Skip Navigation

Cardiovascular Research 2001 50(2):197-209; doi:10.1016/S0008-6363(01)00260-7
© 2001 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Sotoodehnia, N.
Right arrow Articles by Siscovick, D. S
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sotoodehnia, N.
Right arrow Articles by Siscovick, D. S
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2001, European Society of Cardiology

Reducing mortality from sudden cardiac death in the community: lessons from epidemiology and clinical applications research

Nona Sotoodehniaa, Adam Zivina, Gust H Bardya and David S Siscovicka,b,*

aDepartment of Medicine, Cardiovascular Health Research Unit, University of Washington, 1730 Minor Avenue, Suite 1360, MR9, Box 358080, Seattle, WA 98101, USA
bDepartment of Epidemiology, University of Washington, Seattle, WA, USA

* Corresponding author. Tel.: +1-206-287-2787; fax: +1-206-287-2662 dsisk{at}u.washington.edu

Received 9 January 2001; accepted 29 January 2001


   Abstract
Top
 Abstract
1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 
The reduction of mortality from sudden cardiac death (SCD) in the community remains a challenge. Clinical—epidemiologic studies have identified a range of factors that are associated with an increased risk of SCD. While of potential etiologic and prognostic importance, these factors have limited sensitivity and a low positive predictive value for SCD. On the other hand, clinical trials have suggested that a variety of interventions, including risk factor reduction, nutritional interventions, drug therapies, cardiac procedures, and new technologies, have the potential to reduce mortality from SCD. In this review, we examine what is known about the epidemiology and clinical application of interventions to reduce mortality from SCD; and, we consider the impact of both prevention and clinical interventions on mortality from SCD from a community perspective. There is mounting evidence that supports both public health and clinical efforts to prevent the occurrence of SCD. There also is evidence suggesting that new technologies, such as automated external defibrillators, have the potential to reduce case-fatality from SCD. Further progress will depend on improved methods to identify persons-at-risk, reduction of risk factors, and application of techniques — both simple and advanced — to improve survival in victims of SCD.

KEYWORDS Defibrillation; Epidemiology; Sudden death


   1 Introduction
Top
 Abstract
 1 Introduction
2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 
Despite substantial progress in basic, clinical, and epidemiologic research related to life-threatening ventricular arrhythmia, the reduction of mortality from out-of-hospital cardiac arrest due to heart disease remains a challenge for cardiology. Recent advances in molecular biology and family studies have contributed important new information related to the mechanisms that provide a substrate for the occurrence of life-threatening ventricular arrhythmias, the most common proximate event that results in sudden cardiac death (SCD) [1]. However, the importance of these findings for clinical care and public health remains limited, since the prevalence of monogenic disorders that increase susceptibility to SCD is low.

Clinical epidemiologic studies conducted over the past five decades have identified a variety of factors that are associated with an increased risk of SCD in the community [2,3]. While of potential etiologic and prognostic importance, the known risk factors lack sensitivity and fail to identify individuals at risk for SCD, even in high-risk clinical populations. On the other hand, clinical trials have suggested that a variety of interventions, including risk factor reduction, drug therapies, cardiac procedures, and new technologies, reduce the risk of SCD in certain high risk populations [4–10]. The challenge now is to apply this knowledge to enhance the effectiveness and efficiency of clinical and public health efforts to reduce mortality from out-of-hospital cardiac arrest due to heart disease.

In this review, we briefly discuss what is currently known about the epidemiology and clinical application of interventions to reduce mortality from out-of-hospital cardiac arrest due to heart disease. We consider the potential strengths and limitations of the data, and we estimate the potential impact of various interventions. Finally, we suggest that further epidemiology and clinical application research related to factors and interventions that influence the occurrence and outcomes of ventricular fibrillation is needed to reduce further mortality from SCD in the community.


   2 Definition
Top
 Abstract
 1 Introduction
 2 Definition
3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 
SCD is frequently defined as death from unexpected circulatory collapse, usually due to a cardiac arrhythmia occurring within an hour of the onset of symptoms. However, numerous varying criteria have been used to define SCD in the medical literature, partly due to difficulties in deriving a specific definition. For instance, SCD is witnessed in only two-thirds of cases, making the diagnosis and time of onset difficult to establish [11]. Furthermore, the cardiac rhythm at clinical presentation is often unknown. For these reasons, operational criteria for SCD have been proposed that do not rely upon duration of symptoms or the cardiac rhythm at the time of the event. The criteria focus upon the out-of-hospital occurrence of a presumed sudden pulseless condition, the physiologic consequence of ventricular tachyarrhythmia, and the absence of evidence of a non-cardiac condition as the cause of the cardiac arrest.


   3 Epidemiology
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 
In the developed world, SCD represents the single largest cause of natural death accounting for 12–18% of total mortality and 50% of cardiac mortality [11–13]. Each year in the United States alone, 300 000 people die from cardiac arrest [12,13]. The average age of sudden death cases in Seattle, Washington, and Maastricht, Holland, is 66 years and 62 years, respectively, and the incidence increases with age [11]. Men are two to four times more affected than are women (age-adjusted mortality) [14]. African—Americans are twice as likely as Caucasians to experience cardiac arrest, and half as likely to survive an event [15,16].

Out-of-hospital cardiac arrest is due most commonly to ventricular fibrillation (VF). In cases where the time elapsed from sudden loss of consciousness to the first electrocardiographic tracing is less than 4 min, 95% of patients have VF as their presenting rhythm. With time, the proportion of patients in VF decreases. Because of delays in patient access, only about 40–50% of arrest victims are in VF by the time of medic arrival, with the remainder in electrical asystole or pulseless electrical activity [17–19].

For those who suffer out-of-hospital cardiac arrest due to heart disease, survival rates are low, even in the setting of witnessed arrests found in ventricular fibrillation. Long-term survival rates of 20% have been reported from urban centers with the ability to provide rapid-response, defibrillator-equipped emergency medical services [20]. However, national averages of successful resuscitation from out-of-hospital cardiac arrest due to heart disease are much lower (1–2%).


   4 Pathophysiolgy and mechanisms
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 
The exact mechanism of ventricular fibrillation is poorly understood. Two conditions appear to be important for the initiation of ventricular fibrillation: an abnormal myocardial substrate (e.g. abnormality of the myocardium, coronary arteries, or cell membrane ion channels) and a transient modulating event (e.g. ischemia). It is the effect of a transient disturbance on a susceptible substrate that is thought to lead to electrical instability.

4.1 Abnormal myocardial substrate
Eighty-five percent of those older than 40 years of age dying from cardiac arrest have underlying coronary artery disease on autopsy studies. Ten percent have other structural cardiac abnormalities, such as cardiomyopathy and valvular disease, and 5% have no macroscopic structural cardiac abnormality [2]. Patients with known molecular abnormalities, such as membrane ion channel defects seen in the monogenic disorders of the long QT and Brugada syndromes, represent a small proportion of the total burden. However, the role of sub-clinical molecular abnormalities has not been well elucidated for SCD in the general population.

Although the link between SCD and coronary artery disease is well established, the anatomic distribution of disease does not help identify those at highest risk. What is notable is that most victims of SCD have severe diffuse multivessel coronary artery disease [21]. Healed myocardial infarctions are present in approximately 50% of victims of SCD [21].

4.2 Transient modulating factors
A number of potential modulating factors have been identified, including ischemia, autonomic disturbances, electrolyte and pH derangement, hypoxemia, and drugs. Epidemiologic studies regarding these transient factors have furthered our understanding of SCD and guided clinical care in order to prevent an event. In the following discussion, specific transient factors will be addressed with a focus on the relevant epidemiologic and clinical studies.

Forty to 50% of cardiac arrest survivors develop electrocardiographic changes consistent with acute myocardial infarction, and an additional one-third develop changes consistent with ischemia without infarction [22,23]. Furthermore, on autopsy studies, coronary thrombus has been reported in approximately 75% of SCD victims [24]. Although the exact percentage of patients who experience cardiac arrest secondary to ischemia is unclear, it is evident that in a significant number, ischemia plays an important role. Interventions aimed at reducing the frequency and severity of ischemia, such as thrombolytic therapy and coronary artery bypass grafting, have been associated with decreased incidence of SCD and reduced overall cardiac mortality [4,5].

Evidence from epidemiologic studies, animal experimentation, and clinical research implicates the autonomic nervous system in the etiology of SCD, particularly in the setting of ischemia. Epidemiologic studies have shown that emotional stress and vigorous physical exertion which result in the elevation of circulating catecholamines may be important triggers for SCD [25–27]. There appears to be a circadian pattern to the timing of SCD, with significantly more events occurring in the morning perhaps due to increased sympathetic activation [28]. As will be discussed later in this review, blocking the adrenergic system with beta-receptor blockade therapy reduces the incidence of SCD.

Clinically, it is well recognized that derangements of electrolyte levels can result in malignant ventricular tachyarrhythmias. Electrolyte abnormalities, such as hypokalemia and hypomagnesemia, are often due to diuretic use. Results of the Multiple Risk Factor Intervention Trial and observational studies have shown a direct dose-related increase in the risk of out-of-hospital cardiac arrest associated with thiazide diuretic therapy for high blood pressure: compared to low-dose (25 mg) thiazide diuretic therapy, moderate-dose (50 mg) therapy is associated with a modest 1.6-fold increase in risk and high-dose (100 mg) thiazide diuretic therapy is associated with a three-fold increase in the risk of SCD [29,30]. The addition of potassium sparing agents to thiazide diuretic therapy may reduce the risk associated with thiazide therapy alone.

The Cardiac Arrhythmia Suppression Trial showed that treatment with class Ic antiarrhythmic agents to suppress ventricular arrhythmias post myocardial infarction paradoxically increased mortality from SCD [31]. Subsequent studies came to similar conclusions for Ia, Ib, and pure class III antiarrhythmic drugs. Additionally, a number of non-cardiac medications that prolong the QT interval, such as erythromycin and tricyclic antidepressants, also are potentially proarrhythmic. The role that these commonly prescribed medications play in out-of-hospital cardiac arrest has not been well established.


   5 Risk factors
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 
The most powerful predictor of sudden cardiac death is poor left ventricular function [32]. Other risk factors for developing SCD mirror those of coronary heart disease and include hypercholesterolemia, hypertension, cigarette smoking, alcohol consumption, physical inactivity, obesity, dietary n-3 polyunsaturated fatty acid intake, diabetes, and left ventricular hypertrophy by electrocardiographic criteria [2,33,34]. Certain risk factors, however, impact the incidence of SCD beyond their effect on coronary heart disease.

Among persons without prior clinically recognized heart disease, dietary intake of long-chain n-3 long polyunsaturated fatty acids (PUFAs) from fatty fish (1 or more servings per week) and higher levels of cell-membrane long-chain n-3 polyunsaturated fatty acids are associated with a lower risk of out-of-hospital cardiac arrest. In contrast, the intake of these fatty acids is not related to the risk of non-fatal myocardial infarction [35,36].

Aside from the Mendelian familial syndromes of long QT or Brugada, a hereditary risk for SCD in the general population exists. Those who suffer cardiac arrest are significantly more likely to have had a parent who had SCD [3,33]. This finding is independent of a familial risk of myocardial infarction. More work needs to be done on the genetic etiology of increased risk.


   6 Identification of persons at risk
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 
Despite increasing insight into the mechanisms and risk factors of SCD, the populations at high risk for a primary event have not effectively been identified. The population that experiences SCD can broadly be divided into three groups with increasing incidence: (1) primary events in the general population, (2) primary events specifically in persons with known heart disease, and (3) secondary events in individuals with a prior episode of malignant ventricular tachyarrythmia.

Although SCD accounts for 300 000 deaths in the United States each year, its overall incidence in the general population is only 0.1% per year. Predicting SCD in the general population is problematic. In approximately 40–50% of cases of out-of-hospital cardiac arrest due to heart disease, there is no history of clinically recognized heart disease [2,37]. This accounts for approximately 120 000–150 000 sudden unexpected deaths due to unrecognized heart disease each year in the US alone. Efforts to identify high-risk patients using known risk factors in the general population has proved challenging. Combining the risk factors of body mass, cigarette smoking, hypertension, hyperlipidemia, and left ventricular hypertrophy by electrocardiographic criteria, a multivariate model was developed using prospective data on 4120 middle-aged men from the Albany and Framingham studies to estimate the probability of SCD [38]. While there was a 16-fold increase in risk of SCD from the lowest to the highest risk group, even in the highest risk sub-group of persons without clinically-recognized heart disease, the annual incidence of SCD was only 0.7%.

Based on the data from the Seattle experience, the 55% of victims of out-of-hospital cardiac arrest with a known history of coronary heart disease or heart failure prior to their episode of SCD account for 165 000 cases of SCD in the United States each year. Among patients with prior CHD and CHF, the risk of SCD is increased 6–10-fold compared with persons without these conditions, but the absolute risk of SCD among these clinical subsets remains relatively low in the aggregate. Further attempts at risk stratification using techniques such as heart rate variability, QT-dispersion, and signal averaged EKG, have had limited sensitivity and specificity in identifying those at risk.

Interestingly, the risk of SCD varies over time among patients with known heart disease. The highest risk of out-of-hospital cardiac arrest is in the first 6 months after a major cardiovascular event, such as myocardial infarction or new onset heart failure, and then declines rapidly over the next 18 months. This temporal nonlinearity of risk has potential implications for the timing of preventative and therapeutic interventions.

Of those with known structural heart disease, the subgroup at highest risk is that of patients with severe left ventricular dysfunction. Total mortality in these patients is 10–15% per year; some have estimated that approximately 40% of these deaths is due to SCD. In our study at Group Health Cooperative (King County, Washington), 30% of out-of-hospital cardiac arrest victims had prior physician-diagnosed heart failure. In the United States, we estimate that patients with left ventricular dysfunction account for 90 000 cases of SCD each year.

The highest risk group of patients are survivors of out-of-hospital cardiac arrest or patients with malignant ventricular tachyarrhythmias in the convalescent phase of an acute myocardial infarction. Because these patients have an incidence of SCD in their first year following a ventricular fibrillation episode of approximately 15%, aggressive intervention in these patients has been proposed [39,40]. While interventions in this patient group, such as implantable defibrillators (ICDs), are effective, cases of secondary cardiac arrest account for only a small proportion of the total burden of SCD.

To summarize, clinical and public health efforts to significantly reduce mortality from SCD through the identification of persons at risk face numerous challenges. First, the incidence of SCD in the population is low, even in common high-risk clinical populations. Second, the current risk factors for SCD have a low positive predictive value (most of the patients with the risk factor will not experience sudden death in a particular year) and are not sensitive (many victims of SCD do not have the particular risk factor). Therefore, the use of currently identified risk factors to characterize progressively higher risk groups comes at the cost of decreasing sensitivity, and hence, overlooking large numbers of SCD victims.


   7 Strategies to decrease mortality
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 
Several strategies must be employed simultaneously to decrease the mortality from cardiac arrest, aimed at both reduction in event rate and improvement in event survival. First are primary preventive measures in the general population targeting reductions in known cardiovascular risk factors. Because of the low incidence of SCD in the general population, these interventions will have to be broad-based, safe, easily administered, acceptable to the general population, and inexpensive. Second is primary prevention of SCD in patients with known heart disease with a focus on pharmacologic therapies. And finally, interventions to improve event survival will be reviewed, with reevaluation of current emergency medical guidelines and applications of new technologies.


   8 Primary prevention
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
9 Improving event survival
 10 Conclusion
 References
 
Because of the logistic difficulty of successful cardiac resuscitation, any strategy that aims to have an impact on the magnitude of the problem in the community should emphasize primary prevention. Will primary prevention have an effect? Temporal trends in SCD over the past 40 years suggest so. The age-adjusted death rate from SCD has decreased by approximately 40% since the late 1960s, paralleling the decrease in incidence of ischemic heart disease [41,42]. Given the low rate of successful out-of-hospital cardiac resuscitation, the decrease in mortality over the past 40 years is likely due to primary prevention with population-wide reductions in cardiovascular disease risk factors, as well as drug therapies and procedures in those with known heart disease.

8.1 Primary prevention in the general population
Since many of the traditional risk factors associated with the development of coronary artery disease, such as hypercholesterolemia and hypertension, are also associated with SCD, clinical and public health efforts that promote the effective treatment of these risk factors are likely to reduce the incidence of out-of-hospital cardiac arrest in the general population. Specifically, for the following risk factors, evidence from either observational studies or clinical trials support behavioral modification to reduce risk of SCD.

Observational studies have shown that the dietary intake of long-chain n-3 polyunsaturated fatty acids from fatty fish is associated with a reduced risk of SCD, possibly by reducing vulnerability to life-threatening cardiac arrhythmia. The consumption of at least one fatty fish meal per week is associated with a 48% reduction in the risk of SCD [35]. Furthermore, the GISSI—Prevenzione trial has demonstrated a 45% reduction in rates of SCD related to treatment with long-chain n-3 polyunsaturated fatty acid supplements in post myocardial infarction patients [6]. Interestingly, the mortality benefit seen was predominantly due to reduction in the incidence of SCD; there was no significant reduction in the rate of non-fatal myocardial infarction.

Current cigarette smoking and the number of cigarettes smoked per day among current smokers are strongly related to the risk of SCD. Clinical trials of smoking cessation have not focused upon major disease outcomes such as cardiac arrest. Nevertheless, given the observations that the risk of cardiac arrest is particularly large among current smokers and declines rapidly after stopping smoking, smoking cessation will likely have an impact in reducing the risk of SCD.

Regular exercise is associated with an overall reduction in the risk of SCD. Some exercise is better than none, regardless of the intensity of the activity. The risk of SCD is transiently increased during strenuous exercise. However, this transient increase in risk is outweighed by an overall reduction in the risk of cardiac arrest [27,34,43,44].

In the Physicians Health Study, men who had two to four drinks of alcohol per week had a significantly reduced risk for SCD (relative risk 0.40), compared to men who never drank [45]. Heavy alcohol consumption (six or more drinks per day) or binge drinking was shown to increase the risk of SCD.

8.2 Patients with known heart disease
Prospective randomized controlled trials of beta-receptor blockade therapy after acute myocardial infarction have demonstrated a decrease in total mortality, primarily due to a decreased incidence of SCD. The benefit was notable in the first few months and persisted on long-term follow-up. With a 1–2-year follow-up period, these studies (BHAT, MIS, and NIS) show a 30–45% relative reduction in SCD, with an absolute sudden death incidence reduction of 1.3–6.2% [7,46,47]. Thus, for every 1000 patients treated, 13–62 lives were saved from SCD. In one study (NIS) these benefits persisted up to 6 years.

In the subgroup of patients with heart failure, the beta-blocking medications bisoprolol, metoprolol, and carvedilol have been shown to reduce total mortality in multiple studies [8,48,49]. In patients with left ventricular dysfunction and class III—IV heart failure, bisoprolol significantly decreased mortality from SCD by 42% with an absolute risk reduction of 2.7% over a mean follow-up period of 1.3 years [8]. The mortality benefit conferred by beta-blockade therapy may be due to its effect of decreasing episodes of ischemia, as well as due to its protection against ischemia-mediated ventricular fibrillation [50].

Angiotensin converting enzyme (ACE) inhibitor therapy has been shown to reduce SCD mortality in high risk patients. Recently, the HOPE study showed that in high risk patients (those with either coronary artery disease, stroke, peripheral vascular disease, or diabetes and at least one other cardiovascular risk factor), ACE inhibitor therapy decreased the risk of SCD. In a mean follow-up period of five years, the relative risk of SCD was reduced by approximately 40%, although the absolute risk was low in both treatment and control groups (0.8 vs. 1.3%, respectively) [9].

ACE inhibitors have repeatedly demonstrated significant mortality benefit in patients with heart failure. However, controversy still exists about how much of the mortality benefit is due to reduction of incidence of SCD. The CONSENSUS trial showed a 31% risk reduction of total mortality at one year in the enalapril vs. the placebo group [51]. However, no difference in the number of sudden deaths was evident. In the TRACE study, on the other hand, the ACE inhibitor trandolapril significantly reduced the risk of SCD in post myocardial infarction patients with left ventricular dysfunction. Over a 4-year period, there was a 22% relative decrease in SCD and a 3.2% absolute decrease [52]. The method by which ACE inhibitors prevent SCD is not clear.

Recently spironolactone, an aldosterone receptor blocker, has been shown to significantly reduces the morbidity and mortality in patients with severe heart failure. In the RALES trial, the relative risk of SCD was reduced by 29% with an absolute risk reduction of 3% over a 2-year period [10].

It is important to emphasize that these interventions have now been shown to significantly reduce the risk of SCD by 20–45% in readily targeted, high-risk groups of patients. It is particularly noteworthy that these high risk patients account for a significant proportion of those presenting with SCD. Unfortunately, these effective interventions are underutilized. Only fifty percent of patients who qualify for beta-blockade therapy after suffering a myocardial infarction are discharged home on this therapy [53]. The dissemination of this information, and its incorporation into clinical practice is paramount.


   9 Improving event survival
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
10 Conclusion
 References
 
While treatment of critically ill hospitalized patients has improved, the survival rate from cardiac arrest (both in-hospital and out-of-hospital) has remained dismal and essentially unchanged for the last 20 years. Survival to discharge ranges from 1.6 to 20% with congested urban areas and remote suburban areas generally faring the worst [19,54–56]. To truly improve survival among the 300 000 victims of SCD will require a paradigm shift in the delivery of emergency care and resuscitation.

The ‘chain of survival’ concept has been developed as a framework for approaching the patient who has arrested; the ‘links’ of the chain being: Early access (call for help); early cardiopulmonary resuscitation (CPR); early defibrillation; and early advanced cardiac life support (ACLS). This is the fundamental approach in the teaching of basic life support (BLS).

9.1 Early access
Prompt summoning of help in the event of cardiac arrest is of paramount importance, and this has been greatly facilitated by universal emergency telephone numbers (‘911’ in the US and Canada) to call for help. The popularity of wireless telephone systems provides an opportunity to further streamline access to emergency services. Bystander rescuers with wireless phones do not need to leave the patient to seek a phone to call for help, and GPS and other technologies will make locating the source of the call an automatic process. The Federal Communications Commission will require this ‘enhanced’ wireless service capable of locating the source of a wireless call within 125 meters by October 2001. This technology will soon be available in automatic external defibrillators (AEDs), to automatically call the emergency medical system (EMS) with activation of the device. Nonetheless, after the call is received at the EMS dispatch center, crucial time will be lost waiting for paramedics or other first-responder emergency medical technicians (EMTs) — typically police or fire — to arrive. Even in the best of circumstances, this is rarely less than 3–4 min [57–59]. In congested urban areas, traffic and the realities of access to buildings, apartments, etc. delay this significantly, often with response times of 8–10 min or longer [15,56,60,61]. In rural areas, it is sheer distance that limits response time [62]. It is in these two settings that survival is the worst. The addition of a two-tiered EMS system with BLS/AED trained first responders has improved the situation little to none because first responders encounter the same fundamental limitations faced by paramedics in a single-tiered system [61,63]. Even a couple of minutes early in the course of cardiac arrest has a significant impact on survival. By 10–12 min, the probability of meaningful recovery rapidly approaches zero [59,64].

9.2 CPR
Since the initial description in 1960, closed-chest cardiopulmonary resuscitation has become accepted as an important part of the resuscitation of cardiac arrest victims [65]. The American Heart Association chain of survival places primary importance on bystander and first responder CPR; Basic Life Support courses for health care professionals and lay-providers alike emphasize this [66]. CPR has been advocated as a low-tech life-support strategy while awaiting definitive treatment, i.e. defibrillation and ACLS. Despite this de facto standard, CPR has never been tested in a randomized, controlled setting. The evidence supporting its efficacy is largely anecdotal and retrospective, without adequate control for the most crucial variable dictating survival: time interval from arrest to intervention.

There has been considerable debate about the hemodynamic consequences of CPR, and while this issue is not going to be addressed at length here, even controlled experiments in animal models have not consistently demonstrated that CPR can provide oxygenated blood flow adequate to maintain end-organ viability; most importantly in the central nervous system [67–71]. The standard taught to verify adequate chest compressions is a palpable pulse during the compression phase. Mechanistically, a peripheral pulse does not necessarily equate with peripheral flow. Compression and release of the thorax can as easily result in ‘sloshing’ back and forth of blood in the central circulation without any flow in the peripheral beds. Physiologic measurements during CPR have generally recorded cardiac output of 15–50% of baseline, with systolic blood pressure of 45–60 mmHg, and diastolic pressure of 15–20 mmHg [72,73]. Typical mean right atrial pressures are 19–25 mmHg, but right atrial peak pressures of 80–115 mmHg have been recorded during CPR during the compression phase when forward arterial flow and arterial pressure would be maximum [72]. This equalization of venous and arterial perfusion pressure will compromise cerebral perfusion pressure. Maintenance of cortical viability requires blood flows of at least 20% of baseline, a level only marginally achievable with closed-chest CPR [74,75]. Among survivors of cardiac arrest, CPR has not improved neurologic outcome [76,77]. ‘Diastolic’ vascular pressures also equalize during the relaxation phase of CPR, compromising coronary artery flow. Usually, 15 mmHg is considered the threshold for adequate coronary perfusion pressure, but CPP of only 2–13 mmHg during CPR have been measured, again only marginally adequate.

CPR is not a benign procedure, with rib fracture; bone marrow embolization; cardiac and pulmonary laceration and contusion; aortic, esophageal and gastric rupture, and aspiration of gastric contents all well described [78–82]. Experimental animal data has shown disruption of the blood—brain barrier with CPR, which could be harmful in the reperfusion phase after resuscitation [83]. Pulmonary edema has been reported in 28% of short-term survivors and 46% of non-survivors of out-of-hospital arrest [84,85]. This may, in part, be due to near-systemic pulmonary artery pressures during closed-chest CPR [73].

Physiologic and pathologic considerations aside, the efficacy of CPR in enhancing survival has not been demonstrated with adequate control for the most important variable — time from arrest to defibrillation; and demonstration of a beneficial effect of CPR has been inconsistent [57,64,76,86]. For practical reasons, all available studies of community based CPR have used bystander estimations of time from arrest to CPR and arrest to defibrillation. Time estimates, especially under conditions of duress, are notoriously inaccurate. Isaacs et al. [87] examined this issue by comparing actual time from 911 call to ambulance arrival with bystander estimates of the same. Despite similar averages, correlation for individual events was extremely poor. In a study evaluating an automatic defibrillator for in-hospital cardiac arrest, mean time to defibrillation as documented by telemetry recordings was just over 4 min despite observer estimates of 30 s to 1 min [88]. Additionally, comparing survival with and without CPR by controlling for times as estimated by bystanders ignores a key issue: the likelihood that bystanders who have had BLS/CPR training are also likely to activate the EMS system more quickly than bystanders unfamiliar with BLS or CPR. This is the most probable explanation for any perceived survival differences, rather than the administration of CPR per se.

The same would be expected when comparing the outcomes between responders who administer ‘effective’ vs. ‘ineffective’ CPR [89]. Given that the proportion of patients in VF declines over time, this possibility is supported by data showing that arrest victims who received CPR were more likely to be in VF at the time of first recording and that EMS call-to-bystander CPR intervals were shorter in patients in VF [90,91]. Experimental animal data has suggested that a period of CPR prior to defibrillation in arrest victims with longer down times may be beneficial [92]. Strong clinical data to support this is lacking however. A recent retrospective observational study of survival in King County, WA after change in arrest protocol based on this data is difficult to interpret as the initial implementation of EMT defibrillation in the mid-1980s and the change in protocol in 1994 coincided with a period of dramatic population growth and demographic change in the Seattle area [77]. Particularly in the case of VF arrest, the value of CPR needs to be conclusively demonstrated in a randomized, controlled fashion. The potential value of external chest compression in cases of massive pulmonary embolus, or of mouth-to-mouth ventilation in primary respiratory arrest remains a separate issue, but assessment of arrest etiology by a bystander or BLS provider is unlikely to be accurate and cannot be part of a practical algorithm.

Variations in CPR techniques are also under investigation. Interposed abdominal compression CPR (IAC-CPR), in which abdominal compression is done between chest compressions to facilitate venous return, has been tried with variable results. Initial animal experiments were very promising, but clinical trials of IAC-CPR have been less consistent possibly due to patient-specific variables [93–95]. In addition, because of the risk of aspiration of gastric contents, IAC-CPR needs to be done on intubated patients. Active compression—decompression CPR (ACD-CPR) utilizes a plumbers helper-like suction device to deliver both chest compression and active decompression to facilitate venous return by bringing intrathoracic pressure below atmospheric pressure. Again, despite promising early results, follow-up clinical studies have been variable, with a higher rate of complications [96–99]. Given that the fundamental value of closed-chest compression remains in question, whether augmented means of CPR with its higher complication rate is justified, remains unproven.

9.3 Minimally invasive direct cardiac massage (MID-CM)
MID-CM is a newer technique now in use in an international randomized clinical trial. Through a small thoracostomy, an umbrella-like device is applied directly to the outside of the heart. Like open cardiac massage, venous pressure and intrathoracic pressure is not elevated, thereby maintaining an arterio-venous pressure differential and experimental data suggests physiologic efficacy similar to open-chest cardiac massage (OCCM) [100,101]. Experimental data in swine has demonstrated improved coronary perfusion pressure compared with conventional CPR and average carotid artery flow of 35% of baseline compared with 20% for standard CPR [102]. These data compare favorably with results seen with OCCM [103,104]. A randomized clinical trial of MID-CM vs. standard CPR in out-of-hospital arrest is now ongoing in an international cooperative study. While early results are promising in terms of hemodynamic efficacy compared with conventional CPR, the invasive nature of the therapy makes it necessary for MID-CM to prove its potential value in terms of survival to discharge from out-of-hospital cardiac arrest.

9.4 Pharmacologic adjuncts
The revised AHA/ACC guidelines for ACLS acknowledge the paucity of compelling data for the efficacy of pharmacologic agents such as epinephrine, atropine, or even time-honored lidocaine in the resuscitation of cardiac arrest victims. The only antiarrhythmic tested in a randomized placebo-controlled trial is amiodarone [105]. The drug was used late, in shock-refractory ventricular arrhythmias and demonstrated a statistically significant improvement in survival to hospital admission, but not to hospital discharge. Use of epinephrine, atropine, or any antiarrhythmic drugs has shown no improvement in survival in either in-hospital or out-of-hospital resuscitation [106,107]. Thus, there is little evidence that any drug therapy increases survival for the majority of arrest victims.

9.5 Public access defibrillation (PAD)
A paradox in out-of-hospital cardiac arrest is that while the majority of arrests are due to ventricular fibrillation, because of delays in patient access only about 40–50% of arrest victims are in VF by the time of medic arrival, with the remainder in electrical asystole or pulseless electrical activity (PEA) [17–19]. In crowded cities such as Chicago or Hong Kong (where mean defibrillation time was 23.8 min), the percentage of arrest victims still in VF is much lower; 22 and 22.5%, with survival to hospital discharge correspondingly worse (2 and 1.6%, respectively) [55,56]. In witnessed arrest, 65% of victims will be in VF at the time of first rhythm recording with improved survival compared with unwitnessed arrest because of more timely notification and arrival of EMS; but only 40–50% of out-of-hospital arrests are witnessed [57,86]. While VF can be terminated with success rates of 80–95% with successful return of spontaneous circulation (ROSC) when shocked early, asystole and PEA are more often terminal rhythms in the setting of cardiac arrest, with survival rates of 0–2% in most series [108–112].

The ‘successful’ defibrillation, however, defined as return of a spontaneous, perfusing rhythm, does not equate to patient survival if the intervention is delayed. This has been demonstrated for in-hospital resuscitation where times of witnessed arrest and resuscitation were recorded; ROSC was 84% in patients defibrillated within 2 min, and 52% for those with ‘delayed’ defibrillation, with survival to discharge of 48 and 14%, respectively [113]. The out-of-hospital survival rate of arrest victims defibrillated within 3 min is nearly 75% but falls 7–10% per minute [112]. When external defibrillation requires cumbersome equipment and training in arrhythmia recognition for safe delivery, the motivation for conventional CPR in the chain of survival is to buy time until the arrival of trained emergency personnel. With the advent of the automatic external defibrillator (AED) comes the potential to eliminate the need for temporizing strategies and dramatically shorten time to defibrillation especially in those settings where defibrillation by EMS tends to be long (rural and dense urban areas). The paradigm then becomes ‘shock first, and if all else fails, try CPR’. The data supporting the value of early defibrillation is robust, and defibrillation by immediately available lay-users may be the key to shortening this interval dramatically. While conceptually appealing, the efficacy or cost-effectiveness of widespread PAD awaits study. Theoretical calculations based on available resuscitation data and expected costs have estimated survival improvement of 24–30% compared with present rates [114,115]. Nichol et al. [114] estimated an incremental cost/year of live saved of $44 000 for lay person PAD and $27 200 for PAD by police, with greater than 4000 lives saved/year by lay-person PAD and greater than 20 000 by police defibrillation. While 4–6 h of specific training in AED use as part of BLS has been proposed as a standard by the AHA for proper use of an AED, current generation AEDs are self-explanatory and practically fool-proof, and can be appropriately and safely activated by untrained persons [116]. A recent study demonstrated that untrained, uncoached sixth-grade children were able to appropriately use an AED in a mock cardiac arrest scenario only 27 s slower than fully trained paramedics [117].

A recent study conducted in Las Vegas, Nevada placed AEDs in casinos with security guards trained in their use. In this specific setting, arrest to defibrillation times of 2–4 min were routinely achieved with survival rates to hospital discharge of 76% [112]. This differs little from response times achieved in-hospital. Paramedics summoned at the time of arrest reportedly arrived after 5–7 min to provide ACLS and rescue defibrillation if required. The experience in casinos obviously differs from the general setting of out-of-hospital arrest in several important ways: casinos provide a concentration of largely elderly (and therefore higher risk) persons in a well-populated and continuously video-monitored environment. This is the ideal setting to demonstrate proof of principle for lay person defibrillation, but does not prove the practicality of generalized PAD.

In an observational study of cardiac arrest in King County, Washington, only 25% of arrests occurred in public places, and with individual site rates even in the ‘higher rate’ category of 0.03/year at senior centers to 7/year at the airport [118]. Of note, ‘government offices’, which are specifically targeted in the recently enacted Cardiac Arrest Survival Act (CASA), had an annualized rate of only 0.003/site. Furthermore, while 75% of cardiac arrests occur at home, per-home event rates are very low and only 50–60% of out-of-hospital arrests are witnessed and would benefit from PAD [56,57,86]. While these observations do not disprove the potential value of widespread placement of AEDs, until the cost of these devices comes down dramatically, routine placement of AEDs will remain financially unattractive and cost-ineffective. The PAD1 trial sponsored by NHLBI will attempt to address the effectiveness of more widespread AED use. Until such a time that cost and liability issues can be resolved, placement of AEDs with populations at risk will be most cost-effective and will bring the greatest benefit in terms of improving survival from out-of-hospital arrest. Appropriate settings might include not only casinos but, for example, nursing homes and assisted living housing, airports, rural areas, and in homes of persons with known risk factors (following MI, congestive heart failure, etc.). The Rural Access to Emergency Device Act (Rural-AED Act) provides for $25 million in federal funding to encourage dissemination of AEDs into rural areas that are underserved by conventional EMS systems. These applications of AEDs could complement the use of implantable defibrillators (ICDs) in some high risk patients.

9.6 Implantable defibrillators
While the value of ICD therapy in some persons is unquestionable, because they are ‘already patients’ known or suspected to be at high risk for sudden death, this group who benefits from ICD therapy constitute a small fraction of all persons experiencing cardiac arrest. The strongest data at present applies to the use of ICDs in secondary prevention of SCD, i.e. in patients with a previous event. Three recently completed trials have examined the value of ICD vs. antiarrhythmic therapy in the treatment of patients with documented ventricular arrhythmias. CIDS (the Canadian Implantable Defibrillator Study) enrolled patients with EF ≤35% presenting with VF or hemodynamically unstable VT [119]. Patients were randomized to undergo implantation of an ICD or treatment with empiric amiodarone. At 3-year follow-up, there was a non-significant 20% reduction in all cause mortality in the ICD group. AVID (antiarrhythmics versus implantable defibrillators) randomized patients with EF ≤40% and VF or sustained VT to ICD vs. empiric dosing of a class III drug (primarily amiodarone) [40]. At 3 years follow-up, there was a statistically significant 31% reduction in total deaths in the ICD arm. CASH (Cardiac Arrest Study Hamburg) randomized SCD survivors to ICD vs. drug therapy with propafenone, amiodarone, or beta-blockade [120]. The propafenone arm was terminated prematurely because of excess mortality. CASH did not restrict enrollment to patients with impaired LV function, but again demonstrated 37% lower mortality in the ICD group, with no difference observed between metoprolol and amiodarone. These studies remain the only available data on secondary prevention of sudden death. Consensus supports the use of ICDs in this high-risk group of patients who have survived sudden death or hemodynamically destabilizing VT when no treatable trigger can be identified.

The focus of prophylactic devise-based treatment of ventricular arrhythmias should be on patient with structural heart disease who are at higher risk of ventricular fibrillation. As noted previously, the largest such group is patients with dilated cardiomyopathy, whether ischemic or non-ischemic in etiology. Mortality at 2 years ranges from 12 to 15% in asymptomatic patients to 70–75% in class IV heart failure [121,122]. The combined incidence of sustained ventricular arrhythmias and sudden, presumably arrhythmic, death in infarct survivors and patients with known coronary disease ranges from 11 to 66% at 2 years with highest total mortality observed in those with concomitant congestive heart failure [123,124]. Several recent trials have addressed, either directly or indirectly, the issue of primary prevention in patients with dilated cardiomyopathy. The MUSTT study randomized patients with CAD, EF ≤40% and NSVT who were inducible at EPS to no antiarrhythmic therapy vs. EPS guided antiarrhythmic treatment (including ICD implantation as last resort) [125]. The 27% reduction in the primary endpoint of arrhythmic death or cardiac arrest in the EP guided group was entirely due to the benefit of ICD implantation. Reduction in total mortality, a secondary endpoint in MUSTT but the endpoint of value in primary prevention, did not reach statistical significance at a mean follow-up of 39 months.

Two trials have specifically addressed the value of ICDs in patients with ischemic cardiomyopathy. CABG-Patch included patients with EF ≤36% and positive signal-averaged ECG scheduled to undergo clinically indicated coronary artery bypass surgery [126]. Half of the patients were randomized to undergo simultaneous prophylactic epicardial defibrillator implantation. No reduction in all-cause mortality was observed in the defibrillator group, despite a 1-year actuarial incidence of first ICD discharge of 50%. MADIT also targeted patients with ischemic cardiomyopathy, selecting a ‘high-risk’ population by randomizing patients with NSVT, who were not suppressible at EPS with procainamide, to ‘conventional’ therapy vs. ICD [127]. In sharp contrast to CABG-Patch, MADIT reached a predetermined statistical endpoint after enrolling 196 patients, with a 5-year total mortality of 16% in the ICD group compared with 39% in the conventional arm. Antiarrhythmic therapy was at the physician's discretion, and while 45% of conventionally treated patients were on amiodarone at last contact, the study was underpowered to draw any conclusions about relative efficacy of pharmacologic vs. device-based antiarrhythmic therapy.

Two additional trials are underway, hoping to further clarify the value of primary prevention in patients at high risk for arrhythmic death. SCD-HeFT is a placebo-controlled trial of amiodarone vs. ICD in NYHA class II—III patients with EF ≤35% (ischemic and non-ischemic), and no history of sustained ventricular arrhythmias. The primary endpoint is total mortality, with specific guidelines for maximizing other therapies known to improve survival, e.g. β-blockers, ACEI and statins. The MADIT II trial will attempt to extend the results of MADIT I by removing the criteria of inducibility at EPS, and will randomize 1200 patients post-MI with EF ≤30% to ICD vs. ‘conventional’ therapy. ICD therapy is expensive, with a need for periodic device replacement, risk of system infection and failure, and significant impact on quality of life [128]. It is unlikely to have a significant overall impact on the problem of sudden death in the community.

9.7 Dissemination of AEDs in the community
AEDs may prove to be an appropriate non-invasive alternative to ICDs in those patients who fall into intermediate risk groups who are at increased risk, but do not appear to benefit from ICD therapy. Multicenter studies are in review to examine, for example, the placement of AEDs in the homes of patients with recent anterior Q-wave myocardial infarction.

Widespread dissemination of AEDs will not occur until device costs come down, liability issues are resolved (exemption of both the user and the site of use) and the requirement for physician involvement (i.e. prescription) is eliminated. All states, with the exception of Maine, have some legal provision for use of AEDs, but not all specify conditions of legal immunity, in particular with respect to health-care professionals and the site of use. The federal Cardiac Arrest Survival Act (CASA) approved in May of 2000 took a step in this regard, but unfortunately falls far short. Ambiguous language does not explicitly protect, for example, the site of use (regardless of AED ownership). To make matters more cumbersome, the ‘acquirer’ of the AED is only protected if they can demonstrate compliance with multiple conditions including training of users, automatic notification of authorities of the presence of the device, all under the supervision of a physician (who is also not protected from liability). Given the litigious environment in the United States at least, the unfortunate consequence of the current legislation is to discourage dissemination of AEDs or any other public health initiative requiring public participation. In parts of Canada (Alberta, Ontario), the requirement for physician direction or prescription has already been lifted, and we can only hope that this progressive attitude will spread. The best hope for truly improving survival after cardiac arrest is to make AEDs readily available, like a fire extinguisher, for purchase and placement so anyone can access the device off a nearby wall and provide effective therapy.


   10 Conclusion
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
References
 
Sudden cardiac death remains a major public health issue. Real progress in reducing its impact will depend on identification of persons at risk, reduction in those risk factors, and application of techniques — both simple and advanced — to improve survival in victims. Emerging data from genetic and molecular analysis of SCD victims may help identify persons whom we currently do not recognize to be ‘high risk’. Ongoing trials in patients with known risk factors will hopefully clarify those interventions that will reduce the incidence of cardiac arrest. Emerging and maturing technologies such as AEDs and minimally invasive cardiac massage hold promise to improve survival. Nonetheless, the efficacy of all of these should not go unchallenged. Large randomized controlled trials, even of established practices such as CPR, should be undertaken before assumptions are made about efficacy, and widespread and costly policies are implemented. This will require the cooperation and commitment of medical and public health researchers and clinicians, interested laypersons, the legal community, and makers of public policy.

Time for primary review 13 days.


   Acknowledgements
 
NS thanks Dr Sina Gharib for discussions and critical readings of the manuscript.


   References
Top
 Abstract
 1 Introduction
 2 Definition
 3 Epidemiology
 4 Pathophysiolgy and mechanisms
 5 Risk factors
 6 Identification of persons...
 7 Strategies to decrease...
 8 Primary prevention
 9 Improving event survival
 10 Conclusion
 References
 

  1. Towbin J.A., Vatta M. The genetics of cardiac arrhythmias. Pacing Clin Electrophysiol (2000) 23(1):106.[CrossRef][Medline]
  2. Kannel W.B., Thomas H.E. Jr. Sudden coronary death: the Framingham Study. Ann NY Acad Sci (1982) 382:3.[Web of Science][Medline]
  3. Friedlander Y., Siscovick D.S., Weinmann S., et al. Family history as a risk factor for primary cardiac arrest. Circulation (1998) 97(2):155.[Abstract/Free Full Text]
  4. Volpi A., Cavalli A., Santoro E., Tognoni G. Incidence and prognosis of secondary ventricular fibrillation in acute myocardial infarction. Evidence for a protective effect of thrombolytic therapy. GISSI Investigators. Circulation (1990) 82(4):1279.[Abstract/Free Full Text]
  5. Holmes D.R. Jr., Davis K.B., Mock M.B., et al. The effect of medical and surgical treatment on subsequent sudden cardiac death in patients with coronary artery disease: a report from the Coronary Artery Surgery Study. Circulation (1986) 73(6):1254.[Abstract/Free Full Text]
  6. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI—Prevenzione trial. Lancet (1999) 354(9177):447. see comments.[CrossRef][Web of Science][Medline]
  7. Anon. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. J Am Med Assoc (1982) 247(12):1707.[Abstract/Free Full Text]
  8. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II). A randomised trial. Lancet (1999) 353(9146):9. see comments.[CrossRef][Web of Science][Medline]
  9. Yusuf S., Sleight P., Pogue J., Bosch J., Davies R., Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators [see comments] [published errata appear in New Engl J Med 2000 Mar 9;342(10):748 and 2000 May 4;342(18):1376]. New Engl J Med (2000) 342(3):145.[Abstract/Free Full Text]
  10. Pitt B., Zannad F., Remme W.J., et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators [see comments]. New Engl J Med (1999) 341(10):709.[Abstract/Free Full Text]
  11. de Vreede-Swagemakers J.J., Gorgels A.P., Dubois-Arbouw W.I., et al. Out-of-hospital cardiac arrest in the 1990s: a population-based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol (1997) 30(6):1500.[Abstract]
  12. Demirovic J., Myerburg R.J. Epidemiology of sudden coronary death: an overview. Prog Cardiovasc Dis (1994) 37(1):39.[Web of Science][Medline]
  13. Gillum R.F. Sudden coronary death in the United States: 1980–1985. Circulation (1989) 79(4):756.[Abstract/Free Full Text]
  14. Albert C.M., McGovern B.A., Newell J.B., Ruskin J.N. Sex differences in cardiac arrest survivors. Circulation (1996) 93(6):1170.[Abstract/Free Full Text]
  15. Becker L.B., Han B.H., Meyer P.M., Wright F.A., Rhodes K.V., Smith D.W., Barrett J. Racial differences in the incidence of cardiac arrest and subsequent survival. The CPR Chicago Project [see comments]. New Engl J Med (1993) 329(9):600.[Abstract/Free Full Text]
  16. Kuller L., Perper J., Cooper M. Demographic characteristics and trends in arteriosclerotic heart disease mortality: Sudden death and myocardial infarction. Circulation (1975) 52(Suppl_6):III1.[Medline]
  17. Hallstrom A.P., Eisenberg M.S., Bergner L. The persistence of ventricular fibrillation and its implication for evaluating EMS. Emerg Health Serv Q (1982) 1(4):41.[Medline]
  18. Valenzuela T.D., Roe D.J., Cretin S., Spaite D.W., Larsen M.P. Estimating effectiveness of cardiac arrest interventions: a logistic regression survival model. Circulation (1997) 96(10):3308.[Abstract/Free Full Text]
  19. Holmberg M., Holmberg S., Herlitz J., Gardelov B. Survival after cardiac arrest outside hospital in Sweden. Swedish Cardiac Arrest Registry. Resuscitation (1998) 36(1):29.[CrossRef][Web of Science][Medline]
  20. Eisenberg M.S., Horwood B.T., Cummins R.O., Reynolds-Haertle R., Hearne T.R. Cardiac arrest and resuscitation: a tale of 29 cities. Ann Emerg Med (1990) 19(2):179.[CrossRef][Web of Science][Medline]
  21. Reichenbach D.D., Moss N.S., Meyer E. Pathology of the heart in sudden cardiac death. Am J Cardiol (1977) 39(6):865.[CrossRef][Web of Science][Medline]
  22. Liberthson R.R., Nagel E.L., Hirschman J.C., Nussenfeld S.R., Blackbourne B.D., Davis J.H. Pathophysiologic observations in prehospital ventricular fibrillation and sudden cardiac death. Circulation (1974) 49(5):790.[Abstract/Free Full Text]
  23. de Vreede-Swagemakers J.J., Gorgels A.P., Dubois-Arbouw W.I., et al. Circumstances and causes of out-of-hospital cardiac arrest in sudden death survivors. Heart (1998) 79(4):356.[Abstract/Free Full Text]
  24. Davies M.J., Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. New Engl J Med (1984) 310(18):1137.[Abstract]
  25. Trichopoulos D., Katsouyanni K., Zavitsanos X., Tzonou A., Dalla-Vorgia P. Psychological stress and fatal heart attack: the Athens (1981) earthquake natural experiment. Lancet (1983) 1(8322):441.[CrossRef][Web of Science][Medline]
  26. Leor J., Poole W.K., Kloner R.A. Sudden cardiac death triggered by an earthquake [see comments]. New Engl J Med (1996) 334(7):413.[Abstract/Free Full Text]
  27. Albert C.M., Mittleman M.A., Chae C.U., Lee I.M., Hennekens C.H., Manson J.E. Triggering of sudden death from cardiac causes by vigorous exertion. New Engl J Med (2000) 343(19):1355.[Abstract/Free Full Text]
  28. Cohen M.C., Rohtla K.M., Lavery C.E., Muller J.E., Mittleman M.A. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death [published erratum appears in Am J Cardiol 1998 Jan 15;81(2):260]. Am J Cardiol (1997) 79(11):1512.[CrossRef][Web of Science][Medline]
  29. Multiple Risk Factor Intervention Trial Research Group. Baseline rest electrocardiographic abnormalities, antihypertensive treatment, and mortality in the Multiple Risk Factor Intervention Trial. Am J Cardiol (1985) 55(1):1.[CrossRef][Medline]
  30. Siscovick D.S., Raghunathan T.E., Psaty B.M., et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest [see comments]. New Engl J Med (1994) 330(26):1852.[Abstract/Free Full Text]
  31. Echt D.S., Liebson P.R., Mitchell L.B., et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial [see comments]. New Engl J Med (1991) 324(12):781.[Abstract]
  32. Hammermeister K.E., DeRouen T.A., Dodge H.T. Variables predictive of survival in patients with coronary disease. Selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations. Circulation (1979) 59(3):421.[Abstract/Free Full Text]
  33. Jouven X., Desnos M., Guerot C., Ducimetiere P. Predicting sudden death in the population: the Paris Prospective Study I. Circulation (1999) 99(15):1978.[Abstract/Free Full Text]
  34. Siscovick D.S., Weiss N.S., Hallstrom A.P., Inui T.S., Peterson D.R. Physical activity and primary cardiac arrest. J Am Med Assoc (1982) 248(23):3113.[Abstract/Free Full Text]
  35. Albert C.M., Hennekens C.H., O'Donnell C.J., et al. Fish consumption and risk of sudden cardiac death [see comments]. J Am Med Assoc (1998) 279(1):23.[Abstract/Free Full Text]
  36. Siscovick D.S., Raghunathan T.E., King I., et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest [see comments]. J Am Med Assoc (1995) 274(17):1363.[Abstract/Free Full Text]
  37. Kannel W.B., Cupples L.A., D'Agostino R.B. Sudden death risk in overt coronary heart disease: the Framingham Study. Am Heart J (1987) 113(3):799.[CrossRef][Web of Science][Medline]
  38. Kannel W.B., Doyle J.T., McNamara P.M., Quickenton P., Gordon T. Precursors of sudden coronary death. Factors related to the incidence of sudden death. Circulation (1975) 51(4):606.[Abstract/Free Full Text]
  39. Furukawa T., Rozanski J.J., Nogami A., Moroe K., Gosselin A.J., Lister J.W. Time-dependent risk of and predictors for cardiac arrest recurrence in survivors of out-of-hospital cardiac arrest with chronic coronary artery disease. Circulation (1989) 80(3):599.[Abstract/Free Full Text]
  40. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. New Engl J Med (1997) 337(22):1576. see comments.[Abstract/Free Full Text]
  41. Sytkowski P.A., Kannel W.B., D'Agostino R.B. Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Heart Study [see comments]. New Engl J Med (1990) 322(23):1635.[Abstract]
  42. Goldberg R.J., Gore J.M., Alpert J.S., Dalen J.E. Incidence and case fatality rates of acute myocardial infarction (1975–1984): the Worcester Heart Attack Study. Am Heart J (1988) 115(4):761.[CrossRef][Web of Science][Medline]
  43. Siscovick D.S., Weiss N.S., Fletcher R.H., Lasky T. The incidence of primary cardiac arrest during vigorous exercise. New Engl J Med (1984) 311(14):874.[Abstract]
  44. Lemaitre R.N., Siscovick D.S., Raghunathan T.E., Weinmann S., Arbogast P., Lin D.Y. Leisure-time physical activity and the risk of primary cardiac arrest. Arch Intern Med (1999) 159(7):686.[Abstract/Free Full Text]
  45. Albert C.M., Manson J.E., Cook N.R., Ajani U.A., Gaziano J.M., Hennekens C.H. Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians. Circulation (1999) 100(9):944.[Abstract/Free Full Text]
  46. Anon. Reduction in mortality after myocardial infarction with long-term beta-adrenoceptor blockade. Multicentre international study: supplementary report. Br Med J (1977) 2(6084):419.[Abstract/Free Full Text]
  47. Pedersen T.R. Six-year follow-up of the Norwegian multicenter study on timolol after acute myocardial infarction. New Engl J Med (1985) 313(17):1055.[Abstract]
  48. MERIT-HF. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure. Lancet (1999) 353(9169):2001. see comments.[CrossRef][Web of Science][Medline]
  49. Packer M., Bristow M.R., Cohn J.N., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group [see comments]. New Engl J Med (1996) 334(21):1349.[Abstract/Free Full Text]
  50. Anderson J.L., Rodier H.E., Green L.S. Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold. Am J Cardiol (1983) 51(7):1196.[CrossRef][Web of Science][Medline]
  51. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). New Engl J Med (1987) 316(23):1429.[Abstract]
  52. Kober L., Torp-Pedersen C., Carlsen J.E., et al. A clinical trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group [see comments]. New Engl J Med (1995) 333(25):1670.[Abstract/Free Full Text]
  53. Kennedy H.L., Rosenson R.S. Physician use of beta-adrenergic blocking therapy: a changing perspective [editorial]. J Am Coll Cardiol (1995) 26(2):547.[Web of Science][Medline]
  54. Mitchell R.G., Brady W., Guly U.M., Pirrallo R.G., Robertson C.E. Comparison of two emergency response systems and their effect on survival from out of hospital cardiac arrest. Resuscitation (1997) 35(3):225.[CrossRef][Web of Science][Medline]
  55. Lui J.C. Evaluation of the use of automatic external defibrillation in out-of-hospital cardiac arrest in Hong Kong. Resuscitation (1999) 41(2):113.[CrossRef][Web of Science][Medline]
  56. Becker L.B., Ostrander M.P., Barrett J., Kondos G.T. Outcome of CPR in a large metropolitan area — where are the survivors? [see comments]. Ann Emerg Med (1991) 20(4):355.[CrossRef][Web of Science][Medline]
  57. Stiell I.G., Wells G.A., DeMaio V.J., et al. Modifiable factors associated with improved cardiac arrest survival in a multicenter basic life support/defibrillation system: OPALS Study Phase I results. Ontario Prehospital Advanced Life Support. Ann Emerg Med (1999) 33(1):44.[CrossRef][Web of Science][Medline]
  58. Valenzuela T.D., Spaite D.W., Meislin H.W., Clark L.L., Wright A.L., Ewy G.A. Emergency vehicle intervals versus collapse-to-CPR and collapse-to-defibrillation intervals: monitoring emergency medical services system performance in sudden cardiac arrest. Ann Emerg Med (1993) 22(11):1678.[CrossRef][Web of Science][Medline]
  59. Torp-Pedersen C., Birk-Madsen E., Pedersen A. The time factor in resuscitation initiated by ambulance drivers. Eur Heart J (1989) 10(6):555.[Abstract/Free Full Text]
  60. Tanigawa K., Tanaka K., Shigematsu A. Outcomes of out-of-hospital ventricular fibrillation: their association with time to defibrillation and related issues in the defibrillation program in Japan [In Process Citation]. Resuscitation (2000) 45(2):83.[CrossRef][Web of Science][Medline]
  61. Sweeney T.A., Runge J.W., Gibbs M.A., et al. defibrillation does not increase survival from sudden cardiac death in a two-tiered urban-suburban EMS system. Ann Emerg Med (1998) 31(2):234.[CrossRef][Web of Science][Medline]
  62. Eisenberg M.S., Copass M.K., Hallstrom A., Cobb L.A., Bergner L. Management of out-of-hospital cardiac arrest. Failure of basic emergency medical technician services. J Am Med Assoc (1980) 243(10):1049.[Abstract/Free Full Text]
  63. Leslie W.S., Fitzpatrick B., Morrison C.E., Watt G.C., Tunstall-Pedoe H. Out-of-hospital cardiac arrest due to coronary heart disease: a comparison of survival before and after the introduction of defribrillators in ambulances. Heart (1996) 75(2):195.[Abstract/Free Full Text]
  64. Stueven H.A., Waite E.M., Troiano P., Mateer J.R. Prehospital cardiac arrest — a critical analysis of factors affecting survival. Resuscitation (1989) 17(3):251.[CrossRef][Web of Science][Medline]
  65. Kouwenhoven W.B., Jude J.R., Knickerbocker G.G. Closed-chest cardiac massage. J Am Med Assoc (1960) 173(10):1064.[Abstract/Free Full Text]
  66. Anon. Adult basic life support. Circulation (2000) 102(Suppl I):I23.
  67. Berkowitz I.D., Rogers M.C. The physiology of cerebral blood flow during cardiopulmonary resuscitation. Can J Anaesth (1988) 35(3):S23.[Medline]
  68. Deshmukh H.G., Weil M.H., Gudipati C.V., Trevino R.P., Bisera J., Rackow E.C. Mechanism of blood flow generated by precordial compression during CPR. I. Studies on closed chest precordial compression. Chest (1989) 95(5):1092.[CrossRef][Web of Science][Medline]
  69. Maier G.W., Tyson G.S. Jr., Olsen C.O., et al. The physiology of external cardiac massage: high-impulse cardiopulmonary resuscitation. Circulation (1984) 70(1):86.[Abstract/Free Full Text]
  70. Redberg R.F., Tucker K.J., Cohen T.J., Dutton J.P., Callaham M.L., Schiller N.B. Physiology of blood flow during cardiopulmonary resuscitation. A transesophageal echocardiographic study. Circulation (1993) 88(2):534.[Abstract/Free Full Text]
  71. Werner J.A., Greene H.L., Janko C.L., Cobb L.A. Two-dimensional echocardiography during CPR in man: implications regarding the mechanism of blood flow. Crit Care Med (1981) 9(5):375.[Web of Science][Medline]
  72. MacKenzie G.J., Taylor S.H., McDonald A.H., Donald K.W. Haemodynamic effects of external cardiac compression. Lancet (1964) i:1342.
  73. Ornato J.P. Hemodynamic monitoring during CPR. Ann Emerg Med (1993) 22(2):289.[CrossRef][Web of Science][Medline]
  74. Lee S.K., Vaagenes P., Safar P., Stezoski S.W., Scanlon M. Effect of cardiac arrest time on cortical cerebral blood flow during subsequent standard external cardiopulmonary resuscitation in rabbits. Resuscitation (1989) 17(2):105.[CrossRef][Web of Science][Medline]
  75. Shaffner D.H., Eleff S.M., Brambrink A.M., et al. Effect of arrest time and cerebral perfusion pressure during cardiopulmonary resuscitation on cerebral blood flow, metabolism, adenosine triphosphate recovery, and pH in dogs [see comments]. Crit Care Med (1999) 27(7):1335.[CrossRef][Web of Science][Medline]
  76. Troiano P., Masaryk J., Stueven H.A., Olson D., Barthell E., Waite E.M. The effect of bystander CPR on neurologic outcome in survivors of prehospital cardiac arrests. Resuscitation (1989) 17(1):91.[CrossRef][Web of Science][Medline]
  77. Cobb L.A., Fahrenbruch C.E., Walsh T.R., et al. Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation [see comments]. J Am Med Assoc (1999) 281(13):1182.[Abstract/Free Full Text]
  78. Corbett S.W., O'Callaghan T. Detection of traumatic complications of cardiopulmonary resuscitation by ultrasound. Ann Emerg Med (1997) 29(3):317.[CrossRef][Web of Science][Medline]
  79. Enarson D.A., Gracey D.R. Complications of cardiopulmonary resuscitation. Heart Lung (1976) 5(5):805.[Medline]
  80. Greenberg H.B. Aspiration pneumonia after cardiac arrest and resuscitation. J Am Geriatr Soc (1967) 15(2):148.[Web of Science][Medline]
  81. Rabl W., Baubin M., Broinger G., Scheithauer R. Serious complications from active compression—decompression cardiopulmonary resuscitation. Int J Leg Med (1996) 109(2):84.[CrossRef][Web of Science][Medline]
  82. Scholz K.H., Tebbe U., Herrmann C., et al. Frequency of complications of cardiopulmonary resuscitation after thrombolysis during acute myocardial infarction [see comments]. Am J Cardiol (1992) 69(8):724.[CrossRef][Web of Science][Medline]
  83. Arai T., Watanabe T., Nagaro T., Matsuo S. Blood—brain barrier impairment after cardiac resuscitation. Crit Care Med (1981) 9(6):444.[Web of Science][Medline]
  84. Dohi S. Postcardiopulmonary resuscitation pulmonary edema. Crit Care Med (1983) 11(6):434.[Web of Science][Medline]
  85. Nagel E.L., Fine E.G., Krischer J.P., Davis J.H. Complications of CPR. Crit Care Med (1981) 9(5):424.[CrossRef][Web of Science][Medline]
  86. Swor R.A., Jackson R.E., Cynar M., et al. Bystander CPR, ventricular fibrillation, and survival in witnessed, unmonitored out-of-hospital cardiac arrest. Ann Emerg Med (1995) 25(6):780.[CrossRef][Web of Science][Medline]
  87. Isaacs E., Callaham M.L. Ability of laypersons to estimate short time intervals in cardiac arrest. Ann Emerg Med (2000) 35(2):147.[CrossRef][Web of Science][Medline]
  88. Mattioni T.A., Nademanee K., Brodsky M., et al. Initial clinical experience with a fully automatic in-hospital external cardioverter defibrillator. PACE (1999) 22:1648–1655.[Medline]
  89. Gallagher E.J., Lombardi G., Gennis P. Effectiveness of bystander cardiopulmonary resuscitation and survival following out-of-hospital cardiac arrest. J Am Med Assoc (1995) 274(24):1922.[Abstract/Free Full Text]
  90. Herlitz J., Ekstrom L., Wennerblom B., Axelsson A., Bang A., Holmberg S. Effect of bystander initiated cardiopulmonary resuscitation on ventricular fibrillation and survival after witnessed cardiac arrest outside hospital. Br Heart J (1994) 72(5):408.[Abstract/Free Full Text]
  91. Martens P.R., Mullie A., Calle P., Van Hoeyweghen R. Influence on outcome after cardiac arrest of time elapsed between call for help and start of bystander basic CPR. The Belgian Cerebral Resuscitation Study Group. Resuscitation (1993) 25(3):227.[CrossRef][Web of Science][Medline]
  92. Niemann J.T., Cairns C.B., Sharma J., Lewis R.J. Treatment of prolonged ventricular fibrillation. Immediate countershock versus high-dose epinephrine and CPR preceding countershock. Circulation (1992) 85(1):281.[Abstract/Free Full Text]
  93. Ward K.R., Sullivan R.J., Zelenak R.R., Summer W.R. A comparison of interposed abdominal compression CPR and standard CPR by monitoring end-tidal pCO2 [see comments]. Ann Emerg Med (1989) 18(8):831.[CrossRef][Web of Science][Medline]
  94. Kern K.B., Carter A.B., Showen R.L., et al. Twenty-four hour survival in a canine model of cardiac arrest comparing three methods of manual cardiopulmonary resuscitation. J Am Coll Cardiol (1986) 7(4):859.[Abstract]
  95. Sack J.B., Kesselbrenner M.B. Hemodynamics, survival benefits, and complications of interposed abdominal compression during cardiopulmonary resuscitation. Acad Emerg Med (1994) 1(5):490.[Medline]
  96. Rabl W., Baubin M., Haid C., Pfeiffer K.P., Scheithauer R. Review of active compression-decompression cardiopulmonary resuscitation (ACD-CPR). Analysis of iatrogenic complications and their biomechanical explanation. Forensic Sci Int (1997) 89(3):175.[CrossRef][Web of Science][Medline]
  97. Schwab T.M., Callaham M.L., Madsen C.D., Utecht T.A. A randomized clinical trial of active compression—decompression CPR vs. standard CPR in out-of-hospital cardiac arrest in two cities [see comments]. J Am Med Assoc (1995) 273(16):1261.[Abstract/Free Full Text]
  98. Mauer D.K., Nolan J., Plaisance P., et al. Effect of active compression—decompression resuscitation (ACD-CPR) on survival: a combined analysis using individual patient data. Resuscitation (1999) 41(3):249.[CrossRef][Web of Science][Medline]
  99. Plaisance P., Lurie K.G., Vicaut E., Adnet F., Petit J.L., Epain D., Ecollan P., Gruat R., Cavagna P., Biens J., Payen D. A comparison of standard cardiopulmonary resuscitation and active compression—decompression resuscitation for out-of-hospital cardiac arrest. French Active Compression—Decompression Cardiopulmonary Resuscitation Study Group [see comments]. New Engl J Med (1999) 341(8):569.[Abstract/Free Full Text]
  100. Buckman R.F. Jr., Badellino M.M., Mauro L.H., et al. Direct cardiac massage without major thoracotomy: feasibility and systemic blood flow. Resuscitation (1995) 29(3):237.[CrossRef][Web of Science][Medline]
  101. Buckman R.F. Jr., Badellino M.M., Eynon C.A., et al. Open-chest cardiac massage without major thoracotomy: metabolic indicators of coronary and cerebral perfusion. Resuscitation (1997) 34(3):247.[CrossRef][Web of Science][Medline]
  102. Jackson R.E., Joyce K., Donosi S. Blood flow in the cerebral cortex during cardiac resuscitation in dogs. Ann Emerg Med (1984) 13:657.[CrossRef][Web of Science][Medline]
  103. Boczar M.E., Howard M.A., Rivers E.P., et al. A technique revisited: hemodynamic comparison of closed- and open-chest cardiac massage during human cardiopulmonary resuscitation. Crit Care Med (1995) 23(3):498.[CrossRef][Web of Science][Medline]
  104. Rubertsson S., Grenvik A., Wiklund L. Blood flow and perfusion pressure during open-chest versus closed-chest cardiopulmonary resuscitation in pigs. Crit Care Med (1995) 23(4):715.[CrossRef][Web of Science][Medline]
  105. Kudenchuk P.J., Cobb L.A., Copass M.K., et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation [see comments]. New Engl J Med (1999) 341(12):871.[Abstract/Free Full Text]
  106. van Walraven C., Stiell I.G., Wells G.A., Hebert P.C., Vandemheen K. Do advanced cardiac life support drugs increase resuscitation rates from in-hospital cardiac arrest? The OTAC Study Group. Ann Emerg Med (1998) 32(5):544.[CrossRef][Web of Science][Medline]
  107. Mitchell R.G., Guly U.M., Rainer T.H., Robertson C.E. Paramedic activities, drug administration and survival from out of hospital cardiac arrest. Resuscitation (2000) 43(2):95.[CrossRef][Web of Science][Medline]
  108. Gliner B.E., Jorgenson D.B., Poole J.E., et al. Treatment of out-of-hospital cardiac arrest with a low-energy impedance-compensating biphasic waveform automatic external defibrillator. The LIFE Investigators. Biomed Instrum Technol (1998) 32(6):631.[Medline]
  109. Schneider T., Martens P.R., Paschen H., et al. Multicenter, randomized, controlled trial of 150-J biphasic shocks compared with 200- to 360-J monophasic shocks in the resuscitation of out-of-hospital cardiac arrest victims [In Process Citation]. Circulation (2000) 102(15):1780.[Abstract/Free Full Text]
  110. Lindholm D.J., Campbell J.P. Predicting survival from out-of-hospital cardiac arrest. Prehospital Disaster Med (1998) 13(2–4):51.[Medline]
  111. Herlitz J., Estrom L., Wennerblom B., Axelsson A., Bang A., Holmberg S. Survival among patients with out-of-hospital cardiac arrest found in electromechanical dissociation. Resuscitation (1995) 29(2):97.[CrossRef][Web of Science][Medline]
  112. Valenzuela T.D., Roe D.J., Nichol G., Clark L.L., Spaite D.W., Hardman R.G. Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. New Engl J Med (2000) 343(17):1206.[Abstract/Free Full Text]
  113. Spearpoint K.G., McLean C.P., Zideman D.A. Early defibrillation and the chain of survival in ‘in-hospital’ adult cardiac arrest; minutes count. Resuscitation (2000) 44(3):165.[CrossRef][Web of Science][Medline]
  114. Nichol G., Hallstrom A.P., Ornato J.P., et al. Potential cost-effectiveness of public access defibrillation in the United States. Circulation (1998) 97(13):1315.[Abstract/Free Full Text]
  115. Martens P., Calle P., Vanhaute O. Theoretical calculation of maximum attainable benefit of public access defibrillation in Belgium. Belgian Cardio Pulmonary Cerebral Resuscitation Study Group. Resuscitation (1998) 36(3):161.[CrossRef][Web of Science][Medline]
  116. Domanovits H., Meron G., Sterz F., et al. Successful automatic external defibrillator operation by people trained only in basic life support in a simulated cardiac arrest situation. Resuscitation (1998) 39(1–2):47.[CrossRef][Web of Science][Medline]
  117. Gundry J.W., Comess K.A., DeRook F.A., Jorgenson D., Bardy G.H. Comparison of naive sixth-grade children with trained professionals in the use of an automated external defibrillator. Circulation (1999) 100(16):1703.[Abstract/Free Full Text]
  118. Becker L., Eisenberg M., Fahrenbruch C., Cobb L. Public locations of cardiac arrest. Implications for public access defibrillation. Circulation (1998) 97(21):2106.[Abstract/Free Full Text]
  119. Connolly S.J., Gent M., Roberts R.S., et al. Canadian implantable defibrillator study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone [see comments]. Circulation (2000) 101(11):1297.[Abstract/Free Full Text]
  120. Kuck K.H., Cappato R., Siebels J., Ruppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation (2000) 102(7):748.[Abstract/Free Full Text]
  121. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. New Engl J Med [see comments] [published erratum appears in New Engl J Med 1992 Dec 10;327(24):1768] (1992) 327(10):685.
  122. Swerdlow C.D., Winkle R.A., Mason J.W. Determinants of survival in patients with ventricular tachyarrhythmias. New Engl J Med (1983) 308(24):1436.[Abstract]
  123. Bigger J.T. Jr., Fleiss J.L., Kleiger R., Miller J.P., Rolnitzky L.M. The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation (1984) 69(2):250.[Abstract/Free Full Text]
  124. Trappe H.J., Brugada P., Talajic M., et al. Prognosis of patients with ventricular tachycardia and ventricular fibrillation: role of the underlying etiology. J Am Coll Cardiol (1988) 12(1):166.[Abstract]
  125. Buxton A.E., Lee K.L., Fisher J.D., Josephson M.E., Prystowsky E.N., Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators [see comments] [published erratum appears in New Engl J Med 2000 Apr 27;342(17):1300]. New Engl J Med (1999) 341(25):1882.[Abstract/Free Full Text]
  126. Bigger J.T. Jr. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators [see comments]. New Engl J Med (1997) 337(22):1569.[Abstract/Free Full Text]
  127. Moss A.J., Hall W.J., Cannom D.S., et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators [see comments]. New Engl J Med (1996) 335(26):1933.[Abstract/Free Full Text]
  128. Grimm W., Menz V., Hoffmann J., et al. Complications of third-generation implantable cardioverter defibrillator therapy. Pacing Clin Electrophysiol (1999) 22(1):206.[CrossRef][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Sotoodehnia, N.
Right arrow Articles by Siscovick, D. S
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sotoodehnia, N.
Right arrow Articles by Siscovick, D. S
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?