Sudden Cardiac Arrest Research Paper

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Definition

Sudden cardiac arrest (SCA) is a substantial public health problem that is challenging to investigate, prevent, and treat in part because there are no universally accepted criteria to readily classify the condition. The fundamental elements of the definition are comprised of (1) an unexpected event, (2) characterized by cardiovascular collapse, and (3) due to an underlying cardiac cause. Translation of these conceptual tenets to clinical circumstances can be problematic. For example, one consensus definition defines SCA as ‘natural death due to cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms; pre-existing heart disease may have been known to be present, but the time and mode of death are unexpected’ (Priori et al., 2002; Myerburg and Castellanos, 1997).

Even this well-reasoned definition has important limitations. Not all SCA is fatal and in fact hundreds of thousands of persons receive attempted resuscitation in North America and Europe each year (Rea et al., 2004a; Atwood et al., 2005). Though survival is modest, resuscitation has a measurable public health impact as tens of thousands of persons survive each year (Rea et al., 2003a, 2004; Atwood et al., 2005). The exact mode of the event may not be readily determined. Most patients do not receive medical monitoring during the event or an autopsy afterward. Symptoms such as dyspnea prior to collapse in an individual with both heart and lung disease may obscure the primary etiology. Moreover, many deaths potentially attributable to SCA are not witnessed so that symptoms and diagnostics are not available to help determine etiology. The lack of a witness can also make application of a discrete, time-based requisite such as 1 h often infeasible. (Whether 1 h has specific clinical or research importance is not certain.) As a consequence, supplemental information may be used to assess the etiology and time course. For example, death certificates that code cause of death as heart disease and location of death as occurring outside the hospital can be used as an alternative approach (Fox et al., 2005). However, death certificates alone tend to overclassify death due to heart disease (Narang et al., 1994; Iribarren et al., 1998; Lloyd-Jones et al., 1998; Chugh et al., 2004). Although the out-of-hospital location provides a surrogate for an unexpected event, some heart disease deaths outside the hospital are expected and/or gradual (Narang et al., 1994). Conversely, SCA also occurs in hospital, though the relative magnitude of in-hospital SCA is unclear (Peberdy et al., 2003).

Taken together, a universal and readily applied definition of SCA is not available. The choice of an SCA definition will be influenced by the aims of particular investigation or clinical program and the availability of resources to derive the SCA population of interest. Given the consequent heterogeneity of SCA definitions, one must appreciate the strengths and limitations of a particular definition when considering studies of SCA incidence and outcome.

Epidemiology

Attributable Mortality

Even with the limitations of the definition, SCA appears to be one of the most common causes of death worldwide. More deaths are attributed to SCA in Western, industrialized societies than other diseases such as stroke, lung cancer, breast cancer, or AIDS. Given the limitations inherent in the definition, estimates of the total mortality attributed to SCA vary from 5% to 15%, or one-quarter to one-half of heart disease death (Zheng et al., 2001; Chugh et al., 2004; Siscovick and Podrid, 2007). Applied to the US population for example, out-of-hospital SCA would account for between 150 000 and 450 000 deaths annually. The population burden of SCA in developing societies is not well investigated, although attributable mortality appears to be less but perhaps increasing. The lower attributable mortality is likely due to a number of factors including the younger populations and the greater competing causes of mortality in these countries.

Incidence

Incidence is the number of SCA events per population per year and similarly reflects the particular definition used to determine SCA. For example, incidence of SCA was 162 per 100 000 residents in the US using death certificate ascertainment (Zheng et al., 2001). In contrast, the incidence of SCA receiving attempted resuscitation was 54 per 100 000 person-years in the United States and 37 per 100 000 person-years in Europe (Rea et al., 2004a; Atwood et al., 2005). A third approach incorporating death certificate, clinical information, and emergency medical services information in an attempt to both accurately and comprehensively identify SCA produced an overall SCA incidence estimate of 190 per 100 000 person-years among persons age 50–79 in a large U.S. health maintenance organization (Rea et al., 2004b). Based on published reports from the World Health Organization, incidence of heart disease death varies greatly; for example, the age-adjusted mortality rate from CHD is sevenfold greater in Russia than in Japan (Rosamond et al., 2007). Such variation in total heart disease mortality likely translates to substantial variation in SCA incidence across countries.

Importantly, the incidence of SCA appears to be declining over time in many developed nations (Goldberg, 1989; de Vreede-Swagemakers et al., 1997; Kuisma et al., 1999; Herlitz et al., 2000; Zheng et al., 2001; Rea et al., 2004b). The absolute rate of decline is not clear, but multiple studies evaluating different populations and using distinct methodologies have consistently indicated a temporal decline in SCA incidence. The pattern to some extent mirrors the overall decline in total mortality due to heart disease (Figure 1) (Fox et al., 2004). The reasons for the decline are not completely understood but likely reflect better health behaviors and clinical treatments aimed at both primary and secondary prevention of coronary heart disease. Conversely, the incidence of total heart disease mortality in the developing portions of the world appears to be increasing; such that the incidence of SCA worldwide may be expected to increase (Leeder et al., 2004; Yach et al., 2004; Zipes, 2005).

Sudden Cardiac Arrest Research Paper

Pathophysiology And Risk Factors

The pathophysiology that manifests as SCA is complex and not fully explained. More than 90% of persons who suffer SCA have evidence of structural heart disease, approximately 80% have coronary artery disease with or without cardiomyopathy, another 10–15% have nonischemic cardiomyopathy such as dilated or hypertrophic cardiomyopathy, with the remaining 5–10% having no evidence of structural disease (Huikuri et al., 2001). The prevalent pathophysiology can depend on geography or clinical population; for example Southeast Asia Sudden Unexpected Death Syndrome is a condition where apparently healthy young and middle-aged men unexpectedly die, typically at night, without an identifiable cause. In most cases, however, structural heart disease provides the substrate for an arrhythmic focus that in some instances requires an additional trigger such as acute coronary ischemia, electrolyte abnormality, stimulant exposure, or physical exertion. For example, scarred myocardium from prior infarction can cause reentry circuits that result in autonomous, abnormal conduction in the ventricle. Most commonly in SCA, a ventricular tachyarrhythmia is produced, which typically presents clinically as ventricular fibrillation (Figure 2) (Weiss et al., 2000).

Sudden Cardiac Arrest Research Paper

Ventricular fibrillation is characterized electrically by chaotic but measurable electrical activity (Callaway and Menegazzi, 2005). The underlying electrical basis for ventricular fibrillation is not yet completely defined. Processes that may contribute include (1) reentrant mechanisms whereby anatomically specific mother rotors produce scroll waves, (2) nonreentrant mechanisms such as rapid triggered activity or automaticity, or (3) a combination of reentrant and nonreentrant mechanisms (Chen et al., 2005; Thomas et al., 2005; Nash et al., 2006). Both chronic local cardiac tissue heterogeneity (in diseased myocardium) and dynamic factors (cellular membrane voltage and calcium ion cycling between sarcoplasmic reticulum and cytoplasm) may promote fibrillation (Weiss et al., 2005). Over minutes, the electrical organization of the ventricular fibrillation signal deteriorates into asystole (Callaway and Menegazzi, 2005).

Risk Factors For SCA

Our understanding of why some individuals experience SCA but other clinically comparable persons do not is incomplete and constitutes a major public health challenge. Collectively, risk factors consist of both chronic or persistent and acute or transient factors. Since underlying coronary heart disease is common in SCA, most research indicates that traditional chronic risk factors for coronary artery disease such as older age, African American race, hypertension, diabetes, dyslipidemia, and smoking are also risk factors for SCA (Kannel and Schatzkin, 1985; Gillum, 1989; Cupples et al., 1992; Becker et al., 1993; Kannel et al., 1998; Albert et al., 2003; Goldenberg et al., 2003; Rea et al., 2004b). Decreased left ventricular function, regardless of ischemic or nonischemic etiology, is one of the strongest predictors of SCA such that those with ejection fraction less than 30% have a risk that is fiveto tenfold greater than the age-matched population (Myerburg and Castellanos, 2005).

Other risk (or protective) factors appear to be more specific for SCA rather than coronary heart disease. Male sex appears to be a particularly strong risk factor, with men at twoto threefold higher risk of SCA than women. A greater prevalence of coronary artery disease does not explain this sex-specific risk difference. Based on the results of family studies, genetic differences also contribute to SCA risk (Friedlander et al., 1998; Jouven et al., 1999). Several autosomal conditions that increase SCA risk have been identified and mapped to particular chromosomes. Persons with one of these rare, monogenetic traits have a functional abnormality in ion channels that predispose to ventricular tachyarrhythmia (Shah et al., 2005). More common genetic variation, with population prevalence typically greater than 5% and hence with potential to influence public health, may also influence SCA risk; though whether and how such an understanding is to be incorporated into clinical use for risk stratification and prevention is not yet clear (Arking et al., 2004, 2006; Sotoodehnia et al., 2006).

Health behaviors also affect SCA risk. The relationship between exercise and SCA is complex and may reflect the balance of sympathetic and parasympathetic tone. Overall regular exercise substantially lowers SCA risk, though risk is transiently elevated during and immediately following the period of exercise (Siscovick et al., 1984; Lemaitre et al., 1999; Albert et al., 2000). Moderate alcohol consumption is associated with a lower risk of SCA compared to nondrinkers, while heavy consumption has been associated with increased risk (Siscovick et al., 1986; Wannamethee and Shaper, 1992; Albert et al., 1999). A diet that includes fatty fish such as salmon once or twice per week and is rich in n-3 polyunsaturated fatty acids (PUFA) has been associated with a lower risk of SCA. Molecular evidence suggests that n-3 PUFA modulate sodium and calcium ion channels in cardiac myocytes to stabilize action potentials (Leaf et al., 2003). In some studies, acute psychological stress has been linked to an increase in SCA risk (Leor et al., 1996; Hemingway et al., 2001; Whang et al., 2005). Finally, in some circumstances, medications can increase risk. Particular antiarrhythmics, high-dose (compared to low-dose) thiazide diuretics, and antipsychotic medications have been associated with elevated SCA risk (Siscovick et al., 1994; Pratt and Moye, 1995; Hennessy et al., 2002).

Prevention

Population-Attributable Risk

A strategy to efficiently decrease the public health burden of SCA requires an understanding of SCA risk factors, their distribution in the population, approaches to identify individuals at risk, and therapies to reduce risk (Figure 3) (Rea et al., 2004b). Our current understanding is not sensitive and/or specific enough to accurately identify those who will (or will not) suffer SCA. As a consequence, efforts directed at prevention in particular high-risk clinical groups will not capture the majority of persons who suffer SCA. Though such focused strategies can improve public health, the approach will not address the largest portion of the SCA burden. Moreover, the prevention modality for one clinical group may not be appropriate for another, necessitating that prevention strategies be tailored to the individual risk profile.

Sudden Cardiac Arrest Research Paper

Prevention

Since most SCA events occur in individuals with underlying structural heart disease, most often coronary artery disease and/or cardiomyopathy, identification and treatment of conditions causing coronary artery disease and/or congestive heart failure provide a cornerstone for SCA prevention. Lifestyle choices that include regular exercise, weight control, a low-saturated-fat and cholesterol diet, abstinence from tobacco, and limited alcohol consumption are recommended regardless of SCA risk profile and hence should be incorporated as part of broad-based, population efforts to reduce SCA. Evidence-based and consensus guidelines direct screening and treatment of clinical conditions such as hypertension, diabetes, and dyslipidemia associated with coronary heart disease (Smith et al., 2006; Mosca et al., 2007). For those with clinically established coronary heart disease, additional pharmacologic treatments including antiplatelet therapy, lipid-lowering treatment, and beta blockers are often indicated to lower the risk of SCA. Coronary revascularization in selected persons can also reduce SCA risk. Finally, persons with ischemic or nonischemic cardiomyopathy, characterized by decreased left ventricular function, experience an especially high risk of SCA. Risk of total mortality including death from SCA can be reduced in this clinical group with pharmacologic therapies including angiotensin converting enzyme inhibitors, beta blockers, angiotensin receptor blockers, and aldosterone inhibitors (Hunt et al., 2005). Taken together, a multifaceted approach suited to the individual that addresses health behaviors, medication treatment, and coronary revascularization can lower risk of coronary heart disease and congestive heart failure and in turn lower risk of SCA.

Some prevention measures are associated with specific SCA risk reduction. In several epidemiological studies, diets rich in n-3 PUFA have been associated with a lower risk of SCA but not other fatal heart disease (Siscovick et al., 1995; Albert et al., 1998; Siscovick et al., 2003). The observational relationship was strengthened by the results of a large randomized trial of postmyocardial infarction patients, demonstrating a reduction in SCA for persons treated with n-3 PUFA versus placebo. However, other randomized trials in especially high-risk patients have not demonstrated a benefit of n-3 PUFA supplementation (Mozaffarian, 2007).

The implantable cardioverter defibrillator (ICD) is a device that monitors the heart rhythm continuously and provides a shock typically designed to terminate a sustained ventricular tachyarrhythmia. Clinical indications for ICD placement have expanded as a result of findings from randomized clinical trials, supporting its use in secondary and primary prevention of SCA (Goldberger and Lampert, 2006). Typically in these trials, ICD therapy was compared to treatment with antiarrhythmic medication such as beta-blockers or amiodarone. In the secondary prevention setting (persons successfully resuscitated following ventricular fibrillation SCA), ICD reduces the risk of SCA by 50% and risk of death by 25%. Randomized trials also support a mortality benefit of the ICD in primary prevention among specific clinical groups characterized by ischemic or nonischemic cardiomyopathy with decreased systolic left ventricular function. Although these indications continue to evolve, frequently mentioned indications for ICD among heart failure patients includes New York Heart Association class II and III heart failure with ejection fraction less than 35%, and postmyocardial infarction with ejection fraction less than 30%. In these clinical groups, the ICD reduces mortality by 25–50%, with most of the mortality reduction due to a decrease in SCA. Placement of ICDs is also currently recommended in consensus guidelines for relatively rare conditions such as hypertrophic cardiomyopathy right ventricular dysplasia, long QT syndrome, and Brugada syndrome; such recommendations are supported by some case-series data since these conditions are too uncommon to make large prospective trials feasible (Begley et al., 2003; Corrado et al., 2003; Maron et al., 2003). The lack of definitive evidence can produce controversies regarding precise indications.

Over the past two decades, ICD indications have broadened initially from patients with inducible arrhythmias in electrophysiology studies, to SCA survivors, to postmyocardial infarction patients with heart failure, to patients with ischemic or nonischemic systolic heart failure. The expanding indications have produced an exponential increase in ICD placement (Figure 4). The increasing use of this relatively expensive therapy yields questions of cost and cost-effectiveness. Some but not all studies suggest ICDs meet traditional cost-effectiveness benchmarks; such evaluations are typically sensitive to the clinical group’s risk of SCA and the cost of the ICD (Lynd and O’Brien, 2003). However, cost may make ICD placement impractical in some areas of the globe where other health conditions have public health priority or economic resources are more limited.

Sudden Cardiac Arrest Research Paper

Ongoing investigation and clinical improvements may limit complications and enhance the effectiveness of the ICD. For example, complications associated with ICDs include device infection (2%), lead fracture (3%), dislodgement (1%), and bleeding (1%) and can cause substantial morbidity and rarely even death (Kron et al., 2001). Some ICDs are now equipped with biventricular pacing to synchronize right and left ventricular contraction, which may improve cardiac function, ameliorate symptoms, and potentially improve the cardiac outcomes (Bristow et al., 2004; Goldberger and Lampert, 2006). Thus the ICD has an established and yet evolving role in SCA prevention, though current ICD indications may account for only about one-quarter to one-third of the population suffering SCA (Stecker et al., 2006). Improved approaches for SCA risk stratification could better allocate ICD distribution as well as other SCA prevention therapies.

Challenges Of Risk Stratification

A number of clinical tests have been proposed to help identify individuals at high risk for SCA ( Josephson and Wellens, 2004). Electrocardiogram findings that correlate with increased risk of SCD include increased QRS width, left bundle branch block, left ventricular hypertrophy, T wave alternans, and QT dispersion. Signal averaged electrocardiograms use special techniques to further improve prediction. Interventional electrophysiology studies may also provide additional risk stratification in clinical subsets. Many of these measures, recorded as part of ICD trials, have been used to derive SCA prediction models and require prospective validation (Bailey et al., 2007). These measures may improve specificity within an already high-risk population but may have a much more limited role in the larger, lower-risk general population. Thus ongoing efforts are needed to refine SCA risk prediction in order to better allocate interventional and intensive therapies among high-risk groups and to identify novel risk predictors among the general population to better target limited resources and treatments among those who might otherwise not be considered at-risk.

Resuscitation

Epidemiology

Despite progress with prevention, hundreds of thousands of persons suffer SCA each year in North America and Europe and receive attempted resuscitation (Rea et al., 2004a; Atwood et al., 2005). In one study in the out-of-hospital setting, for example, approximately one-third of persons suffered heart disease death without an organized emergency response aimed at resuscitation, another third received an emergency response but without attempted resuscitation given that death had progressed, making a resuscitation attempt futile, and the final third received an emergency response and attempted resuscitation by emergency medical services (EMS) (Rea et al., 2003b). Taken together, the incidence of out-of-hospital SCA with attempted resuscitation has been estimated between 38 per 100 000 in Europe and 51 per 100 000 in the United States. The incidence of in-hospital SCA with attempted resuscitation is uncertain but these events also appear to have an important public health impact, while the frequency of resuscitation efforts in developing countries has not been defined (Peberdy et al., 2003).

The outcome of resuscitation is poor. In many communities, only 5% of treated SCA victims are successfully resuscitated and survive to return home (Rea et al., 2004a; Atwood et al., 2005). Importantly, however, survival of treated SCA varies substantially across communities. For example, survival to hospital discharge following ventricular fibrillation SCA approaches 40% in some communities with organized EMS and hospital care, far exceeding survival following ventricular fibrillation SCA in most settings (Cobb et al., 1999; White et al., 2005; Rea et al., 2006). These findings indicate that improvement in resuscitation care across communities could have public health implications and potentially translate to thousands of additional lives saved each year. Importantly, long-term prognosis of persons surviving SCA to be discharged from hospital appears to be improving over time, with evidence indicating median survival following hospital discharge of at least 7 years, nearly twice the expected survival compared to survivors from two decades earlier (Rea et al., 2003a). Most persons who survive appear to enjoy satisfactory functional status and quality of life (Rea and Paredes, 2004).

Links In The Chain Of Survival

Hence, efforts to improve SCA survival are necessary. Investigation and evaluation have established at least some of the important prognostic determinants of SCA and provide the basis for efforts to improve outcomes following SCA. The health service determinants have been collectively termed the links in the chain of survival and include early activation of emergency response, early cardiopulmonary resuscitation (CPR), early defibrillation (electrical shock), and timely advanced medical care (AHA, 2005). For example, observational studies have consistently demonstrated that the chance of survival decreases as the interval from collapse to defibrillation increases for ventricular fibrillation SCA (Valenzuela et al., 1997). The Public Access Defibrillation randomized trial rigorously confirmed this time-to-shock – survival relationship and highlighted one strategy – public access defibrillation – to improve survival by evaluating the effects of equipping laypersons with automated external defibrillators (AEDs). The AED is a device typically the size of a laptop computer that enables accurate cardiac rhythm assessment and appropriate shock by persons not trained in rhythm interpretation, and hence may be widely disseminated to enable the potential for early defibrillation (Rho and Page, 2007). In the Public Access Defibrillation Trial, SCA survival was doubled in select public locations where laypersons were equipped with AEDs as well as CPR training compared to locations where laypersons were trained in CPR but not equipped with AEDs (Hallstrom et al., 2004). Although layperson defibrillation appears promising, this strategy is challenged by the reality that most SCA occurs in the home so that large public health impacts of this approach will require far greater dissemination of AEDs and their accompanying training requirements and support resources (Culley et al., 2004). Novel approaches that deliver defibrillation earlier after collapse also have promise. Such programs enlist and equip nontraditional medical responders such as police, security officers, or flight attendants with lifesaving skills including AEDs (Page et al., 2000; Valenzuela et al., 2000; White et al., 2005).

Cardiopulmonary resuscitation, or CPR, consists of a series of chest compressions often alternating with ventilations (AHA, 2005). These rescuer actions provide some measure of oxygenated blood circulation to vital organs (the brain and heart) until native circulation can be restored. Observational studies generally indicate that early CPR provided by laypersons prior to arrival of EMS can improve the relative chances of survival, especially as the interval from collapse to EMS arrival increases (Cobb et al., 1999; AHA, 2005; Gilmore et al., 2006). In most SCA events, however, the victim does not receive layperson CPR. Ongoing approaches may address this gap by increasing layperson CPR training, simplifying CPR techniques, and enhancing emergency dispatcher programs to assist CPR. Additional research aims to identify (1) the ideal composition of CPR with regard to CPR duration, the ratio of chest compressions and ventilations, as well as the depth and rate of chest compression and volume of ventilations; (2) whether mechanical devices can improve CPR and affect survival; and (3) the best interface between CPR and other components of resuscitation such as defibrillation (AHA, 2005a, 2005b).

Advanced therapies also potentially have an important role in improving survival following SCA. Specifically, based on the results of randomized trials, active induction and maintenance of hypothermia following restoration of native circulation improves survival following ventricular fibrillation SCA (Bernard et al., 2002; Hypothermia After Cardiac Arrest Study Group, 2002). Hypothermia moderates reperfusion processes that occur when critically ischemic tissues receive oxygen. Pathologic reperfusion produces oxidative radicals that damage cells, a process that seems especially relevant to the brain (Ambrosio and Tritto, 1999; Becker, 2004). The timing, extent, duration, modality, and ease of implementation are all potentially important aspects of hypothermia therapy that may influence its effectiveness and in turn continue to require ongoing investigation. Additional advanced therapy also may improve outcome following SCA. For example, timely coronary artery revascularization may be appropriate in select SCA patients (Spaulding et al., 1997). Additional ongoing research tries to understand if treatments aimed at sepsis syndromes might be relevant for patients early on following resuscitation (Laurent et al., 2005).

These health service measures likely only account for a portion of the variability in outcome, indicating that other characteristics influence the likelihood of survival (Hallstrom et al., 1996). Evidence indicates that patient characteristics such as underlying chronic health conditions influence the likelihood of resuscitation (Hallstrom et al., 1996; Carew et al., 2007). This relationship suggests that individual characteristics influence the pathophysiology of SCA and in turn may guide the choice of specific resuscitation treatments. In some studies, higher levels of socioeconomic status are associated with a greater chance of survival (Hallstrom et al., 1993; Clarke et al., 2005). Whether socioeconomic status is simply a surrogate for health status or identifies disparity in health delivery is not clear, but again provides one area to address and potentially improve resuscitation. Ultimately, a more complete understanding of the pathophysiology and prognostic determinants of SCA provides the best opportunity to achieve successful outcomes. With such knowledge, resuscitation care may be refined to best match treatment to the individual patient. Taken together, ongoing efforts to improve our understanding of SCA coupled with better and more complete dissemination and implementation of effective treatments will hopefully enable public health gains in resuscitation of SCA.

Challenges Of SCA Research

Research to improve prevention and outcome of SCA is imperative if we are to reduce the burden of SCA. However, SCA research, especially resuscitation research, can present particular challenges not typical of most medical research. Because SCA is unexpected, the victim is unconscious, and delays of even a few moments can adversely affect the chances of resuscitation, normal research procedures whereby potential study participants provide informed consent are not possible. In an effort to address this set of challenges, the federal government in the United States, for example, has developed regulations to guide researchers and oversight groups so that such research can proceed. However, the regulations have in some circumstances produced confusion among different stakeholders and in turn may have paradoxically hindered scientific progress (Nichol et al., 2006; Miros, 2007). Ongoing efforts hope to clarify the regulations so that future research may move forward while assuring the safety and protection of human subjects.

Conclusions

Sudden cardiac arrest is a substantial public health challenge. Successful advances targeting prevention in some Western societies may be countered as the prevalence of heart disease increases in other parts of the world. Efforts focused at prevention, diagnosis, and treatment of coronary artery disease and congestive heart failure remain a cornerstone of SCA preventive therapy. Refinement of established SCA risk factors as well as identification of novel predictors that are specific to SCA risk are an important public health priority. Improvements in resuscitation also offer a meaningful opportunity to reduce mortality from SCA. Public health gains through better resuscitation will require more complete implementation of established health service tenets (i.e., layperson CPR and hypothermia) as well as improvements in our understanding that enable innovative treatments. When combined, advances in prevention and resuscitation of SCA are a complementary and effective approach to reduce mortality from SCA and in turn improve public health.

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