http://www.jhltonline.org
ORIGINAL CLINICAL SCIENCE
Lung transplantation from donation after cardiocirculatory death: a systematic review and meta-analysis Dustin Krutsinger, MD,a Robert M. Reed, MD,b Amy Blevins, MALS,c Varun Puri, MD,d Nilto C. De Oliveira, MD,e Bartlomiej Zych, MD,f Servet Bolukbas, MD,g Dirk Van Raemdonck, MD, PhD,h Gregory I. Snell, MBBS, FRACP, MD,i and Michael Eberlein, MD, PhDa,j From the aDepartment of Medicine, University of Iowa, Iowa City, Iowa; bDivision of Pulmonary and Critical Care Medicine, University of Maryland, Baltimore, Maryland; cHardin Library for the Health Sciences, University of Iowa, Iowa City, Iowa; dDepartment of Surgery, Washington University, St. Louis, Missouri; eDivision of Cardiothoracic Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; fDepartment of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, London, United Kingdom; gDepartment of Thoracic Surgery, Dr. Korst Schmidt Klinik, Wiesbaden, Germany; h Department of Thoracic Surgery and Lung Transplant Unit, University Hospitals Leuven, Leuven, Belgium; iLung Transplant Service, Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Australia; and the jDivision of Pulmonary, Critical Care and Occupational Medicine, University of Iowa, Iowa City, Iowa.
KEYWORDS: lung transplantation; donation after cardiac death; circulatory determination of death; cardiocirculatory death; non–heart-beating donor
BACKGROUND: Lung transplantation (LTx) can extend life expectancy and enhance the quality of life for select patients with end-stage lung disease. In the setting of donor lung shortage and waiting list mortality, the interest in donation after cardiocirculatory death (DCD) is increasing. We performed a systematic review and meta-analysis to compare outcomes between DCD and conventional donation after brain death (DBD). METHODS: PubMed, CINAHL, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and ClinicalTrials.gov were searched. We identified original research studies with 1-year post-transplant survival data involving 45 DCD transplants. We performed meta-analyses examining 1-year survival, primary graft dysfunction, and acute rejection after LTx. RESULTS: We identified 519 citations; 11 observational cohort studies met our inclusion criteria for systematic review, and 6 met our inclusion criteria for meta-analysis. There were no differences found in 1-year mortality after LTx between DCD and DBD cohorts in individual studies or in the meta-analysis (DCD [n ¼ 271] vs DBD [n ¼ 2,369], relative risk [RR] 0.88, 95% confidence interval [CI] 0.59–1.31, p ¼ 0.52, I2 ¼ 0%). There was also no difference between DCD and DBD in a pooled analysis of 5 studies reporting on primary graft dysfunction (RR 1.09, 95% CI 0.68–1.73, p ¼ 0.7, I2 ¼ 0%) and 4 studies reporting on acute rejection (RR 0.72, 95% CI 0.49–1.05, p ¼ 0.09, I2 ¼ 0%). CONCLUSIONS: Survival after LTx from DCD is comparable to survival after LTx from DBD in observational cohort studies. DCD appears to be a safe and effective method to expand the donor pool. J Heart Lung Transplant 2015;34:675–684 r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: Michael Eberlein, MD, PhD, Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, C 33 GH, Iowa City, IA 52242. Telephone: 319-512-8160. Fax: 319-356-6406. E-mail address: [email protected]
Lung transplantation (LTx) represents a potentially lifesaving therapy for select patients with end-stage lung disease, but organs are in short supply. The number of patients actively awaiting LTx in the United States increased
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.11.009
676
The Journal of Heart and Lung Transplantation, Vol 34, No 5, May 2015
from 1,052 in 2007 to 1,317 in 2012.1 As of May 2014, there were 1,674 patients awaiting LTx.2 This donor shortage is aggravated by the low usage rates of donor lungs partly as a result of pre-existing lung disease, pneumonia, and acute lung injury caused by brain death and chest trauma. In the United States, for every 100 eligible organ donors, only 18.5 result in donated lungs compared with 67 for kidneys.3 In 2012, of the 2,294 patients removed from the United Network for Organ Sharing (UNOS) waiting list, 303 (13.2%) died, and 110 (4.8%) became too sick to be transplanted.1 The donor shortage has led investigators to search for ways to increase the donor pool, including the use of extended criteria donors, donation after cardiocirculatory death (DCD), ex vivo lung perfusion and evaluation, and living lobar LTx.4 The first successful deceased human organ transplant,5 human LTx,6 and the first long-term successful human LTx7 all used organs donated after cardiocirculatory death. Contemporary to the surgical and medical advances that allowed these early transplant successes, the concept of brain death and organ donation after brain death (DBD) became more widely accepted. As brain death became codified into legislation, such donors quickly became the primary source of organs, and DCD was largely abandoned. In an attempt to expand the lung donor pool, Love et al8 resumed using DCD. With seemingly acceptable early-term and intermediate-term results, other LTx groups followed cautiously in their footsteps.9–19 Return to DCD was slow to be accepted partly because of concerns of ischemia during the period between discontinuation of life support and organ procurement. Notwithstanding these concerns, it is unclear if LTx using DCD is associated with differences in survival compared with DBD because the current literature consists generally of small, mostly single-center studies.9–19 We performed a systematic review and meta-analysis to test our hypothesis that survival rates do not significantly differ between LTx recipients from DCD compared with DBD donors.
Methods Data sources A health sciences librarian performed literature searches in PubMed, CINAHL, Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus (which includes EMBASE abstracts), Web of Science, and ClinicalTrials.gov. No filters for date, language, or any other parameter were used. The search strategy is detailed in section 1 of the Supplement (available on the jhltonline.org Web site). The authors of the studies selected for inclusion in the meta-analysis were contacted to seek unpublished updated center data.
Study selection criteria For an identified study to be included in the systematic review, it had to (1) include human subjects, (2) have full text available in English, (3) report 1-year survival for LTx recipients from DCD donors, and (4) have at least 5 DCD recipients. For an identified study to be included in the meta-analysis, it had to meet the
following additional criteria: (1) a DBD recipient cohort from the same center(s) as the reported DCD recipient cohort and (2) DCD donors had to be controlled Maastricht category 3 or 4.20 In the presence of overlapping data (i.e., several publications from the same center or multi-center data overlapping with single-center data), only the most recent data were included.
Quality assessment The methodologic quality of the selected studies was evaluated using criteria from the U.S. Preventive Services Task Force (section 2 of the Supplement [available on the jhltonline.org Web site].21
Data Extraction Extracted data included author name, year of publication, location of center(s), number of patients in DCD and DBD cohorts, time frame of study, reasons for LTx, use of extended criteria donors, heparinization before procurement, Maastricht classification, warm and cold ischemic times, and length of follow-up. Outcome data extracted included rates of primary graft dysfunction (PGD), acute cellular rejection (ACR), airway complications, bronchiolitis obliterans syndrome (BOS), intensive care unit (ICU) and hospital length of stay (LOS), and survival.
Definition of outcomes The primary outcome of the meta-analysis was 1-year survival. Secondary outcomes included occurrence of PGD,22 ICU and hospital LOS, rate of ACR,23 airway complication rate, occurrence of BOS,24 and 3- and 5-year survival.
Statistical analysis Dichotomous data from all studies reporting on the outcome of interest in DCD and DBD recipients were pooled to calculate relative risks (RRs) with 95% confidence interval (CI). We used the I2 statistic to test for heterogeneity.25 Statistical heterogeneity was defined as an I2 statistic value 4 50%.25,26 We performed a sensitivity analysis in which a study was removed at a time while the remaining data were analyzed to evaluate whether the results could have been markedly affected by that single study. Publication bias was assessed using Egger precision-weighted linear regression tests and by generating a funnel plot.27,28 All analyses were performed with Stata (Version 11.0; Stata Corp, College Station, TX). A 2-tailed p value o 0.05 was considered statistically significant.
Results Study selection A flow diagram detailing study screening and selection for inclusion in the systematic review and the meta-analysis is presented in Figure 1. Reviewer agreement on selection of citations for full review was 97% (K ¼ 0.83). Reviewer agreement for selection of full review texts for systematic review (n ¼ 11) was 100% and for meta-analysis (n ¼ 6) was 100% (K ¼ 1.0).
Krutsinger et al.
Lung Donation After Cardiocirculatory Death
Study characteristics All 11 studies were retrospective observational studies, and most (n ¼ 8) were single-center studies (Table 1).9–11,14,16–19 One study reported multi-center data from all organs donated by DCD in Ontario, but only 1 center performed LTx.12 There were 2 multi-center studies; one examined the data available in UNOS,15 whereas the other looked at data available at all the centers performing DCD LTx throughout Australia.13 Of studies, 7 explicitly stated that extended criteria donors were used for both cohorts,9,10,13,14,16,18,19
677 1 reported extended criteria donor use among DBD but not DCD cohorts,17 and the others did not specify. Heparin was administered before the declaration of death in 6 studies.9–14 All but 2 studies were restricted to controlled, Maastricht category 3 and 4 donors.9,10,12–15,17–19
Primary outcomes The extracted data regarding the primary and secondary outcomes are presented in Table 2.
1151 Citaons Idenfied and Screened: PubMed: 248 Scopus: 336 Web of Science: 281 CDSR: 2 CINAHL: 25 ClinicalTrials.gov: 80 CENTRAL: 0 DARE: 0 Hand Searched References: 178 Hand Searched (5) Journals: 1 632 Duplicates 519 Unique Citaons
461 Excluded Based on Eligibility Criteria Aer Title and/or Abstract Review. 58 Selected for Full-Text Review 47 Excluded for Systemac Review Abstract Only: 20 No Primary Outcome Data: 12 Updated Center Data: 9
ORIGINAL CLINICAL SCIENCE
Lung transplantation from donation after cardiocirculatory death: a systematic review and meta-analysis Dustin Krutsinger, MD,a Robert M. Reed, MD,b Amy Blevins, MALS,c Varun Puri, MD,d Nilto C. De Oliveira, MD,e Bartlomiej Zych, MD,f Servet Bolukbas, MD,g Dirk Van Raemdonck, MD, PhD,h Gregory I. Snell, MBBS, FRACP, MD,i and Michael Eberlein, MD, PhDa,j From the aDepartment of Medicine, University of Iowa, Iowa City, Iowa; bDivision of Pulmonary and Critical Care Medicine, University of Maryland, Baltimore, Maryland; cHardin Library for the Health Sciences, University of Iowa, Iowa City, Iowa; dDepartment of Surgery, Washington University, St. Louis, Missouri; eDivision of Cardiothoracic Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; fDepartment of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, London, United Kingdom; gDepartment of Thoracic Surgery, Dr. Korst Schmidt Klinik, Wiesbaden, Germany; h Department of Thoracic Surgery and Lung Transplant Unit, University Hospitals Leuven, Leuven, Belgium; iLung Transplant Service, Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Australia; and the jDivision of Pulmonary, Critical Care and Occupational Medicine, University of Iowa, Iowa City, Iowa.
KEYWORDS: lung transplantation; donation after cardiac death; circulatory determination of death; cardiocirculatory death; non–heart-beating donor
BACKGROUND: Lung transplantation (LTx) can extend life expectancy and enhance the quality of life for select patients with end-stage lung disease. In the setting of donor lung shortage and waiting list mortality, the interest in donation after cardiocirculatory death (DCD) is increasing. We performed a systematic review and meta-analysis to compare outcomes between DCD and conventional donation after brain death (DBD). METHODS: PubMed, CINAHL, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and ClinicalTrials.gov were searched. We identified original research studies with 1-year post-transplant survival data involving 45 DCD transplants. We performed meta-analyses examining 1-year survival, primary graft dysfunction, and acute rejection after LTx. RESULTS: We identified 519 citations; 11 observational cohort studies met our inclusion criteria for systematic review, and 6 met our inclusion criteria for meta-analysis. There were no differences found in 1-year mortality after LTx between DCD and DBD cohorts in individual studies or in the meta-analysis (DCD [n ¼ 271] vs DBD [n ¼ 2,369], relative risk [RR] 0.88, 95% confidence interval [CI] 0.59–1.31, p ¼ 0.52, I2 ¼ 0%). There was also no difference between DCD and DBD in a pooled analysis of 5 studies reporting on primary graft dysfunction (RR 1.09, 95% CI 0.68–1.73, p ¼ 0.7, I2 ¼ 0%) and 4 studies reporting on acute rejection (RR 0.72, 95% CI 0.49–1.05, p ¼ 0.09, I2 ¼ 0%). CONCLUSIONS: Survival after LTx from DCD is comparable to survival after LTx from DBD in observational cohort studies. DCD appears to be a safe and effective method to expand the donor pool. J Heart Lung Transplant 2015;34:675–684 r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: Michael Eberlein, MD, PhD, Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, C 33 GH, Iowa City, IA 52242. Telephone: 319-512-8160. Fax: 319-356-6406. E-mail address: [email protected]
Lung transplantation (LTx) represents a potentially lifesaving therapy for select patients with end-stage lung disease, but organs are in short supply. The number of patients actively awaiting LTx in the United States increased
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.11.009
676
The Journal of Heart and Lung Transplantation, Vol 34, No 5, May 2015
from 1,052 in 2007 to 1,317 in 2012.1 As of May 2014, there were 1,674 patients awaiting LTx.2 This donor shortage is aggravated by the low usage rates of donor lungs partly as a result of pre-existing lung disease, pneumonia, and acute lung injury caused by brain death and chest trauma. In the United States, for every 100 eligible organ donors, only 18.5 result in donated lungs compared with 67 for kidneys.3 In 2012, of the 2,294 patients removed from the United Network for Organ Sharing (UNOS) waiting list, 303 (13.2%) died, and 110 (4.8%) became too sick to be transplanted.1 The donor shortage has led investigators to search for ways to increase the donor pool, including the use of extended criteria donors, donation after cardiocirculatory death (DCD), ex vivo lung perfusion and evaluation, and living lobar LTx.4 The first successful deceased human organ transplant,5 human LTx,6 and the first long-term successful human LTx7 all used organs donated after cardiocirculatory death. Contemporary to the surgical and medical advances that allowed these early transplant successes, the concept of brain death and organ donation after brain death (DBD) became more widely accepted. As brain death became codified into legislation, such donors quickly became the primary source of organs, and DCD was largely abandoned. In an attempt to expand the lung donor pool, Love et al8 resumed using DCD. With seemingly acceptable early-term and intermediate-term results, other LTx groups followed cautiously in their footsteps.9–19 Return to DCD was slow to be accepted partly because of concerns of ischemia during the period between discontinuation of life support and organ procurement. Notwithstanding these concerns, it is unclear if LTx using DCD is associated with differences in survival compared with DBD because the current literature consists generally of small, mostly single-center studies.9–19 We performed a systematic review and meta-analysis to test our hypothesis that survival rates do not significantly differ between LTx recipients from DCD compared with DBD donors.
Methods Data sources A health sciences librarian performed literature searches in PubMed, CINAHL, Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus (which includes EMBASE abstracts), Web of Science, and ClinicalTrials.gov. No filters for date, language, or any other parameter were used. The search strategy is detailed in section 1 of the Supplement (available on the jhltonline.org Web site). The authors of the studies selected for inclusion in the meta-analysis were contacted to seek unpublished updated center data.
Study selection criteria For an identified study to be included in the systematic review, it had to (1) include human subjects, (2) have full text available in English, (3) report 1-year survival for LTx recipients from DCD donors, and (4) have at least 5 DCD recipients. For an identified study to be included in the meta-analysis, it had to meet the
following additional criteria: (1) a DBD recipient cohort from the same center(s) as the reported DCD recipient cohort and (2) DCD donors had to be controlled Maastricht category 3 or 4.20 In the presence of overlapping data (i.e., several publications from the same center or multi-center data overlapping with single-center data), only the most recent data were included.
Quality assessment The methodologic quality of the selected studies was evaluated using criteria from the U.S. Preventive Services Task Force (section 2 of the Supplement [available on the jhltonline.org Web site].21
Data Extraction Extracted data included author name, year of publication, location of center(s), number of patients in DCD and DBD cohorts, time frame of study, reasons for LTx, use of extended criteria donors, heparinization before procurement, Maastricht classification, warm and cold ischemic times, and length of follow-up. Outcome data extracted included rates of primary graft dysfunction (PGD), acute cellular rejection (ACR), airway complications, bronchiolitis obliterans syndrome (BOS), intensive care unit (ICU) and hospital length of stay (LOS), and survival.
Definition of outcomes The primary outcome of the meta-analysis was 1-year survival. Secondary outcomes included occurrence of PGD,22 ICU and hospital LOS, rate of ACR,23 airway complication rate, occurrence of BOS,24 and 3- and 5-year survival.
Statistical analysis Dichotomous data from all studies reporting on the outcome of interest in DCD and DBD recipients were pooled to calculate relative risks (RRs) with 95% confidence interval (CI). We used the I2 statistic to test for heterogeneity.25 Statistical heterogeneity was defined as an I2 statistic value 4 50%.25,26 We performed a sensitivity analysis in which a study was removed at a time while the remaining data were analyzed to evaluate whether the results could have been markedly affected by that single study. Publication bias was assessed using Egger precision-weighted linear regression tests and by generating a funnel plot.27,28 All analyses were performed with Stata (Version 11.0; Stata Corp, College Station, TX). A 2-tailed p value o 0.05 was considered statistically significant.
Results Study selection A flow diagram detailing study screening and selection for inclusion in the systematic review and the meta-analysis is presented in Figure 1. Reviewer agreement on selection of citations for full review was 97% (K ¼ 0.83). Reviewer agreement for selection of full review texts for systematic review (n ¼ 11) was 100% and for meta-analysis (n ¼ 6) was 100% (K ¼ 1.0).
Krutsinger et al.
Lung Donation After Cardiocirculatory Death
Study characteristics All 11 studies were retrospective observational studies, and most (n ¼ 8) were single-center studies (Table 1).9–11,14,16–19 One study reported multi-center data from all organs donated by DCD in Ontario, but only 1 center performed LTx.12 There were 2 multi-center studies; one examined the data available in UNOS,15 whereas the other looked at data available at all the centers performing DCD LTx throughout Australia.13 Of studies, 7 explicitly stated that extended criteria donors were used for both cohorts,9,10,13,14,16,18,19
677 1 reported extended criteria donor use among DBD but not DCD cohorts,17 and the others did not specify. Heparin was administered before the declaration of death in 6 studies.9–14 All but 2 studies were restricted to controlled, Maastricht category 3 and 4 donors.9,10,12–15,17–19
Primary outcomes The extracted data regarding the primary and secondary outcomes are presented in Table 2.
1151 Citaons Idenfied and Screened: PubMed: 248 Scopus: 336 Web of Science: 281 CDSR: 2 CINAHL: 25 ClinicalTrials.gov: 80 CENTRAL: 0 DARE: 0 Hand Searched References: 178 Hand Searched (5) Journals: 1 632 Duplicates 519 Unique Citaons
461 Excluded Based on Eligibility Criteria Aer Title and/or Abstract Review. 58 Selected for Full-Text Review 47 Excluded for Systemac Review Abstract Only: 20 No Primary Outcome Data: 12 Updated Center Data: 9
