Does lobar or size-reduced lung transplantation offer satisfactory early and late outcomes?

Summary

A best evidence topic was constructed according to a structured protocol. The question addressed was whether size-reduced or lobar lung transplantation (LLTx) offers the same benefit as classic lung transplantation (LTx). Of the 147 papers found using the reported search, 9 were selected to provide the best evidence. Details of the studies regarding authors, date, journal, country of publication, study type, group studied, relevant outcomes and results are given. All studies reported survival rates of LLTx and most compared it with classical LTx. No statistical differences were reported in medium term and long term. Two of the studies reported a higher incidence of postoperative complications, such as the need for cardiopulmonary bypass, reperfusion oedema or primary graft dysfunction, and longer intubation or intensive care unit stay times. Although the largest study showed a significantly worse 1-year survival in LLTx, a sub-analysis considering patients successfully discharged showed similar outcomes at 1, 3 and 5 years when compared with classic LTx patients. We conclude that LLTx is a valid therapeutic option for recipients with significant donor size mismatch, offering similar outcomes as classical LTx in the medium term and long term.

INTRODUCTION

A best evidence topic was constructed according to a structured protocol as fully described in the ICVTS [1].

THREE-PART QUESTION

In [patients requiring lung transplantation], is the use of [lobar or size-reduced cadaveric lungs] associated with [inferior outcomes] with regard to [early postoperative] and [long-term outcome]?

CLINICAL SCENARIO

Organ shortage remains the main limitation of lung transplantation (LTx) programmes. Our team received a lung proposal from a 1.79-m tall donor compatible with a 14-year-old boy, 1.5 m tall with cystic fibrosis. We were planning on offering a lobar transplantation and were questioned by a colleague with respect to long-term outcomes. We conducted a literature analysis to support our planned strategy.

SEARCH STRATEGY

Medline search using PubMed interface was performed with the following query: ‘lobar[Title] AND lung[Title] AND transplantation[Title]’. Only results in English and published between January 2000 and December 2019 were considered. References from the retrieved studies were subsequently looked up manually.

SEARCH OUTCOME

A total of 147 articles were found and 9 were selected for providing the best evidence on the topic. Table 1 summarizes the papers.

Table 1:

 Overview of the studies

Author, date, journal and country Study type (level of evidence)	Patient group	Outcomes	Key results	Comments/weaknesses
Mitilian et al. (2014), Eur J Cardiothorac Surg, France [2] Observational study (level 3)	495 LTx Classical LTx group—445 patients Lobar LTx group—50 patients 24-Year period (1988–2011)	In-hospital overall mortality Postoperative ECMO Postoperative tracheostomy 3-Year survival 5-Year survival Survival analysis	28% in lobar LTx group 20% in lobar LTx group 50% in lobar LTx group 60% in lobar LTx group 46% in lobar LTx group No differences between groups using Kaplan–Meier curve	No direct comparison between lobar LTx and classical LTx No report of early postoperative complications in classical LTx group Heterogeneous group of lobar LTx recipients No P-value reported in the survival analysis between groups
Aigners et al. (2004), Eur J Cardiothorac Surg, Austria [3] Observational study (level 3)	98 LTx Size-reduced LTx group—27 patients, including 9 lobar transplants Classical LTx group—71 patients 2-Year period (2001–2002)	Bronchial complications Postoperative bleeding rates Ischaemic times (h) 3-Month survival rate	11% vs 10% in size-reduced LTx and classical LTx groups, respectively (P = 0.85) 24% vs 17% in size-reduced LTx and classical LTx groups, respectively (P = 0.85) 6.3 vs 6.0 in size-reduced LTx and classical LTx groups, respectively (P = 0.427) 85.2% vs 92.9% in size-reduced LTx and classical LTx groups, respectively (P = 0.13)	Single centre and small study sample size Heterogeneous group of size-reduced transplantation including lobar transplants (n = 9), split-lung transplants (n = 2) and peripheral resection (n = 16)
Inci et al. (2013), Eur J Cardiothorac Surg, Switzerland [4] Observational study (level 3)	342 LTx Classic bilateral LTx group—219 patients Bilateral lobar LTx group—23 patients 12-Year period (2000–2011)	30-Day mortality 90-Day mortality 1-Year survival 5-Year survival Survival analysis	No mortality in bilateral lobar LTx group 8.6% in bilateral lobar LTx group 88% vs 82% in classic bilateral LTx group and bilateral lobar LTx group, respectively (P = 0.56) 69% vs 64% in classic bilateral LTx group and bilateral lobar LTx group, respectively (P = 0.56) No difference between groups (hazard ratio = 0.808)	Single centre and small study sample size No data regarding early postoperative period for classic bilateral LTx group
Slama et al. (2014), Transplant Int, Austria [5] Observational study (level 3)	945 LTx Group 1—807 classic LTx; Group 2—138 lobar LTx 12-Year period (2001–2012)	Surgical revision Reperfusion oedema In-hospital mortality 1-, 3- and 5-year overall survival	8.4% vs 18.8% in group 1 and 2, respectively (P < 0.001) 17.8% vs 44.1% in group 1 and 2, respectively (P < 0.001) 7.3% vs 20.3% in group 1 and 2, respectively (P < 0.001) 1-Year 84.8% vs 65.1%, 3-year 77.1% vs 63.1% and 5-year 69.9% vs 54.9%, in groups 1 and 2, respectively (P < 0.001)	Significantly higher proportion of patients bridged to transplantation in group 2: 7.3% vs 3.6% for intubated patients and 13.1% vs 2.5% for ECMO support Significant negative impact on survival of preoperative bridging with intubation—HR 2.06 (P = 0.010)—and with ECMO support—HR 1.90 (P = 0.016) Transplants with graft size reduced by peripheral resections were included in group 1
Marasco et al. (2012), Ann Thorac Surg, Australia [6] Observational study (level 3)	Lobar reduction group—23 patients Non-lobar reduction group—320 patients 7-Year period (2005–2012)	Need for CPB or ECMO Median ICU stay Median hospital stay Survival analysis	56% vs 13.4% in lobar reduction group and non-lobar reduction group, respectively 12 vs 4 days in lobar reduction group and non-lobar reduction group, respectively 30 vs 21 days in lobar reduction group and non-lobar reduction group, respectively No significant difference between groups (P = 0.115)	Small sample size Short follow-up time of 18 months 10 out of 23 lobar reduction patients were in high-urgency status
Stanzi et al. (2014), Transplant Proc, Belgium [7] Observational study (level 3)	74 LTx for cystic fibrosis Lobar LTx group—8 patients Classic LTx group—66 patients 20-Year period (1991–2011)	Need for CPB PGD grade 3 Intensive care unit stay Hospital stay In-hospital mortality 1-Year survival	75% in Lobar LTx vs 30% in classic LTx, P < 0.05 75% in Lobar LTx vs 51% in classic LTx 12 days (range 4–49) in Lobar LTx vs 4 days (1–60) in classic LTx, P < 0.01 37 days (range 25–67) in Lobar LTx vs 24 days (11–91) in classic LTx, P < 0.01 0% in Lobar LTx vs 3% in classic LTx 100% in Lobar LTx vs 84% in classic LTx	Small sample size Short follow-up time Only cystic fibrosis patients included in the study
Espinosa et al. (2010), Transplant Proc, Spain [8] Observational study (level 3)	155 LTx Lobar LTx—6 cases No control group 7-Year period (2003–2009)	Need for CPB 30-Day mortality 1-Year survival 2-Year survival	100% 16.7% 50.5% 33.3%	Small sample size No direct comparison between lobar and classic lung transplantation
Santos et al. (2005), Transplant Proc, Spain [9] Observational study (level 3)	159 LTx LTx with graft volume reduction—13 patients, including 4 lobar transplants LTx without graft volume reduction—146 LTx 10-Year period (1993–2003)	FVC at 6 months PaO2 at 6 months Overall survival	71.7% in LTx with volume reduction group vs 72.4% in LTx without graft volume reduction group 89.2 mmHg in LTx with volume reduction group vs 86.7 mmHg in LTx without graft volume reduction group Kaplan–Meier survival curve showed no significant difference between groups (P = 0.46)	Heterogeneous study group with both lobar lung transplantations (n = 4) and peripheral wedge resections (n = 9) Small sample size No details on the recipients No specific survival time reported
Keating et al. (2010), J Heart Lung Transplant, Australia [10] Observational study (level 3)	208 LTx Classic LTx group—199 patients Lobar LTx group—9 patients 7-Year period (2003–2010)	30-Day mortality 2-Year survival rate Overall survival	No 30-Day mortality in LTx group 85% in both groups No significant difference between groups (P = 0.94)	6 out of 9 lobar LTx patients were in urgent status Small sample size

CPB: cardiopulmonary bypass; ECMO: extracorporeal membrane oxygenation; FVC: functional vital capacity; HR: hazard ratio; ICU: intensive care unit; LTx: lung transplantation; PaO₂: partial pressure of oxygen; PGD: primary graft dysfunction.

RESULTS

Mitilian et al. [2] reported data of 495 LTx over a 24-year period: 445 patients in the classical LTx group and 50 patients in the lobar LTx group. The authors do not report direct comparisons between groups or publish results of the classical LTx group (except for the Kaplan–Meier survival curves). They do report early postoperative complications in the lobar LTx group, including 20% requiring postoperative extracorporeal membrane oxygenation (ECMO) due to primary graft dysfunction, and 50% tracheostomy. The authors reported a 28% rate of in-hospital mortality in the lobar LTx group. Six (12%) of the 50 lobar LTx cases were emergencies, including 2 on ECMO as a bridge to transplantation (these 2 outcomes were not reported). Survival analysis using Kaplan–Meier method showed no differences between classical LTx and lobar LTx groups, with similar 3- and 5-year survival rates in both groups.

Aigner et al. [3] compared outcomes between a group of size-reduced LTx with 27 patients and a group of classical LTx with 71 patients over a 2-year period. The size-reduced group included 9 lobar transplants, 2 split lung transplants and 16 grafts reduced by peripheral resections. They reported no differences in bronchial healing problems, rate of postoperative bleeding or ischaemic time. Three-month survival rates were comparable with 85.2% and 92.9% for size-reduced LTx and classic LTx, respectively. Analysis of the survival curve allowed estimating a 2-year survival rate of 75% and 80% for size-reduced LTx and classic LTx, respectively.

Inci et al. [4] studied an LTx population over a 12-year period with special regard in bilateral lobar lung transplantation (LLTx). The authors describe a group of classic bilateral LTx with 219 patients and a group of bilateral lobar LTx with 23 patients. The authors reported no 30-day mortality and 8.6% 90-day mortality in the bilateral lobar LTx group. No short-term results for classic bilateral LTx were reported. The 1- and 5-year survival rates were 88% and 69% vs 82% and 64% for classic bilateral LTx and lobar bilateral LTx, respectively. Survival analysis using Kaplan–Meier curve showed no significant difference between the 2 groups, with a hazard ratio of 0.808 (95% confidence interval 0.387–1.686).

Slama et al. [5] compared 778 classic LTx—group 1—and 138 lobar LTx—group 2. This is the largest series of lobar LTx reported. The study period extended from January 2001 until December 2012. Minor size reductions were included in group 1. A higher rate of postoperative complications was found in group 2. Early in-hospital mortality was also higher in group 2. Survival analysis showed significantly better results in group 1 with 84.8% vs 65.1% at 1 year, 77.1% vs 63.1% at 3 years and 69.9% vs 54.9% at 5 years. However, no significant difference in survival was found after a second analysis that included only patients successfully discharged. Increased rate of early postoperative complications and mortality may be attributed to the increased rate of urgent status patients in group 2 due to prolonged waiting times in small-sized recipients, which in themselves increase perioperative risk. The authors concluded that LLTx was a valid, important variant of LTx due to its role in offering organs on time to urgent and small-sized recipients with similar 5-year survival if non-survivors excluded.

Marasco et al. [6] report 343 lung transplants between 2005 and February 2012. The LLTx group had 23 patients, with all patients having the grafts reduced by lobectomies, and the classic LTx group had 320 patients. Median intensive care stay was higher for the LLTx group, with 12 days compared to 4 days for the classic LTx group. Median hospital stay was also higher in the LLTx group, with 30 days compared to 21 days for the classic LTx group. Survival was similar for both groups. Analysis of the Kaplan–Meier curve allows an estimate for 18-month survival of approximately 80% for both groups. The authors reported that 10 out of the 23 lobar transplants were in urgent status.

Stanzi et al. [7] reported 74 lung transplants for cystic fibrosis between 1991 and 2011. The authors described 8 lobar lung transplants—Lobar LTx group—and 66 classic lung transplants—classic LTx group. The authors report a higher rate of extracorporeal support in the lobar LTx group and also a higher rate of PGD grade 3 on the first day. Nevertheless, both groups showed similar recovery rates. The authors also report longer intensive care unit and hospital stay in the lobar LTx group.

In-hospital mortality rate was null in lobar LTx group and 3% in classic LTx group. Overall 1-year survival was 100% in the lobar LTx group and 88.4% in the classic LTx group. The authors concluded LLTx to be a safe and viable option, even though there appears to be a higher predisposition to PGD. However, rapid graft function recovery allows for excellent 1-year survival.

Espinosa et al. [8] report 155 lung transplants during a 7-year period, including a group of 6 lobar LTx. The authors do not report direct comparisons between lobar LTx group and classic LTx. The authors report a 100% need for cardiopulmonary bypass in the lobar LTx group and a 30-day mortality of 16.7%. The 1- and 2-year survival rates were 50.6% and 33.3%, respectively, in the lobar LTx group. The authors concluded that LLTx is a reliable and safe procedure.

Santos et al. [9] reported a group of 13 LTx with graft volume reduction, including both grafts submitted to peripheral resections (n = 9) and lobectomies (n = 4), and another group of 146 LTx without volume graft reduction. The authors analysed 2 variables after 6 months: functional vital capacity and partial pressure of oxygen, with similar results between groups. In conclusion, the authors show no difference in survival analysis using Kaplan–Meier curve but do not report any specific survival time. They report that 6 out of the 13 procedures with lung graft reduction were given high-urgency transplantations. This paper presents important limitations regarding the mixed group of graft volume reduction by lobectomy and peripheral wedges and absence of data on the recipients.

Keating et al. [10] reported a 7-year Australian experience of 208 LTx, from 2003 to 2010. The authors described a group of 9 lobar LTx and a group of 199 classic LTx. They report the occurrence of complications including the need for ECMO in 1 patient and 1 case of readmission within the first 3 months. Survival analysis between lobar and classical LTx showed no difference in overall survival between groups within the study period (P = 0.94). Analysis of the Kaplan–Meier curve allows to infer a 2-year survival rate of approximately 85% for both groups. No 30-day mortality is reported in the lobar LTx cohort. Six of 9 cases in the lobar LTx group were transplanted in urgent status. The authors concluded that lobar LTx is an important tool in transplantation for smaller individuals with critical illness, with acceptable 2-year survival rate.

CLINICAL BOTTOM LINE

In conclusion, current evidence supports the use of LLTx as a valid alternative to classical LTx, with similar medium- and long-term outcomes.