a case-crossover analysis of particulate matter air pollution and out-of-hospital primary

8/3/2019 A Case-Crossover Analysis of Particulate Matter Air Pollution and Out-Of-Hospital Primary

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A Case-Crossover Analysis of Particulate Matter Air Pollution and Out-of-Hospital PrimaryCardiac ArrestAuthor(s): Drew Levy, Lianne Sheppard, Harvey Checkoway, Joel Kaufman, Thomas Lumley,Jane Koenig, David SiscovickReviewed work(s):Source: Epidemiology, Vol. 12, No. 2 (Mar., 2001), pp. 193-199Published by: Lippincott Williams & WilkinsStable URL: http://www.jstor.org/stable/3703622 .

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A Case^Crossover Analysis of Particulate Matter AirPollution and Out-of^Hospital Primary Cardiac Arrest

Drew Levy,1 Lianne Sheppard,2,3 Harvey Checkoway,1,3 Joel Kaufman,3,4 Thomas Lumley,2Jane Koenig,3 and David Siscovick1,4

Numerous epidemiologic studies have reported increases in thedaily incidence of cardiovascular mortality and morbidity as?sociated with increases in daily levels of particulate matter airpollution. We studied the association between the incidence ofprimary cardiac arrest and two daily measures of particulatematter using a case-crossover study of 362 cases of out-of-hospital cardiac arrest. All cases were attended by paramedicsand had no history of clinically recognized heart disease orlife-threatening comorbidities. We compared particulate mat?ter levels at index times with particulate matter levels fromreferent days matched on day of week within strata defined bymonth and year. The estimated relative risk at a lag of 1 day foran interquartile range (IQR) change in nephelometry (0.51 X

10'1km'1) was 0.893 (95% CI = 0.779-1.024). The estimatedrelative risk at a lag of 1 day for an IQR change in PM10(19.3jiLgm'3)was 0.868 (95% CI = 0.744-1.012). Other lag periodsgave similar results. We did not find evidence of confoundingby carbon monoxide or sulfur dioxide. Analysis of effect mod?ification by individual-level variables did not reveal any sus?ceptible subgroups. These findings do no support an associationbetween particulate matter and increased risk of primary car?diac arrest among persons without clinically recognized heartdisease. The null results of this study may result from severalfactors, including the highly selected nature of this case seriesand the relatively low particulate matter levels in the Seattlemetropolitan area. (Epidemiology 2001;12:193-199)

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

There is accumulating epidemiologic evidence that in?creases in ambient air pollutants are associated withincreases in non-accidental daily mortality. Most evi?dence comes from ecologic time-series studies in NorthAmerica and Western Europe.1'7 Overall, daily variationin levels of ambient particulate matter (PM) air pollu?tion as commonly found in urban environments hasbeen associated with daily total mortality increases of0.5% per 10 /ig/m3 increase in particulate matter lessthan 10 jLtm in diameter (PM10).8 For cardiovascularmortality, summary estimates of 1.4% per 10 /xg/m3 havebeen reported.1,3,9 Corroborative evidence has been ob-

Fromdepartment f Epidemiology,Departmentf Biostatistics,Departmentof Environmentalealth, DepartmentfMedicine, niversityfWashington,Seattle,WA98195-7232.Address orrespondenceo: LianneSheppard,Box 357232,DepartmentfBiostatistics,niversityf Washington,eattle,WA 98195-7232.This researchwasfunded n partby the Health Effects nstituteResearchAgreement7-2-2and n partbythe UnitedStatesEnvironmentalrotectionAgency hrough greement 827355or the EPANorthwestResearch enterfor Particulate ir Pollution ndHealth.Thisresearchoesnotnecessarilyeflecthe viewsof either undinggency ndno official ndorsementhouldbe inferred.Submitted pril25, 2000; inalversion cceptedAugust1, 2000.Copyright 2001by LippincottWilliams& Wilkins,nc.

tained from analyses of cardiovascular hospitaladmissions.10'13Despite the apparent consistency of the epidemiologic

findings for PM effects on daily cardiovascular diseasemortality, there remain important unresolved issues thatlimit causal interpretation. These include design limita?tions, the non-specificity of disease outcomes analyzed inmost time-series studies, uncertainties regarding themost toxic components of PM, and the frequently notedproblems of exposure misclassification, and potentialconfounding by climatic factors, co-pollutants, andother putative disease risk factors. The ecologic time-series design, where in exposures and health outcomesare investigated at the population level, rather than atthe individual level, is used in the majority of existingstudies. In addition to the utilization of ambient pollu?tion measures as a proxy for personal exposure, theecologic design requires additional fundamental assump?tions before relative risk estimates can have individual-level interpretation.14 Furthermore, the absence of per-sonal-level risk factor data also limits the ability to assesseffect modification by other risk factors. Characteriza?tion of effect modification, which can assist in the iden?tification of susceptible subgroups in the population,becomes especially important in epidemiologic studies ofPM because of the small population-wide relative risksthat are usually observed. Few studies have been able toevaluate specific forms of cardiovascular effects attribut?able to PM because of the challenges of sensitive and

193


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194 Levy et al Epidemiology March 2001, Vol. 12 No. 2

specific population-based outcome surveillance andascertainment.Cardiovascular disease accounts for a sizeable propor?tion of daily mortality and is thus an important area offocus for PM research. Possible effects to the cardiovas?

cular system from transient changes in PM levels shouldbe most readily detected in studies of acute-onset events.Schwartz15 found a disproportionate increase in suddendeath on high air pollution days, indicating cardiacarrest 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-threat-ening arrythia, and is usually fatal. Death from primarycardiac arrest accounts for about 10% of mortality in USadults.16 The proximate cause of fatal cardiac arrest istypically ventricular tacharrhythmia, which may be pro-voked by a series of triggering events acting on themyocardium.17 No biologic mechanism(s) for particulateair pollution effects on cardiac arrest have been eluci-dated, although some candidate models, such as electri?cal disburbances and inflammatory reactions, have beenproposed.18'22

Ideally the exposure measures used in a cardiovascularhealth effects study will represent the biologically activeexposure. In the Seattle metropolitan area several PMmeasurements are routinely collected. These includegravimetric measures of PM10 and nephelometry mea?sures of fine PM. Measures of light scattering from anintegrating nephelometer are highly correlated with themass concentration of particles between 0.1 and 1.4 jutmin diameter.23,24 Since the submicrometer fraction con?tains a large portion of the respirable particles and thesehave a composition that may affect health, the lightscattering measurement should provide a useful exposuremetric for health studies. We hypothesize that if the finefraction of PM is the biologically active component,then the relative risks observed for light scattering willbe stronger than that for PM10.This study assessed the association between PM andincidence of primary cardiac arrest, also known as sud?den cardiac death, in a well-defined existing case-seriesof primary cardiac arrests among persons without histo?ries of clinically detected cardiovascular disease, andwho were free of other life-threatening conditions. Weanticipated that the specificity of the case identificationprocess for this group may facilitate inference about thepossible underlying pathophysiologic mechanisms ofPM. Our secondary objectives were to contrast associa?tions for two measures of PM and to evaluate potentialeffect modifiers.

MethodsStudy Subjects

We used data from a population-based case-controlstudy of out-of-hospital primary cardiac arrest conductedby Siscovick and colleagues.25 The 362 cases were asubset of all cases of paramedic-attended out-of-hospitalprimary cardiac arrest in Seattle and suburban KingCounty, Washington from October 3, 1988 to July 25,

1994- To be eligible for inclusion, cases had a suddenpulseless condition in the absence of a non-cardiac con?dition. We reviewed emergency medical service reports,death certificates, and (when available) medical exam-iner and autopsy reports to confirm the absence of non-cardiac causes. We excluded cases if they had a history ofclinically recognized heart disease (including angina,myocardial infarction, coronary artery bypass surgery, orangioplasty, congestive heart failure, arrhythmias, car-diomyopathy, valvular, or congenital disease), or life-threatening comorbidities (cancer, or end-stage lung,liver, or renal disease). The series was further restrictedto 25- to 75-year-old married King County residentswhose spouses participated in an in-person interview(83% of those eligible) to ensure uniform data collectionfor survivors and non-survivors of primary cardiac arrest.

Air Pollution DataAir pollution data were obtained from the PugetSound Clean Air Agency (PSCAA) for the study period(October 3, 1988 - July 25, 1994). Data for daily averagetemperature at Seattle-Tacoma airport were obtainedfrom the National Oceanic and AtmosphericAdministration.

The primary exposure metric used in this study was24-hour average particulate matter measured by nephe?lometry (reported as bsp in units of km'1, and referred toas the light scattering extinction coefficient). We alsohad gravimetric measures of PM10. Both were obtainedfrom three King County monitoring sites: Duwamish,Lake Forest Park and Kent (Figure 1). We used the meanof daily average values from the three sites as our expo?sure measurement. Where data were missing for a par?ticular monitoring station on a given day, the valuesfrom the remaining monitors were used to compute theaverage. Missing data prevented us from using PM2 5 inanalyses. Nephelometry measures, however, are a goodsurrogate for PM2 5 since nephelometry data correlatewell with gravimetric particle measurements in the 0.1-1.4 aerodynamic diameter range23,24 and we have foundnephelometry data to be highly correlated with PM2 5 inthe greater Seattle metropolitan area.26We obtained daily average sulfur dioxide (SOz) mea?surements from a monitor co-located with the PM mon?itors situated at the urban industrial Duwamish site. Forcarbon monoxide (CO), we combined daily averagesfrom four street canyon locations into a single dailymean value. Ozone was measured only in the summermonths and therefore we did not consider ozone in theseanalyses. We summarize distributions of all available airpollutant measurements and temperature in Table 2 andgive correlations among all variables we consider inhealth effects analyses in Table 3. Further descriptivedetail of these data can be found in Sheppard et al.26

Statistical AnalysisThe case-crossover study design was proposed by Ma-clure27 to study the effects of transient, intermittent

exposures on the subsequent risk of rare acute-onset


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Epidemiology March 2001, Vol. 12 No. 2 PM AIR POLLUTION AND CARDIAC ARREST 195

Map reatedbyUniversityfWashington ibraries ISDatacopyright HyofSeattle,1909 .

FIGURE 1. Map of air pollution monitors and case residences.


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TABLE 1. Characteristics of Cases

events in close temporal proximity to exposure. Thisdesign can be regarded as a special type of case-controlstudy in which each case serves as his or her ownreferent. It requires exposure data only for cases. Expo?sures for each case during an "at risk" (index) periodbefore the event are compared with the distribution ofexposure during a referent period. The referent expo?sures should be representative of the expected distribu?tion of exposure for follow-up times that do not result ina case. Selection of the index period (usually a single dayin air pollution studies) follows similar logic to conven?tional air pollution time-series studies - the index daymay be the day of the event or some previous dayallowing for a lag between exposure and manifestation ofthe event. The choice of referent days in air pollutionresearch poses greater methodologic challenges becauseof the need to minimize multiple competing biases ow?ing to lack of stationarity in the air pollution timeseries.28'32 These include biases from long-term timetrends, seasonal patterns, autocorrelation in exposures,and day-of-week effects. Methodologic work stemmingfrom this study31,32suggests that time should be stratifiedprior to analysis (eg, into separate months) and referentsselected to be all days falling on the same day of theweek within the same stratum as the index day.We performed conditional logistic regression to ob?tain estimates of relative risks and 95% confidence in?tervals associated with interquartile range (IQR) expo?sures from nephelometry (0.51 X IO'1 km'1 bsp) and PM10(19.3 /xg/m3). We conducted separate analyses for lags of0 through 5 days since the induction period for anassociation between PM and out-of-hospital sudden car-

diac arrest is unknown. We then selected a single lag formultipollutant models of PM with either CO or S02.We examined effect modification by considering cate?gories of selected variables, specifically age, current cig?arette smoke exposure, aspirin use, consumption of al?coholic beverages, long-chain N-3 polyunsaturated fattyacid consumption, physical activity, and a composite ofrisk factors quantifying risk for coronary heart disease.We classified current cigarette smoke exposure as cur?rent smokers and subjects exposed to passive smoking forone or more hours in an average week. Aspirin usepertained to subjects taking the equivalent of two ormore aspirin tablets per week. Alcoholic beverage con?sumers imbibed one or more alcoholic beverages per day.We classified subjects with consumption above the me?dian of a Fish Intake Scale25 along with those whoreported taking fish oil supplements as exposed to long-chain N-3 polyunsaturated fatty acid. We classified casesas physically active if their average total kilocalories ofrecreational physical activity expended per week wasgreater than or equal to one.33 For indications of coro?nary heart disease risk, we included treatment for diabe?tes mellitus, high blood total cholesterol, or hyperten?sion, or family history of early myocardial infarction orsudden death (any parent or sibling experiencing myo?cardial infarction or sudden death before age 56 formales and before age 66 for females). We also assessedthe role of time by examining effect modification byseason and time categories (before or after the midpointof the study period).

ResultsWe assumed a linear exposure-effect model and esti?mated interquartile range relative risks and 95% confi?dence intervals for PM from light scattering for lags of 0to 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 setof the lags suggestive of a relation between PM and theincidence of out-of-hospital primary cardiac arrest. Thecorresponding findings for PM10 display a generally sim?ilar pattern of no strong or consistent association withcardiac arrest. We selected lag 1 for subsequent analysesbecause, absent any compelling evidence for any otherlag, it is the most proximal to the exposure amongnon-zero lags. At lag 0 we could not rule out that thetime of the cardiac arrest may have preceded most of the

TABLE 2. Distributions of Daily Means of Air Pollution Variables and Temperature


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TABLE 3. Pearson Correlation Coefficients among Air PollutantsVariable Nephelometer PM10 SOz CO Temperature

Nephelometer 1PM10so2COTemperature

exposure. We assessed the potential for a nonlinearexposure effect at lag 1 by estimating effects by quartileand by using regression spline smoothers with one andthree knots. None of these models was an improvementover the linear exposure-effect model.Table 4 gives relative risk estimates for single- andmulti-pollutant models at lag 1. The two PM effectestimates are essentially the same. There is no indicationof association between either CO or S02 and out-of-hospital primary cardiac arrest. The multi-pollutantmodels do not give evidence of confounding of the PMeffect by any of the pollutant variables.Table 5 summarizes the results of analyses for PMmeasured by nephelometry stratified by potential effectmodifiers. We did not observe any apparent susceptiblesubgroups for the cardiovascular risk factors examined,although we did observe heterogeneity in estimatesacross seasons. The estimate for autumn was greater thanone while those for the remaining seasons were less thanone. If PM is indeed associated with primary cardiacarrest, we would expect at least as large relative risks tooccur in winter owing to the prevalence of residentialwood burning and the potentially greater toxicity ofthese particles. This expectation is not consistent withthe results. We repeated the analyses for the remaininglags, for PM10, and for other categorizations of the effectmodifiers. These results were not materially differentfrom those reported in Table 5.

DiscussionThe possibility of detrimental health effects from par?ticulate matter air pollution remains controversial. A

large number of studies have found associations betweenPM and both morbidity and mortality outcomes. Moststudies have linked daily variation in ambient PM con-

TABLE 4. Interquartile Range Relative Risk Estimatesfor PM from Light Scattering, PM10, CO, and SOz at lag 1

centrations to daily variation in totaland cause-specific mortality, hospitaladmissions, or emergency departmentvisits. For instance, Schwartz and Mor?ris11 observed an association betweenPM10 and hospital admissions for isch?emic heart disease, congestive heartfailure and dysrhythmias in Detroit,Michigan. Burnett et al.10 reportedthat fine sulfate particles were associated with heartdisease admissions in Ontario, Canada. Schwartz12 found

associations between PM10 and cardiovascular diseaseadmissions in Tucson, Arizona. He also observed thatdaily variation in PM10 was associated with hospitaladmissions for heart disease in eight US counties fromvarious parts of the country, although the relation wasweakest for Seattle among the eight metropolitan areasstudied.13 His summary relative risk estimate was 1.025(95% confidence limits = 1.018, 1.032) for a 25 jug/m3increase in PM10. He posited that approximately 5% ofhospital admissions for heart disease may be attributableto air pollution.The mechanisms of PM action on the cardiovascularsystem are uncertain. Pope et a!34 tested the hypothesisthat exposure to PM acutely reduces blood oxygenation.While they did not observe an effect on blood oxygen?ation, they did find an association with slightly increasedheart rate. The biological significance of this findingremains unclear. Liao et al35 reported transient reduc?tions in heart rate variability associated with increases inexposure to PM, suggesting a reduction in parasympa-thetic control of heart rate among elderly persons. Otherhypotheses concerning effects of PM on the cardiovas?cular system have suggested ultrafine PM may inducealveolar inflammation, with the release of mediatorscapable of increasing blood coagubility, possibly increas?ing the risk for ischemic events.36 Peters et al31 foundincreases in plasma viscosity to be associated with an airpollution episode marked by elevations in total sus?pended particles and other pollutants. Their data, how?ever, did not distinguish between contributions fromultrafine particles, other air pollutants, or other unmea?sured confounding factors.Our results do not support an association between PMand out-of-hospital primary cardiac arrest. The patternsof results were nearly identical for PM measured bynephelometry and gravimetrically (PM10). Furthermore,we did not find evidence of effect modification byknown personal risk factors for sudden cardiac arrest.Time-series studies of PM and cardiovascular disease arein the range of 1.4-4.2% increases in daily cardiovas?cular mortality for a 10 jLtg/m3 increase in PM10.13,38Because we have a refined endpoint, however, we ex?pected a priori that the effect of PM on out-of-hospitalprimary cardiac arrest would show stronger associations.Instead, our results suggest there is no association be?tween PM and out-of-hospital primary cardiac arrest.The null findings were similar across the range of 0 to5 day lags, although there were fluctuations of the effectestimates. While it is tempting to select the lag most


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TABLE 5. Interquartile Range Relative Risks for PM from Light Scatteringat a Lag of 1 Day, Stratified by Potential Effect Modifiers

*ETS,environmentalobacco moke.t DM,history f treatmentordiabetesmellitus;Chol,history f treatmentorhighcholesterol; tn,history f treatmentorhypertension;Hx, amily istory fearlymyocardialnfarctionrsudden eath.

consistent with our prior hypothesis of a positive effect,the plausibility of selected positive associations must beevaluated in the context of all the effects estimated.Otherwise, we introduce model selection bias into ourreported results.39 For instance, even though the pointestimate of the relative risk for PM10 at lag 4 suggests an8% increase in risk is possible, the lag 1 effect is evengreater in absolute value, but for an inverse association.Furthermore, lag 1 represents the most plausible induc?tion period for PM health effects on cardiac arrest apriori.There are several plausible explanations for the ab?sence of an observed effect of PM on risk of primarycardiac arrest in this case series. Our study relied on dailycity-wide exposure measurements. Seattle is topograph-ically diverse and has localized PM sources from woodburning, particularly in the winter. While we foundlocation effects on PM levels that varied with atmo?spheric conditions in a small exposure substudy, a re-fined analysis accounting for measurement error did notsuggest bias due to exposure misclassification masked anassociation in this study.40 Furthermore, it may be pos?sible that exposures in Seattle are overall of the wrongcomposition or too low to cause an effect. Supportingevidence comes from a time-series analysis from thesame location and general time period. That study isconsistent with these case-crossover results; it showed noelevated risks related to PM for cardiovascular and isch?emic heart disease mortality.41 Another explanation

might be that the mechanisms of PM-related cardiovascular toxicity do notinvolve short-term triggers that culmi-nate in cardiac arrest. The most likelyexplanation, however, relates to thehighly select group of study subjectscomprising our case series. They werefree of major comorbidity and any his?tory of clinical evidence of coronaryartery disease.25 In contrast, Peters etal42 studied patients implanted withcardioverter defibrillators to assesswhether potentially life-threateningarrhythmias are associated with partic?ulate air pollution episodes. Theyfound an increase in N02 was associ?ated with increased tachycardia andventricular fibrillation 2 days later,and that the most susceptible patients(those with repeated events) were es?pecially at risk of experiencing ar?rhythmia after increases in PM2 5 andNOz. Together these two studies sug?gest that air pollution effects on therisk of potentially life-threatening ar?rhythmia are more plausible in suscep?tible individuals, eg, people with a his?tory of severe cardiovascular disease.

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39. Lumley ,Sheppard.Assessingeasonalonfoundingndmodel electionbias n airpollution pidemiologysingpositive ndnegativeontrol nal?yses.Environmetrics000;11:705-717.40. Sheppard ,LevyD, Checkoway . Correctingorthe effectsof locationandatmosphericonditions n airpollution xposuresn a case-crossoverstudy. ExpAnal EnvironEpidemiolin press).41. LevyD. A Case-Crossovertudyof ParticulateMatterAir Pollution ndOut-of-Hospitalrimaryardiac rrest nKingCounty,Washington.hDThesis,Universityf Washington,eattle,WA, 1999.42. PetersA, LiuE,Verrier L,Schwartz,GoldDR,MittlemanM,Baliff ,OhJA,AllenG, MonahanK, DockeryDW. Air pollution nd incidence fcardiacrrhythmia.pidemiology000;11:11-17.

a case-crossover analysis of particulate matter air pollution and out-of-hospital primary

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