​Extracorporeal Cardiopulmonary Resuscitation (ECPR) for Cardiac Arrest – Adults (ALS): Systematic Review

I strongly recommend that "in any setting" needs to be altered to "in a setting where the patient is normothermic" or "where the cause of cardiac arrest is not accidental hypothermia". The survival outcomes for Hypothermic Cardiac arrest is totally different from normothrmic cardiac arrest as is eloquently described in the article "Normothermic and hypothermic cardiac arrest—Beware of Jekyll and Hyde" Article in Resuscitation 129 · April 2018  DOI: 10.1016/j.resuscitation.2018.04.020 The survival data particularly form Dr Tomasz Darocha and his team in Krakow are not approaching 70% with neurological intact outcome. The overall European survival of hypothermic cardiac arrest treated with mechanical CPR and ECLS with intact neurological status is about 50% , thus way better than in normothermic cardiac arrest

To be fair, "the continuous evidence evaluation process for the production of the Consensus on Science with Treatment Recommendations (CoSTR)" actually did not started with a systematic review of ECPR (Holmberg 2018 91 – PROSPERO Registration CRD42018085404) as stated in this provided link, but with another one (2016 Ortega-Deballon I et al. Resuscitation. 2016;101:12-20. PROSPERO, CRD 42014015259). http://dx.doi.org/10.1016/j.resuscitation.2016.01.018. This PREVIOUS, and to our knowledge the first systematic review performed on ECPR topic until that moment, followed PICOTS question format, PRISMA format, explored both level of evidence (following the LOE scale tool proposed by ILCOR) and quality of guidelines (following AGREE II) from ECPR for refractory OHCA of cardiac origin in adults. In short, did pretty the same that Holmberg et al have been published. We do not understand, at first, why previous work is not referenced at any moment, why the research question, methodology and search strategy is close to duplicate and already did research and why if findings are pretty a duplication of our previous systematic review, the efforts were not focused on reducing knowledge gap while recognizing previous research work from colleagues instead. In any case, although, again, findings and results from the latter (2018 Holmberg et al) are practically identical to the former that we authorized (and conducted less than 2 years later) we are sure that running RCTs will help to really increase LOE and reduce knowledge gap in order to inform future research. At the same time, many other questions will remain despite of RCT publication, as such a methodology have also limitations when referred to Resuscitation Research environment. Finally, from a comprehensive approach to sudden cardiac arrest in the prehospital environment, we suggest that the option of Deceased Organ Donation (both after neurologic determination of death -NDD- and after circulatory determination of death -DCD-) should be explored between non eligible for/non survivors from "ECPR strategy", as also between patients with a very poor neurologic prognosis (CPC>3) despite of ROSC after ECPR strategy. This approach, has been already encouraged by ILCOR in 2015 Guidelines and should not be disregarded from a more effective, efficient and ethically sound point of view. Rowing together, both Resuscitationists/ECMOlogists community and Organ Donation & Transplant community, we really will do our best for both patients, their proxies, health providers confidence and thrutfulness of whole system from society according with best scientific evidence and ethical principles, taking into account the specific legal frame and cultural believes at each country. We really stress that this opportunity should not be lost again. We will continue working on it. The final goal, to increase survival from OHCA with QOL first and organ donation pool to reduce organ shortage for transplant when not possible, deserve to do so.

May I suggest that an additional recommendation should focus on the PROSPECTIVE capture of treatment episodes in a multicenter and pre-defined way. This is still nowhere near a randomised trial but will identify confounders in a less biased fashion and could potentially give further evidence to answer questions 2,3,4 and 6. Currently knowledge is mostly drawn from single center observations and is hence prone to publication bias. ECPR is a complex intervention and its outcome is dependent on the right logistics, infrastructure, training and protocols. As with many complex intervention the best results will be achieved when the 'ifs', 'whens' and 'hows' are clear.

PRE-AMBLE: We comment on behalf of the GRC working group ECMO/ eCPR, an independent scientific working group within the German Resuscitation Council newly founded in 2018. Individual members of the WG may have specific COIs, which may be made available upon request. We will emphasize three major aspects, which will be discussed in detail. i. We recommend transferring knowledge and paradigms about conventional advanced life support measures to eCPR. In addition to medical management, this pertains to process organization, non-technical skills, conceptual, planning and training aspects. The integration of eCPR into already existing processes, an emphasis on the role of the ALS (ACLS) team and the communication at specific intersection points, as well as – most importantly – the maintaining of high quality CPR with minimal interruptions deserve special attention by the ILCOR. ii. Further emphasis should be put on the embedment of eCPR into current or emerging concepts on cardiac arrest and cardiopulmonary resuscitation, which are increasingly adding up to a paradigm change in resuscitation science: a. The consideration of therapy bundles, „multifaceted approaches“, systemic interventions and strategies, rather than an isolated view of single measures and treatment options, especially regarding OHCA. (Adabag et al., 2017; Belohlavek et al., 2012; Lazzeri et al., 2015, 2016; Michels et al., 2018; Stub et al., 2015; Yannopoulos et al., 2016) b. Instead of a One Size Fits All approach, an individualized, goal directed concept is increasingly being regarded as the future of resuscitation (Meaney et al., 2013; Morgan et al., 2017; Sutton et al., 2014). Some aspects are already part of the ALS- and the post-resuscitation care chapters of the guidelines. This concept should also be transferred to eCPR: targeted eCPR. c. Other than a mere cardio-respiratory, more or less uncontrolled, external support, the buying of time through bridging to other life-saving therapies, eCPR might be a distinct therapy option in itself. This is due to its organoprotective effects and the potential to limit the ischemia-reperfusion injury (Meaney et al., 2013; Morgan et al., 2017; Sutton et al., 2014). iii. The dealing with ethical aspects of organ donation following unsuccessful eCPR. From our (German) point of view, this highly complex topic, as well as the topic of ethics in eCPR in general, urgently deserves special attention and critical appraisal. (Dalle Ave et al., 2016) COMMENTS #1 The ECMO/ eCPR working group of the German Resuscitation Council, welcomes the ILCOR CoSTR draft and endorses the recommendation. #2 In the review process, as started with the publication by Holmberg and co-workers, a high risk of bias and confounding is portrayed for the eCPR studies. We emphasize the complexity and immense challenges in research on cardiopulmonary resuscitation and ECMO/ eCPR. We would like to put up for discussion, to what extent at all, in the field of contemporary resuscitation research: - highest level evidence can be expected - despite an RCT design, confounding can be reduced or eliminated. (Pellegrino V at EuroELSO 2017 conference in Maastricht: “The importance of well-designed study in cardiac arrest: the CHEER study.”) #3 For the literature review, studies without a control group were excluded. Because of the missing control group, these studies yield a lower level of evidence than the studies included. However, robust data on outcome following conventional CPR do exist, which could inform a comparison. Especially the very unfavorable natural course and outcome of potentially eCPR-eligible candidates with increasing duration of CPR and „refractory“ cardiac arrest has been characterized in large populations, which in our opinion deserves attention. On the other hand, several eCPR studies without a control group, but with a thorough study design on a given evidence level (propensity score matchings e.g.), show considerable outcome results. We therefore recommend further analysis of and comment on the excluded eCPR studies. (Grunau et al., 2016; Reynolds et al., 2017) #4 With regard to the danger of bias, we would like to point out, that at least selection bias should be viewed in the context of the highly selective indication which is required for eCPR by most providers. This remains a dilemma. It is being quoted in the „Justification“ section: “ The published studies use select patients for ECPR and not the general population of all cardiac arrest cases. Guidelines for clinical practice should ideally apply to similar populations, although RCTs have not been performed to define the optimal population.” #5 A more harmonized and uniform reporting in eCPR research should be pursued, for the sake of comparability of studies. The addition of eCPR-related datasets to existing resuscitation registries might support this aim. (Haywood et al., 2018; Seewald et al.) #6 The uniform definition of a „refractory cardiac arrest“ is a key question when indicating eCPR, as well as regarding comparability of eCPR studies. We recommend that the search for such a uniform definition be added as an aim to further guideline work. #7 The role of the „second part“/ ALS (ACLS-) part of the eCPR-team is under-represented in research and guidelines. It should be more emphasized, especially in OHCA management. This will be further discussed in the following section. #8 The importance of the communication at the intersection with the ALS- (ACLS-) part has little been described. It should be further differentiated and emphasized. #9 Little has been described about how medical management during conventional cardiopulmonary resuscitation should change, and deviate from the universal ALS- (ACLS-) algorithms, once the decision has been made to convert to eCPR. #10 The ALS- (ACLS-) conformed integration of eCPR into the whole resuscitation process has not been defined, although it can have a significant impact on the benefit of eCPR for the patient; e.g. through realization of an eCPR-implementation within sixty minutes or less from collapse, or through maintaining qCPR throughout. This aspect should urgently be further addressed. (Michels et al., 2018; Spangenberg et al., 2016; Wengenmayer et al., 2017) #11 We recommend that communication and cooperation with the ALS- (ACLS-) part of the team, as well as the algorithm-compliant integration of eCPR into the overall resuscitation process, including possible changes in conventional resuscitation management for the Non-ECMO-part of the team, be defined as a distinct „Knowledge Gap“ #12 In the consensus statement published by Michels and colleagues, structural requirements and institutional framework for eCPR have been described in detail. This description is unique in its form and scope. We recommend that this publication be specially considered in further exploration and elaboration on framework and intersection management with the ALS- (ACLS-) part. (Michels et al., 2018) #13. The optimal practical application of eCPR poses significant challenges on workflows, process organization and collaboration between two resuscitation teams. The addition of eCPR, or a second resuscitation team, respectively, may significantly increase complexity of the scenario and cognitive load of the team members. In this context, education, training and simulation play an important role in task training as well as in terms of process analysis and optimization. Because of their potential impact on patient outcome, we recommend that the topic of interprofessional education, training and simulation in eCPR be defined as a distinct Knowledge Gap. Scott et al., 2017) #14 Knowledge Gap #7 defines a lack of knowledge regarding quality of life in ECPR survivors. We would like to reference the work by Spangenberg et al which already offers some insights (limited patient number, retrospective design), as well as contributions by other working groups. (Jäämaa-Holmberg et al., 2018; Spangenberg et al., 2018) #15 We explicitly respect and value the most engaged work of international groups regarding organ donation following eCPR, as conducted with highest ethical measures. However, from our point of view, this topic is still a major, and unresolved ethical dilemma. Public discussions tend to be emotional, as do those on eCPR. In our perception, the way and extent of these discussions, especially their combination, has a potential, to discredit eCPR as well as organ donation in the general public as well as the scientific community, and to jeopardize corresponding programs. As the German partner within the European Resuscitation Council, we refer to the situation in Germany. Decreasing transplant numbers and a most current discussion on an opt out regulation are prevailing in the current public discourse and therefore will inevitably have their impact on the dealing with eCPR and organ donation – two terms that in our country often are referred to as crossing boundaries. As resuscitationists and experts in the field, we invest huge efforts to foster a mature and informed discussion within our society. However, In its current form and state, we assume that the impact of combining these two topics likely will be negative. We therefore recommend, that in the full text version of the guideline recommendations which will contain discussion or background information on organ donation following eCPR, as well as in public discussions, extreme caution be exercised. Organ donation following eCPR must most explicitly stand back behind the rescue of the current patient. In no case should it be over-emphasized. We are aware that this recommendation reflects only the viewpoint from one country. (Dalle Ave et al., 2016; Makdisi and Makdisi, 2017; Riggs et al., 2015); https://www.ethikrat.org/forum-bioethik/pro-contra-widerspruchsregelung-bei-der-organspende/; https://www.euronews.com/2018/09/03/germany-debates-opt-out-system-for-organ-donations; https://www.dso.de/ #16 We strongly recommend that „ethics in eCPR, including organ donation following eCPR“ be considered a distinct and urgent Knowledge Gap. #17 Contemporary resuscitation science has been recommended to use patient centered outcomes, and to involve patients/ survivors, relatives and the general population in the planning and reporting of resuscitation studies as well as the public discussion. In eCPR this is, apart from neurologically favorable survival as defined by CPC 1-2, rarely the case. We recommend to emphasize the use of patient centered outcomes in eCPR studies. We also recommend to define „attitudes and perceptions of the general public, as well as patients/ survivors and relatives towards eCPR“ as a distinct knowledge Gap. The leading question might be: „Would wish, in case of a refractory cardiac arrest, to have this therapy, and which outcome would you accept?“. As an impressive example of patient and public involvement, we consider the PARAMEDIC 2 (Adrenalin) trial. (Haywood et al., 2018; Perkins et al., 2018) #18 eCPR is increasingly being viewed in the context of additional systemic interventions, therapy bundles and treatment pathways, instead of an isolated view of the mere technological option. Examples are the concurrent use of targeted temperature management and accelerated PCI pathways. This is also reflected by the design of recent or current clinical eCPR studies: e.g. CHEER studies, Prague Hyperinvasive Approach, Minnesota Resuscitation Consortium’s approach and others. It is therefore increasingly challenging to evaluate eCPR as an isolated intervention or factor, and to interpret studies accordingly. We recommend to emphasize the embedment of eCPR into systems, therapy bundles and pathways. (Adabag et al., 2017; Belohlavek et al., 2012; Lazzeri et al., 2015; Stub et al., 2015; Yannopoulos et al., 2016) #19 The use of a targeted, individualized therapy for conventional resuscitation is increasingly being favored, and some aspects are already mentioned in the current resuscitation guidelines. For eCPR, this appears reasonable as well, e.g. in terms of oxygen and CO2 titration, temperature management et cetera, but less literature exists. We therefore recommend to define a Knowledge Gap as follows: „What is the optimal eCPR-strategy and targeted therapy“? (Meaney et al., 2013; Morgan et al., 2017; Soar et al., 2015; Sutton et al., 2014) #20 Translational as well as clinical research is increasingly considering specific therapeutic effects of eCPR which go beyond a mere support or replacement of blood flow, oxygenation and elimination of CO2 („ROSC equivalent“), and beyond the mere bridging to causal interventions such as emergency PCI e.g. Organoprotection and the limitation of ischemia-reperfusion injury are increasingly recognized as leading therapeutic concepts in other resuscitative efforts as well, including the related clinical research. We therefore recommend to define a Knowledge Gap as follows: „Are there specific therapeutic effects inherent to eCPR (beyond the cardio-respiratory support itself)?“ (Lazzeri et al., 2015, 2016; Patil et al., 2015) REFERENCES Adabag, S., Hodgson, L., Garcia, S., Anand, V., Frascone, R., Conterato, M., Lick, C., Wesley, K., Mahoney, B., and Yannopoulos, D. (2017). 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Thank you for all your comments and opinions. ILCOR realised ECPR is a hot topic and hence it was prioritised for systematic review and an ILCOR CoSTR. The Task Forces will review each point when considering any update to the CoSTR. ILCOR currently does its own systematic review and follows the GRADE process, including an evidence to decision table. The systematic review is already published in Resuscitation [Holmberg et al. Resuscitation 2016; 131: 91-100], and any specific comments regarding it can be addressed further by a letter to the Editor. The ECPR CoSTR is generic for all cardiac arrests. It will be up to individual Councils to develop guidelines for actual clinical practice and I am sure that many of the issues raised regarding the specifics of delivering ECPR in certain settings/types of patients will be addressed in the guidelines. For example, the 2015 ERC guidelines for special circumstances already mention the role of ECLS/ECPR interventions in hypothermia. Many of the issues raised need to be addressed through national council’s and their guideline groups. It wasn’t the remit of the Task Force to identify how we will resolve the knowledge gaps, but everyone appreciates that it’s not easy to do RCTs for ECPR, and that looking at other sources of information remains important. I think there is consensus that ECPR requires considerable resource to implement and is feasible in a variety of settings, by different groups of clinicians, and can lead to good outcomes in individuals who would have otherwise died. The CoSTR as written is aimed at the global resuscitation community and we need to recognise that in many communities an ECPR program may not be appropriate or feasible. Individual Councils, are best positioned to produce guidelines based on local values and preferences, and the CoSTR as written aims to recognise and facilitate this. The Task Force is aware of the publications mentioned by those who have commented, and ongoing trials in this area. Regards Jasmeet Soar ILCOR ALS TF Chair [Conflict of interest - Editor, Resuscitation, a journal that publishes numerous ECPR studies, and reviews, many mentioned by those who have commented].