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doi:10.1378/chest.06-2017
(Chest. 2007; 131:1479-1485)
© 2007 American College of Chest Physicians
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Acute Effects of Smoking on Skeletal Muscle Microcirculation Monitored by Near-Infrared Spectroscopy*

Angeliki Siafaka, MD; Epameinondas Angelopoulos, MD; Konstantinos Kritikos, MD; Magdalini Poriazi, MD; Neofitos Basios, MD; Vasiliki Gerovasili, MD; Antonios Andreou, MD; Charis Roussos, MD, PhD, FCCP and Serafim Nanas, MD

* From the First Critical Care Department, Evangelismos Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Correspondence to: Serafim Nanas, MD, First Critical Care Department, Evangelismos Hospital, National and Kapodistrian University of Athens, Athens, Greece; e-mail: snanas{at}cc.uoa.gr

Abstract

Background: Cigarette smoking predisposes to vascular disease. Our study aimed to assess the acute effects of cigarette smoking on peripheral microcirculation using near-infrared spectroscopy (NIRS) and to compare microcirculatory function of smokers with that of nonsmokers.

Methods: We examined 65 healthy volunteers: 25 smokers (14 men and 11 women; age range, 20 to 27 years) and 40 nonsmokers (31 men and 9 women; age range, 19 to 38 years). Smokers had refrained from smoking for 2 h prior to the examination. Tissue O2 saturation (StO2), defined as the percentage of hemoglobin saturation in the microvasculature compartments, was measured with a probe placed on the thenar muscle. StO2 baseline values were recorded for 5 min. Subsequently, the brachial artery occlusion technique was applied to evaluate microcirculatory function before, during, and after smoking one cigarette.

Results: StO2 before smoking was 85 ± 6% (mean ± SD), not differing significantly between men and women (84.4 ± 6.6% vs 85.6 ± 5.8%, respectively; p = 0.721). StO2 did not change significantly during smoking. O2 consumption rate was significantly greater in women (33.4 ± 6.7 StO2 U/min vs 25.7 ± 7.1 StO2 U/min, p = 0.032) at baseline and throughout the smoking session. O2 consumption rate was reduced during smoking (p < 0.001) and at 5 min after the smoking session. Smoking had a significant effect on vascular reactivity (p = 0.015), with no significant differences between genders. Five minutes after smoking, vascular reactivity had returned to approximately normal levels.

Conclusion: Smoking acutely affects microcirculatory function. NIRS is a noninvasive, operator-independent technique that can document these effects. It seems promising for the prospective evaluation of the effects of long-term exposure to cigarette smoke.

Key Words: microcirculation • near-infrared spectroscopy • smoking • vascular reactivity

Cigarette smoking constitutes a well-established risk factor for stroke, coronary heart disease, and occlusive peripheral vascular disease, and thus represents a main cause of death worldwide. Currently, effort is being made to clarify the effects of tobacco smoke on the microcirculation. It is accepted that the presence of endothelial dysfunction is an early marker of vascular injury, predisposing to the development of atherosclerotic lesions.1

A common way to assess endothelial function is to determine the reactive hyperemia that occurs in the forearm after a transient interruption of the circulation in the brachial artery. It has been shown that the endothelial vasodilatory response to transient ischemia is altered in chronic smokers, while no clear alterations have been reported for younger smokers.2 Impaired endothelium-dependent vasodilation has also been reported in investigations of flow-mediated dilation of the brachial artery in chronic smokers34 and even in passive smokers.5 Similarly, impaired endothelium-dependent vasodilation has been reported as an acute effect of cigarette smoking in habitual smokers.67

Near-infrared spectroscopy (NIRS) has been introduced as a way to monitor noninvasively the microcirculation in a variety of clinical settings. NIRS enables continuous assessment of parameters such as tissue hemoglobin saturation, local O2 consumption rate, and vascular reactivity in patients with septic shock, trauma, and peripheral vascular disease, as well as in studies of exercise physiology.8910 The aim of our study was thus to characterize the acute effects of cigarette smoking on microcirculatory parameters of young, healthy male and female smokers, as measured with NIRS, and to compare them with healthy nonsmokers of both genders and of similar age.

Materials and Methods

Subjects
We examined 65 healthy volunteers: 25 smokers (14 men; median age, 25 years; range, 20 to 27 years; median, 3 pack-years; range, 0.5 to 20 pack-years; and 11 women; median age, 25 years; range, 22 to 26 years; median, 4 pack-years; range, 0.5 to 14 pack-years) and 40 nonsmokers (31 men; median age, 25 years; range, 19 to 33 years; and 9 women; median age, 26 years; range, 23 to 38 years).

NIRS
The principles of NIRS and its application in vivo have been described previously.1112 In brief, while visible light is not able to penetrate biological tissue for more than approximately 1 cm because it is strongly absorbed and scattered by tissue constituents (mainly water), light in the near-infrared region can easily reach much deeper biological structures. What is more, in that specific region, certain light-absorbing molecules (chromophores) such as hemoglobin, myoglobin, and cytochrome oxidase absorbs light differently according to their oxygenation status, producing characteristic absorption spectra. The use of a modified Beer-Lambert law permits to estimate the concentrations of chromophores of interest in tissue. A crucial factor in this process is estimation of the optical path length, ie, the distance that light travels from the point of emission to the point of detection. In tissue, this is not the straight-line distance between the two points, owing to the effects of light absorption and scattering. Several algorithms have been developed and validated to account for this.

In our study, thenar muscle tissue oxygen saturation (StO2) was measured using wide-gap second-derivative NIRS (InSpectra; Hutchinson Technology). This technology provides an estimate of the hemoglobin saturation (StO2) in the microvasculature of muscle tissue, comprising the arteriolar, capillary and venular compartments, according to principles described previously.13 StO2 values were continuously monitored and stored using InSpectra software. StO2 curves were analyzed offline (InSpectra Analysis Program, version 2.0; Hutchinson Technology; Hutchinson, MN; running in MatLab 7.0; The MathWorks; Novi, MI).

Experimental Protocol
Subjects were informed as to the aims and the technicalities of the study and gave their informed consent. The study was reviewed and approved by the Human Study Committee of our institution. All measurements took place in a temperature-controlled environment. Smokers had been instructed to refrain from smoking for at least 2 h prior to the measurements.

Baseline measurements were obtained for all subjects. Smokers were then instructed to light a cigarette of their habitual brand and to smoke it, maintaining their usual aspiration pattern. Subsequent measurements were taken at midcourse and 5 min after completion.

The measurements at each time point were made while a brachial artery occlusion protocol was applied: after an initial resting StO2 value had been recorded, a pneumatic cuff was rapidly inflated to 220 mm Hg and maintained for 3 min, after which it was released. StO2 signal acquisition proceeded during the occlusion period and until StO2 values were again stabilized following cuff release.

The rate of StO2 decrease during the period of stagnant hypoxia was calculated as an index of O2 consumption rate. NIRS methodology has been validated as a means to determine tissue metabolic rate during stagnant ischemia.14 Using this approach, ie, the application of the arterial occlusion protocol, the rate of hemoglobin desaturation reflects the tissue O2 consumption when O2 delivery is halted.1215 During reperfusion, reactive hyperemia in the upper limb caused the StO2 signal to become transiently elevated above its resting value. The area under the curve was calculated as an index of the endothelial hyperemic response.

Statistical Analysis
Baseline values for resting StO2, O2 consumption rate, and postocclusive hyperemic response were compared in smokers and nonsmokers of both genders using two-way analysis of variance (ANOVA). Values for male and female smokers during the cigarette smoking session were compared using two-way, repeated-measures ANOVA. When the sphericity assumption did not hold, the multivariate results are reported. For pairwise comparisons of adjacent time points, Bonferroni-adjusted p values are reported. All analyses were performed using statistical software (SPSS version 11.5; SPSS; Chicago, IL). Values are presented as mean ± SD.

Results

Between-Gender and Smoking Status Comparisons
Baseline values of StO2 did not differ between smokers and nonsmokers, and also they did not differ between men and women. The same was true for the hyperemic response after the brachial artery occlusion test. O2 consumption rate during the occlusion period was found to be similar in smokers and nonsmokers. However, O2 consumption rate was found to be significantly higher in women independently of smoking status. The main effect for gender was statistically significant (p = 0.032). These results are shown in Table 1 .


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  		Table 1. Microcirculatory Parameters Assessed by NIRS According to Gender and Smoking Status*

 
Acute Effects of Smoking
The results of the smoking session are summarized in Table 2 . During the smoking experiment, StO2 remained unaffected (Fig 1 ). This was in contrast to the O2 consumption rate during the brachial artery occlusion test, which was markedly reduced at midcourse of the cigarette, yielding a statistically significant difference for both genders (p < 0.001) between the initial value and the one at midcourse and continued to decrease even 5 min after the end of the cigarette. O2 consumption rate differed between men and women throughout the experiment (p = 0.046). The interaction term in the ANOVA model was not significant, indicating that smoking had a similar effect on O2 consumption rate across genders (Fig 2 ).


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  		Table 2. Microcirculatory Parameters Assessed by NIRS During the Smoking Session According to Gender*

 

Figure 1
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  		Figure 1. StO2 during the smoking interval in 25 smokers (14 men and 11 women) before smoking, while smoking, and 5 min after smoking. Horizontal bars represent median values; boxes represent interquartile ranges; and whiskers show ranges.

 

Figure 2
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  		Figure 2. O2 consumption rate during the smoking interval in 25 smokers (14 men and 11 women) before smoking, while smoking, and 5 min after smoking. Horizontal bars represent median values; boxes represent interquartile ranges; and whiskers show ranges. *Indicates significant decrease.

 
Vascular reactivity was assessed using the hyperemic response of the StO2 signal. The multivariate ANOVA test indicated an overall effect of smoking on vascular reactivity during the experiment (p = 0.015), with no statistically significant differences between men and women. Pairwise comparisons of the three time points indicated a significant decrease in hyperemic response when the subject had smoked roughly half of the cigarette (p = 0.05, Bonferroni adjustment). However, the hyperemic response had returned to approximately normal levels 5 min after the end of the cigarette, yielding a statistically significant difference between midcourse and the final measurement (p = 0.013, Bonferroni adjustment). This trend is depicted in Figure 3 .


Figure 3
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  		Figure 3. Reactive hyperemia during the smoking interval in 25 smokers (14 men and 11 women) before smoking, while smoking, and 5 min after smoking. Horizontal bars represent median values; boxes represent interquartile ranges; and whiskers show ranges. *Indicates significant decrease.

 
Discussion

The main finding of our study is that in young healthy smokers with relatively limited exposure, vascular reactivity showed a prompt and dramatic decline during the smoking session. Application of the arterial occlusion technique with NIRS enabled us to assess several aspects of peripheral tissue microcirculation. Although laser Doppler flowmeter has been used in previous studies, this is the first time to our knowledge that NIRS methodology is employed to estimate the effect of cigarette smoke on tissue microcirculation. This methodology is particularly suited for studies of the microcirculation, since spectroscopy principles dictate that the NIRS signal is derived predominantly from hemoglobin in small arterioles, capillaries, and venules. This happens because light emitted into larger vessels (ie, arteries and veins) is almost completely absorbed since the molar quantity of blood, and therefore of water, is so comparatively large.16

Several reports67 have demonstrated that the influence of a single cigarette can be detected as soon as 5 min after completion; however, we have been able to document an effect on microcirculation that appeared even before the subject had finished smoking one single cigarette. The fact that 5 min after smoking reactivity values were nearly normal merits some attention, since most reports6717 indicate more prolonged effects. A notable exception is the study by Pellaton et al2 that targeted young smokers. They did not find any impairment in reactive hyperemia 5 min after the smoking of one cigarette, while the effects on older smokers persisted for as long as 70 min. This could mean that the effects of smoking are not yet irreversible.

The mechanism responsible for this acute endothelial dysfunction is not yet established. Endothelial dysfunction is usually defined as an impaired nitric oxide (NO)-mediated relaxation associated with a preserved endothelium-independent vasodilation, and it has been shown to long precede the appearance of atherosclerotic lesions. The release of NO by endothelial cells is particularly important because it can also inhibit monocyte adhesion, platelet aggregation, and smooth-muscle proliferation, as well as being a vasodilator.18 Interference of smoke with the production of NO by the endothelium has been observed in vitro as well as in vivo.1920 More dramatically, it seems now established that passive smokers can present acute endothelial dysfunction after exposure to cigarette smoke in a manner similar to active smokers.21 It has been shown that reactive hyperemia is partially related, at least during the late phase, to the endothelial release of NO.22 Recently though, the role of NO in mediating postocclusive reactive hyperemia has been questioned.23

Which component(s) of cigarette smoke is responsible for the effect is, understandably, equally disputed. A role for nicotine has been suggested by some investigators.724 Neunteufl et al24 were thus able to demonstrate an acute decrease of vascular reactivity in subjects within 20 min of cigarette smoke inhalation. The same investigators reported a similar, although to a lesser degree, decrease of flow-mediated dilation of the brachial artery in the same subjects after receiving a spray of a nicotine nasal spray. This suggest that nicotine has the potential to interfere within minutes with endothelial function, although it would seem unlikely that it should be the only mediator of endothelial damage, considering the myriad of substances contained in cigarette smoke. Similar results were obtained by Sarabi and Lind,7 who compared the effects of cigarette smoke and nicotine chewing gum on endothelial-dependent vasodilation of young healthy habitual smokers and found similar effects 30 min after the exposure to smoke or nicotine.

The second finding from our study is that the local O2 consumption rate as assessed by NIRS technology during the arterial occlusion protocol was found to differ significantly between genders, with women having consistently higher values. We are not aware of a similar finding in resting subjects. In exercise physiology experiments however, it has been reported that gender-specific differences exist in adductor pollicis muscle performance under hypoxic conditions. Fulco et al25 thus found that women showed a markedly slower development of muscle fatigue. It is not clear why this would be, since in both men and women the adductor pollicis muscle contains a uniformly high percentage of slow-twitch, high-oxidative-capacity fibers. The researchers postulated a greater capacity for oxidative phosphorylation in specific fast-twitch fibers of women, a fact that could account for a more rapid consumption of the available O2. Similarly, there are several reports2627 that indicate a preferential utilization of oxygen by women in various exercising conditions, with men relying on glycolytic pathways of metabolism to a greater extent.

Regardless of eventual metabolic differences between men and women, O2 consumption rate was acutely and similarly affected by smoking in both genders, with a marked decrease that became apparent after only half of the cigarette was smoked and that continued 5 min after it was finished. This effect could probably be attributed to the mild CO poisoning that is long known to occur within minutes in smoking conditions. CO causes a leftward shift in the hemoglobin-O2 dissociation curve and a reduction in the cooperative binding properties of hemoglobin with O2. In exercising humans, muscle O2 extraction has been shown to be decreased in conditions of experimental exposure to determined percentages of CO in the inspired gas mix.2829 In addition, it has been demonstrated that smoking can reversibly inhibit mitochondrial complex IV activity in several cell types.3031 This effect could be crucial in explaining why O2 extraction by the tissue is impeded when CO is inhaled. According to an older line of evidence, experimental acute inhibition of electron transport capacity of skeletal muscle in vitro causes a decrease in peak O2 consumption of isolated rat hindlimb preparation, as well as a decrease in O2 extraction in the same muscle.32

In our study, StO2 did not differ between smokers and nonsmokers and between men and women. A study33 employing the same NIRS methodology on 707 adult volunteers found a somewhat higher mean StO2 value of 87 ± 6%. It is noteworthy, however, that a very high proportion of their sample was of Hispanic and black ethnic origin, which tended to have higher StO2 values than whites. The mean StO2 for whites was 82 ± 7%, a value very close to our findings. The same study33 indicated that StO2 is higher in smokers (89 ± 5%) than in nonsmokers (86 ± 7%). A statistically significant difference was also reported for StO2 between genders, with men having higher values (88 ± 6%) than women (85 ± 7%). Since StO2 values according to gender and smoking status were not reported separately for each ethnic group, we believe that these differences could reflect different proportions of subjects of the several ethnic groups in the smoking and gender categories, thus biasing the results. In our considerably more homogeneous, albeit smaller sample of young white subjects, StO2 values were virtually identical for male and female subjects and only slightly higher in smokers.

Postocclusive reactive hyperemia (before the smoking session) also did not differ significantly between smokers and nonsmokers. This contrasts most studies that have examined vascular reactivity to transient ischemia. Using either the flow-mediated dilation of the brachial artery technique, or by directly assessing limb blood flow by laser Doppler flowmeter, most such studies3 report a decreased hyperemic response in smokers, a sign of early endothelial dysfunction. However, an important feature of most such studies is that smokers of all ages were evaluated together, thus not taking into account the total time of exposure. An important study that specifically tried to address the question of whether younger smokers exhibit similar alterations in vascular reactivity as older ones was by Pellaton et al,2 who showed that smokers and nonsmokers 20 to 35 years of age had no significant differences in postischemic reactive hyperemia test results. In the same study,2 smokers 40 to 60 years of age had markedly reduced reactive hyperemic responses compared to nonsmokers of the same age. These age-specific differences were also shown to exist for both endothelium-dependent and endothelium-independent dilation. Our subjects are very similar to the younger group of that study, both in terms of age and of smoking habit. This implies that it takes chronic exposure to cigarette smoke to produce permanent modifications in endothelial function, and is in accordance with studies3 that found an improvement (although not normalization) of vascular reactivity in former smokers.

Limitations
The major limitation of our study was the variability of our subjects in terms of duration of their exposure to cigarette smoke (pack-years). Furthermore, the acute effect of smoking on microcirculation has been shown to be dose dependent, an aspect that we did not specifically address since we did not evaluate the amount of smoke inhaled. This could be different for each participant depending on the pattern of smoke inhalation, or on the type of cigarette. Despite these potential sources of variability, the noninvasive method of NIRS showed significant acute effects of smoking.

Conclusions

Our study showed significant effects on the microcirculation during a smoking session in young healthy smokers with a relatively limited exposure. All parameters measured in our study were assessed by NIRS, which, when combined with the arterial occlusion technique, provides us with the opportunity to take advantage of both the ischemic and the reperfusion phases to investigate different functional aspects of the peripheral microcirculation in the same subject. Our findings offer some mechanistic insights regarding cigarette smoke-induced acute endothelial damage. Furthermore, they point to reversibility of this effect, a notion corroborated by epidemiologic evidence of cardiovascular risk reduction in former smokers. Similar research on populations of more chronic and of passive smokers could potentially generate data useful for risk quantification and perhaps of prognostic value regarding cardiovascular and respiratory adverse outcomes of exposure to cigarette smoke.

Acknowledgements

The authors would like to acknowledge the substantial assistance provided by the Hellenic Air Force in terms of personnel and facilities. The authors also acknowledge the contributions of Panagiotis Renieris, MD, and Apostolos Kontzias, MD, in the preparation of the article.

Footnotes

Abbreviations: ANOVA = analysis of variance; NIRS = near-infrared spectroscopy; NO = nitric oxide; StO2 = tissue oxygen saturation

This study was partly funded by a grant from the Special Account for Research Grants of the National and Kapodistrian University of Athens, Greece, and by the Thorax Foundation.

The authors have no conflicts of interest to disclose.

Received for publication August 19, 2006. Accepted for publication December 20, 2006.

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