Published ahead of print on May 13, 2004, doi:10.1164/rccm.200402-244OC
© 2004 American Thoracic Society
Ambient Air Pollution and Oxygen SaturationChanning Laboratory, Department of Medicine, and Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School; and Exposure, Epidemiology, and Risk Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts Correspondence and requests for reprints should be addressed to Dawn L. DeMeo, M.D., M.P.H., Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail: redld{at}channing.harvard.edu
We investigated the association between fine particulate air pollution and oxygen saturation as measured with a peripheral oxygen saturation monitor during a 12-week repeated-measures study of 28 older Boston residents. Oxygen saturation and air pollution particulates with a mean diameter less than or equal to 2.5 µm were measured continuously during a protocol of rest, standing, exercise, postexercise rest, and 20 cycles of slow, paced breathing. In fixed-effect models, mean pollution concentration was associated with reduced oxygen saturation during the baseline rest period (6 hours: mean, –0.173%; 95% confidence interval [CI], –0.345 to –0.001), postexercise (6 hours: mean, –0.173%; 95% CI, –0.332 to –0.014), with a trend toward decrease during postexercise paced breathing (6 hours: mean, –0.142%; 95% CI, –0.292 to 0.007) but not during exercise. Participants taking ß-blockers had a greater pollution-related decrease in oxygen saturation at rest (6 hours: mean, –0.769%; 95% CI, –1.210 to –0.327) (interaction for particulates with a mean diameter less than or equal to 2.5 µm by ß-blocker, p < 0.0005) than did those not taking ß-blockers (p > 0.25). The reduction in oxygen saturation associated with air pollution may result from subtle particulate-related pulmonary vascular and/or inflammatory changes. Further investigation may contribute to our understanding of the mechanisms through which particulates may increase respiratory and cardiac morbidity among vulnerable populations.
Key Words: air pollution • epidemiology • respiratory physiology Epidemiologic studies have demonstrated that particulate air pollution is associated with an increase in respiratory and cardiovascular morbidity and mortality (1–3). Pollution-associated hypoxia has been proposed as a mechanism through which pollution might increase the risk for acute coronary or other cardiovascular events (4, 5), but scant evidence of pollution-related hypoxia has been demonstrated. One repeated-measures study in Utah of elderly participants suggested no consistent effect of particulates with a mean aerodynamic diameter less than or equal to 10 µm (PM10) on oxygen (O2) saturation. On stratifying the analysis by age, significant negative association between O2 saturation and lagged pollution measures were observed in male participants 80 years of age and older (4). Our study investigated the association of longitudinal repeated measures of particulate air pollution and changes in oxygen saturation during a rest and exercise protocol in older urban dwelling individuals, adjusting for the influence of individual comorbidities and medication use as potentially relevant factors influencing oxygen saturation outcomes. We hypothesize that particulate air pollution has measurable effects on oxygen saturation in a panel of healthy, older individuals. Results from a similar analysis have been reported previously in the form of an abstract (6).
Recruitment of Participants To examine associations of ambient pollution with outcomes including changes in oxygen saturation, heart rate variability, and electrocardiographic segment level, volunteers were recruited from a housing community in the city of Boston, Massachusetts between May and June of 1999, and if eligible were evaluated between July and August of 1999. A screening questionnaire provided information concerning demographics, self-reports of doctor-diagnosed pulmonary and cardiac disease, medication use, diet, and smoking behaviors. Exclusion criteria included unstable angina, arrhythmias (such as atrial flutter or fibrillation), and the presence of a pacemaker. All participants were required to be able to ambulate on level ground.
Research Protocol The experimental protocol involved 5 minutes of rest in the seated position, 5 minutes of standing, 5 minutes of outdoor exercise (involving a 5-minute walk with a climb up a slight incline), 5 minutes of recovery during a postexercise rest period, and 5 minutes of slow, paced breathing. Paced breathing consisted of 20 cycles during which the participant was asked to breathe in for 5 seconds and then out for 5 seconds, as coached by a research assistant. Continuous oxygen saturation and pulse monitoring were performed during all parts of the protocol, using an oximeter (Nellcor, Pleasanton, CA). These measures, which represent instantaneous measures of oxygen saturation and pulse rate, were printed at 30-second intervals for all parts of the protocol on oximeter-generated data strips; these data strips included the protocol start and stop times and the date of testing. A total of 18,497 data points for oxygen saturation were analyzed.
Exposure Monitoring Hourly meteorologic measures, such as mean temperature (°C), dew point temperature (°C), and barometric pressure (inches of mercury), were obtained from the National Weather Service at Logan Airport in East Boston, and were extracted from climatic records (EarthInfo, Inc., Boulder, CO).
Quality Assurance
Statistical Analysis In the first phase of analysis we used fixed-effect modeling with an indicator variable for each participant in the study. With this approach individual participants served as their own controls. To examine the association of pollution with oxygen saturation over the entire study period, we also performed a nonstratified repeated-measure analysis using SAS (SAS Institute, Cary, NC), in which oxygen saturation at each portion of the protocol was considered a continuous outcome and part of the protocol (first rest, standing, exercise, postexercise rest, and paced breathing) was a covariate in the analyses. We followed with a second phase of analysis using random effects models, to investigate the interaction between covariates and PM2.5. This part of the analysis was to obtain specific effect estimates for measured covariates and to examine interactions between time-varying or time-invariant covariates and PM2.5, with a focus on the interaction between air pollution and medication use. These models included a random intercept and a random slope to explain the heterogeneity by subject and the heterogeneity in response to air pollution, after accounting for differences in medication use.
Characteristics of the 28 individuals who completed more than 1 visit are demonstrated in Table 1 . The majority of participants were elderly white females; all participants had normal oxygen saturations at rest. Approximately 10% reported a history of angina, heart attack, or heart failure. The mean pack-years of cigarette smokers was 36.6 pack-years, among those classified as ever having smoked. Fewer than 10% had a diagnosed lung disease, although about 40% of the participants had a history of hypertension. All individuals taking ß-blockers (n = 5) were taking at least one other antihypertensive agent (three combined diuretic with ß-blocker; one angiotensin-converting enzyme inhibitor with ß blocker; and one angiotensin-converting enzyme, ß-blocker, and calcium blocker combination).
For first rest, postexercise rest, and paced breathing, but not for the exercise portion of the protocol, small, often statistically significant inverse associations were detected with individual hourly lags of PM2.5 concentrations measured between 2 and 7 hours before exercise, using fixed-effect models. For the first rest, this effect was most pronounced at 6 hours, demonstrating a 0.172% (95% confidence interval [CI]: –0.313 to –0.031) decrement in oxygen saturation for each 11.45-µg/m3 increase (1 interquartile range) in PM2.5. The trend for the variation in oxygen saturation during the first rest by the individual lags for air pollution is presented in Figure 1 .
For first rest, postexercise rest, and paced breathing, the mean 6-, 12-, 24-, and 48-hour PM2.5 concentrations also tended to be associated with a small reduction in oxygen saturation. However, during exercise no significant reduction in oxygen saturation was observed. In the postexercise rest period that followed exercise, the effect for the 6-hour mean returned to the level observed during the first rest period (Table 2) . When oxygen saturation was considered for the overall protocol (and not stratified by part of the experimental protocol), there was a significant inverse association of increasing PM2.5 on oxygen saturation (Table 2).
The effect of PM2.5 on oxygen saturation was modified by the use of ß-blocker medications (p value for PM2.5 by ß-blocker interaction, less than 0.0005). Those taking ß-blockers had the most significant decrease in oxygen saturation at rest. For each increase in PM2.5 of 13.42 µg/m3 (1 interquartile range), there was a significant decrease in 6-hour mean oxygen saturation of –0.769% (95% CI: –1.21 to –0.327); the decrease was not significant in those individuals not taking ß-blockers (mean, –0.062%; 95% CI: –0.248 to 0.123; p value for interaction, greater than 0.25). This finding was not observed during other parts of the protocol. Compared with those not taking ß-blocker medications, the five individuals taking ß-blocker medications had higher mean resting supine and exercise systolic blood pressures (132 vs. 125 mm Hg during resting supine measurement and 155 vs. 139 mm Hg during exercise) and overall mean lower heart rates during the protocol (65 vs. 80 beats per minute). The effect of PM2.5 on oxygen saturation was not modified by age, sex, smoking status or smoking history, self-report of hypertension, or other self-reported diagnoses.
In a repeated-measures panel study of older individuals studied during the summer of 1999, we found a small but statistically significant inverse association of ambient PM2.5 level and oxygen saturation. Older individuals (65 years of age or older) are potentially more susceptible to the health effects of air pollution (7) and represent an important vulnerable group to include in studies of pollution-related health effects. Past studies have demonstrated the associations of particulate air pollution with cardiac and respiratory morbidity and mortality, but epidemiologic evidence of particulate-related decreases in oxygen saturation as an explanation for these associations has been scant. Pope and colleagues have demonstrated a statistically significant negative association between PM10 and oxygen saturation among elderly, male individuals who were at least 80 years of age. They concluded that the effects of particulates on hypoxia might be most relevant in older and sicker individuals (4). In this study, Pope and colleagues (4) suggested that a study design that relies on the pulse oximeter for readings is robust. Past studies have investigated clinical characteristics that may designate an increased susceptibility to air pollution, such as chronic obstructive pulmonary disease (8), coronary artery disease (9), arrhythmias (10), and congestive heart failure (9). These studies have been performed in cohorts of frail individuals. De Leon and colleagues investigated the association between PM10 and mortality in New York City between 1985 and 1994. In participants older than 75 years of age, they observed that individuals with respiratory disease had a higher mortality from circulatory deaths, leading to the conclusion that older individuals may be more at risk for deleterious effects of air pollution in the setting of respiratory disease (11). Our cohort represents a population of older, independent individuals, most of whom rate their health as good, very good, or excellent. However, the findings of effect modification in this cohort by ß-blocker use but not by other cardiac or pulmonary factors may define a true subpopulation at risk. All the individuals taking ß-blockers were administered more than one antihypertensive medication and demonstrated higher systolic blood pressure than the remainder of the cohort, possibly representing a group with more difficult-to-control blood pressure. Such a group may be more susceptible to pollution-related vascular effects of inflammation, leading to subtle changes in oxygenation. In our participants, the magnitude of the decline in oxygen saturation is small, potentially representing a subtle local airway and alveolar inflammatory effect. Conversely, these effects might be greater and more clinically relevant in a more debilitated population on ß-blockers. The negative association between oxygen saturation and PM2.5 is not apparent during exercise and suggests we are dealing with a relatively healthy group, or may be due to the noise associated with peripheral oxygen saturation measurements during rapid movement. Strengths of this study include the repeated measures for oxygen saturation both during the experimental protocol as well as through longitudinal follow-up during 12 summer weeks, with varying levels of particulate exposures. There was little to no intercurrent illness and thus each subject acted effectively as his or her own control during the study. Potential limitations include the lack of pulmonary function data, which would identify the presence of occult pulmonary disease that may contribute to the finding of decreased oxygen saturation. We do not have information about environmental tobacco smoke exposure in the home (but the majority of the participants lived alone and were nonsmokers), nor was direct monitoring of particulates in the home performed as part of this study. As well, we do not have measures of arterial oxygen levels, but we believe that the investigation of changes in oximetry provided a reliable and reproducible assessment for this epidemiologic investigation. Nine individuals completed only one visit and were excluded from the analysis. However, comparison of those who completed only one visit with those who completed more that one visit did not reveal any systematic differences between the two groups. Pollution-associated airway and alveolar endothelial inflammation may result in impairment of oxygen diffusion and subtle decrements in oxygen saturation levels due to edema formation. These subtle oxygen saturation changes may directly influence cardiovascular responses, or, more likely, the process involved in producing these small decreases in oxygen saturation may lead to subsequent adverse cardiovascular physiology. The local inflammatory process associated with small changes in oxygen saturation may lead to systemic inflammation capable of influencing cardiovascular outcomes. In another study we found that elevated ambient particle levels predicted increased exhaled nitric oxide, a marker of pulmonary inflammation (12). Seaton and colleagues suggested that particulate air pollution might influence alveolar inflammation. They also suggested that particles lead to inflammatory mediator release, potentially exacerbating lung disease and hypercoagulability (3). Pulmonary inflammatory effects from particulate air pollution have been observed in bronchoalveolar lavage and mucosal biopsy specimens in healthy young people exposed to diesel exhaust, with evidence of upregulation of cytokines (such as interleukin-8). Increased expression of endothelial adhesion molecules and increased neutrophils, mast cells, and lymphocyte burden in the lung have also been observed in response to diesel exhaust exposure (13, 14). Human investigations into the systemic inflammatory effects of particulate air pollution have demonstrated increased C-reactive protein (15), plasma fibrinogen (16), and plasma viscosity (17) in association with air pollution. The relative decrease in oxygen saturation may also be a marker of oxidative stress that may result in neural feedback to the heart, or may alter cardiovascular physiology through changes in local pulmonary and cardiac vascular inflammation and blood coagulability. Particulate pollution-related pulmonary inflammation and cytokine cascades may influence autonomic responses via stimulation of pulmonary vagal receptors. In multiple epidemiologic investigations, air pollution has been associated with increased heart rate (4, 18) and decreased heart rate variability (19–21). Recent studies on air pollution and heart rate have suggested that autonomic imbalances, as evidenced by increases in heart rate and decreases in heart rate variability, may specifically contribute to the increased mortality (19–21). In conclusion, we demonstrate a statistically significant effect of ambient particulate air pollution on decreased oxygen saturation at rest in a population of free-living older individuals, with a more significant interaction in the individuals taking ß-blockers. The biological and/or clinical relevance of this magnitude of effect in terms of hypoxia may be small, but we hypothesize that this finding reflects subtle effects of the inflammatory cascade, which results from exposure to ambient particulate pollution. Further investigation is needed to characterize susceptibility characteristics and to elucidate the functional/mechanistic significance of these findings.
Supported by HL07427 and K08 HL072918-01 (D.L.M.); also supported by EPA 826780-01-0 and NIH grant 1P01ES 09825-01. Conflict of Interest Statement: D.L.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.A.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; B.A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.R.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form February 25, 2004; accepted in final form May 11, 2004
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production in healthy human airways. Am J Respir Crit Care Med 2000;161:550–557.
