4,6,18 While VA ECMO offers hemodynamic stability and adequate gas exchange, and facilitates controlled allograft reperfusion,^3,8,18,28 several reports have demonstrated higher rates of grade 3 PGD among patients who underwent BOLT with versus without ECMO support.^9,10,13 Notably, these studies used planned VA ECMO selectively for high-risk cases, leading to selection bias in planned VA ECMO versus off-pump strata.^9,10,13 Examination of these cohorts reveals significant differences between more complex patients with higher LAS, primary or secondary PH, pulmonary fibrosis, preoperative ECMO, and lobar LTx in planned VA ECMO versus off-pump groups.^9,10,13,14 In our study of patients without PH, rates of grade 3 PGD at 48 or 72 hours were similar between planned VA ECMO and off-pump strata. Moreover, recipient characteristics including age, disease group, LAS, mPAP, and preoperative ECMO were similar between groups. We know from prior work that recipient characteristics including primary PH or pulmonary fibrosis and increasing mPAP are risk factors for PGD.^29–31 In this context, our findings suggest that previously reported associations between planned VA ECMO and increased grade 3 PGD are likely confounded by differences in underlying physiology and illness severity between planned support strata.^9,10,13 Recent observational data suggests that non-selective use of VA ECMO may actually reduce rates of grade 3 PGD after BOLT.¹⁸ Although we did not find a reduction in grade 3 PGD among planned VA ECMO versus off-pump BOLTs, our planned VA ECMO group included a higher proportion of technically complex redo LTx with higher intraoperative transfusion requirements and longer ischemic times. Accordingly, our study expands upon prior findings by providing promising evidence to suggest that non-selective use of planned VA ECMO does not increase the risk of severe PGD among patients who have traditionally undergone BOLT without MCS.

Use of VA ECMO may also increase the risk of bleeding complications due to the combination of cannulation, hemodilution, external circulation, and anticoagulation that is absent with off-pump support.^3,28 Our group previously compared perioperative transfusion requirements between matched off-pump and planned VA ECMO BOLTs, demonstrating no difference in total 72-hour transfusions between groups.²¹ Conversely, several others have reported higher rates of post-transplant revision surgery and re-exploration for bleeding among patients who underwent BOLT with versus without ECMO support.^9,10,13 In the present study, patients who underwent BOLT with planned VA ECMO required more intraoperative transfusions and were more likely to require reintervention within 30 days than those who underwent planned off-pump BOLT; however, bleeding complications were common in both groups, accounting for 63.8% and 75.0% of reoperations among planned off-pump and VA ECMO patients, respectively. A higher rate of postoperative reintervention among patients who underwent BOLT with planned VA ECMO may seem to favor off-pump BOLT for recipients without PH. However, in the context of improved odds of TO among planned VA ECMO patients, our findings suggest that planned VA ECMO may increase odds of achieving an overall optimal perioperative outcome, free of multiple, interconnected complications that may compromise long-term post-transplant survival.^22,23 As such, our findings suggest that planned use of VA ECMO may offer an opportunity to optimize post-transplant outcomes for a greater proportion of BOLT recipients without PH, despite need for reintervention in a subset of these patients.

Our group previously found that DCD LTx was associated with failure to achieve TO.^22,23 In the current study, however, patients who underwent BOLT with planned VA ECMO had higher odds of TO achievement despite a greater proportion of DCD LTx than the planned off-pump group. Multiple reports have demonstrated comparable survival between recipients of donation after brain death and DCD donor lungs.^32,33 However, DCD LTx may still portend higher rates of early complications including postoperative ECMO, prolonged mechanical ventilation, and longer length of stay,^33,34 all of which may contribute to TO failure in this group. Amidst increasing performance of DCD LTx,¹ new strategies are required to optimize perioperative outcomes for these patients. Our findings suggest that planned use of VA ECMO represents one means to reduce complications and improve outcomes for recipients of DCD donor lungs.

In conjunction with intraoperative VA ECMO, some institutions favor continuation of ECMO for patients with suboptimal allograft function intraoperatively and those with risk factors for severe PGD.^4,9,14,18 In these cases, postoperatively prolonged ECMO is employed “prophylactically” to prevent further functional deterioration or volume overflow of newly implanted allografts that may culminate in severe PGD.^4,9,18 While ECMO has traditionally been employed therapeutically to support gas exchange and facilitate lung-protective ventilation in patients with severe PGD,^4,35,36 limited experience suggests that preemptive use of postoperative ECMO successfully mitigates progressive allograft damage and consequent severe PGD.¹⁸ In our study, postoperative ECMO was used more frequently among patients who underwent BOLT with planned VA ECMO versus off-pump support. We routinely use ECMO to treat patients with established severe PGD, considering its initiation when supporting ventilator requirements reach peak inspiratory pressures of 35 cm H₂O and inspired oxygen content exceeds 0.60. Importantly, however, the final decision to initiate or prolong ECMO support is made by attending transplant surgeons, and may therefore deviate from these parameters in some instances.³⁷ It is conceivable that surgeons invoke a lower threshold to transition to venovenous ECMO in patients undergoing BOLT with intraoperative ECMO. In this context, a higher rate of postoperative ECMO despite a similar rate of grade 3 PGD and a lower rate of intubation >48 hours post-transplant among patients who underwent BOLT with planned VA ECMO versus off-pump support suggests that we may favor prophylactic postoperative ECMO in a subset of patients undergoing BOLT with intraoperative VA ECMO. Future work should identify additional factors that motivate use of postoperative ECMO to test this hypothesis.

To our knowledge, ours is the first study to characterize the association between planned VA ECMO and perioperative outcomes in BOLT recipients without PH, and to apply the TO metric. In LTx, safety and utility of intraoperative support modalities are traditionally assessed using rates of individual events such as severe PGD.^13,18 Alternatively, composite metrics like TO unify complications that reflect multiple aspects of complex treatment processes to provide more holistic representations of surgical outcomes and quality of care upon which providers, patients, and payors may base quality and performance assessments.³⁸ A central benefit of TO is its ability to align clinical outcome assessments with patient experiences and prognoses, and hospital resource utilization. Our group found that patients are likely to experience multiple complications after LTx; however, absence of any complication as defined by TO was associated with improved long-term survival and lower index hospitalization costs among patients at our center.²³ In this context, our finding of higher odds of TO achievement among planned VA ECMO versus off-pump patients in this study suggests that planned VA ECMO may streamline intraoperative management of BOLT recipients without PH to not only facilitate attainment of optimal perioperative outcomes, but also improve post-transplant prognosis, promote cost-savings, and motivate patient-centered care. Accordingly, our findings support broader use of planned VA ECMO for BOLT recipients without PH and motivate further application of TO as a means to identify avenues to optimize the multifaceted management of these patients to improve post-transplant outcomes and quality of care moving forward.

There are several limitations to our study. As we examined a series of BOLTs performed at a single, high-volume institution, our experience may not generalize to other programs. Nevertheless, institutional data allowed for granular examination of perioperative outcomes that is not possible with national databases. Additionally, UNOS does not capture intraoperative data, precluding national comparison of planned VA ECMO and off-pump support. The Extracorporeal Life Support Organization (ELSO) registry, which records indications, modes, and complications associated with ECMO,³⁹ may offer an alternative means to compare intraoperative support modalities and associated outcomes in larger cohorts. However, the ELSO registry is not specific to LTx and may not capture the most relevant perioperative and long-term survival data necessary to evaluate the utility of planned VA ECMO in this population.³⁶ Given the limitations of available data sources, 11 institutions internationally have collaborated to form a prospective multicenter database designed to study associations between intraoperative practices and outcomes after LTx.⁶ Future studies should capitalize upon this novel data source to investigate the association between planned VA ECMO and outcomes after BOLT in a multi-institutional cohort of patients without PH. As intraoperative support plans were specified at transplant listing, we were unable to account for last minute adjustments due to rapid changes in patients’ clinical conditions or consideration of donor factors (i.e., smoking history, DCD). Additionally, our TO metric was designed to capture perioperative complications for all LTx recipients and does not include measurement of ECMO-related cerebral or extremity complications. As we continue to gain experience with use of planned VA ECMO, future work should investigate the frequency and nature of ECMO-related complications to further elucidate the safety of this strategy for patients without PH, and identify means to optimize outcomes for these patients.

Our modest cohort size and small number of planned VA ECMO patients meant that we could include only a subset of relevant covariates in our multivariable model; future studies should make provisions for rigorous risk adjustment to better elucidate the effect of planned VA ECMO on TO achievement after BOLT. Given our cohort size, we are likely underpowered to detect small but potentially meaningful between-group differences in risk factors; although we included an overall risk index (LAS) in our model, residual confounding may exist. Moreover, the available sample size and rarity of TO sub-events precluded multivariable analysis to investigate relationships between planned VA ECMO and individual complications adjusting for characteristics such as redo LTx that are known to portend worse post-transplant outcomes.^25–27 We therefore provided a descriptive summary of individual TO-defining complications, but did not perform inference testing. As described elsewhere, TO was defined based on clinician consensus at a single institution and is therefore subject to bias based on our practices.^22,23 However, TO effectively predicts post-transplant prognosis,^22,23 and thus represents a robust, multidimensional metric through which to investigate the safety and utility of planned VA ECMO for BOLT recipients without PH. Finally, VA ECMO has been our standard planned intraoperative support strategy for only two years, limiting the duration of available follow-up in our study. Indeed, one-year follow-up was not available for all patients; among those for whom it was available, one-year mortality was rare, precluding risk-adjusted comparison of survival between groups. As patients accrue follow-up time, future studies should investigate long-term outcomes among patients without PH who underwent BOLT with planned VA ECMO to further elucidate the implications of this strategy for this population.

CONCLUSIONS

In this single-center analysis, we found that planned use of VA ECMO for isolated BOLT was associated with higher odds of TO achievement than planned off-pump support among patients without PH. Amidst growing enthusiasm for non-selective use of VA ECMO as the standard planned intraoperative support strategy during BOLT, our findings provide promising new evidence to support broader adoption of this strategy to improve perioperative outcomes among patients without PH. Future studies should capitalize upon emerging multi-institutional data sources to further elucidate the utility of this strategy and identify the optimal intraoperative support strategy for BOLT recipients without PH.

Abbreviations:

aOR

adjusted odds ratio

BOLT

bilateral orthotopic lung transplantation

CI

confidence interval

CPB

cardiopulmonary bypass

DCD

donation after circulatory death

ECMO

extracorporeal membrane oxygenation

ELSO

Extracorporeal Life Support Organization

LAS

lung allocation score

LTx

lung transplantation

MCS

mechanical circulatory support

mPAP

mean pulmonary artery pressure

PGD

primary graft dysfunction

PH

pulmonary hypertension

TO

textbook outcome

UNOS

United Network for Organ Sharing

VA

venoarterial

VAV

venoarteriovenous

VV

venovenous