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A Case-Crossover Analysis of Particulate Matter Air Pollution and Out-of-Hospital Primary Cardiac Arrest

Levy, Drew1; Sheppard, Lianne2,3; Checkoway, Harvey1,3; Kaufman, Joel3,4; Lumley, Thomas2; Koenig, Jane3; Siscovick, David1,4

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Numerous epidemiologic studies have reported increases in the daily incidence of cardiovascular mortality and morbidity associated with increases in daily levels of particulate matter air pollution. We studied the association between the incidence of primary cardiac arrest and two daily measures of particulate matter using a case-crossover study of 362 cases of out-of-hospital cardiac arrest. All cases were attended by paramedics and had no history of clinically recognized heart disease or life-threatening comorbidities. We compared particulate matter levels at index times with particulate matter levels from referent days matched on day of week within strata defined by month and year. The estimated relative risk at a lag of 1 day for an interquartile range (IQR) change in nephelometry (0.51 × 10-1 km-1) was 0.893 (95% CI = 0.779–1.024). The estimated relative risk at a lag of 1 day for an IQR change in PM10 (19.3 μgm-3) was 0.868 (95% CI = 0.744–1.012). Other lag periods gave similar results. We did not find evidence of confounding by carbon monoxide or sulfur dioxide. Analysis of effect modification by individual-level variables did not reveal any susceptible subgroups. These findings do no support an association between particulate matter and increased risk of primary cardiac arrest among persons without clinically recognized heart disease. The null results of this study may result from several factors, including the highly selected nature of this case series and the relatively low particulate matter levels in the Seattle metropolitan area.

From 1Department of Epidemiology, 2Department of Biostatistics, 3Department of Environmental Health, 4Department of Medicine, University of Washington, Seattle, WA 98195-7232.

Address correspondence to: Lianne Sheppard, Box 357232, Department of Biostatistics, University of Washington, Seattle, WA 98195-7232.

This research was funded in part by the Health Effects Institute Research Agreement 97–2-2 and in part by the United States Environmental Protection Agency through agreement R827355 for the EPA Northwest Research Center for Particulate Air Pollution and Health.

This research does not necessarily reflect the views of either funding agency and no official endorsement should be inferred.

Submitted April 25, 2000; final version accepted August 1, 2000.

There is accumulating epidemiologic evidence that increases in ambient air pollutants are associated with increases in non-accidental daily mortality. Most evidence comes from ecologic time-series studies in North America and Western Europe. 1-7 Overall, daily variation in levels of ambient particulate matter (PM) air pollution as commonly found in urban environments has been associated with daily total mortality increases of 0.5% per 10 μg/m3 increase in particulate matter less than 10 μm in diameter (PM10). 8 For cardiovascular mortality, summary estimates of 1.4% per 10 μg/m3 have been reported. 1,3,9 Corroborative evidence has been obtained from analyses of cardiovascular hospital admissions. 10-13

Despite the apparent consistency of the epidemiologic findings for PM effects on daily cardiovascular disease mortality, there remain important unresolved issues that limit causal interpretation. These include design limitations, the non-specificity of disease outcomes analyzed in most time-series studies, uncertainties regarding the most toxic components of PM, and the frequently noted problems of exposure misclassification, and potential confounding by climatic factors, co-pollutants, and other putative disease risk factors. The ecologic time-series design, wherein exposures and health outcomes are investigated at the population level, rather than at the individual level, is used in the majority of existing studies. In addition to the utilization of ambient pollution measures as a proxy for personal exposure, the ecologic design requires additional fundamental assumptions before relative risk estimates can have individual-level interpretation. 14 Furthermore, the absence of personal-level risk factor data also limits the ability to assess effect modification by other risk factors. Characterization of effect modification, which can assist in the identification of susceptible subgroups in the population, becomes especially important in epidemiologic studies of PM because of the small population-wide relative risks that are usually observed. Few studies have been able to evaluate specific forms of cardiovascular effects attributable to PM because of the challenges of sensitive and specific population-based outcome surveillance and ascertainment.

Cardiovascular disease accounts for a sizeable proportion of daily mortality and is thus an important area of focus for PM research. Possible effects to the cardiovascular system from transient changes in PM levels should be most readily detected in studies of acute-onset events. Schwartz 15 found a disproportionate increase in sudden death on high air pollution days, indicating cardiac arrest may be an important component of the PM-mortality association. Cardiac arrest refers to the abrupt, unexpected loss of cardiac function due to a life-threatening arrythia, and is usually fatal. Death from primary cardiac arrest accounts for about 10% of mortality in US adults. 16 The proximate cause of fatal cardiac arrest is typically ventricular tacharrhythmia, which may be provoked by a series of triggering events acting on the myocardium. 17 No biologic mechanism(s) for particulate air pollution effects on cardiac arrest have been elucidated, although some candidate models, such as electrical disburbances and inflammatory reactions, have been proposed. 18-22

Ideally the exposure measures used in a cardiovascular health effects study will represent the biologically active exposure. In the Seattle metropolitan area several PM measurements are routinely collected. These include gravimetric measures of PM10 and nephelometry measures of fine PM. Measures of light scattering from an integrating nephelometer are highly correlated with the mass concentration of particles between 0.1 and 1.4 μm in diameter. 23,24 Since the submicrometer fraction contains a large portion of the respirable particles and these have a composition that may affect health, the light scattering measurement should provide a useful exposure metric for health studies. We hypothesize that if the fine fraction of PM is the biologically active component, then the relative risks observed for light scattering will be stronger than that for PM10.

This study assessed the association between PM and incidence of primary cardiac arrest, also known as sudden cardiac death, in a well-defined existing case-series of primary cardiac arrests among persons without histories of clinically detected cardiovascular disease, and who were free of other life-threatening conditions. We anticipated that the specificity of the case identification process for this group may facilitate inference about the possible underlying pathophysiologic mechanisms of PM. Our secondary objectives were to contrast associations for two measures of PM and to evaluate potential effect modifiers.

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Methods

Study Subjects

We used data from a population-based case-control study of out-of-hospital primary cardiac arrest conducted by Siscovick and colleagues. 25 The 362 cases were a subset of all cases of paramedic-attended out-of-hospital primary cardiac arrest in Seattle and suburban King County, Washington from October 3, 1988 to July 25, 1994. To be eligible for inclusion, cases had a sudden pulseless condition in the absence of a non-cardiac condition. We reviewed emergency medical service reports, death certificates, and (when available) medical examiner and autopsy reports to confirm the absence of non-cardiac causes. We excluded cases if they had a history of clinically recognized heart disease (including angina, myocardial infarction, coronary artery bypass surgery, or angioplasty, congestive heart failure, arrhythmias, cardiomyopathy, valvular, or congenital disease), or life-threatening comorbidities (cancer, or end-stage lung, liver, or renal disease). The series was further restricted to 25- to 75-year-old married King County residents whose spouses participated in an in-person interview (83% of those eligible) to ensure uniform data collection for survivors and non-survivors of primary cardiac arrest.

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Air Pollution Data

Air pollution data were obtained from the Puget Sound Clean Air Agency (PSCAA) for the study period (October 3, 1988 - July 25, 1994). Data for daily average temperature at Seattle-Tacoma airport were obtained from the National Oceanic and Atmospheric Administration.

The primary exposure metric used in this study was 24-hour average particulate matter measured by nephelometry (reported as bsp in units of km-1, and referred to as the light scattering extinction coefficient). We also had gravimetric measures of PM10. Both were obtained from three King County monitoring sites: Duwamish, Lake Forest Park and Kent (Figure 1). We used the mean of daily average values from the three sites as our exposure measurement. Where data were missing for a particular monitoring station on a given day, the values from the remaining monitors were used to compute the average. Missing data prevented us from using PM2.5 in analyses. Nephelometry measures, however, are a good surrogate for PM2.5 since nephelometry data correlate well with gravimetric particle measurements in the 0.1–1.4 aerodynamic diameter range 23,24 and we have found nephelometry data to be highly correlated with PM2.5 in the greater Seattle metropolitan area. 26

FIGURE 1

FIGURE 1

We obtained daily average sulfur dioxide (SO2) measurements from a monitor co-located with the PM monitors situated at the urban industrial Duwamish site. For carbon monoxide (CO), we combined daily averages from four street canyon locations into a single daily mean value. Ozone was measured only in the summer months and therefore we did not consider ozone in these analyses. We summarize distributions of all available air pollutant measurements and temperature in Table 2 and give correlations among all variables we consider in health effects analyses in Table 3. Further descriptive detail of these data can be found in Sheppard et al. 26

Table 2

Table 2

Table 3

Table 3

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Statistical Analysis

The case-crossover study design was proposed by Maclure 27 to study the effects of transient, intermittent exposures on the subsequent risk of rare acute-onset events in close temporal proximity to exposure. This design can be regarded as a special type of case-control study in which each case serves as his or her own referent. It requires exposure data only for cases. Exposures for each case during an “at risk” (index) period before the event are compared with the distribution of exposure during a referent period. The referent exposures should be representative of the expected distribution of exposure for follow-up times that do not result in a case. Selection of the index period (usually a single day in air pollution studies) follows similar logic to conventional air pollution time-series studies – the index day may be the day of the event or some previous day allowing for a lag between exposure and manifestation of the event. The choice of referent days in air pollution research poses greater methodologic challenges because of the need to minimize multiple competing biases owing to lack of stationarity in the air pollution time series. 28-32 These include biases from long-term time trends, seasonal patterns, autocorrelation in exposures, and day-of-week effects. Methodologic work stemming from this study 31,32 suggests that time should be stratified prior to analysis (eg, into separate months) and referents selected to be all days falling on the same day of the week within the same stratum as the index day.TABLE

Table 1

Table 1

We performed conditional logistic regression to obtain estimates of relative risks and 95% confidence intervals associated with interquartile range (IQR) exposures from nephelometry (0.51 × 10-1 km-1 bsp) and PM10 (19.3 μg/m3). We conducted separate analyses for lags of 0 through 5 days since the induction period for an association between PM and out-of-hospital sudden cardiac arrest is unknown. We then selected a single lag for multipollutant models of PM with either CO or SO2. We examined effect modification by considering categories of selected variables, specifically age, current cigarette smoke exposure, aspirin use, consumption of alcoholic beverages, long-chain N-3 polyunsaturated fatty acid consumption, physical activity, and a composite of risk factors quantifying risk for coronary heart disease. We classified current cigarette smoke exposure as current smokers and subjects exposed to passive smoking for one or more hours in an average week. Aspirin use pertained to subjects taking the equivalent of two or more aspirin tablets per week. Alcoholic beverage consumers imbibed one or more alcoholic beverages per day. We classified subjects with consumption above the median of a Fish Intake Scale 25 along with those who reported taking fish oil supplements as exposed to long-chain N-3 polyunsaturated fatty acid. We classified cases as physically active if their average total kilocalories of recreational physical activity expended per week was greater than or equal to one. 33 For indications of coronary heart disease risk, we included treatment for diabetes mellitus, high blood total cholesterol, or hypertension, or family history of early myocardial infarction or sudden death (any parent or sibling experiencing myocardial infarction or sudden death before age 56 for males and before age 66 for females). We also assessed the role of time by examining effect modification by season and time categories (before or after the midpoint of the study period).

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Results

We assumed a linear exposure-effect model and estimated interquartile range relative risks and 95% confidence intervals for PM from light scattering for lags of 0 to 5 days. Effect estimates range from 0.89 (0 day lag; 95% CI = 0.78–1.02) to 1.01 (3 day lag; 95% CI = 0.90–1.12). We did not observe any pattern over the set of the lags suggestive of a relation between PM and the incidence of out-of-hospital primary cardiac arrest. The corresponding findings for PM10 display a generally similar pattern of no strong or consistent association with cardiac arrest. We selected lag 1 for subsequent analyses because, absent any compelling evidence for any other lag, it is the most proximal to the exposure among non-zero lags. At lag 0 we could not rule out that the time of the cardiac arrest may have preceded most of the exposure. We assessed the potential for a nonlinear exposure effect at lag 1 by estimating effects by quartile and by using regression spline smoothers with one and three knots. None of these models was an improvement over the linear exposure-effect model.

Table 4 gives relative risk estimates for single- and multi-pollutant models at lag 1. The two PM effect estimates are essentially the same. There is no indication of association between either CO or SO2 and out-of-hospital primary cardiac arrest. The multi-pollutant models do not give evidence of confounding of the PM effect by any of the pollutant variables.

Table 4

Table 4

Table 5 summarizes the results of analyses for PM measured by nephelometry stratified by potential effect modifiers. We did not observe any apparent susceptible subgroups for the cardiovascular risk factors examined, although we did observe heterogeneity in estimates across seasons. The estimate for autumn was greater than one while those for the remaining seasons were less than one. If PM is indeed associated with primary cardiac arrest, we would expect at least as large relative risks to occur in winter owing to the prevalence of residential wood burning and the potentially greater toxicity of these particles. This expectation is not consistent with the results. We repeated the analyses for the remaining lags, for PM10, and for other categorizations of the effect modifiers. These results were not materially different from those reported in Table 5.

Table 5

Table 5

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Discussion

The possibility of detrimental health effects from particulate matter air pollution remains controversial. A large number of studies have found associations between PM and both morbidity and mortality outcomes. Most studies have linked daily variation in ambient PM concentrations to daily variation in total and cause-specific mortality, hospital admissions, or emergency department visits. For instance, Schwartz and Morris 11 observed an association between PM10 and hospital admissions for ischemic heart disease, congestive heart failure and dysrhythmias in Detroit, Michigan. Burnett et al.10 reported that fine sulfate particles were associated with heart disease admissions in Ontario, Canada. Schwartz 12 found associations between PM10 and cardiovascular disease admissions in Tucson, Arizona. He also observed that daily variation in PM10 was associated with hospital admissions for heart disease in eight US counties from various parts of the country, although the relation was weakest for Seattle among the eight metropolitan areas studied. 13 His summary relative risk estimate was 1.025 (95% confidence limits = 1.018, 1.032) for a 25 μg/m3 increase in PM10. He posited that approximately 5% of hospital admissions for heart disease may be attributable to air pollution.

The mechanisms of PM action on the cardiovascular system are uncertain. Pope et al34 tested the hypothesis that exposure to PM acutely reduces blood oxygenation. While they did not observe an effect on blood oxygenation, they did find an association with slightly increased heart rate. The biological significance of this finding remains unclear. Liao et al35 reported transient reductions in heart rate variability associated with increases in exposure to PM, suggesting a reduction in parasympathetic control of heart rate among elderly persons. Other hypotheses concerning effects of PM on the cardiovascular system have suggested ultrafine PM may induce alveolar inflammation, with the release of mediators capable of increasing blood coagubility, possibly increasing the risk for ischemic events. 36 Peters et al37 found increases in plasma viscosity to be associated with an air pollution episode marked by elevations in total suspended particles and other pollutants. Their data, however, did not distinguish between contributions from ultrafine particles, other air pollutants, or other unmeasured confounding factors.

Our results do not support an association between PM and out-of-hospital primary cardiac arrest. The patterns of results were nearly identical for PM measured by nephelometry and gravimetrically (PM10). Furthermore, we did not find evidence of effect modification by known personal risk factors for sudden cardiac arrest. Time-series studies of PM and cardiovascular disease are in the range of 1.4–4.2% increases in daily cardiovascular mortality for a 10 μg/m3 increase in PM10. 13,38 Because we have a refined endpoint, however, we expected a priori that the effect of PM on out-of-hospital primary cardiac arrest would show stronger associations. Instead, our results suggest there is no association between PM and out-of-hospital primary cardiac arrest.

The null findings were similar across the range of 0 to 5 day lags, although there were fluctuations of the effect estimates. While it is tempting to select the lag most consistent with our prior hypothesis of a positive effect, the plausibility of selected positive associations must be evaluated in the context of all the effects estimated. Otherwise, we introduce model selection bias into our reported results. 39 For instance, even though the point estimate of the relative risk for PM10 at lag 4 suggests an 8% increase in risk is possible, the lag 1 effect is even greater in absolute value, but for an inverse association. Furthermore, lag 1 represents the most plausible induction period for PM health effects on cardiac arrest a priori.

There are several plausible explanations for the absence of an observed effect of PM on risk of primary cardiac arrest in this case series. Our study relied on daily city-wide exposure measurements. Seattle is topographically diverse and has localized PM sources from wood burning, particularly in the winter. While we found location effects on PM levels that varied with atmospheric conditions in a small exposure substudy, a refined analysis accounting for measurement error did not suggest bias due to exposure misclassification masked an association in this study. 40 Furthermore, it may be possible that exposures in Seattle are overall of the wrong composition or too low to cause an effect. Supporting evidence comes from a time-series analysis from the same location and general time period. That study is consistent with these case-crossover results; it showed no elevated risks related to PM for cardiovascular and ischemic heart disease mortality. 41 Another explanation might be that the mechanisms of PM-related cardiovascular toxicity do not involve short-term triggers that culminate in cardiac arrest. The most likely explanation, however, relates to the highly select group of study subjects comprising our case series. They were free of major comorbidity and any history of clinical evidence of coronary artery disease. 25 In contrast, Peters et al42 studied patients implanted with cardioverter defibrillators to assess whether potentially life-threatening arrhythmias are associated with particulate air pollution episodes. They found an increase in NO2 was associated with increased tachycardia and ventricular fibrillation 2 days later, and that the most susceptible patients (those with repeated events) were especially at risk of experiencing arrhythmia after increases in PM2.5 and NO2. Together these two studies suggest that air pollution effects on the risk of potentially life-threatening arrhythmia are more plausible in susceptible individuals, eg, people with a history of severe cardiovascular disease.

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Keywords:

case-crossover studies,; air pollution,; particulate matter,; sudden cardiac arrest

© 2001 Lippincott Williams & Wilkins, Inc.