Cigarette smoking remains a major threat to public health (36
), with increasing numbers of people smoking worldwide and a plateau in the U.S. rate of smoking at 20% (17
). In addition to the harmful effects of cigarette smoke on active smokers, there are increasing data demonstrating the significant biological effects of secondhand, or passive, exposure to cigarette smoke (21
). In this study, we present the results of the first prospective study of the effect of active and passive cigarette smoking on the risk of developing acute lung injury after severe blunt trauma, a major cause of morbidity and mortality worldwide. These data demonstrate that both active smoking and moderate to heavy passive smoking are associated with increased susceptibility to ALI in this setting, even after controlling for other important predictors of ALI, such as injury severity and alcohol abuse. This finding has important implications for both public health and for understanding of the pathogenesis of ALI. Specifically, if replicated, this finding should strengthen support for tighter regulation of exposure to secondhand smoke in public venues; further, it suggests that chronic exposure to cigarette smoke may prime individuals to develop ALI in the setting of a second hit such as severe trauma.
The relationship between cigarette smoke exposure and ALI is both biologically plausible and strongly supported by previous experimental work. In experimental human and animal studies, active smoking has been linked to alterations in lung epithelial and endothelial function similar to those seen in ALI. Studies in human subjects and animal models have demonstrated that asymptomatic smokers have significantly greater lung epithelial permeability, a pathophysiological hallmark of ALI, as compared with nonsmokers (7
). Active smoking also decreases expression of the primary ion channels responsible for resolving alveolar edema, which could impair alveolar fluid clearance and thus increase formation of lung edema (38
). Likewise, both endothelial injury and disordered platelet function are thought to be critical to the pathogenesis of ALI (40
), and the cardiovascular literature has demonstrated the potent effects of both active and secondhand smoke on both of these processes (16
). Furthermore, cigarette smoking induces neutrophil accumulation in the pulmonary circulation, depresses humoral and cell-mediated immunity, impairs mucociliary clearance, and alters alveolar macrophage number and function, any of which could contribute to enhancing susceptibility to ALI (13
Over the past several decades, the deleterious effects of passive smoking have been increasingly appreciated. Secondhand smoke exposure has been conclusively linked to a variety of respiratory, cardiovascular, and neoplastic diseases, including coronary artery disease, lung cancer, sudden infant death syndrome, and exacerbations of obstructive lung disease (21
). Moreover, the effects of passive smoking on endothelial function, platelet activation, and inflammation were estimated in a meta-analysis to be on average 80–90% of those of active smoking; in some cases, the effect of passive smoking was as or more potent than that of active smoking (16
). Despite the demonstration of these adverse effects of secondhand smoke exposure, 40% of Americans are still exposed to secondhand smoke, including 54% of children between ages 3 and 11 years (35
). In some of our analyses, we dichotomized passive smokers at the median into low-level (<0.19 ng/ml) and moderate- to high-level (≥0.19 ng/ml) exposure; a plasma cotinine level of 0.20 ng/ml is roughly equivalent to spending 1 hour in a moderately smoky room, such as a bar or restaurant (43
). Thus, the quantity of passive smoke exposure associated with increased risk of ALI in this study appears to be relatively modest, although this threshold for exposure will need to be further tested in other at-risk groups.
Why might the effects of active and passive smoking on susceptibility to ALI be so similar in our analysis? Several explanations are possible. First, the similar odds ratios observed for active smoking and moderate to heavy passive smoking may represent a threshold effect: once exposure to cigarette smoke passes a certain level, the increase in susceptibility reaches a plateau. Second, the chemical constituents of sidestream smoke, which is the primary type of cigarette smoke inhaled by nonsmokers, differ from those of mainstream smoke and are in many cases more toxic, because of the different burning temperature of the cigarette at its lit end (45
). Thus, smaller doses of these more toxic by-products of tobacco smoke may have a similar effect to the larger doses of mainstream smoke inhaled by the active smoker. Third, as mentioned previously, passive smoking has nearly the same effect on indices of endothelial injury, platelet activation, and inflammation as active smoking (16
); thus, these pathways of injury may be affected equally by active and passive exposure, leading to equivalent susceptibility to ALI. A final possibility is that some of the subjects with cotinine in the heavy passive range are actually intermittent or social smokers (46
), and are thus exposed to similar risk as active smokers.
The use of plasma cotinine to quantify exposure to cigarette smoke in patients with severe trauma has several advantages. First, plasma cotinine has been extensively validated as a biomarker of both active and passive smoking, with excellent accuracy in discriminating active from passive exposure and high specificity (23
). In the Surgeon General's report on secondhand smoking, the prevalence of secondhand smoke exposure was assessed largely via this biomarker and other related nicotine metabolites (21
). Second, the trauma population provides an ideal setting for using plasma cotinine because most trauma victims are presumably healthy and engaged in their normal activities of daily living until shortly before arrival in the emergency department. Thus, plasma cotinine is likely to represent a random and accurate snapshot of their average tobacco exposure. Third, plasma cotinine has a relatively short half-life of 16 hours; however, given our sampling within 10 minutes of emergency department arrival, and the short transport times of patients by emergency medical services in San Francisco (<1 h), cotinine decay should not have a significant impact on our findings. The high prevalence of both active and passive smoking that we detected in this cohort, using plasma cotinine, echoes previous findings in both a randomly selected subset of all admitted patients at the same urban county hospital (47
) as well as in a mixed medical–surgical intensive care unit population in Tennessee (19
We considered alcohol abuse a priori
to be a major potential confounder of the association between cigarette smoke exposure and ALI, given prior evidence that alcohol abuse increases susceptibility to ALI (4
), and therefore we captured this comorbidity in several ways. First, we collected any historical information available on alcohol abuse, including any evidence of alcoholic cirrhosis or alcohol withdrawal, from the medical chart. This is the approach that was used in the original report linking alcohol abuse to the development of the acute respiratory distress syndrome (ARDS) (48
). Second, we administered a previously validated survey instrument, the AUDIT questionnaire, to willing patients and their surrogates to further quantify alcohol use. Unfortunately, patient and surrogate refusal to answer this questionnaire was relatively common, as was patient death before questionnaire administration. Third, we captured blood alcohol levels in all patients in whom this test was performed for clinical reasons. In our multivariable model, we forced the inclusion of a composite variable capturing high blood alcohol levels along with the two previous covariates (chart history of alcohol abuse and high score on the AUDIT) into the initial multivariable regression; however, it was not significantly associated with the development of ALI in this model. Finally, the prevalence of alcohol abuse in our study sample (30%) is similar to the prevalence of alcohol abuse reported in previous studies of alcohol abuse and ALI (30
) and double the prevalence reported in the trauma subgroup in the original study linking alcohol and lung injury (15%) (48
). Despite these best attempts, some residual confounding by alcohol abuse remains possible. However, it should also be appreciated that previous studies of the relationship between alcohol abuse and ALI/ARDS in critically ill patients either did not account for cigarette smoke exposure at all (48
) or used historical data to measure cigarette smoke exposure (4
), which we have demonstrated in this study to be insensitive.
Limitations of our study include that it was conducted at a single center, had a relatively modest sample size, and lacked biomarkers reflective of longer term cigarette smoke exposure.
In conclusion, both active and moderate to heavy passive smoking are independently associated with the development of acute lung injury after severe blunt trauma. This finding has important implications for public health, because both major trauma and ALI are common causes of death, as well as for our understanding of the pathogenesis of ALI.