Extracorporeal CPR (ECPR) for Out-of-hospital Cardiac Arrest

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop on “Extracorporeal Cardiopulmonary Resuscitation (eCPR) for Out-of-Hospital Cardiac Arrest (OHCA).” The virtual workshop brought together national and international multi-disciplinary experts in basic, translational, and clinical research in cardiopulmonary resuscitation, as well as representatives from academic institutions, federal, and non-federal agencies. Extracorporeal membrane oxygenation (ECMO) when used during a cardiac arrest resuscitation is referred to as eCPR. The workshop provided a forum to discuss the latest advances, cutting-edge approaches, research gaps, and opportunities to advance the field with the following objectives:

• Evaluate the gaps and barriers in clinical research needed to expedite understanding and targeting of the restoration of cardiovascular status to improve survival after OHCA with eCPR
• Identify the state of the science and regulatory policy for eCPR with ECMO-facilitated OHCA
• Identify logistical settings where emergency medicine services (EMS) systems might be particularly effective to apply eCPR
• Discuss future opportunities to facilitate the advancement of clinical research while identifying approaches to developing effective eCPR therapies.

The workshop is responsive to the NHLBI Strategic Vision Objectives 3 - 6.

Extracorporeal CPR (ECPR) for Out-of-hospital Cardiac Arrest Workshop Agenda (pdf)

BACKGROUND

Approximately 395,000 people suffer OHCA each year in the U.S. with 10.5% of these patients surviving to hospital discharge, with regional variations in survival rates ranging from 6 - 16% in different racial and ethnic, social economic status (SES), and gender populations. Although OHCA patients may present to EMS with a shockable rhythm, including ventricular tachycardia/fibrillation (VT/VF), 50% of these patients are refractory to standard advanced cardiac life support (ACLS) and thus, have poor prognosis. eCPR followed by immediate coronary angiography and coronary intervention (PCI), called eCPR-facilitated resuscitation, is used to treat refractory VF/VT OHCA.

The NHLBI-supported Advanced Reperfusion Strategies for Refractory Cardiac Arrest (ARREST, NCT03880565) trial found that using eCPR as part of a broader program of care for OHCA resulted in a 43% survival rate compared to 7% survival rate for those receiving high quality standard treatment (cardiopulmonary resuscitation (CPR), defibrillation, intubation, intravenous medications, and post-arrest care). The data and safety monitoring board (DSMB) recommended early trial closure for efficacy on the basis of predetermined parameters, and ARREST was stopped after 30 enrolled patients showed benefit with eCPR. The ethical considerations with the observed benefit were so compelling that they overwhelmed the concern for selecting more conventional stopping boundaries. This is the first trial to show a significant difference in outcomes after hospital admission among OHCA patients treated with a team-based eCPR strategy. The majority treated with the eCPR program improved both functional and neurological measurements over 6 months and then returned to “a near pre-arrest level”.

The ARREST results reflect a well-coordinated high quality local emergency health care delivery system with a highly experienced interventional critical care cardiology team providing continuity of care for all patients. Exploration is needed on whether the ARREST model is generalizable and replicable at other centers; how eCPR-based strategies can be implemented in prehospital settings; how a nationwide eCPR registry can be created; and how to integrate local emergency health care delivery characteristics and an interventional critical care cardiology team to provide eCPR and continuity of care from prehospital to emergency department (ED)/hospital settings for all patients.

DISCUSSIONS

The workshop addressed the following five topic areas: (1) state of the science based on U.S. and international experience; (2) registry data; (3) generalizability of the ARREST model; (4) ethical considerations for inequities in OHCA interventions, systems of care, and outcomes; and (5) eCPR delivery and resources.

Overarching Concepts: Workshop participants identified several key fundamental principles:

• Establish OHCA as a reportable disease
• Build on existing registries to create a national registry of OHCA for surveillance and research studies that includes predefined eCPR variables
• Define eCPR guidelines and related performance metrics for a system of care for OHCA that includes eCPR
• Develop community-based implementation strategies to optimize out-of-hospital systems of care with performance metrics to ensure equity in the quality of resuscitation, survival outcomes, and access to eCPR where appropriate
• Optimize eCPR technology and implementation methodology for non-hospital setting use
• Establish comprehensive multi-disciplinary training programs beginning in animal lab through simulation and human application settings

Workshop participants identified the following scientific gaps and opportunities:

State of Science – U.S. and International Experience

The current U.S. and international clinical trials and cohort studies are inconsistent in their findings. The ARREST trial suggests a significant survival benefit with eCPR compared with standard care in a high-quality EMS system of care with a dedicated ED team to enable performing the protocol quickly and efficiently. Although the ARREST results are impressive, they are based on a small sample size treated in a high-quality EMS with excellent eCPR performance metrics and timely access to eCPR teams in the ED. The unpublished Prague Trial may or may not support a survivor benefit in a pre-specified cohort of included patients. However, international observational cohort comparison studies from Norway, a European Network, and Canada conducted in high-quality EMS systems of care suggest no survival benefit when compared to standard care.

Gap: Replication of the ARREST findings in other settings is lacking.

Opportunities:
Define cardiac arrest patient population(s) most likely to benefit from eCPR, including refining a “refractory” cardiac arrest definition, and defining system of care characteristics that are essential for successful implementation across the American Heart Association (AHA) chain of survival. These approaches include:

• Establish effective training programs
  • Target best strategies to minimize eCPR-related complications
  • Optimize type of cannulation personnel
  • Optimize number of cannulators versus volume of cases to maintain skills
  • Identify best approaches to training for cannulation personnel
• Optimize EMS system of care meeting minimum performance metrics including basic life support CPR and survival metrics, EMS patient selection most likely to benefit from eCPR, continued resuscitation quality during extrication/transport, and accessible reproducible methods to predict EMS transport time
• Optimize the system of care across all disciplines (e.g., EMS, ED, critical care, cardiology, neurology, organ donation) and ensure the minimum criteria for performance metrics are met or exceeded consistently.
• Distinguish eCPR program components necessary for achievement of adequate survival rates, including:
  • Environment where cannulation is performed (e.g., ED, cardiac catheterization laboratory, mobile unit)
  • Best strategies for shortest time from 911 to eCPR cannulation
  • Recalibration of the public and health care opinions to understand the need for a longer process of death when applying eCPR, including the potential viability of this patient population
  • Defining start-up and maintenance costs in personnel, equipment, and expertise

Gap: Community based eCPR-facilitated resuscitation programs are lacking.

Opportunities:
Develop and test strategies for successful implementation of eCPR-facilitated resuscitation programs in a variety of communities (focus on urban and rural).

Gap: Current ICU patterns of treatment of eCPR-facilitated resuscitation patients are highly variable and of unknown effectiveness.

Opportunities: 
Test optimal ICU management of cardiac arrest patients on eCPR, including oxygenation/CO2 removal, hemodynamics, reperfusion injury prevention and therapies, cardiac recovery, reliable neurological prognostication and withdrawal of life sustaining therapy criteria, and development of physiologic criteria and novel biomarkers to improve clinical decision making, when to withdraw therapy, and how to interface with organ donation and procurement.

Gap: Basic and early clinical research examining the development and progression of new eCPR-related discoveries to advance bench-to-bedside implementation are limited.

Opportunities: 
Research to optimize perfusion during prolonged CPR; define reperfusion injury prevention and therapies; investigate intra-arrest cooling during eCPR; optimize eCPR-related cerebral preservation; and advance technology to make eCPR mobile, cheaper, and user-friendly to improve accessibility and ease of implementation.

Value of Registry Data to Advance Science and Guide Implementation

Registries can address several research topics without a comparison group, notably eCPR incidence use, geographic availability, outcomes and complications, and characteristics of patients who undergo eCPR. An eCPR registry would have several key features and advantages. It would: (1) avoid redundancies; (2) harmonize existing case report forms with existing resources by collaborating with the Strategies to Innovate Emergency Care Clinical Trials Network (SIREN), the Extracorporeal Life Support Organization (ELSO), and the Cardiac Arrest Registry to Enhance Survival (CARES); (3) use an EMS Code Review form; (4) use an eCPR Circuit Use form; (5) leverage a centralized-telephone function for outcome assessment; (6) collect data to better understand and longitudinally quantify ECPR use; and (7) inform the planning of future eCPR studies.

Gap: Data infrastructure with common data elements for OHCA surveillance and research is lacking.

Opportunities: 
Review the existing registries (SIREN, ELSO, CARES, ELSO)

• Define core data elements and audit metrics for surveillance and research
• Establish a surveillance registry with a small number of core sets of data points considering limited resources to provide a minimum of granularity required for quality improvement
• Establish a research registry with core data elements for observational research purposes and measurement of long-term outcomes.
• Define sustainable costs for registry infrastructure and maintenance and provide automatic data entry from EMR with case checking/adjudication to limit errors and missing data, as well as reduce costs.

Gap: There is a lack of a reliable data on the number of people experiencing cardiac arrest who might benefit from eCPR.

Opportunities: 
Consider strategies to make cardiac arrest a reportable disease so the denominator of all cardiac arrests would be known and identify surveillance registry data that could inform what proportion of all cardiac arrests may benefit from eCPR by region.

ARREST Model Generalizability

The potential impact of the ARREST trial is significant and could be transformative for the field, but the generalizability of the ARREST trial system of care is not clear. ST elevation myocardial infarction (STEMI) systems of care are internationally recognized as implementation models that have improved survival. Perhaps the STEMI systems of care may be a model to guide regional implementation of eCPR.

Gap: Requirements for successful adaptation of the STEMI system of care approach to eCPR have not been delineated.

Opportunities: 
Evaluate regional STEMI programs to determine whether they can be adapted to support eCPR in cardiac arrest across diverse communities; and define the best model to deliver eCPR for inclusion of all community partners.

Ethical Considerations for Inequities in Current OHCA Interventions and Survival Outcomes

There are known inequities in OHCA treatment and survival outcomes by race, sex, geography, and SES. The primary driver is unequal provision of lifesaving interventions throughout the chain of survival. Interventions intended to address or reduce inequities in time-sensitive emergency or trauma care have fallen short in their intended purpose. Specific barriers include the current geographical arrangement of experienced hospitals, the variable skill in emergency providers, and the current culture that makes eCPR a late consideration during resuscitation rather than a high priority.

Gap: The measurements of key factors and the impact on access, treatment, and overall outcomes after OHCA in each community are lacking.

Opportunities: 
Measure and optimize established metrics for the system of care in each community to optimize outcomes after OHCA;

• Focus on more upstream aspects of the chain of survival (e.g., CPR training, improving telephone CPR, early bystander defibrillation)
• Identify the interventions required to optimize outcomes in each community that may be different – including an essential minimum standard prior to implementing an eCPR program that will ensure that the outcomes seen in the ARREST trial are more likely to be replicated without any host bias
• Conduct a cost-benefit analysis including implementation process mapping to inform where resources should be allocated to improve equity in OHCA outcomes
• Complete additional research to understand the tradeoff and implications for resource allocation and promoting population-level equity
• Measure and report resource allocation and system optimization interventions that worked across regions and communities as a road map for others.

Gap: Intervention testing and tools measuring key factors to improve OHCA outcomes in all populations are needed.

Opportunities: 
Standardize intervention development and testing in the prehospital and in-hospital setting, and assess whether regionalization, designation, decision support tools, checklists, bias education, blinding, or broadening of inclusion/exclusion reduces known inequities; and includes equity as an integral component of quality improvement efforts; specifically in the design of the interventions (in the context of levels of influence: patient, provider, microsystem, organization, and community policy), the implementation, evaluation, and adjustment of intervention(s), and sustainability of intervention(s).

Gap: Definition and measures of potential magnitude of inequity with eCPR implementation are lacking.

Opportunities: Include age, gender self- assignment, sex at birth, race/ethnicity classification, socioeconomic status (SES), body mass index (BMI), and comorbidities as essential data points in an eCPR database/registry and any other eCPR research. Use uniform data elements and epidemiologic data to assess the magnitude of inequity in OHCA treatment and survival outcomes, and measure any inequity in eCPR access.

Gap: Greater understanding of the barriers and facilitators to eCPR implementation is needed.

Opportunities: 
Use implementation science research to bring together key stakeholders from the community and hospital setting (EMS, clinicians (physician, nurse, perfusionist), administrators) to better understand how these factors can impact provision of eCPR, and use implementation science theories, frameworks, and models to inform successful eCPR implementation.

Gap: Metrics to determine equity in eCPR implementation are undefined.

Opportunities: 
Pre-determine equity metrics with rigorous accurate prospective data collection to ensure equitable eCPR implementation, including evidence of population-based racial, ethnic, SES, and sex equity in access to eCPR, receipt of eCPR, and survival from OHCA post-eCPR.

eCPR Delivery in Health Care Systems with Resource Limitations

eCPR implementation in regions with resource limitations will be challenging. Resources should be directed at optimizing the quality of resuscitation and reducing the inequities in outcomes after OHCA before layering on a resource intensive intervention such as eCPR. Clinical data on eCPR application need to be collected in a standardized manner across different eCPR settings. These data need to be supported by laboratory studies, including phenotyping and genotyping information, simulation and training modules accompanied by performance metrics, and identification of key elements that can be targeted for best eCPR application in diverse settings and population.

Gap: Knowledge and development of optimal hardware and software configurations for prolonged use of eCPR, notably when applied in the field, are lacking.

Opportunities: 
Conduct research to facilitate technical optimization of eCPR allowing non-hospital setting use, including portability and potential field eCPR application, with technologic advancements focusing on simplicity vs. performance, reducing costs, reducing waste and single use items, reducing training requirements for a rare procedure; determine when to initiate eCPR and what is the right duration of manual or mechanical CPR prior to initiation of eCPR; and develop wearable or mobile ultrasound devices that could enable remote cannulation using cell phone displays.

Gap: Knowledge on circulatory and hemostatic physiology and eCPR bio/physics during prolonged CPR is limited.

Opportunities: 
Develop and test optimal concurrent medical management during eCPR which includes but not limited to pump flow characteristics, anticoagulation, temperature, and metabolic support; determine optimal time to initiate eCPR during resuscitation; and integrate and synchronize brain and cardiac circulation support, including performing laboratory studies to guide eCPR optimization and sustainability of cerebral blood flow during prolonged CPR (+40 mins).

PUBLICATION PLANS

A white paper outlining the gaps and opportunities that were identified at the workshop is in preparation.