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CARDIOVASCULAR ANESTHESIA

Acute Smoking Increases ST Depression in Humans During General Anesthesia

Harvey J. Woehlck, MD^*, Lois A. Connolly, MD^*, Michael P. Cinquegrani, MD, Marshall B. Dunning, III, PhD, and Raymond G. Hoffmann, PhD^§

Departments of *Anesthesiology, Cardiology, Pulmonary and Critical Care Medicine, and §Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin

Address correspondence and reprint requests to Harvey J. Woehlck, MD, Froedtert Memorial Lutheran Hospital, 9200 West Wisconsin Avenue, Milwaukee, WI 53226.

	Abstract

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We tested the hypothesis that acute smoking is associated with ST segment depression during general anesthesia in patients without ischemic heart disease. The carbon monoxide (CO) concentration in expired gas and hemodynamic data was measured during general anesthesia for noncardiac or nonperipheral vascular surgery in patients without symptoms or evidence of ischemic heart disease. Increased expired CO concentrations are indicators of recent smoking. Logistic regression analysis identified significant predictors of ST segment depression 1 mm. Both rate pressure product (odds ratio 1.20 for each increase of 1000, 95% confidence interval = 1.04–1.41, P = 0.007) and expired CO concentration (odds ratio 1.05 for each part per million increase, 95% confidence interval = 1.03–1.08, P = 0.001) were significant predictors of ST segment depression when considered simultaneously. Males demonstrated a lower probability of having an episode of ST depression (odds ratio = 0.16, P = 0.01), but this did not change the relationship between rate pressure product and CO as predictors of ST depression. Approximately 25% of chronically smoking patients smoked on the morning of surgery despite instructions not to smoke.

Implications: Patients under age 65 without symptoms of ischemic heart disease who smoked shortly before surgery had more episodes of rate pressure product-related ST segment depression than nonsmokers, prior smokers, or chronic smokers who did not smoke before surgery. Females were at greater risk of ST depression than males.

	Introduction

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Despite requests to the contrary, patients who smoke tobacco may do so in the preoperative period when oral intake is prohibited. Increasing use of outpatient surgery may enhance the accessibility of cigarettes to preoperative patients in the hours immediately preceding surgery, increasing the likelihood that effects of acute smoking are present during anesthesia. It is known that acute smoking worsens myocardial ischemia measured by exercise stress testing in patients with ischemic heart disease (1–4), but the effects of acute smoking before routine anesthesia and surgery have not been studied. We tested the hypothesis that, in patients without symptoms or evidence of ischemic heart disease, acute smoking is associated with ST depression during increased myocardial work. This study uses expired carbon monoxide concentration (CO) as a marker for recent smoking. A logistic regression analysis was used to identify variables predictive of ST segment depression.

	Methods

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This study was approved by our Human Research Review Committee. Surgical patients receiving general anesthesia at our hospital during this study were routinely monitored for gas phase CO as part of continuing efforts to identify and terminate iatrogenic CO poisoning resulting from the chemical breakdown of inhaled anesthetics by desiccated CO₂ absorbents (5,6). This study was performed as an epidemiologic, observational (cross-sectional) study, during which no interventions were performed. Therefore, informed consent was waived for recording the concentrations of gas phase CO and patient data that were already acquired as part of routine anesthesia care. We confirmed that the source of CO was not from intraoperative anesthetic breakdown via the absence of trifluoromethane (7). CO concentrations in expired gas were measured with gas chromatography or a portable CO monitor (8) (CO Sleuth, Breathe EZ Systems, Inc., Shawnee Mission, KS). These measurements were generally performed 30–60 min after induction of anesthesia and therefore usually after intubation was performed, after positioning was completed, and after fresh gas flow rates were decreased to maintenance levels. All patients were ventilated through a circle circuit. The management of anesthesia was not controlled and was conducted without regard for this study. Instead, the hemodynamic responses to the existing anesthetics were quantified by the rate pressure product (RPP), which was defined as the systolic blood pressure (mm Hg) multiplied by the heart rate (bpm). Heart rate, blood pressure, and ST segment trends were electronically measured at the J-point + 60 ms (Tramscope 12C, Marquette Medical Systems, Inc., Milwaukee, WI) and were automatically stored in memory as part of standard intraoperative monitoring. These were retrieved and examined in tabular and graphic forms during or after each case to identify episodes of ST depression.

Patients undergoing nonemergency, noncardiac, and nonmajor vascular surgery were chosen for this study. They were excluded if symptoms or documentation of ischemic heart disease or atherosclerotic peripheral vascular disease existed, if pregnant, if hematocrit was <30%, or if over 65 years of age. Patients were also excluded if electrocardiograph (EKG) characteristics were present that would invalidate ST segment monitoring. These included baseline ST segment depression, pacemaker-dependent rhythms, or QRS duration >0.12 s, as well as arrhythmias other than sinus arrhythmia. Episodes of ST depression were excluded from further analysis if the patients were hypotensive (>25% decrease in mean arterial pressure from preoperative values, systolic blood pressure <90 mm Hg, or diastolic blood pressure <45 mm Hg), if the patients were known to be hypoxemic at the time of ST segment depression with an SpO₂ of less than 90%, or if >500 mL of blood loss simultaneously occurred. Patients were categorized by the RPP that existed at the time of maximum ST depression, or in the absence of ST depression, the maximum RPP was recorded. We defined patients as smokers if they smoked on a daily basis, although not necessarily on the day of surgery. We defined patients as recent or acute smokers if they also smoked on the morning of surgery so that increased concentrations of CO were present in the expired breath.

A logistic regression model was used to determine the probability of having ST depression as a function of the RPP, expired CO concentration, age, gender, and smoking status. The significance of the relationship was expressed as the odds ratio. Two sample t-tests with equal variances were used to identify differences in RPP between smokers, acute smokers, and nonsmokers.

	Results

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Patient Assignment
CO was identified in all 911 patients screened in this study, and the distribution of expiratory CO concentrations is shown in Fig. 1. A total of 740 patients satisfied the criteria for inclusion in the comparative analysis. The average age of patients who identified themselves as smokers (42 ± 12) was similar to prior smokers (49 ± 10) and nonsmokers (41 ± 13). Chronic smokers with increased expired CO concentrations had similar self-reported cigarette intake (1.3 ± 0.6 packs/d) to chronic smokers who presumably did not smoke before surgery and had normal expiratory CO concentrations (1.1 ± 0.5 packs/d). Three of the 344 patients (0.9%) who claimed to be nonsmokers and 5 of the 115 patients (4.3%) who claimed to be prior smokers were found to have elevated CO concentrations that could not be explained by sources other than smoking. Therefore, 8 of 459 patients (1.7%) initially claimed not to be smokers, but later admitted to smoking or had biochemical evidence of smoking shortly before surgery and were categorized as smokers. Among those categorized as smokers, 67 of 274 (24.5%) had smoked recently, despite the fact that all patients had received standard preoperative written instructions not to smoke preoperatively. Although the CO concentration was considered as a continuous variable, acute smokers typically expired greater than 35 ppm CO into the anesthesia breathing circuit. The average fresh gas flow rate was 2.9 ± 0.9 L/min. Isoflurane was used in 66% of all cases, sevoflurane 26%, desflurane 8%, nitrous oxide only <1%, and total IV anesthesia in <1% of cases. Among those patients with 1 mm ST depression, isoflurane was used in 74% of cases, sevoflurane 18%, and desflurane 8%.

View larger version (29K): [in this window] [in a new window]   Figure 1. Histogram of expired carbon monoxide (CO) concentrations for active smokers, and the combined group of nonsmokers and prior smokers who had no evidence of acute smoking.

View larger version (28K): [in this window] [in a new window]   Figure 2. Typical heart rate and ST segment trend. The severity of ST depression does not correlate with the instantaneous heart rate, but becomes progressively more severe as the tachycardia persists. This implies that the ST depression is not a J-point measurement artifact.

View larger version (19K): [in this window] [in a new window]   Figure 3. Probability of ST depression versus carbon monoxide (CO) concentration in parts per million for male and female subjects. Data points indicate that at least one patient with each identified CO value was incorporated into the logistic regression.

	Discussion

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Association of Smoking and RPP with ST Segment Depression
Although simplistic, the RPP remains a useful reflection of myocardial work that can be obtained from routine intraoperative monitoring. Both CO concentrations and increases in RPP were found to be predictors of ST depression. This is consistent with work-related myocardial ischemia.

Expired CO concentrations were used as markers of acute smoking. No threshold concentration of CO was identified below which the risk of ST depression was not increased. These results confirm the hypothesis that acute smoking is associated with ST depression during episodes of increased myocardial work. Although the odds ratio for CO appears small at 1.05 per ppm of CO, the mean CO concentration in the recent smokers is 52.4 ppm CO compared with nonsmokers with 9.4 ppm CO. This resulted in a calculated relative risk of ST depression of 1.05^(45.0) = 9.0 for the acute smokers compared with nonsmokers. Patients with extreme concentrations of CO would have correspondingly greater calculated relative risks for ST depression.

Association of Smoking and RPP
As a group, smokers in this study had greater peak RPP, and even greater changes were identified in patients who smoked recently before surgery. One can speculate that chronic changes due to smoking or the effects of smoke-related toxins, such as nicotine, may cause greater heart rate and/or blood pressure responses during surgical or intubation stimuli.

Monitoring of CO Concentrations
Expired breath CO monitoring is a reasonable monitor for acute smoke exposure (8–10). Preoperative questioning regarding a patient’s smoking habits may be flawed by incentives to deceive healthcare professionals, and 1.7% of patients attempted to deceive in this study. Increased inspired oxygen concentrations were common during anesthesia in this study. These increase expired CO concentrations as a result of competitive binding to and displacement of CO from hemoglobin (11). Therefore, at similar carboxyhemoglobin (COHb) concentrations, the expired CO concentrations found in this study will be greater than those when a patient breathes air.

Patient Selection and Exclusion Criteria
Patients without evidence of coronary artery disease were studied to simplify data analysis and interpretation. We suggest that metabolic poisoning may be the mechanism for the ST depression. We therefore made all possible efforts to exclude patients who may have other reasons for myocardial ischemia. Hypoxemic, hypotensive, anemic, or hypovolemic patients may also have problems with myocardial oxygen supply unrelated to coronary artery disease, and these patients were excluded because their inclusion may confound the relationship between ST depression, smoking, and increased myocardial work.

Limitations of the Study
Because this was an observational, epidemiologic study, blood sampling for COHb, cyanide, nicotine, or their metabolites could not be performed. Direct measurement of COHb would have been a better indicator of CO stores, eliminating measurement errors associated with pulmonary disease and dead space ventilation. However, in defense of monitoring respiratory CO concentrations, Goldbaum et al. (12) found that respiratory concentrations were more important than COHb concentrations in predicting death during CO poisoning, and postulated that this represented mitochondrial poisoning. Although this study used expiratory CO as a marker for acute smoking, other smoke-related toxins may have been present. Neither a mechanism for the ST depression nor any possible effects of the known smoke-related toxins could be determined by the methods used in this study. Although efforts were made to exclude patients with known ischemic heart disease, silent ischemic heart disease could not be excluded.

Several studies debate the significance of intraoperative ST depression. As a method of detecting myocardial ischemia, Leung et al. (13) recently compared on-line computerized ST segment trending using three different operating room monitors with off-line Holter EKG analysis. They found that the Marquette monitors used in our study were the best of those tested, and were found to have a sensitivity of 75% and a specificity of 89% compared with Holter EKG analysis. ST trending inaccuracies were associated with small R-wave amplitude in the monitored lead, drifting baseline, conduction abnormalities, and pacing. These latter two conditions were excluded in our study. Subsequent studies have confirmed the reliability of modern electrocardiogram monitors to detect and record ST depression when compared with Holter monitoring (14).

Significance of ST Depression
Fleisher et al. (15) stated that ST depression is rare in asymptomatic patients without cardiovascular dysfunction or systemic atherosclerosis, and that ST monitoring may be associated with a high number of false-positive results in this population. However, Fleisher’s study considered EKG indicators of ischemia to be falsely positive if angiographically demonstrable coronary artery disease was absent. No other possible mechanisms for physiologically mediated ST depression were considered. The prediction of a ninefold increase in relative risk for the group of acute smokers suggests that a physiological correlate exists for this phenomenon. Structural coronary artery disease is not necessary for these toxins to interfere with myocardial oxygen metabolism. The literature supports the contention that metabolic poisoning with ST depression may be caused by toxins absorbed from cigarette smoke, which may interfere with the transport and use of oxygen (CO or cyanide) or the regulation of blood flow (CO or nicotine) as summarized herein.

COHb concentrations are elevated after smoking (10). CO produces toxicity via the impairment of oxygen transport by hemoglobin caused by the occupation of oxygen binding sites, and via impaired oxygen release from oxyhemoglobin resulting from its lower P₅₀ (12,16–18). In addition to this classic mechanism, Stamler et al. (19) recently demonstrated that blood itself autoregulates its own regional flow via a heme-saturation-dependent nitric oxide release from S-nitroso-deoxyhemoglobin. Saturation of hemoglobin by CO may impair this release of nitric oxide, resulting in mismatching regional blood flow to oxygen consumption.

To facilitate oxygen diffusion to mitochondria, cardiac muscle contains a high concentration of myoglobin. Coburn (20) calculated that, although only 10%–15% of CO is bound to myoglobin and cytochromes during normoxia, CO shifts to myoglobin during cellular hypoxia producing carboxymyoglobin saturations three times greater than the COHb saturation. If oxygen consumption is increased and delivery is impaired by COHb, this shift in CO may severely impair oxygen transport through cardiac muscle during times of increased work (18). Stewart (21) suggested that any concentration of CO poses a hypoxic stress to the cardiovascular system, which is consistent with the lack of a threshold in relative risk to CO concentration we found. In patients with ischemic heart disease, myocardial ischemia during exercise is increased by only 2%–6% COHb (1–4) which is in the range typical for smokers (9,10).

Many believe that nicotine is the primary constituent responsible for the acute adverse effects of smoking on myocardial oxygen supply and demand (22). The effects of nicotine may be brief and may not be directly related to plasma nicotine concentrations, but these effects are consistent with our finding of greater RPP in patients who smoked shortly before surgery. However, even in the absence of nicotine, cigarette smoke exacerbated myocardial ischemia more than equivalent COHb concentrations (4), suggesting additional smoke-related toxins. Cyanides are likely candidates because they are produced by burning tobacco (23), are absorbed (24), and synergistically impair oxygen use by inhibiting mitochondrial cytochrome C oxidase (25).

We speculate that the combination of these known tobacco-smoke-related toxins may result in a functional state of myocardial hypoxia similar to myocardial ischemia during increased myocardial work, but does not require the presence of structural coronary artery disease. If this is true, preoperative cigarette smoking may pose cardiac risk in addition to the effects of chronic tobacco use. These results suggest that further study on the effects of acute smoking before anesthesia and surgery should be performed.

	Acknowledgments

 
This research was supported with departmental funds.

	Footnotes

 
Portions of this paper have been presented at the ASA annual convention in San Diego, CA, October 1997.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999