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The evolving use of ECMO: The impact of the CESAR trial
International Journal of Surgery 35 (2016) 95e99
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Before and After Study
The evolving use of ECMO: The impact of the CESAR trial Jialin Mao a, *, Subroto Paul a, b, Art Sedrakyan a a b
Department of Healthcare Policy and Research, Weill Medical College of Cornell University, New York, NY, USA Department of Cardiothoracic Surgery, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY, USA
h i g h l i g h t s There was a significant increase from in ECMO use from 2008 to 2011 (960e1995 cases). Patients receiving ECMO after Q1 of 2008 were more likely to be older and have two or more comorbidities. After adjustment, there was no significant difference in patient mortality between the two time periods. There was a significant increase in number of publications after 2008 (from 65 in 2007 to 156 in 2011).
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 May 2016 Accepted 20 September 2016
Introduction: To compare characteristics and outcomes of patients receiving extracorporeal membrane oxygenation (ECMO) therapy as well as medical research activities related to ECMO before and after release of preliminary results of the CESAR trial. Methods: We assessed trends in EMCO use among adults, patient and institutional characteristics, inhospital mortality, peri-procedural complications and resource use before and after first quarter of 2008 in Nationwide Inpatient Sample Database. Literature review was conducted to evaluate publications related to adult ECMO during the same time period. Results: Overall, 8389 patients received ECMO therapy between 2001 and 2011. ECMO use remained stable between 2001 and 2007 and increased significantly from 2008 to 2011. Comparing time periods before and after first quarter of 2008, patients on ECMO in later years were more likely to be older (Before vs. After: (age 65þ) 18.9% vs. 23.1%) and have two or more comorbidities (43.6% vs. 52.3%). After adjusting for patient and institutional characteristics, in-hospital mortality was comparable for the two time periods (Odds Ratio 0.76, 95% CI 0.55e1.05). Between 2001 and 2011, 652 adult ECMO related English literature were identified, published in 181 English journals and by investigators from 31 countries. There was a significant increase in number of publications after 2008. Conclusion: The presence of the CESAR trial was associated with significant increase in the utilization of ECMO in clinical practice and in the research activities related to ECMO. Moreover, ECMO has since been used in patients of older age and higher comorbidities, but with no increase in in-hospital mortality followed. © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Extracorporeal membrane oxygenation Evidence based medicine Outcomes research
1. Introduction Extracorporeal membrane oxygenation (ECMO) therapy in adults was first utilized in the 1970s [1] and has become an established life-support technique for the management of life threatening pulmonary and/or cardiac failure [2]. ECMO has been proved to be an effective therapy among neonates, with survival rates up to 84% [3], but mortality and complications following
* Corresponding author. Weill Cornell Medical College, 402 East 67th Street, New York, NY 10065, USA. E-mail address: [email protected] (J. Mao).
treatment among adults are high. Survival at discharge among adult patients was reported to vary between 33% and 53% [3,4]. The Conventional ventilation or ECMO for Severe Adult Respiratory failure (CESAR) trial was the first randomized controlled trial (RCT) of ECMO in adults with respiratory failure, comparing it to conventional supportive critical care [5]. Preliminary results of CESAR trial was released in February 2008, denoting that ECMO improved survival in adult patients with severe respiratory failure [6]. Since then, literatures have reported significant increase in utilization of ECMO in adult patients [7e9]. RCT has long been recognized as highest level of evidence in medical research and generally has a significant impact on clinical
http://dx.doi.org/10.1016/j.ijsu.2016.09.081 1743-9191/© 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
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J. Mao et al. / International Journal of Surgery 35 (2016) 95e99
practice as well as related research activities [10,11]. Our purpose was to examine patient profile, discharge characteristics and related costs following ECMO therapy as well as medical research activities before and after release of preliminary results of CESAR trial using nationally representative database and literature review.
adjusting for patient demographics, concurrent conditions, comorbidities and hospital characteristics. Statistical analyses were performed using SAS v9.3 (SAS Institute Inc., Cary, NC). 2.4. Literature review and analysis
The Nationwide Inpatient Sample (NIS) is maintained by the Agency for Healthcare Research and Quality, as part of the Healthcare Cost and Utilization Project (HCUP). The NIS is the largest all-payer inpatient care database in the United States and constitutes approximately a 20% stratified sample of all hospital discharges from non-government institutions [12]. This study was approved by the Institutional Review Board of Weill Cornell Medical College and conforms to the data-use agreement for the NIS from HCUP.
Adult ECMO related publications between 2001 and 2011 were retrieved from Pubmed database using MESH terms “Extracorporeal Membrane Oxygenation” and “Adult”. Publications were than reviewed and non-English, non-ECMO related or pediatric and neonatal ECMO related articles were excluded from further analyses. Each publication was further defined as a report if it was a case or technology report, as a study if it was a single-center, multicenter or database/registry research study, or as a review. Trends in number of publications, number of journal and number of countries publishing ECMO related articles over time were examined. Percentages of report or study, average publications per journal per year and average publications per country per year were calculated and compared before/during and after first quarter of 2008.
2.2. Study cohort and variables
3. Results
Patients older than 18 years old who received ECMO therapy between 2001 and 2011 were included in the study, identified by Internal Classification of Diseases, Ninth Revision, and Clinical Modification (ICD-9-CM) procedure code 39.65. Because preliminary results of CESAR trial was released in Feb 2008 and only admission quarter was available in the NIS dataset, we used first quarter of 2008 as our cut-off time point. Cases with unknown procedure time (year and quarter) were excluded from the study. Data collected for each patient admission included: age at time of admission, gender, race, insurance status, concurrent conditions, comorbidities, in-hospital mortality and peri-procedural complications, length of stay (LOS), discharge status, and costs of hospitalization. Institution-related data include hospital bed size and teaching status. Concurrent conditions included cardiotomy, heart and/or lung transplant, implantation ventricular assisted device (VAD) or percutaneous transluminal coronary angioplasty (PTCA), and respiratory failure. Patient co-morbidities were identified from ICD-9-CM diagnosis codes using Elixhauser comorbidity definitions [13]. Other-than-routine (OTR) discharge was determined by discharge disposition. Charge data was provided at the discharge level in the NIS database. Costs were estimated using hospital specific cost to charge ratio, in a pre-established method [14]. When hospital specific cost to charge ratio was unavailable, the group level cost to charge ratio was used, as recommended by HCUP [15]. A Diagnosis Related Group (DRG) based scaling factor released by HCUP in 2009 was then applied to the data. Prolonged LOS and excessive costs were further defined as above 75th percentile.
3.1. Nationwide inpatient sample
2. Methods 2.1. Data source
Overall, 8389 patients who received ECMO therapy between 2001 and 2011 were included in the study. Overall, there was a 646% increase in utilization of ECMO over years, from 309 cases in 2001 to 1995 cases in 2011 (Fig. 1). More specifically, there was no obvious increase in ECMO utilization before 2008 (309 cases in 2001 and 318 cases in 2007), but there was a significant increase from 2008 to 2011 (960 cases in 2008 to 1995 cases in 2011, p < 0.01). Similar trends were observed when examining within patients with different concurrent conditions. 3950 and 4439 patients received ECMO therapy before/during and after first quarter of 2008 respectively (Table 1). There was a trend that in the second time period, patients receiving ECMO therapy comprised of a higher proportion of older patients (Before vs. After: (age 65þ) 18.9% vs. 23.1%, p ¼ 0.08), compared to earlier time period. Patients on ECMO therapy after first quarter of 2008 were also more likely to have 2 or more comorbidities compared to patients being treated before and during first quarter of 2008 (43.6% vs. 52.3%, p < 0.01). Moreover, ECMO was more likely to be used at hospitals of large bed size after the release of CESAR preliminary results (85.4% vs. 91.5%, p < 0.01). In-hospital mortality in patients receiving ECMO therapy before and after CESAR trial was 65.5% and 60.5%, respectively (Table 2). Patients receiving ECMO after Mar 2008 were more likely to have
2.3. Statistical analysis Utilization of ECMO over time was evaluated by graph and for each concurrent condition specifically. Patient demographic, comorbidities, in-hospital mortality, peri-procedural complications, discharge characteristics and costs of hospitalization were examined for patients receiving ECMO therapy prior to and after the release of preliminary result of CESAR trial. Weighted events and percentages were presented for all statistical analysis of categorical variable and compared using chi-square test. Hierarchical logistic regression was performed to assess difference in in-hospital mortality, peri-procedural complications, discharge characteristics and costs of hospitalization between the two time periods,
Fig. 1. Trends in utilization of ECMO in the United States from 2001 to 2011.
J. Mao et al. / International Journal of Surgery 35 (2016) 95e99
97
Table 1 Characteristics of patients receiving ECMO therapy before and after release of CESAR trial preliminary results.
Age groups 18e54 55e64 65þ Female White Racea Insurance Medicare Medicaid Commercial Other Concurrent conditions Cardiotomy Transplant VAD/PTCA Respiratory failure Comorbidities CAD Hypertension CHF Diabetes CPD Obesity Anemia PVD Renal Failure CVD Comorbidity summary 0 1 2þ Hospital Bed Size Small Medium Large Teaching Hospital
Before (N ¼ 3950)
After (N ¼ 4439)
2214 (56.1%) 988 (25.0%) 748 (18.9%) 1594 (40.4%) 2045 (69.2%)
2423 (54.6%) 988 (22.3%) 1027 (23.1%) 1622 (36.5%) 2381 (65.9%)
1079 (27.4%) 607 (15.4%) 1880 (47.7%) 379 (9.6%)
1325 (29.9%) 751 (16.9%) 2001 (45.1%) 356 (8.0%)
1684 (42.6%) 514 (13.0%) 507 (12.8%) 1245 (31.5%)
1571 (35.4%) 689 (15.5%) 717 (16.2%) 1461 (32.9%)
1036 (26.2%) 859 (21.7%) 1632 (41.3%) 597 (15.1%) 506 (12.8%) 327 (8.3%) 378 (9.6%) 452 (11.4%) 251 (6.4%) 174 (4.4%)
1170 (26.4%) 939 (21.2%) 2037 (45.9%) 781 (17.6%) 600 (13.5%) 417 (9.4%) 686 (15.4%) 620 (14.0%) 569 (12.8%) 311 (7.0%)
995 (25.2%) 1231 (31.2%) 1724 (43.6%)
855 (19.3%) 1264 (28.5%) 2319 (52.3%)
95 (2.4%) 479 (12.2%) 3348 (85.4%) 3610 (92.1%)
52 (1.2%) 322 (7.3%) 4048 (91.5%) 4140 (93.6%)
P Value 0.08
0.11 0.21 0.35
0.01 Fig. 2. Trends in publications related to ECMO from 2001 to 2011.
3.2. Literature review 0.95 0.77 0.06 0.17 0.67 0.42 <0.01 0.12 <0.01 0.02 <0.01
<0.01
0.21
Abbreviations: CAD¼Coronary Artery Disease, CHF¼Congestive Heart Failure, CPD¼Chronic Pulmonary Disease, PVD¼Peripheral Vascular Disease, CVD¼Cerebrovascular Disease. a 21.7% patients with missing race information.
prolonged LOS (19.9% vs. 27.7%), excessive costs (22.6% vs. 28.6%) and non-routine discharges (72.5% vs. 81.2%) than those being treated during the earlier time period. After adjusting for patient demographics, concurrent condition, comorbidities and hospital characteristics, there was no significant difference in patient mortality between the two time periods (Odds Ratio (OR) 0.76, 95% CI 0.55e1.05). There was also no significant difference in periprocedure complications, including AMI and sepsis, other-thanroutine discharge, prolonged LOS and excessive costs between the two time periods.
From 2001 to 2011, 890 publications were reviewed and 652 adult ECMO related English literature were included in the final analysis. During the 11 year time period, articles on adult ECMO were published in 181 English journals and by investigators from 31 countries. Similar to the trend of ECMO clinical utilization, there was only a slight increase in number of publications before 2008 (from 29 in 2001 to 44 in 2007), while there was a significant increase in number of publications after 2008 (from 65 in 2007 to 156 in 2011, p < 0.01) (Fig. 2). There was also increases in number of journals publishing ECMO related papers (from 16 in 2001 to 70 in 2011, p < 0.01), and number of countries publishing ECMO related papers (from 12 in 2001, to 22 in 2011, p < 0.01). Among the 652 articles, 318 were published before the end of March 2008, and 334 were published afterwards (Table 3). Comparing time periods before and after March 2008, a higher proportion of publications were case or technology report in the later time period (53.7% vs. 60.2%). When examining annual publications per journal and per country, after the release of preliminary results of CESAR trial, average annual publications were higher on both journal (1.16 vs. 1.46 per journal per year) and country levels (1.91 vs. 3.41 per country per year). 4. Discussion Our study demonstrated the increasing utilization of ECMO in adults and adult ECMO related publications in the United States, especially after the release of preliminary results of CESAR trial in the first quarter of 2008. ECMO was increasingly used in older and sicker patients after 2008, with mortality remained unchanged.
Table 2 In-hospital outcomes of patients receiving ECMO therapy before and after CESAR trial. Unadjusted
Mortality AMI PE/DVT Sepsis OTR Discharge Prolonged LOSa Excessive Costsa
Adjusted
Before (N ¼ 3950)
After (N ¼ 4439)
P value
Odds ratio (95% CI) after vs. Before
P value
2589 (65.5%) 1426 (36.1%) 254 (6.4%) 1072 (27.1%) 986 (72.5%) 786 (19.9%) 696 (22.6%)
2686 (60.5%) 1519 (34.2%) 562 (12.7%) 1613 (36.3%) 1423 (81.2%) 1227 (27.7%) 919 (28.6%)
0.03 0.42 <0.01 <0.01 0.01 <0.01 0.01
0.76 0.94 1.78 0.89 0.74 1.36 1.27
0.10 0.68 0.02 0.27 0.41 0.09 0.20
(0.55e1.05) (0.71e1.25) (1.08e2.91) (0.72e1.10) (0.35e1.53) (0.95e1.95) (0.88e1.83)
Abbreviations: AMI ¼ Acute Myocardial Infarction, PE¼Pulmonary Embolism, DVT ¼ Deep Venous Thrombosis, OTR¼Other Than Routine, LOS ¼ Length of Stay. a Prolonged LOS and Excessive Costs were defined as above 75th percentile.
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Table 3 Publications related to ECMO before and after CESAR trial. Before (N ¼ 318) Type of publication Report 171 (53.7%) Study 121 (38.1%) N Journals 114 Average publication per journal per yeara Mean (Std) 1.16 (0.39) Range 1.00e3.56 N Countries 25 Average publication per country per yeara Mean (Std) 1.91 (1.31) Range 1.00e6.82
After (N ¼ 334) 201 (60.2%) 97 (29.0%) 121 1.46 (1.00) 1.00e7.25 28 3.41 (4.58) 1.00e23.00
a Average publication was calculated for years when journals/countries had related publications.
We found significant increase in ECMO utilization in adults after 2008 overall and among patients with different concurrent conditions. The CESAR trial was conducted among adult patients with respiratory failure [5], and yet the impact was pronounced on clinical practice regardless of concurrent conditions. In addition to the advances in ECMO technology in the last decade, it is possible that the results from the CESAR trial has been encouraging for practitioners to adopt ECMO in care of critically ill patients. Evidence based medicine has been emphasized in modern era clinical practice and it has been recommended that research evidence should be critically appraised and incorporated into clinical practice [16]. While research evidence was not restricted to RCT, evidence from RCT has been ranked among the highest level, and considered superior to observational research [17]. Indeed, 3 years before the release of CESAR trial preliminary results, the 2004 report of ELSO (Extracorporeal Life Support) registry presented moderate to positive results of outcomes following ECMO use in adults with respiratory and cardiac failure [18]. In 2007, analysis based on patients in the ELSO registry receiving ECMO post-lung and/or heart transplant also highlighted the usefulness of ECMO among patients with graft malfunction [19]. However, no significant increase in ECMO utilization was observed after either of these two time points. Apart from the increase in utilization, we also found that after 2008, there has been alteration in characteristics of both patients receiving ECMO therapy and institutions using ECMO therapy. During the second time period of our study (post March 2008), the population of patients receiving ECMO was comprised of a larger proportion of aged and of those with higher comorbidities. The expansion of ECMO use indication in adults may also be associated to the fact that encouraging result from the CESAR trial gave rise to practitioners' confidence in placing older and sicker people on ECMO. In addition, we also found that after 2008, ECMO was more likely to be used in hospitals with large bed size. This mirrored the recommendation by the CESAR trial group that ECMO will be “most efficient in large critical care units” [5]. Despite the extension of use of ECMO to older and sicker patients, in-hospital mortality following ECMO therapy remained stable. The unchanged mortality may actually be attributed to a mixture of use of ECMO among patients with worse-conditions and some improvement in ECMO use strategy and complication management. There has been improved patient care resource and strategies, clinical evaluation of patients before and after the initiation of ECMO and complication management [20e22]. The growing use of resource indicated by the observed prolonged hospitalization, elevated costs and increased use of postdischarge care in our study may also be a reflection of these mixing factors.
Parallel to the increase in ECMO utilization in clinical practice, there was also significant increase in publications related to adult ECMO therapy, the majority of which were case or technology reports. In addition to number of articles, there was also increases in number of countries and journals attentive to ECMO. It is common for new studies to be inspired by previous publications, to confirm, to complement or to challenge, especially when the article has a significant impact like the CESAR trial. The increase, as well, can be linked to the growing acceptance of EBM [23] and the fact that ECMO has been increasingly used in more complicated cases. There are several limitations with our current study. ECMO treatment was identified by procedure codes. Type of ECMO and duration of ECMO use was not available in the discharge record. Thus, cost analyses in the present study were not based on cost of ECMO-specific resource use, but showed cost of care related to ECMO use. Inherent with administrative database, time of occurrence of peri-procedural morbidities cannot be determined. In addition, NIS is a sampled nationwide database, with the hospitals being sampled varying from year to year. In conclusion, with evidence based medicine being underscored in current era, the presence of the CESAR trial was associated with significant increase in the utilization of ECMO in clinical practice and in the research activities related to ECMO. Moreover, ECMO has since been used in patients of older age and higher comorbidities, but with no increase in in-hospital mortality followed. The IDEAL framework emphasizes the appropriate evaluation of technology at different stages [24]. RCT has been among the highest level of evidence at the assessment stage, with significant impact on practice. With ECMO being proposed as a countermeasure in public health emergencies [25], it is also critical that large observational and registry studies will be conducted to provide evidence for technology surveillance after widespread adoption. Ethical approval This study was approved by the institutional review board of Weill Cornell Medical College (Protocol No. EXE-2011-057). Sources of funding Dr. Sedrakyan received funding from the US FDA for establishing the MDEpiNet Science and Infrastructure Center. Author contribution Study Design: All authors. Data analysis and interpretation: All authors. Statistical analysis: Mao, Sedrakyan. Drafting of manuscript: Mao. Critical revision of manuscript: All authors. Conflicts of interest No conflict of interest. Guarantor Dr. Sedrakyan accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. Research registration unique identifying number (UIN) researchregistry1254.
J. Mao et al. / International Journal of Surgery 35 (2016) 95e99
Acknowledgements Acknowledgements to Abu Nasar, MSc and Abby Isaacs, MSc for important analytic contributions. References [1] D. Abrams, A. Combes, D. Brodie, Extracorporeal membrane oxygenation in cardiopulmonary disease in adults, J. Am. Coll. Cardiol. 63 (25 Pt A) (2014) 2769e2778. [2] G. MacLaren, A. Combes, R.H. Bartlett, Contemporary extracorporeal membrane oxygenation for adult respiratory failure: life support in the new era, Intensive care Med. 38 (2) (2012) 210e220. [3] M.L. Paden, S.A. Conrad, P.T. Rycus, R.R. Thiagarajan, E. Registry, Extracorporeal life support organization registry report 2012, ASAIO J. 59 (3) (2013) 202e210. [4] B.W. Gray, J.W. Haft, J.C. Hirsch, G.M. Annich, R.B. Hirschl, R.H. Bartlett, Extracorporeal life support: experience with 2000 patients, ASAIO J. 61 (1) (2015) 2. [5] G.J. Peek, M. Mugford, R. Tiruvoipati, A. Wilson, E. Allen, M.M. Thalanany, et al., Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial, Lancet 374 (9698) (2009) 1351e1363. [6] P. Emma Hitt, CESAR Trial: Extracorporeal Membrane Oxygenation Improves Survival in Patients with Severe Respiratory Failure Medscape Medical News, Medscape Medical News, 2008 [12/16/2014]. Available from: http://www. medscape.com/viewarticle/569740. [7] G. Lafc, A.B. Budak, A.U. Yener, O.F. Cicek, Use of extracorporeal membrane oxygenation in adults, Heart, lung circulation 23 (1) (2014) 10e23. [8] B.G. Maxwell, A.J. Powers, A.Y. Sheikh, P.H. Lee, R.L. Lobato, J.K. Wong, Resource use trends in extracorporeal membrane oxygenation in adults: an analysis of the Nationwide Inpatient Sample 1998-2009, J. Thorac. Cardiovasc. Surg. 148 (2) (2014) 416e421 e1. [9] C.M. Sauer, D.D. Yuh, P. Bonde, Extracorporeal membrane oxygenation (ECMO) use has increased by 433% in adults in the United States from 2006 to 2011, ASAIO J. 61 (1) (2015) 31e36. [10] Medicine CfE-B, OCEBM Levels of Evidence, Centre for Evidence-Based Medicine, 2016 [Jan 14, 2016]. Available from: http://www.cebm.net/ocebmlevels-of-evidence/. [11] S.E. Straus, D.L. Sackett, Using research findings in clinical practice, Bmj 317 (7154) (1998) 339e342.
99
[12] Quality AfHRa, HCUP Databases. Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality, 2016 [Jan 14, 2016]. Available from: http://www.hcup-us.ahrq.gov/nisoverview.jsp. [13] A. Elixhauser, C. Steiner, D.R. Harris, R.M. Coffey, Comorbidity measures for use with administrative data, Med. care 36 (1) (1998) 8e27. [14] A.J. Gadzinski, J.B. Dimick, Z. Ye, D.C. Miller, Utilization and outcomes of inpatient surgical care at critical access hospitals in the United States, JAMA Surg. 148 (7) (2013) 589e596. [15] Quality AfHRa, Cost-to-Charge Ratio Files: 2011 Nationwide Inpatient Sample (NIS) User Guide, Agency for Healthcare Research and Quality, 2013 [12/16/ 2014]. Available from: http://www.hcup-us.ahrq.gov/db/state/ CCR2011NISUserGuide.pdf. [16] D.L. Sackett, W.M. Rosenberg, J.A. Gray, R.B. Haynes, W.S. Richardson, Evidence based medicine: what it is and what it isn't, Bmj 312 (7023) (1996) 71e72. [17] P.B. Burns, R.J. Rohrich, K.C. Chung, The levels of evidence and their role in evidence-based medicine, Plastic Reconstr. Surg. 128 (1) (2011) 305e310. [18] S.A. Conrad, P.T. Rycus, H. Dalton, Extracorporeal life support registry report 2004, ASAIO J. 51 (1) (2005) 4e10. [19] S. Fischer, D. Bohn, P. Rycus, A.F. Pierre, M. de Perrot, T.K. Waddell, et al., Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: analysis of the Extracorporeal Life Support Organization (ELSO) registry, J. heart lung Transplant. official Publ. Int. Soc. Heart Transplant. 26 (5) (2007) 472e477. [20] J. Belohlavek, V. Rohn, J. Tosovsky, J. Kunstyr, M. Semrad, J. Horak, et al., A review of a newly established ECMO program in a university affiliated cardiac center, J. Cardiovasc. Surg. 52 (3) (2011) 445e451. [21] M. Schmidt, M. Bailey, J. Kelly, C. Hodgson, D.J. Cooper, C. Scheinkestel, et al., Impact of fluid balance on outcome of adult patients treated with extracorporeal membrane oxygenation, Intensive care Med. 40 (9) (2014) 1256e1266. [22] D.V. Mullany, T.N. Bull, W. Hunt, K. Shekar, B. Thomson, J.F. Fraser, et al., Outcomes of the first 30 cases of an adult extracorporeal membrane oxygenation program: strategies to manage the “learning curve” and implications for intensive care unit risk adjustment models, Crit. care Resusc. J. Australas. Acad. Crit. Care Med. 14 (2) (2012) 119e129. [23] V.M. Montori, G.H. Guyatt, Progress in evidence-based medicine, Jama 300 (15) (2008) 1814e1816. [24] J.A. Cook, P. McCulloch, J.M. Blazeby, D.J. Beard, D. Marinac-Dabic, A. Sedrakyan, et al., IDEAL framework for surgical innovation 3: randomised controlled trials in the assessment stage and evaluations in the long term study stage, Bmj 346 (2013) f2820. [25] S. Paul, B. Campbell, E.C. Meltzer, A. Sedrakyan, ECMO as an emergency medical countermeasure, Lancet Respir. Med. 2 (9) (2014) 685e687.
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Before and After Study
The evolving use of ECMO: The impact of the CESAR trial Jialin Mao a, *, Subroto Paul a, b, Art Sedrakyan a a b
Department of Healthcare Policy and Research, Weill Medical College of Cornell University, New York, NY, USA Department of Cardiothoracic Surgery, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY, USA
h i g h l i g h t s There was a significant increase from in ECMO use from 2008 to 2011 (960e1995 cases). Patients receiving ECMO after Q1 of 2008 were more likely to be older and have two or more comorbidities. After adjustment, there was no significant difference in patient mortality between the two time periods. There was a significant increase in number of publications after 2008 (from 65 in 2007 to 156 in 2011).
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 May 2016 Accepted 20 September 2016
Introduction: To compare characteristics and outcomes of patients receiving extracorporeal membrane oxygenation (ECMO) therapy as well as medical research activities related to ECMO before and after release of preliminary results of the CESAR trial. Methods: We assessed trends in EMCO use among adults, patient and institutional characteristics, inhospital mortality, peri-procedural complications and resource use before and after first quarter of 2008 in Nationwide Inpatient Sample Database. Literature review was conducted to evaluate publications related to adult ECMO during the same time period. Results: Overall, 8389 patients received ECMO therapy between 2001 and 2011. ECMO use remained stable between 2001 and 2007 and increased significantly from 2008 to 2011. Comparing time periods before and after first quarter of 2008, patients on ECMO in later years were more likely to be older (Before vs. After: (age 65þ) 18.9% vs. 23.1%) and have two or more comorbidities (43.6% vs. 52.3%). After adjusting for patient and institutional characteristics, in-hospital mortality was comparable for the two time periods (Odds Ratio 0.76, 95% CI 0.55e1.05). Between 2001 and 2011, 652 adult ECMO related English literature were identified, published in 181 English journals and by investigators from 31 countries. There was a significant increase in number of publications after 2008. Conclusion: The presence of the CESAR trial was associated with significant increase in the utilization of ECMO in clinical practice and in the research activities related to ECMO. Moreover, ECMO has since been used in patients of older age and higher comorbidities, but with no increase in in-hospital mortality followed. © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Extracorporeal membrane oxygenation Evidence based medicine Outcomes research
1. Introduction Extracorporeal membrane oxygenation (ECMO) therapy in adults was first utilized in the 1970s [1] and has become an established life-support technique for the management of life threatening pulmonary and/or cardiac failure [2]. ECMO has been proved to be an effective therapy among neonates, with survival rates up to 84% [3], but mortality and complications following
* Corresponding author. Weill Cornell Medical College, 402 East 67th Street, New York, NY 10065, USA. E-mail address: [email protected] (J. Mao).
treatment among adults are high. Survival at discharge among adult patients was reported to vary between 33% and 53% [3,4]. The Conventional ventilation or ECMO for Severe Adult Respiratory failure (CESAR) trial was the first randomized controlled trial (RCT) of ECMO in adults with respiratory failure, comparing it to conventional supportive critical care [5]. Preliminary results of CESAR trial was released in February 2008, denoting that ECMO improved survival in adult patients with severe respiratory failure [6]. Since then, literatures have reported significant increase in utilization of ECMO in adult patients [7e9]. RCT has long been recognized as highest level of evidence in medical research and generally has a significant impact on clinical
http://dx.doi.org/10.1016/j.ijsu.2016.09.081 1743-9191/© 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
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J. Mao et al. / International Journal of Surgery 35 (2016) 95e99
practice as well as related research activities [10,11]. Our purpose was to examine patient profile, discharge characteristics and related costs following ECMO therapy as well as medical research activities before and after release of preliminary results of CESAR trial using nationally representative database and literature review.
adjusting for patient demographics, concurrent conditions, comorbidities and hospital characteristics. Statistical analyses were performed using SAS v9.3 (SAS Institute Inc., Cary, NC). 2.4. Literature review and analysis
The Nationwide Inpatient Sample (NIS) is maintained by the Agency for Healthcare Research and Quality, as part of the Healthcare Cost and Utilization Project (HCUP). The NIS is the largest all-payer inpatient care database in the United States and constitutes approximately a 20% stratified sample of all hospital discharges from non-government institutions [12]. This study was approved by the Institutional Review Board of Weill Cornell Medical College and conforms to the data-use agreement for the NIS from HCUP.
Adult ECMO related publications between 2001 and 2011 were retrieved from Pubmed database using MESH terms “Extracorporeal Membrane Oxygenation” and “Adult”. Publications were than reviewed and non-English, non-ECMO related or pediatric and neonatal ECMO related articles were excluded from further analyses. Each publication was further defined as a report if it was a case or technology report, as a study if it was a single-center, multicenter or database/registry research study, or as a review. Trends in number of publications, number of journal and number of countries publishing ECMO related articles over time were examined. Percentages of report or study, average publications per journal per year and average publications per country per year were calculated and compared before/during and after first quarter of 2008.
2.2. Study cohort and variables
3. Results
Patients older than 18 years old who received ECMO therapy between 2001 and 2011 were included in the study, identified by Internal Classification of Diseases, Ninth Revision, and Clinical Modification (ICD-9-CM) procedure code 39.65. Because preliminary results of CESAR trial was released in Feb 2008 and only admission quarter was available in the NIS dataset, we used first quarter of 2008 as our cut-off time point. Cases with unknown procedure time (year and quarter) were excluded from the study. Data collected for each patient admission included: age at time of admission, gender, race, insurance status, concurrent conditions, comorbidities, in-hospital mortality and peri-procedural complications, length of stay (LOS), discharge status, and costs of hospitalization. Institution-related data include hospital bed size and teaching status. Concurrent conditions included cardiotomy, heart and/or lung transplant, implantation ventricular assisted device (VAD) or percutaneous transluminal coronary angioplasty (PTCA), and respiratory failure. Patient co-morbidities were identified from ICD-9-CM diagnosis codes using Elixhauser comorbidity definitions [13]. Other-than-routine (OTR) discharge was determined by discharge disposition. Charge data was provided at the discharge level in the NIS database. Costs were estimated using hospital specific cost to charge ratio, in a pre-established method [14]. When hospital specific cost to charge ratio was unavailable, the group level cost to charge ratio was used, as recommended by HCUP [15]. A Diagnosis Related Group (DRG) based scaling factor released by HCUP in 2009 was then applied to the data. Prolonged LOS and excessive costs were further defined as above 75th percentile.
3.1. Nationwide inpatient sample
2. Methods 2.1. Data source
Overall, 8389 patients who received ECMO therapy between 2001 and 2011 were included in the study. Overall, there was a 646% increase in utilization of ECMO over years, from 309 cases in 2001 to 1995 cases in 2011 (Fig. 1). More specifically, there was no obvious increase in ECMO utilization before 2008 (309 cases in 2001 and 318 cases in 2007), but there was a significant increase from 2008 to 2011 (960 cases in 2008 to 1995 cases in 2011, p < 0.01). Similar trends were observed when examining within patients with different concurrent conditions. 3950 and 4439 patients received ECMO therapy before/during and after first quarter of 2008 respectively (Table 1). There was a trend that in the second time period, patients receiving ECMO therapy comprised of a higher proportion of older patients (Before vs. After: (age 65þ) 18.9% vs. 23.1%, p ¼ 0.08), compared to earlier time period. Patients on ECMO therapy after first quarter of 2008 were also more likely to have 2 or more comorbidities compared to patients being treated before and during first quarter of 2008 (43.6% vs. 52.3%, p < 0.01). Moreover, ECMO was more likely to be used at hospitals of large bed size after the release of CESAR preliminary results (85.4% vs. 91.5%, p < 0.01). In-hospital mortality in patients receiving ECMO therapy before and after CESAR trial was 65.5% and 60.5%, respectively (Table 2). Patients receiving ECMO after Mar 2008 were more likely to have
2.3. Statistical analysis Utilization of ECMO over time was evaluated by graph and for each concurrent condition specifically. Patient demographic, comorbidities, in-hospital mortality, peri-procedural complications, discharge characteristics and costs of hospitalization were examined for patients receiving ECMO therapy prior to and after the release of preliminary result of CESAR trial. Weighted events and percentages were presented for all statistical analysis of categorical variable and compared using chi-square test. Hierarchical logistic regression was performed to assess difference in in-hospital mortality, peri-procedural complications, discharge characteristics and costs of hospitalization between the two time periods,
Fig. 1. Trends in utilization of ECMO in the United States from 2001 to 2011.
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Table 1 Characteristics of patients receiving ECMO therapy before and after release of CESAR trial preliminary results.
Age groups 18e54 55e64 65þ Female White Racea Insurance Medicare Medicaid Commercial Other Concurrent conditions Cardiotomy Transplant VAD/PTCA Respiratory failure Comorbidities CAD Hypertension CHF Diabetes CPD Obesity Anemia PVD Renal Failure CVD Comorbidity summary 0 1 2þ Hospital Bed Size Small Medium Large Teaching Hospital
Before (N ¼ 3950)
After (N ¼ 4439)
2214 (56.1%) 988 (25.0%) 748 (18.9%) 1594 (40.4%) 2045 (69.2%)
2423 (54.6%) 988 (22.3%) 1027 (23.1%) 1622 (36.5%) 2381 (65.9%)
1079 (27.4%) 607 (15.4%) 1880 (47.7%) 379 (9.6%)
1325 (29.9%) 751 (16.9%) 2001 (45.1%) 356 (8.0%)
1684 (42.6%) 514 (13.0%) 507 (12.8%) 1245 (31.5%)
1571 (35.4%) 689 (15.5%) 717 (16.2%) 1461 (32.9%)
1036 (26.2%) 859 (21.7%) 1632 (41.3%) 597 (15.1%) 506 (12.8%) 327 (8.3%) 378 (9.6%) 452 (11.4%) 251 (6.4%) 174 (4.4%)
1170 (26.4%) 939 (21.2%) 2037 (45.9%) 781 (17.6%) 600 (13.5%) 417 (9.4%) 686 (15.4%) 620 (14.0%) 569 (12.8%) 311 (7.0%)
995 (25.2%) 1231 (31.2%) 1724 (43.6%)
855 (19.3%) 1264 (28.5%) 2319 (52.3%)
95 (2.4%) 479 (12.2%) 3348 (85.4%) 3610 (92.1%)
52 (1.2%) 322 (7.3%) 4048 (91.5%) 4140 (93.6%)
P Value 0.08
0.11 0.21 0.35
0.01 Fig. 2. Trends in publications related to ECMO from 2001 to 2011.
3.2. Literature review 0.95 0.77 0.06 0.17 0.67 0.42 <0.01 0.12 <0.01 0.02 <0.01
<0.01
0.21
Abbreviations: CAD¼Coronary Artery Disease, CHF¼Congestive Heart Failure, CPD¼Chronic Pulmonary Disease, PVD¼Peripheral Vascular Disease, CVD¼Cerebrovascular Disease. a 21.7% patients with missing race information.
prolonged LOS (19.9% vs. 27.7%), excessive costs (22.6% vs. 28.6%) and non-routine discharges (72.5% vs. 81.2%) than those being treated during the earlier time period. After adjusting for patient demographics, concurrent condition, comorbidities and hospital characteristics, there was no significant difference in patient mortality between the two time periods (Odds Ratio (OR) 0.76, 95% CI 0.55e1.05). There was also no significant difference in periprocedure complications, including AMI and sepsis, other-thanroutine discharge, prolonged LOS and excessive costs between the two time periods.
From 2001 to 2011, 890 publications were reviewed and 652 adult ECMO related English literature were included in the final analysis. During the 11 year time period, articles on adult ECMO were published in 181 English journals and by investigators from 31 countries. Similar to the trend of ECMO clinical utilization, there was only a slight increase in number of publications before 2008 (from 29 in 2001 to 44 in 2007), while there was a significant increase in number of publications after 2008 (from 65 in 2007 to 156 in 2011, p < 0.01) (Fig. 2). There was also increases in number of journals publishing ECMO related papers (from 16 in 2001 to 70 in 2011, p < 0.01), and number of countries publishing ECMO related papers (from 12 in 2001, to 22 in 2011, p < 0.01). Among the 652 articles, 318 were published before the end of March 2008, and 334 were published afterwards (Table 3). Comparing time periods before and after March 2008, a higher proportion of publications were case or technology report in the later time period (53.7% vs. 60.2%). When examining annual publications per journal and per country, after the release of preliminary results of CESAR trial, average annual publications were higher on both journal (1.16 vs. 1.46 per journal per year) and country levels (1.91 vs. 3.41 per country per year). 4. Discussion Our study demonstrated the increasing utilization of ECMO in adults and adult ECMO related publications in the United States, especially after the release of preliminary results of CESAR trial in the first quarter of 2008. ECMO was increasingly used in older and sicker patients after 2008, with mortality remained unchanged.
Table 2 In-hospital outcomes of patients receiving ECMO therapy before and after CESAR trial. Unadjusted
Mortality AMI PE/DVT Sepsis OTR Discharge Prolonged LOSa Excessive Costsa
Adjusted
Before (N ¼ 3950)
After (N ¼ 4439)
P value
Odds ratio (95% CI) after vs. Before
P value
2589 (65.5%) 1426 (36.1%) 254 (6.4%) 1072 (27.1%) 986 (72.5%) 786 (19.9%) 696 (22.6%)
2686 (60.5%) 1519 (34.2%) 562 (12.7%) 1613 (36.3%) 1423 (81.2%) 1227 (27.7%) 919 (28.6%)
0.03 0.42 <0.01 <0.01 0.01 <0.01 0.01
0.76 0.94 1.78 0.89 0.74 1.36 1.27
0.10 0.68 0.02 0.27 0.41 0.09 0.20
(0.55e1.05) (0.71e1.25) (1.08e2.91) (0.72e1.10) (0.35e1.53) (0.95e1.95) (0.88e1.83)
Abbreviations: AMI ¼ Acute Myocardial Infarction, PE¼Pulmonary Embolism, DVT ¼ Deep Venous Thrombosis, OTR¼Other Than Routine, LOS ¼ Length of Stay. a Prolonged LOS and Excessive Costs were defined as above 75th percentile.
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Table 3 Publications related to ECMO before and after CESAR trial. Before (N ¼ 318) Type of publication Report 171 (53.7%) Study 121 (38.1%) N Journals 114 Average publication per journal per yeara Mean (Std) 1.16 (0.39) Range 1.00e3.56 N Countries 25 Average publication per country per yeara Mean (Std) 1.91 (1.31) Range 1.00e6.82
After (N ¼ 334) 201 (60.2%) 97 (29.0%) 121 1.46 (1.00) 1.00e7.25 28 3.41 (4.58) 1.00e23.00
a Average publication was calculated for years when journals/countries had related publications.
We found significant increase in ECMO utilization in adults after 2008 overall and among patients with different concurrent conditions. The CESAR trial was conducted among adult patients with respiratory failure [5], and yet the impact was pronounced on clinical practice regardless of concurrent conditions. In addition to the advances in ECMO technology in the last decade, it is possible that the results from the CESAR trial has been encouraging for practitioners to adopt ECMO in care of critically ill patients. Evidence based medicine has been emphasized in modern era clinical practice and it has been recommended that research evidence should be critically appraised and incorporated into clinical practice [16]. While research evidence was not restricted to RCT, evidence from RCT has been ranked among the highest level, and considered superior to observational research [17]. Indeed, 3 years before the release of CESAR trial preliminary results, the 2004 report of ELSO (Extracorporeal Life Support) registry presented moderate to positive results of outcomes following ECMO use in adults with respiratory and cardiac failure [18]. In 2007, analysis based on patients in the ELSO registry receiving ECMO post-lung and/or heart transplant also highlighted the usefulness of ECMO among patients with graft malfunction [19]. However, no significant increase in ECMO utilization was observed after either of these two time points. Apart from the increase in utilization, we also found that after 2008, there has been alteration in characteristics of both patients receiving ECMO therapy and institutions using ECMO therapy. During the second time period of our study (post March 2008), the population of patients receiving ECMO was comprised of a larger proportion of aged and of those with higher comorbidities. The expansion of ECMO use indication in adults may also be associated to the fact that encouraging result from the CESAR trial gave rise to practitioners' confidence in placing older and sicker people on ECMO. In addition, we also found that after 2008, ECMO was more likely to be used in hospitals with large bed size. This mirrored the recommendation by the CESAR trial group that ECMO will be “most efficient in large critical care units” [5]. Despite the extension of use of ECMO to older and sicker patients, in-hospital mortality following ECMO therapy remained stable. The unchanged mortality may actually be attributed to a mixture of use of ECMO among patients with worse-conditions and some improvement in ECMO use strategy and complication management. There has been improved patient care resource and strategies, clinical evaluation of patients before and after the initiation of ECMO and complication management [20e22]. The growing use of resource indicated by the observed prolonged hospitalization, elevated costs and increased use of postdischarge care in our study may also be a reflection of these mixing factors.
Parallel to the increase in ECMO utilization in clinical practice, there was also significant increase in publications related to adult ECMO therapy, the majority of which were case or technology reports. In addition to number of articles, there was also increases in number of countries and journals attentive to ECMO. It is common for new studies to be inspired by previous publications, to confirm, to complement or to challenge, especially when the article has a significant impact like the CESAR trial. The increase, as well, can be linked to the growing acceptance of EBM [23] and the fact that ECMO has been increasingly used in more complicated cases. There are several limitations with our current study. ECMO treatment was identified by procedure codes. Type of ECMO and duration of ECMO use was not available in the discharge record. Thus, cost analyses in the present study were not based on cost of ECMO-specific resource use, but showed cost of care related to ECMO use. Inherent with administrative database, time of occurrence of peri-procedural morbidities cannot be determined. In addition, NIS is a sampled nationwide database, with the hospitals being sampled varying from year to year. In conclusion, with evidence based medicine being underscored in current era, the presence of the CESAR trial was associated with significant increase in the utilization of ECMO in clinical practice and in the research activities related to ECMO. Moreover, ECMO has since been used in patients of older age and higher comorbidities, but with no increase in in-hospital mortality followed. The IDEAL framework emphasizes the appropriate evaluation of technology at different stages [24]. RCT has been among the highest level of evidence at the assessment stage, with significant impact on practice. With ECMO being proposed as a countermeasure in public health emergencies [25], it is also critical that large observational and registry studies will be conducted to provide evidence for technology surveillance after widespread adoption. Ethical approval This study was approved by the institutional review board of Weill Cornell Medical College (Protocol No. EXE-2011-057). Sources of funding Dr. Sedrakyan received funding from the US FDA for establishing the MDEpiNet Science and Infrastructure Center. Author contribution Study Design: All authors. Data analysis and interpretation: All authors. Statistical analysis: Mao, Sedrakyan. Drafting of manuscript: Mao. Critical revision of manuscript: All authors. Conflicts of interest No conflict of interest. Guarantor Dr. Sedrakyan accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. Research registration unique identifying number (UIN) researchregistry1254.
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Acknowledgements Acknowledgements to Abu Nasar, MSc and Abby Isaacs, MSc for important analytic contributions. References [1] D. Abrams, A. Combes, D. Brodie, Extracorporeal membrane oxygenation in cardiopulmonary disease in adults, J. Am. Coll. Cardiol. 63 (25 Pt A) (2014) 2769e2778. [2] G. MacLaren, A. Combes, R.H. Bartlett, Contemporary extracorporeal membrane oxygenation for adult respiratory failure: life support in the new era, Intensive care Med. 38 (2) (2012) 210e220. [3] M.L. Paden, S.A. Conrad, P.T. Rycus, R.R. Thiagarajan, E. Registry, Extracorporeal life support organization registry report 2012, ASAIO J. 59 (3) (2013) 202e210. [4] B.W. Gray, J.W. Haft, J.C. Hirsch, G.M. Annich, R.B. Hirschl, R.H. Bartlett, Extracorporeal life support: experience with 2000 patients, ASAIO J. 61 (1) (2015) 2. [5] G.J. Peek, M. Mugford, R. Tiruvoipati, A. Wilson, E. Allen, M.M. Thalanany, et al., Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial, Lancet 374 (9698) (2009) 1351e1363. [6] P. Emma Hitt, CESAR Trial: Extracorporeal Membrane Oxygenation Improves Survival in Patients with Severe Respiratory Failure Medscape Medical News, Medscape Medical News, 2008 [12/16/2014]. Available from: http://www. medscape.com/viewarticle/569740. [7] G. Lafc, A.B. Budak, A.U. Yener, O.F. Cicek, Use of extracorporeal membrane oxygenation in adults, Heart, lung circulation 23 (1) (2014) 10e23. [8] B.G. Maxwell, A.J. Powers, A.Y. Sheikh, P.H. Lee, R.L. Lobato, J.K. Wong, Resource use trends in extracorporeal membrane oxygenation in adults: an analysis of the Nationwide Inpatient Sample 1998-2009, J. Thorac. Cardiovasc. Surg. 148 (2) (2014) 416e421 e1. [9] C.M. Sauer, D.D. Yuh, P. Bonde, Extracorporeal membrane oxygenation (ECMO) use has increased by 433% in adults in the United States from 2006 to 2011, ASAIO J. 61 (1) (2015) 31e36. [10] Medicine CfE-B, OCEBM Levels of Evidence, Centre for Evidence-Based Medicine, 2016 [Jan 14, 2016]. Available from: http://www.cebm.net/ocebmlevels-of-evidence/. [11] S.E. Straus, D.L. Sackett, Using research findings in clinical practice, Bmj 317 (7154) (1998) 339e342.
99
[12] Quality AfHRa, HCUP Databases. Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality, 2016 [Jan 14, 2016]. Available from: http://www.hcup-us.ahrq.gov/nisoverview.jsp. [13] A. Elixhauser, C. Steiner, D.R. Harris, R.M. Coffey, Comorbidity measures for use with administrative data, Med. care 36 (1) (1998) 8e27. [14] A.J. Gadzinski, J.B. Dimick, Z. Ye, D.C. Miller, Utilization and outcomes of inpatient surgical care at critical access hospitals in the United States, JAMA Surg. 148 (7) (2013) 589e596. [15] Quality AfHRa, Cost-to-Charge Ratio Files: 2011 Nationwide Inpatient Sample (NIS) User Guide, Agency for Healthcare Research and Quality, 2013 [12/16/ 2014]. Available from: http://www.hcup-us.ahrq.gov/db/state/ CCR2011NISUserGuide.pdf. [16] D.L. Sackett, W.M. Rosenberg, J.A. Gray, R.B. Haynes, W.S. Richardson, Evidence based medicine: what it is and what it isn't, Bmj 312 (7023) (1996) 71e72. [17] P.B. Burns, R.J. Rohrich, K.C. Chung, The levels of evidence and their role in evidence-based medicine, Plastic Reconstr. Surg. 128 (1) (2011) 305e310. [18] S.A. Conrad, P.T. Rycus, H. Dalton, Extracorporeal life support registry report 2004, ASAIO J. 51 (1) (2005) 4e10. [19] S. Fischer, D. Bohn, P. Rycus, A.F. Pierre, M. de Perrot, T.K. Waddell, et al., Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: analysis of the Extracorporeal Life Support Organization (ELSO) registry, J. heart lung Transplant. official Publ. Int. Soc. Heart Transplant. 26 (5) (2007) 472e477. [20] J. Belohlavek, V. Rohn, J. Tosovsky, J. Kunstyr, M. Semrad, J. Horak, et al., A review of a newly established ECMO program in a university affiliated cardiac center, J. Cardiovasc. Surg. 52 (3) (2011) 445e451. [21] M. Schmidt, M. Bailey, J. Kelly, C. Hodgson, D.J. Cooper, C. Scheinkestel, et al., Impact of fluid balance on outcome of adult patients treated with extracorporeal membrane oxygenation, Intensive care Med. 40 (9) (2014) 1256e1266. [22] D.V. Mullany, T.N. Bull, W. Hunt, K. Shekar, B. Thomson, J.F. Fraser, et al., Outcomes of the first 30 cases of an adult extracorporeal membrane oxygenation program: strategies to manage the “learning curve” and implications for intensive care unit risk adjustment models, Crit. care Resusc. J. Australas. Acad. Crit. Care Med. 14 (2) (2012) 119e129. [23] V.M. Montori, G.H. Guyatt, Progress in evidence-based medicine, Jama 300 (15) (2008) 1814e1816. [24] J.A. Cook, P. McCulloch, J.M. Blazeby, D.J. Beard, D. Marinac-Dabic, A. Sedrakyan, et al., IDEAL framework for surgical innovation 3: randomised controlled trials in the assessment stage and evaluations in the long term study stage, Bmj 346 (2013) f2820. [25] S. Paul, B. Campbell, E.C. Meltzer, A. Sedrakyan, ECMO as an emergency medical countermeasure, Lancet Respir. Med. 2 (9) (2014) 685e687.