THE STATE OF RESUSCITATION RESEARCH: ENHANCING THE SCIENCE

To better understand the physiological, social, and environmental risk factors for cardiac arrest and unfavorable health outcomes associated with cardiac arrest, research and specialized expertise are needed across an array of disciplines. High-quality, innovative investigations across the spectrum of research are needed to support further progress in valuable research areas, such as cellular and molecular medicine. From basic science to the translation of evidence into practice in communities across the country, there are a multitude of opportunities along the translation research continuum where the resuscitation field could benefit from targeted improvements. Figure 6-2 depicts the phases of this continuum.

FIGURE 6-2

Operational phases of translational research (T0-T4). SOURCE: Adapted with permission from Macmillan Publishers Ltd.: Nature Medicine (Blumberg et al., 2012).

Applying the phases of translational research to cardiac arrest, the figure starts with basic science (T0), where diminishing funding has led to a paucity of cardiac arrest research that focuses on the etiology and physiological mechanisms that underlie many of the complexities noted throughout this report. Without an understanding of physiological mechanisms of action, the translation of new therapies to human studies (T1) decreases. When innovative new therapies are not tested in humans, the translation to patients (T2) is not possible. Translation to practice (T3) and the broader community (T4) is then stifled, resulting in missed opportunities to affect the survival and outcomes of individuals and populations within communities. This section assesses the potential of research, new research models, and emerging technologies and devices to improve treatment protocols for cardiac arrest that will improve patient outcomes.

Research to Improve Treatments

In recent years, a new paradigm for cardiac arrest response proposed a three-phase model (i.e., electrical, circulatory, and metabolic phases) “to reflect the time-sensitive progression of resuscitation physiology, which in turn requires time-critical interventions” (Weisfeldt and Becker, 2002, p. 3035). Research has demonstrated that early access to existing therapies during the electrical phase (from time of cardiac arrest to approximately 4 minutes following arrest) and the circulatory phase (between 4 and 10 minutes after arrest) can be highly effective (Weisfeldt and Becker, 2002; see also Ewy et al., 2006). After approximately 10 minutes without treatment, patients enter the metabolic phase of cardiac arrest, which involves a number of cascading biochemical pathways that may extend beyond localized organ damage and can result in full-body systemic injury (Bainey and Armstrong, 2014; Frohlich et al., 2013; Kalogeris et al., 2014). The metabolic phase of cardiac arrest is associated with poor survival rates and neurologic and functional outcomes. In this late phase, the standard guideline-recommended therapies, such as CPR and defibrillation, are usually unsuccessful (Weisfeldt and Becker, 2002). Additional research is needed to define the role of alternate techniques for improving blood flow during a cardiac arrest to maximize the period for successful intervention. Box 6-1 provides other examples of possible research areas by treatment phase.

BOX 6-1

Examples of Possible Research Areas by Treatment Phase. Electrical Phase Research to reduce time to defibrillation, including the use of automated external defibrillators (AEDs), implantable medical devices (e.g., implantable cardioverter defibrillators), (more...)

Metabolic therapies that target specific injury pathways have demonstrated increasing potential to improve survival following prolonged, untreated cardiac arrest (Bartos et al., 2014, 2015; Riess et al., 2014). Furthermore, some studies suggest that the commonly accepted 4-minute time limit beyond which ischemic injuries begin to irreversibly damage critical organs may be extended (Allen and Buckberg, 2012; Allen et al., 2012a,b; Athanasuleas et al., 2006; Trummer et al., 2010, 2014).

Recent investigations have reported that a combination of protective drugs and other treatments may be more effective in delaying the severe biological consequences of prolonged cardiac arrest (Bartos et al., 2015; Boller et al., 2011). Using a combination of therapies targeting the circulatory and metabolic phases of cardiac arrest, animal model research suggests the potential to restore life after sustained periods of clinical death. For example, in a recent laboratory experiment using porcine models, Bartos and colleagues (2015) demonstrated improved rates of survival with minimal or no neurological deficits after 17 minutes of cardiac arrest after administering medications and treatments to mitigate the tissue damage associated with reperfusion injury. Another swine experiment achieved survival following 30 minutes of isolated brain ischemia by infusing a warm blood reperfusate that consisted of free radical scavengers, a calcium chelating compound, inflammatory controls, osmotic controls, and energy substrates for 20 minutes instead of oxygenated blood during reperfusion (Allen et al., 2012a).

In a recent human trial, Australian investigators treated cardiac arrest patients who had an initial cardiac rhythm of ventricular fibrillation (VF), had received traditional advanced cardiac life support (ACLS), but had not achieved return of spontaneous circulation after 30 minutes (among other inclusion criteria) (Stub et al., 2015a). Researchers employed a combination of treatments that included mechanical cardiopulmonary resuscitation (CPR) (due to long periods of resuscitation), intra-arrest cooling via intravenous ice cold saline, rapid initiation of extracorporeal membrane oxygenation, and rapid percutaneous coronary intervention for patients with coronary artery occlusion (Stub et al., 2015a). Of the 26 patients who participated in this study, 14 (54 percent) were discharged from the hospital with favorable neurologic status (Stub et al., 2015a). Although this was a small feasibility study, it demonstrates new possibilities in cardiac arrest recovery and the importance of funding research to explore new treatment models and therapies in efforts to improve patients' lives.

Research Methodology and Trial Design

Over the past 30 years, many large randomized clinical trials for specific cardiac arrest treatments have found no demonstrated benefit (Aufderheide et al., 2011; Stiell et al., 2011). For instance, a recent study found that targeted temperature management at 33^oC did not improve survival or neurological outcomes over targeted temperature management at 36^oC (Nielsen et al., 2013). Similarly, research findings related to the impact of mechanical CPR devices are mixed, with trials demonstrating increases in CPR quality, but only nonsignificant impacts on survival to discharge (Hallstrom et al., 2006; Ong et al., 2012b; Wik et al., 2014).

The lack of measured impact in these trials may be attributable to a variety of systemic factors and methodological limitations. One possible explanation is that specific treatments are simply ineffective. As a result, researchers may focus on therapies with a limited likelihood of measurable benefit, including therapies that are based on insufficient preclinical work, that have unknown or unclear mechanisms of action, or have documented ineffectiveness. Decisions made during the design of clinical trials may also reduce the likelihood that the study will result in a demonstrated benefit or identify optimal use. This is especially true if the trials are based on sparse prior information related to the optimal treatment population, treatment efficacy, and the most appropriate biomarker or patient-centered outcome measure. The urgency of identifying new therapies for cardiac arrest can create incentives for researchers to perform confirmatory or even pragmatic trials before clearly establishing efficacy in more controlled and limited settings.

Resuscitation research investigating the efficacy of new treatments should utilize clinical designs and research strategies that have the highest probability of demonstrating benefit after accounting for the heterogeneous nature of cardiac arrest and cardiac arrest patients. Traditional drug and device development processes, which largely uniformly apply and evaluate one therapy at a time regardless of important variations in patient populations, may fail to detect clinically important benefits when therapies are combined or used in select subsets of patients. The complex nature of cardiac arrest will likely require simultaneous testing of multiple treatment and treatment modalities in order to identify new effective treatments. The biggest successes may materialize when multiple treatment approaches are combined and carefully tailored to individual patient characteristics and responses to treatment (i.e., individualized resuscitation).

There is now broader recognition in the scientific community that the traditional sequential series of individual clinical trials—each testing a single treatment in a relatively homogeneous population—is time consuming, resource intensive, and increasingly leads to failed trials late in the testing phase (Berry et al., 2015). An analysis of research into neuroprotectants for ischemic strokes—an area that involves local effects of ischemia and reperfusion—identified more than 40 failed Phase III trials (Minnerup et al., 2014). Recent analyses of the increasing overall failure rates in Phase III pharmaceutical clinical trials have concluded that inadequate Phase II trials (or “learn phase” trials) contribute to, as a primary factor, the low success rates in Phase III trials (Lavine and Mann, 2012; McAuley et al., 2010; Retzios, 2009).

Examples of research strategies and clinical trial designs that could increase the efficiency and success rate of resuscitation research include the increased use of small, hypothesis-generating studies; a more robust exploration of dose effects and modifiers of efficacy (i.e., interactions between treatments and patient characteristics) in learn phase trials; the use of randomized, withdrawal trials; and the implementation of adaptive clinical trials and platform trials (see Table 6-1). For example, a randomized, withdrawal trial could be used to study the use of therapeutic hypothermia. This type of trial would treat all patients with therapeutic hypothermia and then randomize the time of rewarming (the withdrawal of the treatment) only in the subset of patients who demonstrated some benefit as determined by a defined biomarker. Other novel approaches include adaptive and platform trials, which often use response-adaptive randomization so that patients who are enrolled later in the trial are preferentially randomized to treatment arms that are most likely to be beneficial (Berry et al., 2015; HHS, 2010). This approach may improve the risk-to-benefit balance for research subjects, increase the chance of a definitive trial outcome, and increase the number of subjects ultimately treated with the best-performing treatment arm (Meurer et al., 2012). Criteria for defining a positive adaptive or platform trial result should be selected to ensure protection from false positive results (FDA, 2015a).

A strategic approach to implementation of resuscitation science discoveries and new therapies is required to foster evidence adoption, use, and sustainability. Once a new treatment has demonstrated benefit in controlled clinical trials, it must be tested in increasingly realistic settings to confirm effectiveness and to identify the optimal clinical practice protocols. Translational research focuses on the translation of new findings in basic science into new treatments and the adoption of those treatments in practice (Rubio et al., 2010). Table 6-2 offers a summary of key areas of focus for possible future resuscitation research across the spectrum of translational research. In the resuscitation field, guidelines are a predominant mechanism for translating research into practice. (The strengths and weaknesses of national guidelines related to cardiac arrest treatment are discussed later in this chapter.) The rapid translation of basic research findings into new treatments and the adoption of new treatments into practice is more likely if clinical trials and related studies are designed to produce results that can facilitate evidence-based practice.

TABLE 6-2

Key Areas for Resuscitation Science Research.

Emerging Technologies and Devices

Recent progress in science, engineering, health informatics, and mobile technologies has created the potential to revolutionize treatments and care delivery in the field of cardiac arrest and resuscitation. The committee was charged with evaluating the “research, technology transfer and innovation, and implementation gaps,” as well as promising new strategies that have the potential to improve cardiac arrest outcomes (see Box 1-1). Previous chapters have described innovative new therapies (e.g., hemodynamic support therapies such as extracorporeal membrane oxygenation) and care strategies (e.g., prediction models for early detection of deterioration in IHCA patients) for OHCA and IHCA resuscitation and post-arrest treatment, as well as devices to improve quality of resuscitation treatment (e.g., monitoring and impedance threshold devices). This section examines emerging technologies and devices that are currently in prototype or early preclinical phase testing and, therefore, have not been widely incorporated into clinical practice. Although many of these devices and mobile applications have not yet met the U.S. Food and Drug Administration (FDA) criteria for broad distribution because of the lack of evidence from large-scale clinical trials, the committee recognizes that these state-of-the-art technologies have the potential to significantly improve worldwide survival of cardiac arrest.

Innovations in smartphone and mobile applications, social media, home monitoring devices, and wearable technologies could significantly reduce the time interval between collapse and treatment and substantially improve patient survival rates (Scholten et al., 2011). Collection of data from many of these devices could be used to enhance research and surveillance activities, with appropriate privacy protections, and drive improvements in prevention of cardiac arrest as well as quality of care delivery (Bosley et al., 2013; Chang et al., 2013). Similarly, analytics of patient data from hospital and other health care facilities have the potential to predict cardiac arrest, thereby improving medical treatment and response (Churpek et al., 2012; Ong et al., 2012a). Emerging technologies may support better CPR training and performance by monitoring the rhythm and compression depth with real-time feedback and could be an effective aid in continuing education for first responders (Chang et al., 2015; Fischer et al., 2011; Martin et al., 2013). Finally, outpatient monitoring of patients who are already at greater risk for cardiac arrest (such as a recovering cardiac arrest patient or a patient with a predisposing cardiac condition) could potentially reduce the cost of care across a greater number of patients, especially in rural or underserved areas (Przybylski et al., 2009; Reynolds et al., 2006). Technological innovations for assessing patients undergoing resuscitation have the potential to personalize our approach to patients in cardiac arrest.

Adoption of these mechanical devices and wearable technologies has been limited because of a lack of robust evidence collected from clinical trials, as well as challenges related to data management and patient privacy issues, reliability and interoperability (Honeyman et al., 2014). Moreover, there are few consensus statements on best practices or implementation of these technologies. FDA recently issued guidelines regarding mobile medical applications, but it has not yet evaluated these in the context of cardiac arrest treatment and care strategies (FDA, 2015c). Box 6-2 provides additional examples of new technologies and devices that could enhance the cardiac arrest chain of survival.

BOX 6-2

Examples of Emerging Technologies and Devices. Early Detection and Emergency Alert System A majority of cardiac arrests occur in the home and are often unwitnessed. Mobile applications, technologies, and devices that can track outpatient physiological (more...)

Although the private sector plays an integral role in developing technologies to improve cardiac arrest treatment, the public sector can also support progress through a variety of mechanisms. Research to determine the effectiveness of mobile applications, social media, and innovative devices such as wearable alert systems in improving cardiac arrest survival is paramount. The National Institutes of Health's (NIH's) National Institute of Biomedical Imaging and Bioengineering supports research that integrates physical, engineering, and life sciences to accelerate the development and application of biomedical technologies (NIBIB, 2015). Research into new areas, such as advances in imaging or thermometry, may lead to new therapies to restore spontaneous circulation and diagnose or prevent neurological damage after cardiac arrest. Additional research is necessary to develop more complex devices targeting early recognition and response to cardiac arrest, as well as the quality of resuscitation and post-arrest care.

Regulatory controls, such as the premarket approval process, must promote safety without stifling innovation; this constitutes a major challenge within health policy and translational science, both in general and in the field of cardiac arrest in particular (FDA, 2011). As of February 2015, FDA now requires that AEDs and AED accessories (e.g., batteries, electrodes, and adapters) undergo premarket approval before being released for sale to the general public (FDA, 2015b). This decision was made in light of device recalls and reported problems with the design and manufacture of AEDs. The premarket approval process is meant to provide reasonable assurance of the safety and effectiveness of the device, and it includes review of the methods, facilities, and controls involved in the manufacturing, processing, packing, and installation of devices (FDA, 2014). To improve efficiencies in regulatory approval of technology for cardiac arrest, fast-track review, and expedited premarket approval within FDA may be appropriate with post-market surveillance.

INFRASTUCTURE AND SUPPORT FOR RESUSCITATION RESEARCH

Many barriers within the resuscitation research field limit the impact of much-needed cardiac arrest research. Fragmented administrative oversight and coordination across federal research agencies and in academia complicates efforts to better understand the state of resuscitation research and engage in coordinated, collaborative research and funding efforts. Funding that is available for resuscitation research is disjointedly allocated and lacks transparency. Based in part on these persistent challenges, advocacy efforts have not been able to successfully expand available research resources across all levels—from basic research to population-level studies. Ideally, a robust cardiac arrest research agenda would ensure that research findings at the T0 level are transformed into practices that benefit the community (T4) and improve health. To successfully implement such a broad research agenda, the resuscitation community must first overcome the infrastructure barriers described below in order to ensure a sustainable and active research pipeline that includes sufficient numbers of researchers.

Administrative Oversight and Coordination

Federal agencies charged with activities related to the public's health and high-quality health care play an important role in the success and failure of local, state, and national efforts to improve outcomes from disease, health conditions, and health-related events—such as cardiac arrest. For example, NIH credits its research for major health advances related to declines in mortality from cancer, heart disease, and stroke, as well as improvements in antiviral therapies for people infected with the human immunodeficiency virus (NIH, 2012b). However, fractured federal oversight, a lack of interagency coordination, and overlapping authorities within federal agencies pose substantial barriers to advancing basic, clinical, and translational research in cardiac arrest treatment. At a national level, federal oversight of responding to and treating cardiac arrest has been largely prescribed by the site of cardiac arrest, with OHCA largely the province of EMS and IHCA the responsibility of hospital-based systems of care. For example, agencies or departments involved with EMS, including the U.S. National Highway Transportation and Safety Administration and the U.S. Department of Defense, may view cardiac arrest treatment as one indicator of the quality of the overarching EMS system (NHTSA, 2009).

NIH, the Centers for Disease Control and Prevention (CDC), and the U.S. Health Resources and Services Administration (HRSA) provide traditional support for general resuscitation research through various grant mechanisms that fund individual research studies, large-scale data collection, and infrastructure. However, within agencies, resuscitation research grants may be spread across a wide range of institutes or offices and various topics (e.g., basic science, training, and treatment protocols) related to, but not necessarily dedicated to, the study of cardiac arrest. For example, although the National Heart, Lung, and Blood Institute (NHLBI) is the official lead institute for resuscitation research within the NIH, funding is spread across multiple NIH institutes, including the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHHD) (see Figure 6-3). A pediatric cardiac arrest study that targets the circulatory phase of resuscitation could theoretically be funded as a cardiovascular, neurologic, or pediatric study within different NIH institutes. Because the missions and priorities of individual institutes may overlap, the appropriate funding institute is not always apparent to investigators or the public, leading to confusion and suboptimal coordination of activities within the research community. Although this challenge is not unique to cardiac arrest research, it has an ongoing impact on efforts to streamline cardiac arrest research.

FIGURE 6-3

Location and number of grants related to cardiac arrest within the National Institutes of Health in 2013. SOURCE: Lathrop, 2014.

NIH also houses the Office of Emergency Care Research, which “coordinates, catalyzes and communicates about NIH funding opportunities in emergency care research and fosters the training of future researchers in this field” (NIH, 2013b). It is a trans-NIH office but, unlike other trans-NIH offices, has no budget for funding research (NIH, 2012a). Although it does not focus exclusively on resuscitation research, the office has worked with NINDS and the NICHHD on research and training activities related to post-resuscitation hypothermia (NIH, 2015c). As mentioned in Chapter 2, the office will also play a role in NIH's new cross-collaborative clinical trials network for emergency care, Strategies to Innovate EmeRgeNcy Care Clinical Coordinating Center (SIREN), which could be used for resuscitation research.

In addition to support provided by NIH, CDC, and HRSA, a number of other federal agencies and private organizations provide support for cardiac arrest and resuscitation research or whose missions aligns with improving cardiac arrest treatment and care. The U.S. Department of Veterans Affairs (VA) funds multiple projects with various academic institutions to better understand the incidence and response to cardiac arrest. The VA also requires its care facilities to establish an interdisciplinary committee to “review each episode of care where resuscitation was attempted for the purpose of identifying problems, analyzing trends, and improving processes and outcomes,” but the enforcement of this rule between facilities varies (VA, 2015). Although the Patient-Centered Outcomes Research Institute has not focused on cardiac arrest specifically, its mission “to improve patient care and outcomes through patient-centered comparative clinical effectiveness research” is generally applicable to resuscitation research (PCORI, 2014). The Centers for Medicare & Medicaid Services (CMS) reimburses health care providers for particular services and treatments related to cardiac arrest, but the committee did not find any recent initiative that focuses specifically on cardiac arrest survival.¹

The Need for Sustained and Coordinated Research Funding

The ability of resuscitation research to improve cardiac arrest outcomes relies on sustained funding and widespread implementation of practices based on newly generated evidence (described in greater detail in the next section). In 1962, Senator Hubert H. Humphrey urged “the creation of NIH centers or institutes that focus on the physiology of death, on resuscitation and on related topics,” underscoring the desire to prolong life, postpone death, and possibly reverse death (Humphrey, 1962, emphasis added). This spurred interest and research related to cardiac arrest treatment. Unfortunately, evolving and shifting priorities within federal agencies and among congressional leadership shifted focus away from cardiac arrest treatment as early as the 1990s and continues to affect current research activities (Thompson et al., 1996).

Many federal agencies and private-sector organizations provide research support related to the study and treatment of cardiac arrest. However, even within a single Institute or office, the exact amount of annual research funding is often difficult to calculate. The majority of NIH funding for cardiac arrest, as for other biomedical research funding through NIH, supports investigator-initiated research applications. As a whole, cardiac arrest funding is not reported as a separate line item in NIH's annual research portfolio, as other research and disease areas are (e.g., Alzheimer's disease, brain cancer, traumatic brain injury, and stroke) (NIH, 2015a). Estimates of total annual funding related to cardiac arrest are available, calculated by a search and review of all funded grant awards by search term. The search terms “cardiac arrest” and “resuscitation science” generally identify grants related to the treatment of cardiac arrest, whereas the term “sudden cardiac death” is categorized as an arrhythmia, which also includes prevention-related research on “arrhythmogenesis, genetic and environmental bases of normal cardiac electrical activity and arrhythmias, and etiology of rare and common arrhythmias” (NIH, 2014).

Based on these searches, NIH's total support related to cardiac arrest in fiscal year 2013 was approximately $107.7 million ($40.3 million for cardiac arrest and $67.4 million for sudden cardiac death and resuscitation sciences), of which NHLBI provided $85.4 million (Lathrop, 2014). However, these estimates are likely inflated because of overlap in the awards identified using search terms (i.e., more than one search term may be included in the same grant award). Comparatively, stroke, which kills approximately 130,000 people annually received approximately $282 million of NIH's research budget in 2013 (CDC, 2015; NIH, 2015a). In fiscal year 2013, NIH invested an estimated $5.27 billion on cancer research and about $1.96 billion on cardiovascular disease research (NIH, 2015a). Recent studies have identified potential, untapped sources of funding, including private philanthropy and foundations, the biomedical industry, the insurance industry, and more traditional private-sector organizations, which can be used to complement federal agency investment in resuscitation research (Myerburg and Ullmann, 2015).

Cardiac arrest support falls short when compared to other critical diseases and conditions using additional metrics. A recent study found that, between 1996 and 2006, “advancement in the treatment of acute ST Segment Elevation Myocardial Infarction (STEMI) has led to gradual reduction in the incidence of STEMI related cardiogenic shock irrespective of ethnicities or gender suggesting improving outcome of patients presenting with STEMI” (Movahed et al., 2014). Similarly, acute cardiovascular disease and stroke hospitalizations, mortality, and readmissions rates declined more rapidly between 1999 and 2011 than did other conditions (Krumholz et al., 2014). Figure 6-4 provides a comparison of the number of published randomized control trials, NIH-funded studies, and deaths by STEMI (a specific type of heart attack), stroke, heart failure, and cardiac arrest. Although this is only one study limited by its date of publication, when combined with documented declines in deaths from other, more, well-funded diseases and conditions, this figure further supports assertions of the important relationship between research levels and patient outcomes from cardiac arrest.

FIGURE 6-4

Comparison of four diseases by annual deaths and specific research support. NOTE: NIH = National Institutes of Health; RCT = randomized controlled trial; STEMI = ST segment elevation myocardial infarction. SOURCE: Ornato et al., 2010.

Similarly, the grants supporting resuscitation research are distributed across multiple academic institutions throughout the United States, and the current administrative structure of these grants provides very little incentive for cross-institutional collaboration. Some academic institutions have attempted to create translational “centers of excellence” that conduct research from the bench to the bedside. For example, in 2010, four academic medical centers formed the National Post-Arrest Research Consortium through NIH's Clinical and Translational Research Award program, seeking to “advance science and foster partnerships to speed innovation and accelerate laboratory discoveries into treatments for [cardiac arrest] patients” (Virginia Commonwealth University, 2011). Despite the consortium's potential, its impact was limited by the number of partnerships within the consortium and available funding.

The ability to successfully treat cardiac arrest depends on having a workforce that knows how to conduct research and translate that research into practice. In addition to the lack of population health data for cardiac arrest (see Chapter 2), there is also a striking lack of a viable preclinical research laboratory enterprises. A viable preclinical enterprise must exist that includes sustainable animal laboratories that use robust animal models, but the current number of active basic science and preclinical laboratories working in the area of cardiac arrest in the United States is in the single digits (Yannopoulos, 2014). Some experts suggest that fewer young scientists are choosing to pursue basic, preclinical, and clinical research in resuscitation because of a lack of sustainable funding opportunities (Daniels, 2015; Yannopoulos, 2014). This deficit in the academic pipeline has led some organizations to include programs to develop a new generation of researchers in resuscitation and trauma as part of more traditional resuscitation research grants. For example, the Resuscitation Outcomes Consortium funded five training sites as “core leaders” in resuscitation research training and has trainees attend meetings to learn from mentors as they conduct research (Ornato, 2014). Current funding priorities are not likely to entice individual researchers to pursue careers in the treatment of cardiac arrest, which will affect the potential to develop new, effective treatments and therapies.

TRANSLATING SCIENCE INTO PRACTICE: THE ROLE OF EVIDENCE-BASED GUIDELINES

The Institute of Medicine (IOM) defines a “clinical practice guidelines” as a “systematically developed statement to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” (IOM, 1990, p. 38). “Evidence-based” implies sufficient clinical trial evidence to document the impact and need for each element of a specific guideline. To fully capitalize on the potential of novel research, therapies, and treatment protocols to reduce cardiac arrest death and disability, widespread implementation of evidence-based practice is required. Unfortunately, evidence related to cardiac arrest is lacking.

In the resuscitation field, a number of organizations—including the International Liaison Committee on Resuscitation (ILCOR), the American Heart Association (AHA), American Red Cross, and American College of Cardiology—offer consensus-based guidelines on various cardiac arrest topics (e.g., defibrillation, CPR, IHCA, ACLS, basic life support [BLS], and pediatric treatments). Guidelines, formal recommendations, and advisory statements are updated every 5 years after expert panels analyze all available international science and evidence (see Meaney et al., 2013; Morrison et al., 2013; Nolan et al., 2003; Peberdy et al., 2010). While some guideline-setting organizations have released joint consensus statements on several occasions, there remain slight variations in various guidelines, such as those for pediatric populations or for special circumstances, such as drowning. The availability of different guidelines through different organizations may contribute to general confusion about which guidelines best reflect the current literature and are most appropriate for different audiences.

Because comprehensive data and research studies are largely absent in the resuscitation field, guidelines may reflect extrapolations from existing data and research, as well as practical considerations, rather than a strict interpretation of solid evidence (Neumar, 2010). For example, the AHA and ILCOR guidelines recommend at least 50 millimeters for chest-compression depth during CPR. Yet, there are no high-level studies, such as randomized clinical trials, that compare compression depth. A recent study by Stiell and colleagues (2012) assessed chest compression depth in patients undergoing CPR and found that although a compression depth of 38-51 millimeters was associated with better survival, compression depth greater than 51 millimeters did not further improve rates of return of spontaneous circulation, 1-day survival, or survival to discharge. There was also an inverse relationship between compression depth and compression rate (Stiell et al., 2012). Similar questions about specific guidelines related to optimal chest compression rates or the sequence of treatments in the algorithms for cardiac arrest exist (Wallace et al., 2013). Moreover, the 5-year process for evaluating new evidence and updating recommendations raises questions about whether guidelines can be a timely reflection of a developing evidence base, especially in the time leading up to a new review cycle.

The effect of guidelines, standards, and advisory statements on patient outcomes from cardiac arrest is unclear. Some studies have failed to identify a direct association between implementation of cardiac arrest guidelines and improved patient outcomes (Deasy et al., 2011). For example, a study in which Resuscitation Outcomes Consortium (ROC) investigators assessed the effect of the 2005 Emergency Cardiovascular Care guidelines on survival to hospital discharge using before and after data from 85 EMS agencies found no significant difference in overall survival, which was 5.8 percent prior compared to 6.5 percent after implementation of the new guidelines (Bigham et al., 2011). However, other studies have found that adherence to specific guideline protocols is associated with improved patient outcomes (Kirves et al., 2007; Stub et al., 2015b).

Many factors contribute to difficulties in assessing the impact of guidelines. Numerous organizations, entities, and members of the public rely on guidelines to respond to cardiac arrest, but do not typically engage in systematic analyses of how adherence to guidelines affects cardiac arrest outcomes (Meaney et al., 2013). In addition to the complex nexus of cofounding factors that affect patient outcomes, compliance rates with guideline-recommended practice is low and can be difficult to measure (Kampmeier et al., 2014; Kirves et al., 2007), and compliance with Utstein guidelines for reporting and research design can be incomplete (Donoghue et al., 2005). Many health care organizations rely on BLS and ACLS certificates to ensure that professional staff is sufficiently trained in various emergency skills, but it can be difficult to assess whether professional certification affects patient outcomes (IOM, 2014). More research is needed to demonstrate the impact of guideline adherence on patient outcomes following cardiac arrest.

Despite the limitations described above, guidelines and associated dissemination efforts do contribute to patient care in cardiac arrest. Guidelines and their associated checklists can reduce unnecessary variations in practice and are a reasonable place to begin process and health outcome assessment. However, recommending specific elements that are based on insufficient evidence as a standard of care has the potential to impede beneficial innovation. Systems of care should be encouraged to adopt guidelines and monitor outcomes to determine optimal, local protocols to enhance survival and good neurologic function following cardiac arrest. This approach will allow for local-level innovations that account for local needs and resources while contributing to a broader and more authoritative evidence base from which to update guidelines.

CONTINUOUS QUALITY IMPROVEMENT

Continuous quality improvement (CQI) is a “process-based, data-driven approach to improving the quality of a product or service, [which] operates under the belief that there is always room for improving operations, processes, and activities to increase quality” (RWJF, 2014). The basic premise of CQI involves capturing, analyzing, and regularly reporting data; translating the data and resulting information into actionable opportunities to improve performance at the local level; and developing plans for process changes that will further support effective, efficient, and value-added interventions (IOM, 2013a). An important component of any CQI effort is evaluating interventions and making adjustments, as needed. Even unsuccessful interventions can ultimately be used to improve survival rates, because they may provide evidence about ineffective treatments and protocols.

In the resuscitation field, adoption of CQI initiatives across EMS systems, health care systems, and hospitals has several distinct advantages. First, the chain of survival identifies groups of care providers that already or can naturally engage in CQI activities. Using a CQI process to drive clinical excellence based on familiar guidelines reduces disruption and improves adoption of new practices. Second, CQI processes focus on modifiable structures and processes within existing systems with the goal to improve patient, provider, and system outcomes (National Learning Consortium, 2013). Cardiac arrest research and monitoring implementation of best practices can be a natural extension of established CQI activities in different care settings. Third, standardized data collection is central to CQI. Incorporation of standardized cardiac arrest data elements that are harmonized across multiple settings can be collected for purposes of local and national benchmarking to improve cardiac arrest outcomes.

Numerous experts and studies have found that many systems with documented improvements in cardiac arrest survival rates and neurologic and functional outcomes in patients use CQI strategies (Bobrow et al., 2008b; Cobb et al., 1999; Meaney et al., 2013). In a 2013 consensus statement, the American Heart Association noted that, although measuring, reporting, and reacting to resuscitation performance data can positively influence cardiac arrest survival, such activities are not universally employed by health care systems; consequently, outcomes from cardiac arrest remain at unacceptably low and disparate levels (Meaney et al., 2013). The report goes on to recommend that all health care providers should implement a “CPR CQI program that provides feedback to the director, managers and providers” (Meaney et al., 2013, p. 9). Implementation of novel interventions should be monitored and adjusted based on locally identified needs and resources, areas for improvement, and innovations in order to promote the adoption of evidence-based practice. CQI programs should not be used as a disciplinary tool but may be combined with periodic retraining (Resuscitation Academy, 2013). Specific CQI strategies in cardiac arrest include:

• Measuring processes and outcomes associated with resuscitation activities across all settings,
• Benchmarking against best practices and data from comparable systems,
• Providing feedback to teams of providers, and
• Developing strategies to continually improve resuscitation practices (Travers et al., 2010).

Communities and health care systems that have made the greatest strides in improving outcomes have typically established a culture of data collection, evaluation, and reporting that results in necessary adjustments that best fit local needs and capacities. Most communities that have demonstrated the greatest aptitude for reducing deaths from cardiac arrest share one common characteristic—CQI. The examples included in Box 6-4 highlight select communities within the United States that have adopted CQI approaches and local implementation approaches to available guidelines. Proactive leaders within these communities have encouraged and supported the adoption of innovative and adaptive strategies informed by active CQI programs, which use locally available data to improve cardiac arrest survival rates and health outcomes.

There are a number of commonalities shared across the examples provided in Box 6-3. Each of the examples started with recognizing a gap or an area for improvement that required strong leadership to operationalize needed changes. Success was predicated on the implementation of a reliable database that employed standard outcome parameters that could be used to measure and compare outcomes. The systems continually monitored outcomes data and developed non-punitive strategies and interventions to improve survival. These new interventions relied on a culture of innovation and continuous learning with the understanding that not all new approaches were going to lead to success. These elements, combined with appropriate responsibility and authority, need to serve as the foundation for a new paradigm in the treatment of cardiac arrest.

BOX 6-3

Examples of Local Continuous Quality Programs. Arizona implemented a statewide database to measure OHCA incidence and care processes, and EMS systems throughout Arizona initiated a range of interventions and CQI efforts. Based on evidence from laboratory (more...)

To promote adoption of CQI activities on a widespread scale, organization and agencies have a variety of options, including

• Disseminating guidelines and training materials that incorporate CQI training and examples of innovation;
• Providing forums for exchanging information and sharing experiences in adopting CQI principles;
• Offering and seeking competitive grants for CQI adoption and innovations;
• Hosting regional meetings for EMS agencies to exchange information and best practices for implementing CQI programs on a local level; and
• Creating prizes and other incentives for best innovations, improvement, regional survival rate, and so on.

Effective implementation of CQI programs, whether in the context of OHCA or IHCA, requires ongoing data collection, formal accountability, and flexibility to allow for innovation. As described in Chapter 2, NIH and CDC have supported cardiac arrest data collection and research through various mechanisms, including the ROC Epistry and CARES, respectively. However, CDC shifted funding to the private sector in 2012 for CARES, which has since had to adopt a sustainable, subscription model to support the data set infrastructure and personnel (CDC, 2013a; Slattery and McNally, 2015). Similarly, NIH is not renewing its grant support for ROC, shifting its focus to the newly established SIREN network, which will combine ROC and Neurological Emergencies Treatment Trials resources to better enable research on emergency medicine.² The creation of a national database of cardiac arrest information may capitalize on natural efficiencies and enable CQI efforts to enhance resuscitation science, therapies, and treatment protocols. Benchmarking associated with CQI and the adoption of guidelines by consensus organizations will also contribute to more reliable systems of data collection.

Implementation science is an important concept in cardiac arrest research and has specific relevance to CQI programs. Implementation science—“the scientific study of methods to promote the integration of research findings and evidence-based interventions into healthcare policy and practice”—is a key element of translational research (Schackman, 2010, p. S27). Implementation science seeks “to understand the behavior of [health care] professionals and other stakeholders as a variable in the sustainable uptake, adoption, and implementation of evidence-based interventions” (NIH, 2013a). The principles of implementation science can complement and inform efforts to adopt a meaningful, system-wide CQI program to improve cardiac arrest outcomes.

As part of performance assessment, organizations need to identify and analyze implementation gaps affecting cardiac arrest research, technology transfer and innovation, and adoption of new discoveries and therapies. Analysis of factors affecting implementation can identify barriers to the adoption of new practices and develop strategies to overcome those barriers. Implementation science may also provide information about perceived acceptability, appropriateness, costs, feasibility, sustainability, safety, effectiveness, and patient-centeredness, in addition to patient outcomes (Proctor et al., 2011). Different implementation models with varying degrees of flexibility, emphasis, and applicability exist (Tabak et al., 2012) and can be molded to the specific context and goals of an EMS or health care system (Straus et al., 2013). By integrating CQI programs into existing systems of care, with an understanding of likely barriers affecting both the adoption of CQI principles and implementation of new evidence-based protocols, care providers will learn from their experience and solve problems using a formal, transparent, and systematic approach within the system to achieve improved patient outcomes following cardiac arrest.

STRENGTHENING COORDINATION AND ADVOCACY

Advocacy groups play an important role in providing support for cardiac arrest survivors and for families who have lost loved ones to cardiac arrest. They can also be influential in raising awareness; promoting education and training efforts in communities; lobbying for regulatory changes; and driving policy at the local, state, and national levels. A number of cardiac arrest–related advocacy groups exist, including the Sudden Cardiac Arrest Foundation, Parent Heart Watch, and the Sudden Cardiac Arrest Association. Despite remarkable work in expanding public education and awareness of cardiac arrest, these groups have been less successful at expanding resources for research and education campaigns at a national level when compared with advocacy groups focused on cancer, AIDS, and Alzheimer's disease research.

Lack of progress may be due, in part, to the poor outcomes associated with cardiac arrest. Because of low survival rates, a large cohort of cardiac arrest survivors is not available to serve as living champions for better treatment and health outcomes. Conversely, those living with conditions such as cancer or AIDS have a more visible and vocal presence in the media and are better able to advocate on behalf of others living with the same condition. The field of resuscitation also suffers from fragmentation and the absence of a single, unified voice to generate the necessary political, private, and public support to advance resuscitation research.

Forming partnerships or collaborations is a common strategy used to promote integrated service delivery across health care and public health service systems. Defined as a “process by which groups come together, establishing a formal commitment to work together to achieve common goals and objectives” (NACCO, 2014), formal collaborations can help align programs and activities across different stakeholders with unique knowledge, resources, and skills to achieve greater efficiencies, impact, and political and public support. Meaningful partnerships among researchers, health care providers, advocacy organizations, and the community can build an environment of mutual trust and understanding, information exchange and education, and active support and participation (NACCO, 2014).

Collaboratives can have various structures and purposes. Some collaboratives have focused on expanding research capacity and reach. For example, in 2006, NIH established the Clinical and Translational Science Award (CTSA) program to accelerate the translation of research from the most basic levels through the widespread application of research findings at the population level (IOM, 2013b). In addition to providing research resources and support tools, sites within participating academic health centers are required to actively engage community organizations, health care providers, and public health professionals (NIH, 2015b). As noted in the IOM's 2013 evaluation of the CTSA program, “partnerships with community representatives can identify community health needs and priorities, provide critical input and data on clinically relevant questions, develop culturally appropriate clinical research protocols, promote successful enrollment and retention of research participants, and, ultimately, disseminate and implement research results more effectively” (IOM, 2013b, p. 117). Many of the CTSAs are creating long-term partnerships that are in turn leading to successful community programs and interventions that focus on areas such as diabetes, reducing health disparities, substance abuse, increasing clinical trial participation, and training community leader (IOM, 2013b).

Other collaboratives are formed to promote evidence-based practice. For example, the Brain Attack Coalition was formed to strengthen and promote relationships between its member organizations (including professional, voluntary, and governmental entities) in order to “reduc[e] the occurrence, disabilities and death associated with stroke” (Brain Attack Coalition, n.d.). The Coalition website is maintained by NINDS. The Coalition has engaged in activities related to messaging for National Stroke Awareness Month, a list of stroke systems for public education initiatives, and authored papers outlining guidelines for national stroke centers. The Coalition's success is due, in part, to adoption of an inclusive multidisciplinary approach to advance large projects and overarching goals, adopting a deliberative process, limiting research to high-impact publications, and focusing on big projects and concepts (Alberts, 2015).

Still other collaboratives have a much broader focus, engaging wide ranges of stakeholders at every level of society to advance short- and long-term goals and change a culture. The Partnership for a Healthier America (PHA) has more than 150 private-sector partners and supporters, “who are increasing access to healthier, affordable meals; creating safer places for children to play; offering more opportunities for kids to get up and move before, during and after school; and helping parents understand how to provide healthier meals” (PHA, 2015b). Each year, PHA holds a national summit, which gathers health experts, policy makers, and business and industry leaders to talk with nonprofit, academic, and government counterparts to find actionable solutions to improve health and well-being in the United States (PHA, 2015a). Although its focus is not research necessarily, PHA provides an example of how a public–private partnership can have a rapid impact on the consciousness of individuals within the United States to catalyze large-scale changes in behaviors, interventions, and education.

Similarly, the epilepsy advocacy community provides an exemplar for inclusive collaboration that could be easily adapted and quite beneficial to the cardiac arrest field. Like cardiac arrest, the epilepsy field has struggled with limited research funding despite a large public health burden. The Epilepsy Leadership Council includes advocacy organizations, health professional organizations, government agencies, NIH institutes, health care providers, and researchers, and was created to explore opportunities for collaboration, common areas of interest, and funding possibilities within the epilepsy research community (American Epilepsy Society, 2015). The members of the Epilepsy Leadership Council meet on a semiannual basis and have established working groups that focus on surveillance and prevention; health care providers; patients, families, and education; and clinical trials (Jacobs, 2015). Following the release of an IOM report on the public health dimensions of epilepsy in 2012, sudden unexpected death in epilepsy became a condition monitored by the Sudden Death in the Young Registry—a step forward in epilepsy surveillance that holds promised for future epidemiological research (Epilepsy Foundation, 2015; Sudden Cardiac Arrest Foundation, 2015). The Epilepsy Leadership Council also maintains websites that focus on clinical trials and opportunities for participation (HERO, 2015) and education for patients and their families (Jacobs, 2015).

Federal support for research and infrastructure and engagement in public health campaigns is more likely when a field has a united front of advocates to communicate the urgency of a problem, why that problem should be addressed now, and how best to solve the problem. The resuscitation field has the leaders and tools necessary to develop an advocacy network that can help advance the field as a whole in an effort to save lives. Formal collaboration could shape long-term strategies for the field of resuscitation in general, creating an effective advocacy base, unified platform, and evidence-based policies to improve research support and health outcomes from cardiac arrest over the next decade.

CONCLUSION

In conclusion, the committee urges the reprioritization of resuscitation research within the national research agenda. Research is a key component in any national framework to reduce death and disability from cardiac arrest within the next decade. Basic and clinical research offers insights related to the cardiac arrest etiology, pathophysiology, and treatment, and new approaches to the design and conduct of randomized controlled trials may better address the heterogeneity of affected patient populations, cardiac arrest events, and treatment protocols. New technologies and devices are on the near horizon, and regulatory policies and procedures should facilitate rapid evaluation and approval of successful devices and drugs without sacrificing patient safety. Translational research can also inform decisions about how to implement evidence-based practice and spur adoption of emerging therapies and evolving treatment protocols.

Continuous quality improvement is a relatively simple but essential concept to optimize system performance and contribute evidence related to existing treatments and protocols. As new knowledge emerges, local EMS and health care systems have an important responsibility to translate consensus guidelines into local practice protocols that reflect the resources and needs of a specific community. Numerous communities have demonstrated the ability to improve cardiac arrest outcomes through adoption of CQI programs, and these communities should serve as examples to other lower-performing systems. By implementing CQI programs to capture data and generate timely feedback, EMS and health care systems can produce an environment that promotes innovation and inform guideline-setting processes. As more communities begin to engage in data collection and assessment, these data can be used to benchmark additional CQI initiatives, leading to better-informed cardiac arrest research, practice, and policy at national, state, and local levels.

In order to make substantial gains in cardiac arrest treatment, a renewed commitment to resuscitation research support and infrastructure is needed. This commitment requires enhanced transparency and accountability within research-sponsoring organizations and from policy makers for the level and coordination of support dedicated to the treatment of cardiac arrest. This commitment is not likely to occur in a vacuum, however. Examples of successful stakeholder collaborations in various fields demonstrate the potential to effectuate change through coordinated action. With united leadership from key stakeholders, the resuscitation field can elevate its presence and effectively advocate for needed support to engage local, state, and federal stakeholders in a vision to improve cardiac arrest treatment and outcomes through research, evidence-based practice, innovation, and an unwavering commitment to saving lives in communities across the United States.

REFERENCES

• AHA (American Heart Association). Resuscitation fact sheet. 2014. [June 15, 2015]. http://www​.heart.org​/idc/groups/heart-public​/@private/@wcm/@hcm​/agwtg/documents/downloadable​/ucm_434082.pdf.
• Alberts MJ. Can we apply lessons learned in stroke centers to change aspects of cardiac arrest care? Washington, DC: 2015. (Presentation before the Committee on the Treatment of Cardiac Arrest: Current Status and Future Directions).
• Allen BS, Buckberg GD. Studies of isolated global brain ischaemia: I. Overview of irreversible brain injury and evolution of a new concept—redefining the time of brain death. European Journal Cardio-Thoracic Surgery. 2012;41(5):1132–1137. [PubMed: 22398465]
• Allen BS, Ko Y, Buckberg GD, Tan Z. Studies of isolated global brain ischaemia: II. Controlled reperfusion provides complete neurologic recovery following 30 min of warm ischaemia—the importance of perfusion pressure. European Journal Cardio-Thoracic Surgery. 2012a;41(5):1147–1154. [PMC free article: PMC3327862] [PubMed: 22436245]
• Allen BS, Ko Y, Buckberg GD, Tan Z. Studies of isolated global brain ischaemia: III. Influence of pulsatile flow during cerebral perfusion and its link to consistent full neurological recovery with controlled reperfusion following 30 min of global brain ischaemia. European Journal Cardio-Thoracic Surgery. 2012b;41(5):1155–1163. [PMC free article: PMC3327863] [PubMed: 22436247]
• American Epilepsy Society. Introducing Epilepsy Leadership Council. 2015. [June 15, 2015]. https://www​.aesnet.org​/sites/default/files​/file_attach/AboutAES​/AESConnections/Introducing​%20Epilepsy​%20Leadership%20Council.pdf.
• Anderson TC, Li CQ, Shao ZH, Hoang T, Chan KC, Hamann KJ, Becker LB, Vanden Hoek TL. Transient and partial mitochondrial inhibition for the treatment of postresuscitation injury: Getting it just right. Critical Care Medicine. 2006;34(12 Suppl):S474–S482. [PubMed: 17114980]
• Athanasuleas CL, Buckberg GD, Allen BS, Beyersdorf F, Kirsh MM. Sudden cardiac death: Directing the scope of resuscitation towards the heart and brain. Resuscitation. 2006;70(1):44–51. [PubMed: 16759784]
• Aufderheide TP, Nichol G, Rea TD, Brown SP, Leroux BG, Pepe PE, Kudenchuk PJ, Christenson J, Daya MR, Dorian P, Callaway CW, Idris AH, Andrusiek D, Stephens SW, Hostler D, Davis DP, Dunford JV, Pirrallo RG, Stiell IG, Clement CM, Craig A, Van Ottingham L, Schmidt TA, Wang HE, Weisfeldt ML, Ornato JP, Sopko G. A trial of an impedance threshold device in out-of-hospital cardiac arrest. New England Journal of Medicine. 2011;365(9):798–806. [PMC free article: PMC3204381] [PubMed: 21879897]
• Bainey KR, Armstrong PW. Clinical perspectives on reperfusion injury in acute myocardial infarction. American Heart Journal. 2014;167(5):637–645. [PubMed: 24766972]
• Bartos JA, Debaty G, Matsuura T, Yannopoulos D. Post-conditioning to improve cardiopulmonary resuscitation. Current Opinion in Critical Care. 2014;20(3):242–249. [PubMed: 24751810]
• Bartos JA, Matsuura TR, Sarraf M, Youngquist ST, McKnite SH, Rees JN, Sloper DT, Bates FS, Segal N, Debaty G, Lurie KG, Neumar RW, Metzger JM, Riess ML, Yannopoulos D. Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17 min of untreated cardiac arrest. Resuscitation. 2015;87:7–13. [PMC free article: PMC4391969] [PubMed: 25447036]
• Becker LB. New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovascular Research. 2004;61(3):461–470. [PubMed: 14962477]
• Becker LB, Weisfeldt ML, Weil MH, Budinger T, Carrico J, Kern K, Nichol G, Shechter I, Traystman R, Webb C, Wiedemann H, Wise R, Sopko G. The pulse initiative: Scientific priorities and strategic planning for resuscitation research and life saving therapies. Circulation. 2002;105(21):2562–2570. [PubMed: 12034666]
• Berry SM, Connor JT, Lewis RJ. The platform trial: an efficient strategy for evaluating multiple treatments. Journal of American Medical Association. 2015;313(16):1619–1620. [PubMed: 25799162]
• Bigham BL, Koprowicz K, Rea T, Dorian P, Aufderheide TP, Davis DP, Powell J, Morrison LJ. ROC Investigators. Cardiac arrest survival did not increase in the Resuscitation Outcomes Consortium after implementation of the 2005 AHA CPR and ECC guidelines. Resuscitation. 2011;82(8):979–983. [PMC free article: PMC3744665] [PubMed: 21497983]
• Blumberg RS, Dittel B, Hafler D, von Herrath M, Nestle FO. Unraveling the autoimmune translational research process layer by layer. Nature Medicine. 2012;18(1):35–41. [PMC free article: PMC4592149] [PubMed: 22227670]
• Bobrow BJ, Clark LL, Ewy GA, Chikani V, Sanders AB, Berg RA, Richman PB, Kern KB. Minimally interrupted cardiac resuscitation by emergency medical services for out-of-hospital cardiac arrest. Journal of American Medical Association. 2008a;299(10):1158–1165. [PubMed: 18334691]
• Bobrow BJ, Vadeboncoeur TF, Clark L, Chikani V. Establishing Arizona's statewide cardiac arrest reporting and educational network. Prehospital Emergency Care. 2008b;12(3):381–387. [PubMed: 18584508]
• Bobrow BJ, Spaite DW, Berg RA, Stolz U, Sanders AB, Kern KB, Vadeboncoeur TF, Clark LL, Gallagher JV, Stapczynski JS, LoVecchio F, Mullins TJ, Humble WO, Ewy GA. Chest compression-only CPR by lay rescuers and survival from out-of-hospital cardiac arrest. Journal of American Medical Association. 2010;304(13):1447–1454. [PubMed: 20924010]
• Boller M, Jung SK, Odegaard S, Muehlmatt A, Katz JM, Becker LB. A combination of metabolic strategies plus cardiopulmonary bypass improves short-term resuscitation from prolonged lethal cardiac arrest. Resuscitation. 2011;82(Suppl 2):S27–S34. [PubMed: 22208174]
• Bosley JC, Zhao NW, Hill S, Shofer FS, Asch DA, Becker LB, Merchant RM. Decoding Twitter: Surveillance and trends for cardiac arrest and resuscitation communication. Resuscitation. 2013;84(2):206–212. [PMC free article: PMC3634705] [PubMed: 23108239]
• Brain Attack Coalition. About us. [June 8, 2015]. n.d. http://www​.brainattackcoalition​.org/aboutus.html.
• Bro-Jeppesen J, Kjaergaard J, Wanscher M, Nielsen N, Friberg H, Bjerre M, Hassager C. Systemic inflammatory response and potential prognostic implications after out-of-hospital cardiac arrest: A substudy of the target temperature management trial. Critical Care Medicine. 2015;43(6):1223–1232. [PubMed: 25756419]
• CDC (Centers for Disease Control and Prevention). Latest news: CARES funding. 2013a. [June 15, 2015]. https://mycares​.net/sitepages​/latestnews.jsp.
• CDC. Overview: The Cardiac Arrest Registry to Enhance Survival (CARES). 2013b. [June 15, 2015]. https://mycares​.net/sitepages/overview​.jsp.
• CDC. Stroke facts. 2015. [June 15, 2015]. http://www​.cdc.gov/stroke/facts.htm.
• CDC. Million Hearts: The initiative. [June 15, 2015]. n.d. http:​//millionhearts​.hhs.gov/aboutmh/overview.html.
• Chan PS, Spertus JA, Krumholz HM, Berg RA, Li Y, Sasson C, Nallamothu BK. A validated prediction tool for initial survivors of inhospital cardiac arrest. Archives of Internal Medicine. 2012;172(12):947–953. [PMC free article: PMC3517176] [PubMed: 22641228]
• Chan PS, McNally B, Tang F, Kellermann A. Recent trends in survival from out-of-hospital cardiac arrest in the united states. Circulation. 2014;130(21):1876–1882. [PMC free article: PMC4276415] [PubMed: 25399396]
• Chang AM, Leung AC, Saynisch O, Griffis H, Hill S, Hershey JC, Becker LB, Asch DA, Seidman A, Merchant RM. Using a mobile app and mobile workforce to validate data about emergency public health resources. Emergency Medicine Journal. 2013;31(7):545–548. [PMC free article: PMC3883991] [PubMed: 23666486]
• Chang A, Brown LL, Duff JP, Davidson J, Overly F, Tofil NM, Peterson DT, White ML, Bhanji F, Bank I, Gottesman R, Adler M, Zhong J, Grant V, Grant DJ, Sudikoff SN, Marohn K, Charnovich A, Hunt EA, Kessler DO, Wong H, Robertson N, Lin Y, Doan Q, Duval-Arnould JM, Nadkarni VM. Improving cardiopulmonary resuscitation with a CPR feedback device and refresher simulations (CPR CARES study): A randomized clinical trial. JAMA Pediatrics. 2015;169(2):137–144. [PubMed: 25531167]
• Chatalas H, Plorde M, editors. Division of Emergency Medical Services 2014 Annual Report to the King County Council. Seattle, WA: Emergency Medical Services Division of the Public Health Department—Seattle and King County; 2014. [June 8, 2015]. http://www​.kingcounty​.gov/healthservices​/health/%7e/media/health​/publichealth/documents​/ems/2014AnnualReport.ashx.
• Churpek MM, Yuen TC, Park SY, Meltzer DO, Hall JB, Edelson DP. Derivation of a cardiac arrest prediction model using ward vital signs. Critical Care Medicine. 2012;40(7):2102–2108. [PMC free article: PMC3378796] [PubMed: 22584764]
• Cobb LA, Fahrenbruch CE, Walsh TR, Copass MK, Olsufka M, Breskin M, Hallstrom AP. Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation. Journal of American Medical Association. 1999;281(13):1182–1188. [PubMed: 10199427]
• Cronberg T, Lilja G, Horn J, Kjaergaard J, Wise MP, Pellis T, Hovdenes J, Gasche Y, Aneman A, Stammet P, Erlinge D, Friberg H, Hassager C, Kuiper M, Wanscher M, Bosch F, Cranshaw J, Kleger GR, Persson S, Unden J, Walden A, Winkel P, Wetterslev J, Nielsen N. Neurologic function and health-related quality of life in patients following targeted temperature management at 33 degrees C vs 36 degrees C after out-of-hospital cardiac arrest: a randomized clinical trial. JAMA Neurology. 2015;72(6):634–641. [PubMed: 25844993]
• Crossley GH, Boyle A, Vitense H, Chang Y, Mead RH. The connect (clinical evaluation of remote notification to reduce time to clinical decision) trial: The value of wireless remote monitoring with automatic clinician alerts. Journal of the American College of Cardiology. 2011;57(10):1181–1189. [PubMed: 21255955]
• Daniels RJ. A generation at risk: Young investigators and the future of the biomedical workforce. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(2):313–318. [PMC free article: PMC4299207] [PubMed: 25561560]
• Deasy C, Bray JE, Smith K, Wolfe R, Harriss LR, Bernard SA, Cameron P. Cardiac arrest outcomes before and after the 2005 resuscitation guidelines implementation: Evidence of improvement? Resuscitation. 2011;82(8):984–988. [PubMed: 21536367]
• Donoghue AJ, Nadkarni V, Berg RA, Osmond MH, Wells G, Nesbitt L, Stiell IG. Out-of-hospital pediatric cardiac arrest: An epidemiologic review and assessment of current knowledge. Annals of Emergency Medicine. 2005;46(6):512–522. [PubMed: 16308066]
• Epilepsy Foundation. SUDEP surveillance efforts. 2015. [June 15, 2015]. http://www​.epilepsy.com​/get-help/sudep-institute​/sudep-surveillance-efforts.
• Ewy GA, Kern KB, Sanders AB, Newburn D, Valenzuela TD, Clark L, Hilwig RW, Otto CW, Hayes MM, Martinez P, Berg RA. Cardiocerebral resuscitation for cardiac arrest. The American Journal of Medicine. 2006;119(1):6–9. [PubMed: 16431175]
• FDA (U.S. Food and Drug Administration). Medical devices: Protecting patients and promoting innovation. 2011. [June 15, 2015]. http://www​.fda.gov/NewsEvents​/Testimony/ucm278960.htm.
• FDA. PMA clinical studies. 2014. [June 15, 2015]. http://www​.fda.gov/MedicalDevices​/DeviceRegulationandGuidance​/HowtoMarketYourDevice​/PremarketSubmissions​/PremarketApprovalPMA/ucm050419.htm.
• FDA. Draft guidance for industry and Food and Drug Administration staff: adaptive designs for medical device clinical studies. 2015a. [June 15, 2015]. http://www​.fda.gov/ucm​/groups/fdagov-public​/@fdagov-meddev-gen​/documents/document/ucm446729.pdf.
• FDA. Effective date of requirement for premarket approval for automated external defibrillator systems (republication). Federal Register. 2015b;80:5674–5683. [PubMed: 25730922]
• FDA. Mobile medical applications: Guidance for industry and Food and Drug Administration staff. Code of Federal Regulation. 2015c;21(870):5674–5683.
• Feldman AM, Klein H, Tchou P, Murali S, Hall WJ, Mancini D, Boehmer J, Harvey M, Heilman MS, Szymkiewicz SJ, Moss AJ. Use of a wearable defibrillator in terminating tachyarrhythmias in patients at high risk for sudden death: Results of the WEARIT/BIROAD. Pacing and Clinical Electrophysiology. 2004;27(1):4–9. [PubMed: 14720148]
• Fischer H, Gruber J, Neuhold S, Frantal S, Hochbrugger E, Herkner H, Schochl H, Steinlechner B, Greif R. Effects and limitations of an AED with audiovisual feedback for cardiopulmonary resuscitation: A randomized manikin study. Resuscitation. 2011;82(7):902–907. [PubMed: 21454006]
• Frohlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ. Myocardial reperfusion injury: Looking beyond primary PCI. European Heart Journal. 2013;34(23):1714–1722. [PubMed: 23536610]
• Gazmuri RJ, Nadkarni VM, Nolan JP, Arntz HR, Billi JE, Bossaert L, Deakin CD, Finn J, Hammill WW, Handley AJ, Hazinski MF, Hickey RW, Jacobs I, Jauch EC, Kloeck WGJ, Mattes MH, Montgomery WH, Morley P, Morrison LJ, Nichol G, O'Connor RE, Perlman J, Richmond S, Sayre M, Shuster M, Timerman S, Weil MH, Weisfeldt ML, Zaritsky A, Zideman DA. Scientific knowledge gaps and clinical research priorities for cardiopulmonary resuscitation and emergency cardiovascular care identified during the 2005 international consensus conference on ECC and CPR science with treatment recommendations: A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian Resuscitation Council, European Resuscitaiton Countil, Heart and Stroke Foundation of Canada, Interamerican Heart Foundation, Resuscitation Council of Southern Africa, and the New Zealand Resuscitation Council); the American Heart Association Emergency Cardiovascular Care Committee; the Stroke Council; and the Cardiovascular Nursing Council. Circulation. 2007;116(21):2501–2512. [PubMed: 17993477]
• Hallstrom A, Rea TD, Sayre MR, Christenson J, Anton AR, Mosesso VN Jr., Van Ottingham L, Olsufka M, Pennington S, White LJ, Yahn S, Husar J, Morris MF, Cobb LA. Manual chest compression vs use of an automated chest compression device during resuscitation following out-of-hospital cardiac arrest: A randomized trial. Journal of American Medical Association. 2006;295(22):2620–2628. [PubMed: 16772625]
• HERO (Human Epilepsy Research Opportunities). Heroes and clinical research. 2015. [June 12, 2015]. http://www​.epilepsyhero.org.
• HHS (U.S. Department of Health and Human Services). Guidance for industry: Adaptive design clinical trials for drugs and biologics. 2010. [June 15, 2015]. http://www​.fda.gov/downloads​/Drugs/GuidanceComplianceRegulatoryInformation​/Guidances/UCM201790.pdf.
• Hinchey PR, Myers JB, Lewis R, De Maio VJ, Reyer E, Licatese D, Zalkin J, Snyder G. Improved out-of-hospital cardiac arrest survival after the sequential implementation of 2005 AHA guidelines for compressions, ventilations, and induced hypothermia: The wake county experience. Annals of Emergency Medicine. 2010;56(4):348–357. [PubMed: 20359771]
• Honeyman E, Ding H, Varnfield M, Karunanithi M. Mobile health applications in cardiac care. Interventional Cardiology. 2014;6(2):227–240.
• Humphrey HH. Congressional Record. Oct 13, 1962. pp. A7837–A7839.
• IOM (Institute of Medicine). Clinical practice guidelines: Directions for a new program. Washington, DC: National Academy Press; 1990. [PubMed: 25144032]
• IOM. Small clinical trials issues and challenges. Washington, DC: National Academy Press; 2001. [PubMed: 25057552]
• IOM. Best care at lower cost: The path to continuously learning health care in America. Washington, DC: The National Academies Press; 2013a. [PubMed: 24901184]
• IOM. The CTSA program at NIH: Opportunities for advancing clinical research and translational research. Washington, DC: The National Academies Press; 2013b. [PubMed: 24199260]
• IOM. Future directions of credentialing research in nursing: Workshop summary. Washington, DC: The National Academies Press; 2014. [PubMed: 25927129]
• Jacobs MP. Epilepsy: A model for collaborating—post IOM report. 2015. [June 15, 2015]. http://www​.hhs.gov/advcomcfs​/meetings/presentations​/iom-epilepsy-experiencemargaret-jacobs-june-2014.pdf.
• Johnson NJ, Acker M, Hsu CH, Desai N, Vallabhajosyula P, Lazar S, Horak J, Wald J, McCarthy F, Rame E, Gray K, Perman SM, Becker LB, Cowie D, Grossestreuer A, Smith T, Gaieski DF. Extracorporeal life support as rescue strategy for out-of-hospital and emergency department cardiac arrest. Resuscitation. 2014;85(11):1527–1532. [PubMed: 25201611]
• Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs preconditioning. Redox Biology. 2014;2:702–714. [PMC free article: PMC4060303] [PubMed: 24944913]
• Kampmeier TG, Lukas RP, Steffler C, Sauerland C, Weber TP, Van Aken H, Bohn A. Chest compression depth after change in CPR guidelines—improved but not sufficient. Resuscitation. 2014;85(4):503–508. [PubMed: 24418280]
• Kirves H, Skrifvars MB, Vahakuopus M, Ekstrom K, Martikainen M, Castren M. Adherence to resuscitation guidelines during prehospital care of cardiac arrest patients. European Journal of Emergency Medicine. 2007;14(2):75–81. [PubMed: 17496680]
• Krumholz HM, Normand SL, Wang Y. Trends in hospitalizations and outcomes for acute cardiovascular disease and stroke, 1999-2011. Circulation. 2014;130(12):966–975. [PMC free article: PMC4171056] [PubMed: 25135276]
• Lathrop D. Charge to the consensus study committee treatment of cardiac arrest: Current status and future directions; Presentation at the first meeting of the Committee on Treatment of Cardiac Arrest: Current Status and Future Directions; Washington, DC. 2014. [June 8, 2015]. https://www​.iom.edu/~​/media/Files/Activity%20Files​/PublicHealth​/TreatmentofCardiacArrest​/2014-MAR-12/IOM%20-%20Lathrop​.pdf.
• Lauer MS, D'Agostino RB. The randomized registry trial—the next disruptive technology in clinical research? New England Journal of Medicine. 2013;369(17):1579–1581. [PubMed: 23991657]
• Lavani R, Chang WT, Anderson T, Shao ZH, Wojcik KR, Li CQ, Pietrowski R, Beiser DG, Idris AH, Hamann KJ, Becker LB, Vanden Hoek TL. Altering CO₂ during reperfusion of ischemic cardiomyocytes modifies mitochondrial oxidant injury. Critical Care Medicine. 2007;35(7):1709–1716. [PubMed: 17522572]
• Lavine KJ, Mann DL. Rethinking phase II clinical trial design in heart failure. Clinical Investigation. 2012;3(1):57–68. [PMC free article: PMC4204480] [PubMed: 25343020]
• Lee BK, Olgin JE. Role of wearable and automatic external defibrillators in improving survival in patients at risk for sudden cardiac death. Current Treatment Options in Cardiovascular Mediicne. 2009;11(5):360–365. [PubMed: 19846033]
• Martin P, Theobald P, Kemp A, Maguire S, Maconochie I, Jones M. Real-time feedback can improve infant manikin cardiopulmonary resuscitation by up to 79%—a randomised controlled trial. Resuscitation. 2013;84(8):1125–1130. [PubMed: 23571117]
• Mazor KM, Sabin JE, Boudreau D, Goodman MJ, Gurwitz JH, Herrinton LJ, Raebel MA, Roblin D, Smith DH, Meterko V, Platt R. Cluster randomized trials: Opportunities and barriers identified by leaders of eight health plans. Medical Care. 2007;45(10 Supl 2):S29–S37. [PubMed: 17909379]
• McAuley DF, O'Kane C, Griffiths MJ. A stepwise approach to justify phase III randomized clinical trials and enhance the likelihood of a positive result. Critical Care Medicine. 2010;38(10 Suppl):S523–S527. [PubMed: 21164392]
• Meaney PA, Bobrow BJ, Mancini ME, Christenson J, de Caen AR, Bhanji F, Abella BS, Kleinman ME, Edelson DP, Berg RA, Aufderheide TP, Menon V, Leary M. Cardiopulmonary resuscitation quality: [corrected] improving cardiac resuscitation outcomes both inside and outside the hospital: A consensus statement from the American Heart Association. Circulation. 2013;128(4):417–435. [PubMed: 23801105]
• Meurer WJ, Lewis RJ, Berry DA. Adaptive clinical trials: A partial remedy for the therapeutic misconception? Journal of American Medical Association. 2012;307(22):2377–2378. [PubMed: 22692168]
• Minnerup J, Wersching H, Schilling M, Schabitz WR. Analysis of early phase and subsequent phase III stroke studies of neuroprotectants: Outcomes and predictors for success. Experimental and Translational Stroke Medicine. 2014;6(1):2. [PMC free article: PMC3922860] [PubMed: 24502346]
• Morrison LJ, Neumar RW, Zimmerman JL, Link MS, Newby LK, McMullan PW Jr., Hoek TV, Halverson CC, Doering L, Peberdy MA, Edelson DP. Strategies for improving survival after in-hospital cardiac arrest in the United States: 2013 consensus recommendations: A consensus statement from the American Heart Association. Circulation. 2013;127(14):1538–1563. [PubMed: 23479672]
• Movahed MR, Khan MF, Hashemzadeh M, Hashemzadeh M. Gradual decline in the age-adjusted in-hospital mortality rate from STEMI-related cardiogenic shock irrespective of cause, race or gender with persistent higher mortality rates in women despite multivariate adjustment. Journal of Invasive Cardiology. 2014;26(1):7–12. [PubMed: 24402804]
• Myerburg RJ, Ullmann SG. Alternative research funding to improve clinical outcomes: The model of prediction and prevention of sudden cardiac death. Circulation: Arrhythmia and Electrophysiology. 2015;8(2):492–498. [PubMed: 25669654]
• NACCHO (National Association of County and City Health Organizations). Pulling together 5: Section two: Building collaboration. 2014. [June 8, 2015]. http://www​.naccho.org​/topics/environmental​/pullingtogether/sectiontwo.cfm.
• Nagao K, Hayashi N, Kanmatsuse K, Arima K, Ohtsuki J, Kikushima K, Watanabe I. Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy and mild hypothermia in patients with cardiac arrest outside the hospital. Journal of the American College of Cardiology. 2000;36(3):776–783. [PubMed: 10987599]
• Nagao K, Kikushima K, Watanabe K, Tachibana E, Tominaga Y, Tada K, Ishii M, Chiba N, Kasai A, Soga T, Matsuzaki M, Nishikawa K, Tateda Y, Ikeda H, Yagi T. Early induction of hypothermia during cardiac arrest improves neurological outcomes in patients with out-of-hospital cardiac arrest who undergo emergency cardiopulmonary bypass and percutaneous coronary intervention. Circulation Journal. 2010;74(1):77–85. [PubMed: 19942784]
• National Learning Consortium. Continuous quality improvement (CQI) strategies to optimize your practice. 2013. [June 15, 2015]. https://www​.healthit​.gov/sites/default/files​/tools/nlc_continuousqualityimprovementprimer.pdf.
• Neumar RW. From science to guidelines: The future for resuscitation. Signa Vitae. 2010;5(Suppl 1):10–12.
• Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, Kudenchuk PJ, Ornato JP, McNally B, Silvers SM, Passman RS, White RD, Hess EP, Tang W, Davis D, Sinz E, Morrison LJ. Part 8: Adult advanced cardiovascular life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18 Suppl 3):S729–S767. [PubMed: 20956224]
• NHTSA (National Highway Traffic Safety Administration). Emergency medical services performance measures: Recommended attributes and indicators for system and service performance. Washington, DC: NHTSA; 2009. [June 15, 2015]. http://www​.ems.gov/pdf/811211.pdf.
• NIBIB (National Institute of Biomedical Imaging and Bioengineering). About NIBIB: Mission. 2015. [June 15, 2015]. http://www​.nibib.nih.gov/about-nibib.
• Nichol G, Karmy-Jones R, Salerno C, Cantore L, Becker L. Systematic review of percutaneous cardiopulmonary bypass for cardiac arrest or cardiogenic shock states. Resuscitation. 2006;70(3):381–394. [PubMed: 16828957]
• Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Åneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Køber L, Langørgen J, Lilja G, Møller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H. Targeted temperature management at 33°C versus 36°C after cardiac arrest. New England Journal of Medicine. 2013;369(23):2197–2206. [PubMed: 24237006]
• NIH (National Institutes of Health). News and events: NIH creates Office of Emergency Care Research. 2012a. [June 15, 2015]. http://www​.nih.gov/news​/health/jul2012/nih31.htm.
• NIH. NIH factsheet—NIH: Turning discovery into health. Washington, DC: U.S. Department of Health and Human Services; 2012b. [June 15, 2015]. http://www​.oar.nih.gov​/factsheets/pdfs/NIH​_FS_NIHandNIHAIDSResearch.pdf.
• NIH. Frequently asked questions about implementation science. 2013a. [June 15, 2015]. http://www​.fic.nih.gov​/News/Events/implementation-science​/Pages/faqs.aspx.
• NIH. News and events: Dr. Jeremy Brown to direct NIH Office of Emergency Care Research. 2013b. [June 15, 2015]. http://www​.nih.gov/news​/health/jun2013/nigms-25.htm.
• NIH. Division of Cardiovascular Sciences (DCVS): Heart Failure & Arrhythmias Branch. 2014. [June 15, 2015]. http://www​.nhlbi.nih.gov/about/org/dcvs.
• NIH. Estimates of funding for various research, condition, and disease categories (RCDC). 2015a. [June 15, 2015]. http://report​.nih.gov​/categorical_spending.aspx.
• NIH. National Center for Advancing Translational Sciences: Communities and research. 2015b. [June 8, 2015]. http://www​.ncats.nih.gov/ctsa/community.
• NIH. NIH emergency care research and training activities. 2015c. [June 16, 2015]. http://www​.nigms.nih​.gov/about/overview/OECR/pages/programs​.aspx.
• Nolan JP, Neumar RW, Adrie C, Aibiki M, Berg RA, Bbttiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT, Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP, Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Vanden Hoek T. Post-cardiac arrest syndrome: Epidemiology, pathophysiology, treatment, and prognostication: A scientific statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Council on Stroke (part II). International Emergency Nursing. 2010;18(1):8–28. [PubMed: 20129438]
• Ong ME, Lee Ng CH, Goh K, Liu N, Koh ZX, Shahidah N, Zhang TT, Fook-Chong S, Lin Z. Prediction of cardiac arrest in critically ill patients presenting to the emergency department using a machine learning score incorporating heart rate variability compared with the modified early warning score. Critical Care. 2012a;16(3):R108. [PMC free article: PMC3580666] [PubMed: 22715923]
• Ong ME, Mackey KE, Zhang ZC, Tanaka H, Ma MH, Swor R, Shin SD. Mechanical CPR devices compared to manual CPR during out-of-hospital cardiac arrest and ambulance transport: A systematic review. Scandinavian Journal of Trauma, Resuscitation & Emergency Medicine. 2012b;20:39. [PMC free article: PMC3416709] [PubMed: 22709917]
• Ornato JP. Resuscitation Outcomes Consortium; Presentation before the Committee on the Treatment of Cardiac Arrest: Current Status and Future Directions; Washington, DC. 2015.
• Ornato JP, Becker LB, Weisfeldt ML, Wright BA. Cardiac arrest and resuscitation: An opportunity to align research prioritization and public health need. Circulation. 2010;122(18):1876–1879. [PubMed: 20956205]
• Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues in Clinical NeuroSciences. 2011;13(2):217–224. [PMC free article: PMC3181997] [PubMed: 21842619]
• PCORI (Patient-Centered Outcomes Research Institute). What we do. 2014. [June 15, 2015]. http://www​.pcori.org/about-us/what-we-do.
• Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, Gabrielli A, Silvers SM, Zaritsky AL, Merchant R, Vanden Hoek TL, Kronick SL. American Heart Association. Part 9: Post-cardiac arrest care: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18 Suppl 3):S768–S786. [PubMed: 20956225]
• PHA (Partnership for a Healthier America). Building a healthier future summit. 2015a. [June 12, 2015]. http:​//ahealthieramerica​.org/summit/about-the-summit.
• PHA. The foundation rises: Constructing a legacy of good health. 2015b. [June 8, 2015]. http:​//progressreports​.ahealthieramerica​.org/2014/making-strides.
• PHA. Let's move! 2015c. [June 15, 2015]. http:​//ahealthieramerica​.org/about/lets-move.
• Pirrallo RG, Aufderheide TP, Provo TA, Lurie KG. Effect of an inspiratory impedance threshold device on hemodynamics during conventional manual cardiopulmonary resuscitation. Resuscitation. 2005;66(1):13–20. [PubMed: 15993724]
• Plorde M, Hearne T, Bradshaw C, editors. Division of Emergency Medical Services 2005Annual Report to the King County Council. Seattle, WA: Emergency Medical Services Division of the Public Health Department—Seattle and King County; 2005. [June 8, 2015]. http://www​.kingcounty​.gov/healthservices​/health/%7e/media/health​/publichealth/documents​/ems/2014AnnualReport.ashx.
• Proctor E, Silmere H, Raghavan R, Hovmand P, Aarons G, Bunger A, Griffey R, Hensley M. Outcomes for implementation research: Conceptual distinctions, measurement challenges, and research agenda. Administration and Policy in Mental Health. 2011;38(2):65–76. [PMC free article: PMC3068522] [PubMed: 20957426]
• Przybylski A, Zakrzewska-Koperska J, Maciag A, Derejko P, Orczykowski M, Szumowski L, Walczak F. Technical and practical aspects of remote monitoring of implantable cardioverter-defibrillator patients in poland—preliminary results. Kardiologia Polska. 2009;67(5):505–511. [PubMed: 19521935]
• PulsePoint. PulsePoint. 2015. [June 15, 2015]. http://www​.pulsepoint.org.
• Rea TD, Helbock M, Perry S, Garcia M, Cloyd D, Becker L, Eisenberg M. Increasing use of cardiopulmonary resuscitation during out-of-hospital ventricular fibrillation arrest: Survival implications of guideline changes. Circulation. 2006;114(25):2760–2765. [PubMed: 17159062]
• Resuscitation Academy. 10 steps for improving survival from sudden cardiac arrest. 2013. [June 15, 2015]. http://www​.resuscitationacademy​.com/downloads​/ebook/TenStepsforImprovingSurvivalFromSuddenCardiacArrest-RA-eBook-PDFFinalv1_2.pdf.
• Resuscitation Academy. Strategies to improve survival from sudden cardiac arrest: An evidence based analysis. 2014. [June 15, 2015]. http://www​.resuscitationacademy​.com/downloads​/RA-35-Strategies-to-Improve-CA-SUrvival.pdf.
• Retzios AD. Why do so many phase 3 clinical trials fail? Issues in Clinical Research: Bay Clinical R&D Services. 2009:1–46.
• Reynolds DW, Jayaprasad N, Francis J. Remote monitoring of implantable cardioverter defibrillator. Indian Pacing and Electrophysiology Journal. 2006;6(4):186–188. [PMC free article: PMC1586158] [PubMed: 17031410]
• Rickard J, Ahmed S, Baruch M, Klocman B, Martin DO, Menon V. Utility of a novel watch-based pulse detection system to detect pulselessness in human subjects. Heart Rhythm. 2011;8(12):1895–1899. [PubMed: 21802393]
• Riess ML, Matsuura TR, Bartos JA, Bienengraeber M, Aldakkak M, McKnite SH, Rees JN, Aufderheide TP, Sarraf M, Neumar RW, Yannopoulos D. Anaesthetic postconditioning at the initiation of CPR improves myocardial and mitochondrial function in a pig model of prolonged untreated ventricular fibrillation. Resuscitation. 2014;85(12):1745–1751. [PMC free article: PMC4276313] [PubMed: 25281906]
• Ringh M, Fredman D, Nordberg P, Stark T, Hollenberg J. Mobile phone technology identifies and recruits trained citizens to perform CPR on out-of-hospital cardiac arrest victims prior to ambulance arrival. Resuscitation. 2011;82(12):1514–1518. [PubMed: 21854731]
• Rubio DM, Schoenbaum EE, Lee LS, Schteingart DE, Marantz PR, Anderson KE, Platt LD, Baez A, Esposito K. Defining translational research: Implications for training. Academic Medicine. 2010;85(3):470–475. [PMC free article: PMC2829707] [PubMed: 20182120]
• RWJF (Robert Wood Johnson Foundation). The science of continuous quality improvement. 2014. [June 8, 2015]. http://www​.rwjf.org/en​/how-we-work/rel/researchfeatures​/evaluating-CQI.html.
• Sakai T, Iwami T, Kitamura T, Nishiyama C, Kawamura T, Kajino K, Tanaka H, Marukawa S, Tasaki O, Shiozaki T, Ogura H, Kuwagata Y, Shimazu T. Effectiveness of the new “mobile AED map” to find and retrieve an AED: A randomised controlled trial. Resuscitation. 2011;82(1):69–73. [PubMed: 21051130]
• Sakai T, Kitamura T, Nishiyama C, Murakami Y, Ando M, Kawamura T, Tasaki O, Kuwagata Y, Shimazu T, Iwami T. Cardiopulmonary resuscitation support application on a smartphone-randomized controlled trial. Circulation Journal. 2015;79(5):1052–1057. [PubMed: 25740350]
• Sasson C, Rogers MAM, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: A systematic review and metaanalysis. Circulation: Cardiovascular Quality and Outcomes. 2010;3(1):63–81. [PubMed: 20123673]
• Schackman BR. Implementation science for the prevention and treatment of HIV/AIDS. Journal of Acquired Immune Deficiency Syndrome. 2010;55(Suppl 1):S27–S31. [PMC free article: PMC3058234] [PubMed: 21045596]
• Scholten AC, van Manen JG, van der Worp WE, Ijzerman MJ, Doggen CJ. Early cardiopulmonary resuscitation and use of automated external defibrillators by laypersons in out-of-hospital cardiac arrest using an SMS alert service. Resuscitation. 2011;82(10):1273–1278. [PubMed: 21652136]
• Slattery D, McNally B. CARES sustainability discussion: Subscription model; Presentation during CARES Webinar; 2015. [June 15, 2015]. https://mycares​.net/sitepages​/latestnews.jsp.
• Stiell IG, Nichol G, Leroux BG, Rea TD, Ornato JP, Powell J, Christenson J, Callaway CW, Kudenchuk PJ, Aufderheide TP, Idris AH, Daya MR, Wang HE, Morrison LJ, Davis D, Andrusiek D, Stephens S, Cheskes S, Schmicker RH, Fowler R, Vaillancourt C, Hostler D, Zive D, Pirrallo RG, Vilke GM, Sopko G, Weisfeldt M. Early versus later rhythm analysis in patients with out-of-hospital cardiac arrest. New England Journal of Medicine. 2011;365(9):787–797. [PMC free article: PMC3181067] [PubMed: 21879896]
• Stiell IG, Brown SP, Christenson J, Cheskes S, Nochol G, Powell J, Bigham B, Morrison LJ, Larsen J, Hess E, Vaillancourt C, Davis DP, Callaway CW. Resuscitation Outcomes Consortium (ROC) Investigators. What is the role of chest compression depth during out-of-hospital cardic arrest resuscitation. Critical Care Medicine. 2012;40(4):1192–1198. [PMC free article: PMC3307954] [PubMed: 22202708]
• Straus SE, Moore JE, Uka S, Marquez C, Gulmezoglu AM. Determinants of implementation of maternal health guidelines in Kosovo: Mixed methods study. Implementation Science. 2013;8:108. [PMC free article: PMC3846581] [PubMed: 24016149]
• Stub D, Bernard S, Pellegrino V, Smith K, Walker T, Sheldrake J, Hockings L, Shaw J, Duffy SJ, Burrell A, Cameron P, Smit de V, Kaye DM. Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation. 2015a;86:88–94. [PubMed: 25281189]
• Stub D, Schmicker RH, Anderson ML, Callaway CW, Daya MR, Sayre MR, Elmer J, Grunau BE, Aufderheide TP, Lin S, Buick JE, Zive D, Peterson ED, Nichol G. Association between hospital post-resuscitative performance and clinical outcomes after out-of-hospital cardiac arrest. Resuscitation. 2015b;92:45–52. [PubMed: 25917263]
• Sudden Cardiac Arrest Foundation. NIH and CDC announce grantees for the sudden death in the young registry. 2015. [June 12, 2015]. http://www​.sca-aware​.org/scanews/nih-and-cdc-announce-grantees-for-the-sudden-death-in-the-young-registry.
• Tabak RG, Khoong EC, Chambers DA, Brownson RC. Bridging research and practice: Models for dissemination and implementation research. American Journal of Preventive Medicine. 2012;43(3):337–350. [PMC free article: PMC3592983] [PubMed: 22898128]
• Taniguchi D, Baernstein A, Nichol G. Cardiac arrest: A public health perspective. Emergency Medicine Clinics of North America. 2012;30(1):1–12. [PubMed: 22107970]
• Thompson WL, Bellamy R, Cummins RO, Delooz HH, Dick W, Kochanek PM, Ornato JP, Ricci EM, Weil MH, Winter PM. Funding resuscitation research. Critical Care Medicine. 1996;24(2 Suppl):S90–S94. [PubMed: 8608710]
• Travers AH, Rea TD, Bobrow BJ, Edelson DP, Berg RA, Sayre MR, Berg MD, Chameides L, O'Connor RE, Swor RA. Part 4: CPR overview: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18 Suppl 3):S676–S684. [PubMed: 20956220]
• Trummer G, Foerster K, Buckberg GD, Benk C, Heilmann C, Mader I, Feuerhake F, Liakopoulos O, Brehm K, Beyersdorf F. Successful resuscitation after prolonged periods of cardiac arrest: A new field in cardiac surgery. Journal of Thoracic and Cardiovascular Surgery. 2010;139(5):1325–1332. [PubMed: 20412965]
• Trummer G, Foerster K, Buckberg GD, Benk C, Mader I, Heilmann C, Liakopoulos O, Beyersdorf F. Superior neurologic recovery after 15 minutes of normothermic cardiac arrest using an extracorporeal life support system for optimized blood pressure and flow. Perfusion. 2014;29(2):130–138. [PubMed: 23885022]
• TU Delft (Delft University of Technology). TU Delft's ambulance drone drastically increases chances of survival of cardiac arrest patients. 2014. [June 15, 2015]. http://www​.tudelft.nl​/en/current/latest-news​/article/detail/ambulance-dronetu-delft-vergroot-overlevingskans-bij-hartstilstand-drastisch.
• VA (U.S. Department of Veterans Affairs). Combined assessment program summary report: Evaluation of quality management in Veterans Health Administration facilities fiscal year 2014. Washington, DC: U.S. Department of Veterans Affairs; 2015. [June 15, 2015]. (Report no. 14-00378-208). http://www​.va.gov/oig​/pubs/VAOIG-14-00378-208.pdf.
• Virginia Commonwealth University. Researchers form consortium to study post-cardiac arrest patients. 2011. [June 15, 2015]. http://www​.cctr.vcu.edu​/news/feature/consortium.html.
• Volpicelli G. Usefulness of emergency ultrasound in nontraumatic cardiac arrest. American Journal of Emergency Medicine. 2011;29(2):216–223. [PubMed: 20825919]
• Wallace SK, Abella BS, Becker LB. Quantifying the effect of cardiopulmonary resuscitation quality on cardiac arrest outcome: A systematic review and meta-analysis. Circulation: Cardiovascular Quality and Outcomes. 2013;6(2):148–156. [PubMed: 23481533]
• Wallmuller C, Sterz F, Testori C, Schober A, Stratil P, Horburger D, Stockl M, Weiser C, Kricanac D, Zimpfer D, Deckert Z, Holzer M. Emergency cardio-pulmonary bypass in cardiac arrest: Seventeen years of experience. Resuscitation. 2013;84(3):326–330. [PubMed: 22800860]
• Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: A 3-phase time-sensitive model. Journal of American Medical Association. 2002;288(23):3035–3038. [PubMed: 12479769]
• Wik L, Olsen JA, Persse D, Sterz F, Lozano M Jr., Brouwer MA, Westfall M, Souders CM, Malzer R, van Grunsven PM, Travis DT, Whitehead A, Herken UR, Lerner EB. Manual vs. Integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial. Resuscitation. 2014;85(6):741–748. [PubMed: 24642406]
• Wolcke BB, Mauer DK, Schoefmann MF, Teichmann H, Provo TA, Lindner KH, Dick WF, Aeppli D, Lurie KG. Comparison of standard cardiopulmonary resuscitation versus the combination of active compression-decompression cardiopulmonary resuscitation and an inspiratory impedance threshold device for out-of-hospital cardiac arrest. Circulation. 2003;108(18):2201–2205. [PubMed: 14568898]
• Yannopoulos D. Guiding medical therapy for cardiac arrest with physiological based observations and solutions; Presentation at the third meeting of the IOM's Committee on Treatment of Cardiac Arrest: Current Status and Future Directions; 2014. [June 15, 2015]. https://www​.iom.edu/~​/media/Files/Activity%20Files​/PublicHealth​/TreatmentofCardiacArrest​/August%202014​/Yannopoulos%20IOM​%20presentation%208-25-14.pdf.

Footnotes

1

CMS and CDC are joint leaders of the Million Hearts Initiative, which focuses on the prevention of heart attacks and stroke (CDC, n.d.).

2

Personal communication with J. Brown, NIH, May 22, 2015.