Chronic exposure to cigarette smoke produces profound changes in physiology that may alter responses to perioperative interventions and contribute to perioperative morbidity. Because of smoke-free policies in healthcare facilities, all smokers undergoing surgery are abstinent from cigarettes for at least some period of time so that all are in various stages of recovery from the effects of smoke. Understanding this recovery process will help perioperative physicians better treat these patients. This review examines current knowledge regarding how both short-term (duration ranging from hours to weeks) and long-term smoking cessation affects selected physiology and pathophysiology of particular relevance to perioperative outcomes and how these changes affect perioperative risk. It will also consider current evidence regarding how nicotine replacement therapy, a valuable adjunct to help patients maintain abstinence, may affect perioperative physiology.

APPROXIMATELY 23% of adults in the United States smoke cigarettes,1and millions of these patients undergo surgery annually. Their smoking status can affect many perioperative outcomes. This is not surprising, because smoking can profoundly alter physiology, both by contributing to the pathophysiology of diseases such as chronic obstructive pulmonary disease and atherosclerosis and via  the acute pharmacologic actions of smoke constituents such as carbon monoxide and nicotine (fig. 1). Chronic exposure to nicotine also dramatically changes the function of nicotinic acetylcholine receptors, which are ubiquitous in the nervous system (and many other tissues). Because of smoke-free policies in healthcare facilities, all smokers requiring surgery are abstinent from tobacco for at least some period of time. Although the long-term physiologic consequences of abstinence from smoking are in many instances well characterized, much less is known about the initial responses to smoking cessation. This information is of practical importance to anesthesiologists, who daily encounter patients who are in various stages of recovery from the effects of cigarette smoke. Changes in physiology produced by abstinence from cigarettes may have clinically relevant effects on anesthetic management and perioperative outcome. Important clinical questions such as the optimal timing of preoperative smoking cessation and whether anesthesiologists should recommend brief preoperative abstinence at all depend on such knowledge.

Fig. 1. Categories of mechanisms by which exposure to cigarette smoke may affect responses of patients undergoing anesthesia. The specific examples listed under each category are representative, not exhaustive. nAChR = nicotinic acetylcholine receptor; Po2= partial pressure of oxygen. 
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Fig. 1. Categories of mechanisms by which exposure to cigarette smoke may affect responses of patients undergoing anesthesia. The specific examples listed under each category are representative, not exhaustive. nAChR = nicotinic acetylcholine receptor; Po2= partial pressure of oxygen. 

Fig. 1. Categories of mechanisms by which exposure to cigarette smoke may affect responses of patients undergoing anesthesia. The specific examples listed under each category are representative, not exhaustive. nAChR = nicotinic acetylcholine receptor; Po2= partial pressure of oxygen. 
View largeDownload slide

Fig. 1. Categories of mechanisms by which exposure to cigarette smoke may affect responses of patients undergoing anesthesia. The specific examples listed under each category are representative, not exhaustive. nAChR = nicotinic acetylcholine receptor; Po2= partial pressure of oxygen. 

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This review will survey current knowledge regarding how both short-term (duration ranging from hours to weeks) and long-term smoking cessation affects selected physiology of particular relevance to perioperative outcomes and how these changes affect perioperative risk. It will also examine the effects of nicotine replacement therapy (NRT), a valuable adjunct to help patients maintain abstinence.

Mechanisms of Injury and Recovery

Smoking is clearly a major risk factor for cardiovascular diseases such as coronary artery and peripheral vascular disease.2Smoking increases myocardial work by increasing heart rate, blood pressure, and myocardial contractility,3,4at least in part by increasing sympathetic tone and circulating catecholamines.5Although smoking a cigarette actually increases coronary artery blood flow in people with normal coronary arteries, in those with coronary artery disease, smoking may cause coronary vasoconstriction.6These hemodynamic effects are primarily caused by nicotine, both via  direct peripheral effects and by increasing sympathetic outflow.4,7Oxygen delivery is impaired by carboxyhemoglobin, levels of which may exceed 10% in smokers. Exhaled carbon monoxide, easily measured using a relatively inexpensive handheld device, is a useful tool to quantify smoking behavior.8Carbon monoxide not only binds to hemoglobin, reducing the amount available to carry oxygen, but also shifts the oxyhemoglobin dissociation curve to the left, impeding release of oxygen from hemoglobin.9These effects contribute to exercise-induced angina in smokers with coronary artery disease10–12and increase the frequency of ventricular arrhythmias.13Carbon monoxide may also inhibit other proteins that contain heme, such as cytochrome C oxidase, an effect that could impair mitochondrial respiration.14,15Other substances in cigarette smoke, such as cyanide, may also affect respiration.16In addition to affecting these factors regulating myocardial oxygen supply and demand, smoking promotes atherosclerosis. Salient mechanisms may include endothelial injury,17–21oxidant injury,22enhanced thrombosis,23and adverse effects on blood lipids.24,25The contribution of nicotine to accelerated atherosclerosis is unclear4because there are many other constituents of cigarette smoke that could also play a role. For example, compounds such as tobacco glycoproteins have proinflammatory effects that could contribute to atherosclerosis.26 

Abstinence from cigarettes decreases cardiovascular risk. Quitting decreases the risk for all-cause mortality in smokers with coronary artery disease by approximately one third.27The time needed to fully realize this benefit is unknown, given that some time must elapse before risk can be assessed, but is estimated to be at least several months.28How risk decreases over the first days and weeks of quitting is unclear. To the extent that the acute effects of smoke constituents such as nicotine and carbon monoxide increase the risk of ischemia, cessation should have rapid benefit, because the half-lives of nicotine and carboxyhemoglobin are relatively brief (approximately 1 and 4 h, respectively, although there is wide variability among individuals).29,30Given that smoking acutely decreases measures of integrated cardiovascular function such as maximal exercise capacity31–33and endothelium-mediated vasodilation,19,34it is plausible that even brief cessation (i.e. , over a few hours) may be beneficial.35However, improvement in smoking-related disease such as atherosclerosis may occur more slowly, if at all.

Perioperative Risk

The presence of cardiac disease increases the risk for major perioperative cardiac morbidity and mortality.36Because smoking contributes to cardiac disease, smoking in this way contributes to perioperative cardiac risk. However, it is not clear whether status as an active smoker itself (apart from the presence of smoking-related cardiac disease) increases the perioperative risk of cardiac events.37To the extent that the acute pharmacologic effect of smoke constituents such as nicotine and carbon monoxide contribute to ischemia, even relatively brief abstinence should be beneficial. The concept is supported by a study finding that electrocardiographic signs of ischemia in anesthetized patients were correlated with carbon monoxide levels, an index of recent cigarette use.38However, with some exceptions, most studies have been unable to identify preoperative smoking status as an independent risk factor for major cardiac events (e.g. , myocardial infarction) during and after either cardiac or noncardiac surgery, although few studies have carefully assessed smoking behavior.36,39–42Major indices of cardiac risk do not include preoperative current smoking status as a predictor of cardiac outcomes.36,43Postoperative smoking behavior can affect cardiac outcomes after surgery. For example, sustained postoperative abstinence from cigarettes reduces long-term mortality after cardiac revascularization.44,45 

Cardiovascular Risk of NRT.

Nicotine replacement therapy, via  delivery systems such as patches or gum, is a valuable therapy for tobacco dependence. Because nicotine may contribute to the deleterious effects of smoking on the cardiovascular system, the safety of therapeutic nicotine in patients with cardiovascular disease was initially questioned. However, overwhelming evidence now supports the safety of NRT in patients with cardiac disease.4Available experimental trials suggest that NRT does not adversely affect, or may in fact improve, many of the factors leading to cardiovascular risk. NRT does not affect the patency of experimental coronary artery bypass grafts.46Smokers improve their coagulation profiles when quitting using NRT,47,48and nicotine itself has little effect on human platelet function in vivo .49NRT does not produce significant adverse cardiac effects in healthy volunteers50or in smokers, even if they continue smoking.51,52Multiple clinical trials show that NRT is safe in patients with cardiovascular disease.53–55Transdermal NRT does not increase the frequency of cardiac events in cigarette smokers with coronary artery disease, even if they continue smoking.55,56NRT may even reduce cardiovascular risk if smoking rate is reduced. For example, NRT significantly decreases the extent of exercise-induced myocardial ischemia assessed by exercise thallium perfusion imaging in smokers with coronary artery disease, even if they continue smoking.57 

These results suggest that the benefits of NRT to aid patients with coronary heart disease stop smoking far outweigh the risk of continued smoking or NRT itself.4This is likely due to the facts that (1) other components of cigarette smoke besides nicotine contribute to adverse effects and (2) the serum concentrations of nicotine produced by NRT are less than the peak concentrations produced by cigarettes.30,58Even if patients continue to smoke during NRT, their total nicotine intake is approximately the same as during their usual smoking, because they reduce their cigarette consumption.59These considerations should also apply in the perioperative period, suggesting that NRT could be a valuable tool to manage tobacco dependence in the perioperative period. NRT does have hemodynamic effects that may need to be addressed in patients at risk. For example, increases in heart rate after tracheal intubation are exaggerated in smokers receiving nicotine patches preoperatively.60 

Mechanisms of Injury and Recovery

Smoking is a major cause of pulmonary disease. Symptomatic chronic obstructive pulmonary disease develops in approximately 15% of smokers,61and up to an additional 50% have development of chronic bronchitis without airway obstruction.62Even smokers without overt symptoms demonstrate changes in lung morphometry and immune function.63,64The mechanisms of injury are complex and multifactorial.65Smoking induces an inflammatory state in the lung; the number of inflammatory cells such as macrophages and neutrophils is increased, and their function is altered.66–68Compared with nonsmokers, alveolar macrophage function is impaired in smokers. These cells are less metabolically active and less able to release inflammatory mediators, impairing their ability to mount an effective response to infection.69–73Airway epithelial structure and function are altered, although it may be difficult to separate the effects of smoking per se  from the consequences of smoking-related pathology such as chronic bronchitis. The net effects on mucus production and transport are complex, in part because of difficulties inherent in measuring these parameters. In general, smoking produces goblet cell hyperplasia and other structural epithelial abnormalities, affects the volume and composition of mucus, and decreases mucociliary clearance.74–81Eventually, other structural changes in the airway wall develop, including increased smooth muscle and fibrosis,82and as a result, smokers exhibit an accelerated age-related decline in forced expiratory volume in 1 s compared with nonsmokers.83In smokers without overt chronic obstructive pulmonary disease, airway reactivity in response to inhaled bronchoconstrictors is increased compared with nonsmokers for inhaled muscarinic agonists such as methacholine but not histamine.84However, the ability of inhaled irritants such as aerosols of capsaicin and citric acid to produce cough is diminished in healthy smokers without overt lung disease.85–88These findings may reflect a depletion of neuropeptides from sensory nerves responsible for cough or other means by which smokers become more tolerant to inhaled irritants (including cigarette smoke). These results in humans are in marked distinction to those in animal models, which consistently demonstrate increases in cough and airway reactivity after smoke exposure.89 

The process of how the lung recovers from chronic smoke exposure is complex. Recovery depends on the severity of smoking-related pathology (e.g. , whether the smoker has developed overt obstructive lung disease), but several general principles are apparent.84With abstinence, symptoms of cough and wheezing decrease within weeks.90,91Abstinence slows the accelerated decline in forced expiratory volume in 1 s observed in smokers.92In asymptomatic smokers, goblet cell hyperplasia and mucus production decreases with cessation, and mucociliary clearance improves.75,93,94These improvements probably also occur in smokers with chronic bronchitis and chronic obstructive pulmonary disease, at least in the central airways. Inflammatory markers such as the number of alveolar macrophages decrease with abstinence, but other inflammatory consequences, such as fibrosis, alveolar destruction, and smooth muscle hyperplasia, may be permanent.95Airway hyperreactivity to muscarinic agonists generally decreases.84Many of these changes are inferred from cross-sectional studies comparing smokers and long-term former smokers and thus represent the effects of at least several months of abstinence. Few longitudinal studies of quitters are available, especially those providing information over the first few days and weeks of abstinence. Mucus production over the initial weeks of recovery has not been quantified, although anecdote suggests that it is increased. Cold symptoms and cough may be increased during this time period before subsiding after several months of abstinence.96Mucociliary clearance seems to at least partially improve in smokers, requiring at least 1 week to show improvement.97Measures of lung inflammation such as altered alveolar macrophage number and function change only over a period of months, if at all.98–101 

Perioperative Risk

Smoking status is a consistent univariate risk factor for several perioperative pulmonary complications (PPCs); i.e. , when other factors are not accounted for, smokers are more likely to have development of PPCs.102–105These complications include respiratory failure,106unanticipated intensive care unit admission,107pneumonia,108airway events during induction (cough, laryngospasm),109increased need for postoperative respiratory therapy or aerosol therapy,110,111and various combinations of these individual events with others, such as bronchospasm and increased airway secretions. A lack of standardized definitions of adverse perioperative outcomes among studies often poses difficulties in study interpretation, especially because some outcomes are quite subjective. For example, because clinicians may expect smokers to be at risk for PPCs, they may be more prone to order respiratory or aerosol therapy, which in some studies itself counts as a PPC.

When multivariate analysis is performed, accounting for other factors such as lung disease and pulmonary function, most observational studies find that current smoking status is an independent risk factor for PPCs,106,108,112–116although there are exceptions.114,117,118Because smoking status may affect the severity of pulmonary disease, it still may be difficult to separate the risk posed by smoking itself from the risks caused by smoking-related pulmonary disease. However, exposure of children to environmental tobacco smoke increases their risk of PPCs, suggesting that even relatively low level exposure to smoke has clinical consequences.119 

Several mechanisms may contribute to perioperative risk. Excessive production of mucus itself seems to be a risk factor for pulmonary complications, independent of smoking status, such that smoking-induced bronchitis could be contributory.120,121The clinical impression of more “irritable” airways in smokers is supported by some but not all studies. The sensitivity of upper airway reflexes to chemical stimulants is increased in smokers.122,123Irritation of the airway by desflurane, manifested by increases in pulmonary resistance and coughing, is enhanced in smokers,124,125again suggesting sensitization of reflex responses to chemical irritants. However, pulmonary resistance measured after tracheal intubation is not different between smokers and nonsmokers, although smokers have impaired responses to bronchodilators.126Also, the frequency and amplitude of coughing in intubated patients during emergence from isoflurane anesthesia is not affected by smoking status.127Important elements of lung defenses against infection are impaired during anesthesia to a greater degree in smokers compared with nonsmokers. Bronchial mucus transport during general anesthesia is slowed in smokers compared with nonsmokers.128Prolonged anesthesia increases lung macrophage aggregation and decreases microbicidal activity in all patients, but these changes are markedly greater in smokers compared with nonsmokers.129,130 

Effects of Abstinence on Risk

Observational studies suggest that prolonged abstinence from smoking decreases the risk of many PPCs.105,110,111,116Only a few studies have attempted to define the duration of abstinence necessary for benefit. Two observational studies examined the frequency of PPCs (defined as the need for respiratory therapy that exceeded standard of care) in patients undergoing coronary artery bypass grafting. In a retrospective analysis,110the frequency of PPCs was not different between those who continued to smoke until surgery (48%) and those who quit within 8 weeks before surgery (56%). In contrast, the rate of PPCs was significantly less in smokers who quit more than 8 weeks before surgery (17%), a rate similar to that of nonsmokers (11%). A subsequent prospective study111of 192 patients confirmed these results, although the number of patients who were current smokers18and who had stopped within 8 weeks21was not sufficient to make statistical comparisons between these groups. In multivariate analysis, fewer smoke-free days was an independent predictor of PPCs. A logistic model based on this analysis suggested that at least 12 weeks of abstinence was needed for full benefit. It also suggested a small increase in the predicted rate of PPCs over the first month of abstinence, but again, this finding was based on a relatively small number of patients and could not be statistically evaluated. A recent study of PPCs in thoracic surgery patients attempted to correlate duration of abstinence with PPC frequency but was not sufficiently powered to perform meaningful univariate analysis comparing different durations of abstinence.114Another study of mostly males undergoing noncardiothoracic surgery116found that current smoking was a significant independent risk factor for PPCs (odds ratio, 4.2; 95% confidence interval, 1.2–14.8) but not past smoking (defined as > 2 weeks of abstinence; odds ratio, 1.9; 95% confidence interval, 0.5–6.5). However, in univariate analysis, reducing cigarette consumption (by an average of 34%) within the month before surgery in fact increased the risk of PPCs.

All of these studies were observational, and the possibility for selection bias is high.113In a general population of smokers, those with more severe disease, or those undergoing more extensive medical procedures, are more likely to quit smoking or reduce cigarette consumption.131,132Therefore, because the interval from scheduling to surgery is usually within weeks to months, characteristics of patients who are able to quit within a few weeks of surgery may differ in important ways from those who continue to smoke. Nonetheless, given that recovery of the lung from cigarette smoke apparently requires several weeks to months, it is plausible that a similar duration of time might be required before full benefit in reducing PPCs is observed. Consistent with this concept, Kotani et al.  133found that 6 months of abstinence was required before the response of selected pulmonary cytokines and alveolar macrophages to anesthesia and surgery was similar to that of nonsmokers. The risk profile over time may differ among individual PPCs. For example, increased sensitivity to upper airway stimulation by chemical irritants during anesthesia diminishes within only a few days of smoking abstinence.122 

Although further study is needed, current evidence suggests that in terms of reducing PPCs, the longer the duration of abstinence is, the better, at least within the first few months of cessation. The evidence suggesting an increase in risk during the first weeks of quitting is insufficient to support any recommendation that smokers not strive for preoperative abstinence, even if only for a brief period before surgery.105,116 

Perioperative Risk and Mechanism of Injury

Most (but not all) evidence supports the clinical impression that smokers are more likely to have development of postoperative wound-related complications, such as dehiscence and infection.113,134–143The risk seems to be greatest in wounds requiring wide surgical undermining, such as face-lifts.135Animal models also indicate that exposure to smoke increases wound-related complications,144–146although, of interest, not the viability of free flaps requiring vascular anastomoses.147–149 

Of the multiple mechanisms that could be responsible for impaired wound healing, factors decreasing tissue oxygenation, which is an important determinant of wound healing,150have attracted the most attention. Smoke constituents such as nicotine and carbon monoxide can decrease tissue oxygenation via  peripheral vasoconstriction and impaired carrying capacity of hemoglobin, respectively.151–154Survival of experimental skin flaps in animal models is impaired in animals receiving chronic nicotine,155–157albeit in doses that achieve plasma nicotine levels above those maintained in active smokers—and far above those in patients receiving NRT. At least 2 weeks of nicotine administration is required to observe deleterious effects,157suggesting that these effects are not caused by acute vasoconstriction. Several other factors could contribute to smoking-related wound complications. Smoke constituents could directly affect the function of cells such as fibroblasts and immune cells important to healing.158,159Most of these cells express nicotinic acetylcholine receptors,160making it possible that nicotine could directly inhibit cellular responses to injury,161–164although most studies use concentrations of nicotine that are far above those achieved in vivo . Recent studies suggest that the topical application of nicotine to wounds may in fact stimulate angiogenesis and accelerate wound healing.165–167Microvascular disease caused by smoking may also interfere with angiogenesis via  impaired release of substances such as nitric oxide that are important for wound repair.168–171Nicotine may modulate the neurogenic component of inflammatory response to tissue injury,172,173,via  direct effect on both peripheral and central neural mechanisms and indirect effects on sympathetic tone.174–178The clinical effects of these actions are uncertain because depending on the mode of administration (e.g. , location, acute vs.  chronic) and dose of nicotine used, nicotine can either increase or decrease indices of neurogenic inflammation.

The healing of bone may also be impaired in smokers. Smoking status is a risk factor for nonunion of spinal fusions,179–185especially when smoking is continued postoperatively, and the healing of fractures may be delayed.186–192Smoking has significant effects on bone metabolism and is a major risk factor for osteoporosis, which may itself contribute to impaired bone healing.193As is the case with wound healing, the components of smoke responsible for these effects are not known, but nicotine at relatively high concentrations significantly affects several measures of bone metabolism.194–200However, other studies have found little effect of nicotine alone on bone properties in experimental animals,201and studies of the effect of relatively high-dose nicotine on spinal fusions in animals have found effects on subjective but not objective measures of fusion.202–204 

Effects of Abstinence on Risk

Recent evidence suggests that preoperative smoking cessation can reduce wound-related complications. Møller et al.  137randomized smokers scheduled to undergo hip or knee replacement to a control or smoking intervention group. The latter received counseling and NRT, beginning 6–8 weeks preoperatively. Sixty-four percent of these patients were able to quit smoking (compared with only 8% in the control group), and a further 23% reduced their consumption. The relative risk for wound-related complications was dramatically reduced in the intervention group (by 83%). Sorensen et al.  205performed a series of punch biopsies in healthy volunteers and observed the rate of subsequent wound infection during a 2-week period. Three groups were examined: subjects who had never smoked, smokers who continued to smoke, and smokers who abstained. In smokers, the wound infection rate was 12%, compared with 2% in nonsmokers. Within 4 weeks of abstinence (the minimum period of abstinence studied), wound infection rates were similar in the abstinent smokers and the subjects who had never smoked. In another study, Sorensen et al.  206randomized patients scheduled to undergo colorectal surgery to receive a stop-smoking intervention approximately 2 weeks before surgery or no intervention. They found no difference in the frequency of postoperative wound-related complications. Interpretation of this finding is complicated by (1) the low numbers of subjects studied (approximately 30 in each group), (2) a relatively small difference between groups in the proportion of patients who self-reported preoperative abstinence, and (3) the fact that many patients in the control group also reduced their cigarette consumption postoperatively. In an observational study, Kuri et al.  207reported that prolonged abstinence reduced the rate of wound-related complications in patients undergoing head and neck surgery, but there were insufficient numbers of patients studied to determine whether shorter periods of abstinence were also beneficial. Therefore, the duration of preoperative abstinence needed for benefit remains undefined. To the extent that risk is mediated by the acute pharmacologic effects of smoke constituents such as nicotine and carbon monoxide, benefit should accrue relatively quickly after cessation. If changes in immune function or endothelial function are significant factors increasing risk, a longer period may be required for full benefit. Obviously, postoperative smoking behavior may also affect the risk of complications.

There is little information regarding how smoking cessation affects bone healing. The adverse effects of nicotine on spinal fusion rates in animal models are reversible when nicotine administration is discontinued 1 week before surgery.204In a retrospective observational study of patients undergoing spinal fusion, Glassman et al.  179found that the rate of nonunion was approximately twice as high in patients who continued smoking after surgery compared with never-smokers. For smokers who quit postoperatively, their nonunion rate approached that of the never-smokers. The ability to quit smoking preoperatively did not affect nonunion rates when considered as a univariate factor (i.e. , without considering postoperative smoking behavior), although those patients who were able to quit preoperatively were more likely to also maintain postoperative abstinence. Considering that many weeks are required for healing of spinal fusions,208it is not surprising that postoperative smoking behavior may be more important than preoperative behavior in determining outcome.

Risk of NRT to Wound Healing.

Clinical concerns have been raised regarding whether perioperative nicotine administration will itself contribute to the risks of wound-related complications. As reviewed in the earlier section, “Perioperative Risk and Mechanism of Injury,” the contribution of nicotine to the pathogenesis of wound-related complications is not clear. The doses of nicotine used in animal studies reviewed above produce plasma nicotine levels considerably in excess of those achieved by NRT, such that these studies do not provide useful information regarding the effects of NRT as clinically applied. Two experimental human studies are of relevance. Fulcher et al.  209examined microvascular responses to standardized cold challenge in chronic smokers before smoking cessation, and at 2 and 7 days after quitting and the institution of NRT with patches. During NRT and smoking cessation, microvascular responses were significantly improved compared with before cessation and in fact were similar to that of a control group of nonsmokers. This suggests either that other components of cigarette smoke were responsible for changes in microvascular function observed before quitting or that the dose of nicotine provided by NRT was not sufficient to affect these responses. The study of Sorensen et al.  205(reviewed above) showing that abstinence from smoking reduced the rate of wound infections in volunteers also included an experimental group of smokers that received NRT via  patches to help them maintain abstinence. The infection rate was not different between abstinent smokers who did or did not receive NRT. Therefore, the limited information currently suggests that NRT would not contribute to wound-related complications, although more evidence is needed. Certainly, NRT can decrease exposure to higher nicotine doses and other smoke constituents to the extent that it promotes abstinence, which is otherwise very difficult for smokers to achieve in the postoperative period.132 

Mechanisms of Action and Recovery

Cigarettes function as a means to rapidly deliver nicotine to the central nervous system (CNS). Nicotine activates several subtypes of nicotinic acetylcholine receptors (nAChRs), pentameric complexes of subunits that function as ligand-gated ion channels.210The actions of these receptors, which are ubiquitous in both central and peripheral nervous systems, on integrated neural function are incompletely understood.211Their predominant role in the CNS seems to be the modulation of neurotransmitter release.210Because nAChRs affect multiple neurotransmitter systems, the net effects of nicotine on CNS function are very complex. The psychoactive effects of nicotine (and several other addictive drugs) seem to be mediated in part via  activation of dopaminergic neurons with the ventral tegmental area, which project to the nucleus accumbens,212although other systems are certainly also involved.

Exposure to nicotine can induce feelings of reward and pleasure but also can produce unpleasant effects, especially in subjects naive to the drug. The development of tolerance to nicotine is a prominent characteristic of its actions.211Tolerance may arise from the rapid desensitization during continued nicotine exposure that is characteristic of several nicotinic receptor subtypes. Prolonged exposure to nicotine can also induce long-lasting plastic changes in CNS function. As a result of these changes, both humans and animal models have development of aversive withdrawal symptoms when nicotine intake is reduced or eliminated. Symptoms include both somatic complaints (e.g. , gastrointestinal symptoms, increased appetite) and affective symptoms (e.g. , craving for cigarettes, depressed mood, anxiety, dysphoria, irritability).213,214Prevention of these symptoms may be an important motivational factor in the maintenance of smoking behavior. They may be manifest within hours of abstinence from nicotine and may last for several weeks. The neurobiology of nicotine dependence and withdrawal is complex but probably involves multiple neurotransmitters, including dopamine, opioid peptides, glutamate, and serotonin, that mediate different aspects of withdrawal.211 

Of possible relevance to the perioperative period, neuronal nAChRs modulate pain. In animals, systemic nicotine produces a modest antinociceptive effect.215,216Other nicotinic agonists can have potent analgesic properties, albeit accompanied in many cases by unacceptable systemic toxicity.217Although activation of nAChRs on peripheral nerves produces pain,218,219application of nicotinic agonists to different sites in the central nervous system can have either pronociceptive or antinociceptive effects, depending on location and dose.220–222 

Perioperative Consequences

Several factors might affect the responses of smokers’ nervous systems to anesthesia and surgery, including (1) chronic CNS changes produced by prolonged exposure to smoke, (2) acute effects of nicotine or other smoke constituents still present from recent preoperative smoking, and (3) effects of nicotine withdrawal during abstinence from smoking. The importance of these factors in the perioperative period is only beginning to be explored. Clinically, two issues may be of importance: how smoking status affects requirements for anesthesia and analgesia and how nicotine withdrawal might affect recovery from surgery in abstinent smokers.

Neuronal nAChRs are inhibited by isoflurane and propofol at clinically relevant concentrations, raising the possibility that nicotine could affect anesthetic requirements.223The acute administration of nicotine (but not other nicotinic agonists) produces a small decrease in minimum alveolar concentration in mice.224It is not known whether smoking status affects minimum alveolar concentration in humans.

The effects of smoking on pain perception in humans are complex, and some of the findings of experimental studies are inconsistent.225–230In general, most studies find that smoking a cigarette increases both tolerance and threshold to painful stimulation. In one of the best controlled studies, Pauli et al.  231found that 12 h of smoking abstinence did not affect pain thresholds (to thermal stimulation) in males but that smoking a cigarette itself decreased pain thresholds in these abstinent smokers. Jamner et al.  232found that nicotine administered via  patch increased pain thresholds (to electrical stimulation) in male but not female subjects, both in smokers and in nonsmokers. Compared with nonsmokers, pain thresholds were increased in male smokers abstinent for 6 h but not in females.

Clinically, smoking is a risk factor for a number of painful conditions, including low back and musculoskeletal pain.233–235Increased requirements for postoperative opioids have been reported in smokers after coronary artery bypass grafting,236oral surgery,237and pelvic surgery.238In a general surgical population, smokers reported higher pain scores both before and after surgery but did not experience greater increases in pain postoperatively compared with nonsmokers,132although pain was only a secondary endpoint in this study. Intranasal nicotine administered at the end of surgery significantly reduces pain scores and analgesic requirements in nonsmokers.239Therefore, smoking status and nicotine could clearly affect perioperative pain, but more data are needed to establish the clinical relevance of these effects.

Many smokers view cigarettes as a stress management tool. Most studies suggest that smoking a cigarette reduces measures of stress, but this may simply represent self-medication for incipient nicotine withdrawal symptoms.240Nonetheless, abstinence from cigarettes could exacerbate stress engendered by the surgical experience itself. In a prospective observational study of a general surgical population, Warner et al.  132found that although smokers did report higher baseline levels of stress preoperatively, changes in stress over the perioperative period did not differ between smokers and a control group of nonsmokers. Nicotine withdrawal scores suggested that smokers did not consistently experience withdrawal symptoms in the immediate postoperative period, including patients highly dependent on nicotine preoperatively. Consistent with these results, a subsequent randomized clinical trial in smokers undergoing elective surgery could find no effect of active nicotine patches on stress or nicotine withdrawal compared with placebo patches, although nicotine did affect some aspects of postoperative smoking behavior.241These results may be consistent with previous studies showing that withdrawal symptoms may be lessened under stressful situations that demand forced abstinence, such as military training or prisons.242,243The finding that nicotine withdrawal symptoms may be minimal in the postoperative period suggests that this may be an excellent opportunity for smokers to attempt sustained abstinence.

Chronic exposure to cigarette smoke produces profound changes in the physiology of many organ systems, changes that may alter responses to perioperative interventions and contribute to perioperative morbidity. All smokers undergoing surgery are in various states of recovery from these effects, a process whose initial stages are incompletely understood. Better knowledge of this process would help perioperative physicians better define and manage this process. This is important in part because the perioperative period may present unique opportunities for smokers to attempt prolonged postoperative abstinence.113,132,244–252The potential of the surgical experience to serve as a “teachable moment” for smoking abstinence is only beginning to be explored.252,253A large body of evidence (mostly obtained in ambulatory settings) supports the efficacy of interventions to help smokers quit.254Although more work is necessary to adapt, validate, and disseminate these methods in the perioperative setting (as reviewed elsewhere251,252), the evidence presented in this article suggests at least two general principles that can inform approaches to perioperative smoking interventions.

First, although smokers have development of surprisingly few symptoms of nicotine withdrawal during the first few days after surgery in this setting of forced abstinence, most quickly relapse to smoking in the absence of treatment.132,241NRT has proven to be both safe and effective in treating tobacco dependence, even in patients with smoking-related diseases.254Although more study is needed, available evidence suggests that it may also be safe and effective in the perioperative period241,248,255and should be considered a useful tool in surgical patients. There is little doubt that the use of NRT in this setting is far preferable to continued smoking.

Second, regarding the timing of preoperative smoking cessation, it is likely that the longer the duration of preoperative abstinence is, the better, especially with regard to pulmonary complications. However, there is no evidence that brief preoperative abstinence is harmful; rather, it may be beneficial for some outcomes. Postoperative abstinence may also have benefit for some outcomes, even if preoperative abstinence is not achieved. Therefore, although interventions should target smokers at the earliest opportunity (e.g. , the time of surgical scheduling), those not able to maintain preoperative abstinence should not be ignored as opportune subjects for interventions at any time in the perioperative period. Sustained abstinence produces tremendous benefits to the long-term health of the surgical patient (or anyone) who smokes; this consideration alone provides sufficient justification for concerted efforts to help these patients quit.132,241 

1.
Centers for Disease Control and Prevention: Cigarette smoking among adults—United States, 2000. MMWR Morb Mortal Wkly Rep 2002; 51:642–3
Centers for Disease Control and Prevention
2.
Jousilahti P, Vartiainen E, Korhonen HJ, Puska P, Tuomilehto J: Is the effect of smoking on the risk for coronary heart disease even stronger than was previously thought? J Cardiovasc Risk 1999; 6:293–8
3.
Pickering TG, Schwartz JE, James GD: Ambulatory blood pressure monitoring for evaluating the relationships between lifestyle, hypertension and cardiovascular risk. Clin Exp Pharmacol Physiol 1995; 22:226–31
4.
Benowitz NL, Gourlay SG: Cardiovascular toxicity of nicotine: Implications for nicotine replacement therapy. J Am Coll Cardiol 1997; 29:1422–31
5.
Cryer PE, Haymond MW, Santiago JV, Shah SD: Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. N Engl J Med 1976; 295:573–7
6.
Klein LW, Ambrose J, Pichard A, Holt J, Gorlin R, Teichholz LE: Acute coronary hemodynamic response to cigarette smoking in patients with coronary artery disease. J Am Coll Cardiol 1984; 3:879–86
7.
Narkiewicz K, van de Born PJ, Hausberg M, Cooley RL, Winniford MD, Davison DE, Somers VK: Cigarette smoking increases sympathetic outflow in humans. Circulation 1998; 98:528–34
8.
Gilbert DD: Chemical analyses as validators in smoking cessation programs. J Behav Med 1993; 16:295–308
9.
Rietbrock N, Kunkel S, Worner W, Eyer P: Oxygen-dissociation kinetics in the blood of smokers and non-smokers: Interaction between oxygen and carbon monoxide at the hemoglobin molecule. Naunyn Schmiedebergs Arch Pharmacol 1992; 345:123–8
10.
Allred EN, Bleecker ER, Chaitman BR, Dahms TE, Gottlieb SO, Hackney JD, Pagano M, Selvester RH, Walden SM, Warren J: Short-term effects of carbon monoxide exposure on the exercise performance of subjects with coronary artery disease. N Engl J Med 1989; 321:1426–32
11.
Aronow WS, Cassidy J, Vangrow JS, March H, Kern JC, Goldsmith JR, Khemka M, Pagano J, Vawter M: Effect of cigarette smoking and breathing carbon monoxide on cardiovascular hemodynamics in anginal patients. Circulation 1974; 50:340–7
12.
Adams KF, Koch G, Chatterjee B, Goldstein GM, O’Nei JJ, Bromberg PA, Sheps DS: Acute elevation of blood carboxyhemoglobin to 6% impairs exercise performance and aggravates symptoms in patients with ischemic heart disease. J Am Coll Cardiol 1988; 12:900–9
13.
Sheps DS, Herbst MC, Hinderliter AL, Adams KF, Ekelund LG, O’Nei JJ, Goldstein GM, Bromberg PA, Dalton JL, Ballenger MN: Production of arrhythmias by elevated carboxyhemoglobin in patients with coronary artery disease. Ann Intern Med 1990; 113:343–51
14.
Ryter SW, Otterbein LE: Carbon monoxide in biology and medicine. Bioessays 2004; 26:270–80
15.
Goldbaum LR, Ramirez RG, Absalon KB: What is the mechanism of carbon monoxide toxicity? Aviat Space Environ Med 1975; 46:1289–91
16.
Lundquist P, Rosling H, Sorbo B, Tibbling L: Cyanide concentrations in blood after cigarette smoking, as determined by a sensitive fluorometric method. Clin Chem 1987; 33:1228–30
17.
Pittilo RM: Cigarette smoking and endothelial injury: A review. Adv Exp Med Biol 1990; 273:61–78
18.
Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE: Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993; 88:2149–55
19.
Neunteufl T, Heher S, Kostner K, Mitulovic G, Lehr S, Khoschsorur G, Schmid RW, Maurer G, Stefenelli T: Contribution of nicotine to acute endothelial dysfunction in long-term smokers. J Am Col Cardiol 2002; 39:251–6
20.
Pellaton C, Kubli S, Feihl F, Waeber B: Blunted vasodilatory responses in the cutaneous microcirculation of cigarette smokers. Am Heart J 2002; 144:269–74
21.
Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE: Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 1996; 334:150–4
22.
Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts LJ II: Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers: Smoking as a cause of oxidative damage. N Engl J Med 1995; 332:1198–203
23.
FitzGerald GA, Oates JA, Nowak J: Cigarette smoking and hemostatic function. Am Heart J 1988; 115:267–71
24.
Craig WY, Palomaki GE, Haddow JE: Cigarette smoking and serum lipid and lipoprotein concentrations: An analysis of published data. BMJ 1989; 298:784–8
25.
Harats D, Ben-Naim M, Dabach Y, Hollander G, Stein O, Stein Y: Cigarette smoking renders LDL susceptible to peroxidative modification and enhanced metabolism by macrophages. Atherosclerosis 1989; 79:245–52
26.
Koethe SM, Kuhnmuench JR, Becker CG: Neutrophil priming by cigarette smoke condensate and a tobacco anti-idiotypic antibody. Am J Pathol 2000; 157:1735–43
27.
Critchley JA, Capewell S: Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: A systematic review. JAMA 2003; 290:86–97
28.
Lightwood JM, Glantz SA: Short-term economic and health benefits of smoking cessation: Myocardial infarction and stroke. Circulation 1997; 96:1089–96
29.
Kambam JR, Chen LH, Hyman SA: Effect of short-term smoking halt on carboxyhemoglobin levels and P50 values. Anesth Analg 1986; 65:1186–8
30.
Zevin S, Gourlay SG, Benowitz NL: Clinical pharmacology of nicotine. Clin Dermatol 1998; 16:557–64
31.
Hirsch GL, Sue DY, Wasserman K, Robinson TE, Hansen JE: Immediate effects of cigarette smoking on cardiorespiratory responses to exercise. J Appl Physiol 1985; 58:1975–81
32.
Albrecht AE, Marcus BH, Roberts M, Forman DE, Parisi AF: Effect of smoking cessation on exercise performance in female smokers participating in exercise training. Am J Cardiol 1998; 82:950–5
33.
Klausen K, Andersen C, Nandrup S: Acute effects of cigarette smoking and inhalation of carbon monoxide during maximal exercise. Eur J Appl Physiol Occup Physiol 1983; 51:371–9
34.
Sarabi M, Lind L: Short-term effects of smoking and nicotine chewing gum on endothelium-dependent vasodilation in young healthy habitual smokers. J Cardiovasc Pharmacol 2000; 35:451–6
35.
Anderson ME, Belani KG: Short-term preoperative smoking abstinence. Am Fam Physician 1990; 41:1191–4
36.
Goldman L, Caldera DL, Nussbaum SR, Southwick FS, Krogstad D, Murray B, Burke DS, O’Malle TA, Goroll AH, Caplan CH, Nolan J, Carabello B, Slater EE: Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977; 297:845–50
37.
Gedebou TM, Barr ST, Hunter G, Sinha R, Rappaport W, VillaReal K: Risk factors in patients undergoing major nonvascular abdominal operations that predict perioperative myocardial infarction. Am J Surg 1997; 174:755–8
38.
Woehlck HJ, Connolly LA, Cinquegrani MP, Dunning MB III, Hoffmann RG: Acute smoking increases ST depression in humans during general anesthesia. Anesth Analg 1999; 89:856–60
39.
Utley JR, Leyland SA, Fogarty CM, Smith WP, Knight EB, Feldman GJ, Wilde EF: Smoking is not a predictor of mortality and morbidity following coronary artery bypass grafting. J Card Surg 1996; 11:377–84
40.
He GW, Acuff TE, Ryan WH, Mack MJ: Risk factors for operative mortality in elderly patients undergoing internal mammary artery grafting. Ann Thorac Surg 1994; 57:1453–60
41.
Hollenberg M, Mangano DT, Browner WS, London MJ, Tubau JF, Tateo IM: Predictors of postoperative myocardial ischemia in patients undergoing noncardiac surgery. The Study of Perioperative Ischemia Research Group. JAMA 1992; 268:205–9
42.
Foster ED, Davis KB, Carpenter JA, Abele S, Fray D: Risk of noncardiac operation in patients with defined coronary disease: The Coronary Artery Surgery Study (CASS) registry experience. Ann Thorac Surg 1986; 41:42–50
43.
Mangano DT, Goldman L: Preoperative assessment of patients with known or suspected coronary disease. N Engl J Med 1995; 333:1750–6
44.
van Domburg RT, Meeter K, van Berkel DF, Veldkamp RF, van Herwerden LA, Bogers AJ: Smoking cessation reduces mortality after coronary artery bypass surgery: A 20-year follow-up study. J Am Col Cardiol 2000; 36:878–83
45.
Voors AA, van Brussel BL, Plokker HW, Ernst SM, Ernst NM, Koomen EM, Tijssen JG, Vermeulen FE: Smoking and cardiac events after venous coronary bypass surgery: A 15-year follow-up study. Circulation 1996; 93:42–7
46.
Clouse WD, Yamaguchi H, Phillips MR, Hurt RD, Fitzpatrick LA, Moyer TP, Rowland C, Schaff HV, Miller VM: Effects of transdermal nicotine treatment on structure and function of coronary artery bypass grafts. J Appl Physiol 2000; 89:1213–23
47.
Blann AD, Steele C, McCollum CN: The influence of smoking and of oral and transdermal nicotine on blood pressure, and haematology and coagulation indices. Thromb Haemost 1997; 78:1093–6
48.
Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q: Nicotine effects on eicosanoid formation and hemostatic function: Comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol 1993; 22:1159–67
49.
Nowak J, Andersson K, Benthin G, Chen J, Karlberg KE, Sylven C: Effect of nicotine infusion in humans on platelet aggregation and urinary excretion of a major thromboxane metabolite. Acta Physiol Scand 1996; 157:101–7
50.
Khoury Z, Comans P, Keren A, Lerer T, Gavish A, Tzivoni D: Effects of transdermal nicotine patches on ambulatory ECG monitoring findings: A double-blind study in healthy smokers. Cardiovasc Drugs Ther 1996; 10:179–84
51.
Zevin S, Jacob P III, Benowitz NL: Dose-related cardiovascular and endocrine effects of transdermal nicotine. Clin Pharmacol Ther 1998; 64:87–95
52.
Keeley EC, Pirwitz MJ, Landau C, Lange RA, Hillis LD, Foerster EH, Conrad K, Willard JE: Intranasal nicotine spray does not augment the adverse effects of cigarette smoking on myocardial oxygen demand or coronary arterial dimensions. Am J Med 1996; 101:357–63
53.
McPhail I, Boston U, Hurt RD, Miller VM: Mechanisms of cardiovascular effects of nicotine. Curr Top Pharmacol 1998; 4:265–80
54.
Greenland S, Satterfield MH, Lanes SF: A meta-analysis to assess the incidence of adverse effects associated with the transdermal nicotine patch. Drug Saf 1998; 18:297–308
55.
Joseph AM, Norman SM, Ferry LH, Prochazka AV, Westman EC, Steele BG, Sherman SE, Cleveland M, Antonnucio DO, Hartman N, McGovern PG: The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 1996; 335:1792–8
56.
Tzivoni D, Keren A, Meyler S, Khoury Z, Lerer T, Brunel P: Cardiovascular safety of transdermal nicotine patches in patients with coronary artery disease who try to quit smoking. Cardiovasc Drugs Ther 1998; 12:239–44
57.
Mahmarian JJ, Moye LA, Nasser GA, Nagueh SF, Bloom MF, Benowitz NL, Verani MS, Byrd WG, Pratt CM: Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia. J Am Coll Cardiol 1997; 30:125–30
58.
Netscher DT, Wigoda P, Thornby J, Yip B, Rappaport NH: The hemodynamic and hematologic effects of cigarette smoking versus a nicotine patch. Plast Reconstr Surg 1995; 96:681–8
59.
Foulds J, Stapleton J, Feyerabend C, Vesey C, Jarvis M, Russell MA: Effect of transdermal nicotine patches on cigarette smoking: A double blind crossover study. Psychopharmacology 1992; 106:421–7
60.
Puura A: Transdermal nicotine increases heart rate after endotracheal intubation. Methods Find Exp Clin Pharmacol 2003; 25:383–5
61.
Barnes PJ: Chronic obstructive pulmonary disease. N Engl J Med 2000; 343:269–80
62.
Siafakas NM, Vermeire P, Pride NB, Paoletti P, Gibson J, Howard P, Yernault JC, Decramer M, Higenbottam T, Postma DS: Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Resp J 1995; 8:1398–420
63.
Niewoehner DE, Kleinerman J, Rice DB: Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974; 291:755–8
64.
Holt PG: Immune and inflammatory function in cigarette smokers. Thorax 1987; 42:241–9
65.
Rahman I, MacNee W: Role of oxidants/antioxidants in smoking-induced lung diseases. Free Radic Biol Med 1996; 21:669–81
66.
Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, Mapp CE, Fabbri LM, Donner CF, Saetta M: Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998; 158:1277–85
67.
Lee LY, Hong JL: Involvement of prostanoids in cigarette smoking-induced pathophysiological effects in the lung. Prostaglandins Leukot Essent Fatty Acids 1999; 61:145–55
68.
Johnson JD, Houchens DP, Kluwe WM, Craig DK, Fisher GL: Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans: A review. Crit Rev Toxicol 1990; 20:369–95
69.
Skold CM, Lundahl J, Hallden G, Hallgren M, Eklund A: Chronic smoke exposure alters the phenotype pattern and the metabolic response in human alveolar macrophages. Clin Exp Immunol 1996; 106:108–13
70.
Dandrea T, Tu B, Blomberg A, Sandstrom T, Skold M, Eklund A, Cotgreave I: Differential inhibition of inflammatory cytokine release from cultured alveolar macrophages from smokers and non-smokers by NO2. Hum Exp Toxicol 1997; 16:577–88
71.
Schaberg T, Klein U, Rau M, Eller J, Lode H: Subpopulations of alveolar macrophages in smokers and nonsmokers: Relation to the expression of CD11/CD18 molecules and superoxide anion production. Am J Respir Crit Care Med 1995; 151:1551–8
72.
Lensmar C, Elmberger G, Skold M, Eklund A: Smoking alters the phenotype of macrophages in induced sputum. Respir Med 1998; 92:415–20
73.
Matsunaga K, Klein TW, Friedman H, Yamamoto Y: Involvement of nicotinic acetylcholine receptors in suppression of antimicrobial activity and cytokine responses of alveolar macrophages to Legionella pneumophila infection by nicotine. J Immunol 2001; 167:6518–24
74.
Saetta M, Turato G, Baraldo S, Zanin A, Braccioni F, Mapp CE, Maestrelli P, Cavallesco G, Papi A, Fabbri LM: Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 2000; 161:1016–21
75.
Goodman RM, Yergin BM, Landa JF, Golivanux MH, Sackner MA: Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis. Am Rev Respir Dis 1978; 117:205–14
76.
Foster WM, Langenback EG, Bergofsky EH: Disassociation in the mucociliary function of central and peripheral airways of asymptomatic smokers. Am Rev Respir Dis 1985; 132:633–9
77.
Verra F, Escudier E, Lebargy F, Bernaudin JF, De Cremoux H, Bignon J: Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers. Am J Respir Crit Care Med 1995; 151:630–4
78.
Thomson ML, Pavia D: Long-term tobacco smoking and mucociliary clearance from the human lung in health and respiratory impairment. Arch Environ Health 1973; 26:86–9
79.
Bennett WD, Chapman WF, Gerrity TR: Ineffectiveness of cough for enhancing mucus clearance in asymptomatic smokers. Chest 1992; 102:412–6
80.
Maestrelli P, Saetta M, Mapp CE, Fabbri LM: Remodeling in response to infection and injury: Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164:S76–80
81.
Zayas JG, Man GC, King M: Tracheal mucus rheology in patients undergoing diagnostic bronchoscopy: Interrelations with smoking and cancer. Am Rev Respir Dis 1990; 141:1107–13
82.
Saetta M, Finkelstein R, Cosio MG: Morphological and cellular basis for airflow limitation in smokers. Eur Respir J 1994; 7:1505–15
83.
Lange P, Groth S, Nyboe GJ, Mortensen J, Appleyard M, Jensen G, Schnohr P: Effects of smoking and changes in smoking habits on the decline of FEV1. Eur Respir J 1989; 2:811–6
84.
Willemse BW, Postma DS, Timens W, ten Hacken NH: The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation. Eur Respir J 2004; 23:464–76
85.
Schmidt D, Jorres RA, Magnussen H: Citric acid-induced cough thresholds in normal subjects, patients with bronchial asthma, and smokers. Eur J Med Res 1997; 2:384–8
86.
Dicpinigaitis PV: Cough reflex sensitivity in cigarette smokers. Chest 2003; 123:685–8
87.
Millqvist E, Bende M: Capsaicin cough sensitivity is decreased in smokers. Respir Med 2001; 95:19–21
88.
Bergren DR: Chronic tobacco smoke exposure increases cough to capsaicin in awake guinea pigs. Respir Physiol 2001; 126:127–40
89.
Kwong K, Wu ZX, Kashon ML, Krajnak KM, Wise PM, Lee LY: Chronic smoking enhances tachykinin synthesis and airway responsiveness in guinea pigs. Am J Respir Cell Mol Biol 2001; 25:299–305
90.
Wilhelmsen L: Effects on bronchopulmonary symptoms, ventilation, and lung mechanics of abstinence from tobacco smoking. Scand J Respir Dis 1967; 48:407–14
91.
Friedman GD, Siegelaub AB: Changes after quitting cigarette smoking. Circulation 1980; 61:716–23
92.
Kanner RE: Early intervention in chronic obstructive pulmonary disease: A review of the Lung Health Study results. Med Clin North Am 1996; 80:523–47
93.
Vastag E, Matthys H, Kohler D, Gronbeck L, Daikeler G: Mucociliary clearance and airways obstruction in smokers, ex-smokers and normal subjects who never smoked. Eur J Respir Dis Suppl 1985; 139:93–100
94.
Camner P, Philipson K, Arvidsson T: Withdrawal of cigarette smoking: A study on tracheobronchial clearance. Arch Environ Health 1973; 26:90–2
95.
Wright JL, Hobson JE, Wiggs B, Pare PD, Hogg JC: Airway inflammation and peribronchiolar attachments in the lungs of nonsmokers, current and ex-smokers. Lung 1988; 166:277–86
96.
Ussher M, West R, Steptoe A, McEwen A: Increase in common cold symptoms and mouth ulcers following smoking cessation. Tobacco Control 2003; 12:86–8
97.
Camner P, Mossberg B, Philipson K: Tracheobronchial clearance and chronic obstructive lung disease. Scand J Resp Dis 1973; 54:272–81
98.
Swan GE, Hodgkin JE, Roby T, Mittman C, Jacobo N, Peters J: Reversibility of airways injury over a 12-month period following smoking cessation. Chest 1992; 101:607–12
99.
Skold CM, Forslid J, Eklund A, Hed J: Metabolic activity in human alveolar macrophages increases after cessation of smoking. Inflammation 1993; 17:345–52
100.
Skold CM, Hed J, Eklund A: Smoking cessation rapidly reduces cell recovery in bronchoalveolar lavage fluid, while alveolar macrophage fluorescence remains high. Chest 1992; 101:989–95
101.
Mili F, Flanders WD, Boring JR, Annest JL, Destefano F: The associations of race, cigarette smoking, and smoking cessation to measures of the immune system in middle-aged men. Clin Immunol Immunopathol 1991; 59:187–200
102.
Schwilk B, Bothner U, Schraag S, Georgieff M: Perioperative respiratory events in smokers and nonsmokers undergoing general anaesthesia. Acta Anaesthesiol Scand 1997; 41:348–55
103.
Poe RH, Kallay MC, Dass T, Celebic A: Can postoperative pulmonary complications after elective cholecystectomy be predicted? Am J Med Sci 1988; 295:29–34
104.
Morton HJV: Tobacco smoking and pulmonary complications after operation. Lancet 1944; 1:368–70
105.
Moores LK: Smoking and postoperative pulmonary complications: An evidence-based review of the recent literature. Clin Chest Med 2000; 21:139–46
106.
Svensson LG, Hess KR, Coselli JS, Safi HJ, Crawford ES: A prospective study of respiratory failure after high-risk surgery on the thoracoabdominal aorta. J Vasc Surg 1991; 14:271–82
107.
Moller AM, Maaloe R, Pedersen T: Postoperative intensive care admittance: The role of tobacco smoking. Acta Anaesthesiol Scand 2001; 45:345–8
108.
Dilworth JP, White RJ: Postoperative chest infection after upper abdominal surgery: An important problem for smokers. Respir Med 1992; 86:205–10
109.
Dennis A, Curran J, Sherriff J, Kinnear W: Effects of passive and active smoking on induction of anaesthesia. Br J Anaesth 1994; 73:450–2
110.
Warner MA, Divertie MB, Tinker JH: Preoperative cessation of smoking and pulmonary complications in coronary artery bypass patients. Anesthesiology 1984; 60:380–3
111.
Warner MA, Offord KP, Warner ME, Lennon RL, Conover MA, Jansson-Schumacher U: Role of preoperative cessation of smoking and other factors in postoperative pulmonary complications: A blinded prospective study of coronary artery bypass patients. Mayo Clin Proc 1989; 64:609–16
112.
Forrest JB, Rehder K, Cahalan MK, Goldsmith CH: Multicenter study of general anesthesia: III. Predictors of severe perioperative adverse outcomes. Anesthesiology 1992; 76:3–15
113.
Myles PS, Iacono GA, Hunt JO, Fletcher H, Morris J, McIlroy D, Fritschi L: Risk of respiratory complications and wound infection in patients undergoing ambulatory surgery: Smokers versus  nonsmokers. Anesthesiology 2002; 97:842–7
114.
Nakagawa M, Tanaka H, Tsukuma H, Kishi Y: Relationship between the duration of the preoperative smoke-free period and the incidence of postoperative pulmonary complications after pulmonary surgery. Chest 2001; 120:705–10
115.
Brooks-Brunn JA: Predictors of postoperative pulmonary complications following abdominal surgery. Chest 1997; 111:564–71
116.
Bluman LG, Mosca L, Newman N, Simon DG: Preoperative smoking habits and postoperative pulmonary complications. Chest 1998; 113:883–9
117.
Wong DH, Weber EC, Schell MJ, Wong AB, Anderson CT, Barker SJ: Factors associated with postoperative pulmonary complications in patients with severe chronic obstructive pulmonary disease. Anesth Analg 1995; 80:276–84
118.
Brooks-Brunn JA: Validation of a predictive model for postoperative pulmonary complications. Heart Lung 1998; 27:151–8
119.
Skolnick ET, Vomvolakis MA, Buck KA, Mannino SF, Sun LS: Exposure to environmental tobacco smoke and the risk of adverse respiratory events in children receiving general anesthesia. Anesthesiology 1998; 88:1144–53
120.
Mitchell CK, Smoger SH, Pfeifer MP, Vogel RL, Pandit MK, Donnelly PJ, Garrison RN, Rothschild MA: Multivariate analysis of factors associated with postoperative pulmonary complications following general elective surgery. Arch Surg 1998; 133:194–8
121.
Barisione G, Rovida S, Gazzaniga GM, Fontana L: Upper abdominal surgery: Does a lung function test exist to predict early severe postoperative respiratory complications? Eur Resp J 1997; 10:1301–8
122.
Erskine RJ, Murphy PJ, Langton JA: Sensitivity of upper airway reflexes in cigarette smokers: Effect of abstinence. Br J Anaesth 1994; 73:298–302
123.
Langton JA, Murphy PJ, Barker P, Key A, Smith G: Measurement of the sensitivity of upper airway reflexes. Br J Anaesth 1993; 70:126–30
124.
Wilkes AR, Hall JE, Wright E, Grundler S: The effect of humidification and smoking habit on the incidence of adverse airway events during deepening of anaesthesia with desflurane. Anaesthesia 2000; 55:685–9
125.
Goff MJ, Arain SR, Ficke DJ, Uhrich TD, Ebert TJ: Absence of bronchodilation during desflurane anesthesia: A comparison to sevoflurane and thiopental. Anesthesiology 2000; 93:404–8
126.
Kil HK, Rooke GA, Ryan-Dykes MA, Bishop MJ: Effect of prophylactic bronchodilator treatment on lung resistance after tracheal intubation. Anesthesiology 1994; 81:43–8
127.
Kim ES, Bishop MJ: Cough during emergence from isoflurane anesthesia. Anesth Analg 1998; 87:1170–4
128.
Konrad FX, Schreiber T, Brecht-Kraus D, Georgieff M: Bronchial mucus transport in chronic smokers and nonsmokers during general anesthesia. J Clin Anesth 1993; 5:375–80
129.
Kotani N, Hashimoto H, Sessler DI, Yoshida H, Kimura N, Okawa H, Muraoka M, Matsuki A: Smoking decreases alveolar macrophage function during anesthesia and surgery. Anesthesiology 2000; 92:1268–77
130.
Kotani N, Hashimoto H, Sessler DI, Yatsu Y, Muraoka M, Matsuki A: Exposure to cigarette smoke impairs alveolar macrophage functions during halothane and isoflurane anesthesia in rats. Anesthesiology 1999; 91:1823–33
131.
Crouse JRD, Hagaman AP: Smoking cessation in relation to cardiac procedures. Am J Epidemiol 1991; 134:699–703
132.
Warner DO, Patten CA, Ames SC, Offord K, Schroeder D: Smoking behavior and perceived stress in cigarette smokers undergoing elective surgery. Anesthesiology 2004; 100:1125–37
133.
Kotani N, Kushikata T, Hashimoto H, Sessler DI, Muraoka M, Matsuki A: Recovery of intraoperative microbicidal and inflammatory functions of alveolar immune cells after a tobacco smoke-free period. Anesthesiology 2001; 94:999–1006
134.
Fawcett A, Shembekar M, Church JS, Vashisht R, Springall RG, Nott DM: Smoking, hypertension, and colonic anastomotic healing; a combined clinical and histopathological study. Gut 1996; 38:714–8
135.
Chang LD, Buncke G, Slezak S, Buncke HJ: Cigarette smoking, plastic surgery, and microsurgery. J Reconstr Microsurg 1996; 12:467–74
136.
Moller AM, Pedersen T, Villebro N, Munksgaard A: Effect of smoking on early complications after elective orthopaedic surgery. J Bone Joint Surg Br 2003; 85:178–81
137.
Moller AM, Villebro N, Pedersen T, Tonnesen H: Effect of preoperative smoking intervention on postoperative complications: A randomised clinical trial. Lancet 2002; 359:114–7
138.
Sorensen LT, Horby J, Friis E, Pilsgaard B, Jorgensen T: Smoking as a risk factor for wound healing and infection in breast cancer surgery. Eur J Surg Oncol 2002; 28:815–20
139.
Silverstein P: Smoking and wound healing. Am J Med 1992; 93:22S–4S
140.
Arnez ZM, Bajec J, Bardsley AF, Scamp T, Webster MH: Experience with 50 free TRAM flap breast reconstructions. Plast Reconstr Surg 1991; 87:470–8
141.
Goldminz D, Bennett RG: Cigarette smoking and flap and full-thickness graft necrosis. Arch Dermatol 1991; 127:1012–5
142.
Kurz A, Sessler DI, Lenhardt R: Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med 1996; 334:1209–15
143.
Greif R, Akca O, Horn EP, Kurz A, Sessler DI: Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. N Engl J Med 2000; 342:161–7
144.
Kaufman T, Eichenlaub EH, Levin M, Hurwitz DJ, Klain M: Tobacco smoking: Impairment of experimental flap survival. Ann Plast Surg 1984; 13:468–72
145.
Craig S, Rees TD: The effects of smoking on experimental skin flaps in hamsters. Plast Reconstr Surg 1985; 75:842–6
146.
Lawrence WT, Murphy RC, Robson MC, Heggers JP: The detrimental effect of cigarette smoking on flap survival: An experimental study in the rat. Br J Plast Surg 1984; 37:216–9
147.
Khouri RK, Cooley BC, Kunselman AR, Landis JR, Yeramian P, Ingram D, Natarajan N, Benes CO, Wallemark C: A prospective study of microvascular free-flap surgery and outcome. Plast Reconstr Surg 1998; 102:711–21
148.
Yaffe B, Cushin BJ, Strauch B: Effect of cigarette smoking on experimental microvascular anastomoses. Microsurgery 1984; 5:70–2
149.
Rao VK, Morrison WA, O’Brien BM: Effect of nicotine on blood flow and patency of experimental microvascular anastomosis. Ann Plast Surg 1983; 11:206–9
150.
Hopf HW, Hunt TK, West JM, Blomquist P, Goodson WH III, Jense JA, Jonsson K, Paty PB, Rabkin JM, Upton RA, von Smitten K, Whitney JD: Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg 1997; 132:997–1004
151.
Jensen JA, Goodson WH, Hopf HW, Hunt TK: Cigarette smoking decreases tissue oxygen. Arch Surg 1991; 126:1131–4
152.
Evans WF, Stewart HJ: Effect of smoking cigarets on the peripheral blood flow. Am Heart J 1943; 26:79–91
153.
Monfrecola G, Riccio G, Savarese C, Posteraro G, Procaccini EM: The acute effect of smoking on cutaneous microcirculation blood flow in habitual smokers and nonsmokers. Dermatology 1998; 197:115–8
154.
Richardson D: Effects of tobacco smoke inhalation on capillary blood flow in human skin. Arch Environ Health 1987; 42:19–25
155.
Forrest CR, Xu N, Pang CY: Evidence for nicotine-induced skin flap ischemic necrosis in the pig. Can J Physiol Pharmacol 1994; 72:30–8
156.
Forrest CR, Pang CY, Lindsay WK: Pathogenesis of ischemic necrosis in random-pattern skin flaps induced by long-term low-dose nicotine treatment in the rat. Plast Reconstr Surg 1991; 87:518–28
157.
Forrest CR, Pang CY, Lindsay WK: Dose and time effects of nicotine treatment on the capillary blood flow and viability of random pattern skin flaps in the rat. Br J Plast Surg 1987; 40:295–9
158.
McAllister-Sistilli CG, Caggiula AR, Knopf S, Rose CA, Miller AL, Donny EC: The effects of nicotine on the immune system. Psychoneuroendocrinology 1998; 23:175–87
159.
Goodson WH III, Hunt TK: Wound healing and the diabetic patient. Surg Gynecol Obstet 1979; 149:600–8
160.
Conti-Fine BM, Navaneetham D, Lei S, Maus AD: Neuronal nicotinic receptors in non-neuronal cells: New mediators of tobacco toxicity? Eur J Pharmacol 2000; 393:279–94
161.
Lahmouzi J, Simain-Sato F, Defresne MP, De Pauw MC, Heinen E, Grisar T, Legros JJ, Legrand R: Effect of nicotine on rat gingival fibroblasts in vitro. Connect Tissue Res 2000; 41:69–80
162.
Tipton DA, Dabbous MK: Effects of nicotine on proliferation and extracellular matrix production of human gingival fibroblasts in vitro. J Periodontol 1995; 66:1056–64
163.
Jorgensen LN, Kallehave F, Christensen E, Siana JE, Gottrup F: Less collagen production in smokers. Surgery 1998; 123:450–5
164.
James JA, Sayers NM, Drucker DB, Hull PS: Effects of tobacco products on the attachment and growth of periodontal ligament fibroblasts. J Periodontol 1999; 70:518–25
165.
Cooke JP, Bitterman H: Nicotine and angiogenesis: A new paradigm for tobacco-related diseases. Ann Med 2004; 36:33–40
166.
Heeschen C, Weis M, Cooke JP: Nicotine promotes arteriogenesis. J Am Coll Cardiol 2003; 41:489–96
167.
Jacobi J, Jang JJ, Sundram U, Dayoub H, Fajardo LF, Cooke JP: Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice. Am J Pathol 2002; 161:97–104
168.
Lee PC, Salyapongse AN, Bragdon GA, Shears LL II, Watkins, SC, Edington HD, Billiar TR: Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol 1999; 277:H1600–8
169.
Hashimoto H: Impaired microvascular vasodilator reserve in chronic cigarette smokers: A study of post-occlusive reactive hyperemia in the human finger. Jpn Circ J 1994; 58:29–33
170.
Klede M, Clough G, Lischetzki G, Schmelz M: The effect of the nitric oxide synthase inhibitor N-nitro-L-arginine-methyl ester on neuropeptide-induced vasodilation and protein extravasation in human skin. J Vasc Res 2003; 40:105–14
171.
Sarabi M, Lind L: Short-term effects of smoking and nicotine chewing gum on endothelium-dependent vasodilation in young healthy habitual smokers. J Cardiovasc Pharmacol 2000; 35:451–6
172.
Schaffer M, Beiter T, Becker HD, Hunt TK: Neuropeptides: Mediators of inflammation and tissue repair? Arch Surg 1998; 133:1107–16
173.
Smith PG, Liu M: Impaired cutaneous wound healing after sensory denervation in developing rats: Effects on cell proliferation and apoptosis. Cell Tis Res 2002; 307:281–91
174.
Miao FJ, Green P, Benowitz N, Levine JD: Vagal modulation of spinal nicotine-induced inhibition of the inflammatory response mediated by descending antinociceptive controls. Neuropharmacology 2003; 45:605–11
175.
Miao FJ, Green PG, Benowitz N, Levine JD: Central terminals of nociceptors are targets for nicotine suppression of inflammation. Neuroscience 2004; 123:777–84
176.
Miao FJ, Janig W, Green PG, Levine JD: Inhibition of bradykinin-induced synovial plasma extravasation produced by intrathecal nicotine is mediated by the hypothalamopituitary adrenal axis. J Neurophysiol 1996; 76:2813–21
177.
Miao FJ, Benowitz NL, Levine JD: Endogenous opioids suppress activation of nociceptors by sub-nanomolar nicotine. Br J Pharmacol 2001; 133:23–8
178.
Miao FJ, Benowitz N, Levine JD: Neural and endocrine circuits mediating inhibition of bradykinin-induced plasma extravasation by subcutaneous and spinal-intrathecal nicotine. J Pharmacol Exp Ther 1996; 277:1510–6
179.
Glassman SD, Anagnost SC, Parker A, Burke D, Johnson JR, Dimar JR: The effect of cigarette smoking and smoking cessation on spinal fusion. Spine 2000; 25:2608–15
180.
Hadley MN, Reddy SV: Smoking and the human vertebral column: A review of the impact of cigarette use on vertebral bone metabolism and spinal fusion. Neurosurgery 1997; 41:116–24
181.
Andersen T, Christensen FB, Laursen M, Hoy K, Hansen ES, Bunger C: Smoking as a predictor of negative outcome in lumbar spinal fusion. Spine 2001; 26:2623–8
182.
Martin GJ Jr, Haid RW Jr, MacMillan M, Rodts GE Jr, Berkman R: Anterior cervical discectomy with freeze-dried fibula allograft: Overview of 317 cases and literature review. Spine 1999; 24:852–8
183.
Deguchi M, Rapoff AJ, Zdeblick TA: Posterolateral fusion for isthmic spondylolisthesis in adults: Analysis of fusion rate and clinical results. J Spinal Disord 1998; 11:459–64
184.
Bishop RC, Moore KA, Hadley MN: Anterior cervical interbody fusion using autogeneic and allogeneic bone graft substrate: A prospective comparative analysis. J Neurosurg 1996; 85:206–10
185.
Mooney V, McDermott KL, Song J: Effects of smoking and maturation on long-term maintenance of lumbar spinal fusion success. J Spinal Disord 1999; 12:380–5
186.
W-Dahl A, Toksvig-Larsen S: Cigarette smoking delays bone healing: A prospective study of 200 patients operated on by the hemicallotasis technique. Acta Orthop Scand 2004; 75:347–51
187.
Schmitz MA, Finnegan M, Natarajan R, Champine J: Effect of smoking on tibial shaft fracture healing. Clin Orthop 1999; 365:184–200
188.
Abidi NA, Dhawan S, Gruen GS, Vogt MT, Conti SF: Wound-healing risk factors after open reduction and internal fixation of calcaneal fractures. Foot Ankle Int 1998; 19:856–61
189.
Grossi SG, Zambon J, Machtei EE, Schifferle R, Andreana S, Genco RJ, Cummins D, Harrap G: Effects of smoking and smoking cessation on healing after mechanical periodontal therapy. J Am Dent Assoc 1997; 128:599–607
190.
Haverstock BD, Mandracchia VJ: Cigarette smoking and bone healing: Implications in foot and ankle surgery. J Foot Ankle Surg 1998; 37:69–74
191.
Kwiatkowski TC, Hanley EN Jr, Ramp WK: Cigarette smoking and its orthopedic consequences. Am J Orthop 1996; 25:590–7
192.
Kyro A, Usenius JP, Aarnio M, Kunnamo I, Avikainen V: Are smokers a risk group for delayed healing of tibial shaft fractures? Ann Chir Gynaecol 1993; 82:254–62
193.
Law MR, Hackshaw AK: A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: Recognition of a major effect. BMJ 1997; 315:841–6
194.
Fung YK, Iwaniec U, Cullen DM, Akhter MP, Haven MC, Timmins P: Long-term effects of nicotine on bone and calciotropic hormones in adult female rats. Pharmacol Toxicol 1999; 85:181–7
195.
Ramp WK, Lenz LG, Galvin RJ: Nicotine inhibits collagen synthesis and alkaline phosphatase activity, but stimulates DNA synthesis in osteoblast-like cells. Proc Soc Exp Biol Med 1991; 197:36–43
196.
Broulik PD, Jarab J: The effect of chronic nicotine administration on bone mineral content in mice. Horm Metab Res 1993; 25:219–21
197.
Yuhara S, Kasagi S, Inoue A, Otsuka E, Hirose S, Hagiwara H: Effects of nicotine on cultured cells suggest that it can influence the formation and resorption of bone. Eur J Pharmacol 1999; 383:387–93
198.
Daftari TK, Whitesides TE Jr, Heller JG, Goodrich AC, McCarey BE, Hutton WC: Nicotine on the revascularization of bone graft: An experimental study in rabbits. Spine 1994; 19:904–11
199.
Riebel GD, Boden SD, Whitesides TE, Hutton WC: The effect of nicotine on incorporation of cancellous bone graft in an animal model. Spine 1995; 20:2198–202
200.
Fang MA, Frost PJ, Iida-Klein A, Hahn TJ: Effects of nicotine on cellular function in UMR 106-01 osteoblast-like cells. Bone 1991; 12:283–6
201.
Syversen U, Nordsletten L, Falch JA, Madsen JE, Nilsen OG, Waldum HL: Effect of lifelong nicotine inhalation on bone mass and mechanical properties in female rat femurs. Calcif Tissue Int 1999; 65:246–9
202.
Silcox DH III, Bode SD, Schimandle JH, Johnson P, Whitesides TE, Hutton WC: Reversing the inhibitory effect of nicotine on spinal fusion using an osteoinductive protein extract. Spine 1998; 23:291–6
203.
Silcox DH III, Daftar T, Boden SD, Schimandle JH, Hutton WC, Whitesides TE Jr: The effect of nicotine on spinal fusion. Spine 1995; 20:1549–53
204.
Wing KJ, Fisher CG, O’Connel JX, Wing PC: Stopping nicotine exposure before surgery: The effect on spinal fusion in a rabbit model. Spine 2000; 25:30–4
205.
Sorensen LT, Karlsmark T, Gottrup F: Abstinence from smoking reduces incisional wound infection: A randomized controlled trial. Ann Surg 2003; 238:1–5
206.
Sorensen LT, Jorgensen T: Short-term pre-operative smoking cessation intervention does not affect postoperative complications in colorectal surgery: A randomized clinical trial. Colorect Dis 2003; 5:347–52
207.
Kuri M, Nakagawa M, Tanaka H, Hasuo S, Kishi Y: Determination of the duration of peroperative smoking cessation to improve wound healing after head and neck surgery. Anesthesiology 2005; 102:892–6
208.
Boden SD, Schimandle JH, Hutton WC: An experimental lumbar intertransverse process spinal fusion model: Radiographic, histologic, and biomechanical healing characteristics. Spine 1995; 20:412–20
209.
Fulcher SM, Koman LA, Smith BP, Holden M, Smith TL: The effect of transdermal nicotine on digital perfusion in reformed habitual smokers. J Hand Surg [Am] 1998; 23:792–9
210.
McGehee DS: Molecular diversity of neuronal nicotinic acetylcholine receptors. Ann NY Acad Sci 1999; 868:565–77
211.
Kenny PJ, Markou A: Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav 2001; 70:531–49
212.
Laviolette SR, van der Kooy D: The neurobiology of nicotine addiction: Bridging the gap from molecules to behaviour. Nat Rev Neurosci 2004; 5:55–65
213.
Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW: Symptoms of tobacco withdrawal: A replication and extension. Arch Gen Psychiatry 1991; 48:52–9
214.
Hughes JR, Hatsukami D: Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry 1986; 43:289–94
215.
Tripathi HL, Martin BR, Aceto MD: Nicotine-induced antinociception in rats and mice: Correlation with nicotine brain levels. J Pharmacol Exp Therapeut 1982; 221:91–6
216.
Decker MW, Meyer MD: Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics. Biochem Pharmacol 1999; 58:917–23
217.
Badio B, Daly JW: Epibatidine, a potent analgetic and nicotinic agonist. Mol Pharmacol 1994; 45:563–9
218.
Jinks SL, Carstens E: Activation of spinal wide dynamic range neurons by intracutaneous microinjection of nicotine. J Neurophysiol 1999; 82:3046–55
219.
Schmelz M, Luz O, Averbeck B, Bickel A: Plasma extravasation and neuropeptide release in human skin as measured by intradermal microdialysis. Neurosci Lett 1997; 230:117–20
220.
Puttfarcken PS, Manelli AM, Arneric SP, Donnelly-Roberts DL: Evidence for nicotinic receptors potentially modulating nociceptive transmission at the level of the primary sensory neuron: Studies with F11 cells. J Neurochem 1997; 69:930–8
221.
Khan IM, Buerkle H, Taylor P, Yaksh TL: Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists. Neuropharmacology 1998; 37:1515–25
222.
Garraway SM, Hochman S: Modulatory actions of serotonin, norepinephrine, dopamine, and acetylcholine in spinal cord deep dorsal horn neurons. J Neurophysiol 2001; 86:2183–94
223.
Flood P, Ramirez-Latorre J, Role L: Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology 1997; 86:859–65
224.
Flood P, Sonner JM, Gong D, Coates KM: Heteromeric nicotinic inhibition by isoflurane does not mediate MAC or loss of righting reflex. Anesthesiology 2002; 97:902–5
225.
Silverstein B: Cigarette smoking, nicotine addiction, and relaxation. J Personal Soc Psychol 1982; 42:946–50
226.
Nesbitt PD: Smoking, physiological arousal, and emotional response. J Personal Soc Psychol 1973; 25:137–44
227.
Pomerleau OF, Turk DC, Fertig JB: The effects of cigarette smoking on pain and anxiety. Addict Behav 1984; 9:265–71
228.
Fertig JB, Pomerleau OF, Sanders B: Nicotine-produced antinociception in minimally deprived smokers and ex-smokers. Addict Behav 1986; 11:239–48
229.
Knott VJ: Effects of cigarette smoking on subjective and brain evoked responses to electrical pain stimulation. Pharmacol Biochem Behav 1990; 35:341–6
230.
Waller D, Schalling D, Levander S, Edman G: Smoking, pain tolerance, and physiological activation. Psychopharmacology 1983; 79:193–8
231.
Pauli P, Rau H, Zhuang P, Brody S, Birbaumer N: Effects of smoking on thermal pain threshold in deprived and minimally-deprived habitual smokers. Psychopharmacology 1993; 111:472–6
232.
Jamner LD, Girdler SS, Shapiro D, Jarvik ME: Pain inhibition, nicotine, and gender. Exp Clin Psychopharmacol 1998; 6:96–106
233.
Palmer KT, Syddall H, Cooper C, Coggon D: Smoking and musculoskeletal disorders: Findings from a British national survey. Ann Rheum Dis 2003; 62:33–6
234.
Yunus MB, Arslan S, Aldag JC: Relationship between fibromyalgia features and smoking. Scand J Rheum 2002; 31:301–5
235.
Goldberg MS, Scott SC, Mayo NE: A review of the association between cigarette smoking and the development of nonspecific back pain and related outcomes. Spine 2000; 25:995–1014
236.
Creekmore FM, Lugo RA, Weiland KJ: Postoperative opiate analgesia requirements of smokers and nonsmokers. Ann Pharmacother 2004; 38:949–53
237.
Berge TI: Pattern of self-administered paracetamol and codeine analgesic consumption after mandibular third-molar surgery. Acta Odontol Scand 1997; 55:270–6
238.
Woodside JR Jr: Female smokers have increased postoperative narcotic requirements. J Addict Dis 2000; 19:1–10
239.
Flood P, Daniel D: Intranasal nicotine for postoperative pain treatment. Anesthesiology 2004; 101:1417–21
240.
Parrott AC: Stress modulation over the day in cigarette smokers. Addiction 1995; 90:233–44
241.
Warner DO, Patten CA, Ames SC, Offord KP, Schroeder DR: Effect of nicotine replacement therapy on stress and smoking behavior in surgical patients. Anesthesiology 2005; 102:1138–46
242.
Klesges RC, Haddock CK, Lando H, Talcott GW: Efficacy of forced smoking cessation and an adjunctive behavioral treatment on long-term smoking rates. J Consult Clin Psychol 1999; 67:952–8
243.
Clements-Thompson M, Klesges RC, Haddock K, Lando H, Talcott W: Relationships between stages of change in cigarette smokers and healthy lifestyle behaviors in a population of young military personnel during forced smoking abstinence. J Consult Clin Psychol 1998; 66:1005–11
244.
Myles PS, Leslie K, Angliss M, Mezzavia P, Lee L: Effectiveness of bupropion as an aid to stopping smoking before elective surgery: A randomised controlled trial. Anaesthesia 2004; 59:1053–8
245.
Moller AM, Pedersen T, Villebro N, Norgaard P: Impact of lifestyle on perioperative smoking cessation and postoperative complication rate. Prev Med 2003; 36:704–9
246.
Shannon-Cain J, Webster SF, Cain BS: Prevalence of and reasons for preoperative tobacco use. AANA J 2002; 70:33–40
247.
Shah MV, Watkins G, Latto IP: The effect of written advice on preoperative cigarette consumption. Ann Royal Col Surg Eng 1984; 66:436–7
248.
Simon JA, Solkowitz SN, Carmody TP, Browner WS: Smoking cessation after surgery: A randomized trial. Arch Intern Med 1997; 157:1371–6
249.
Ratner PA, Johnson JL, Richardson CG, Bottorff JL, Moffat B, Mackay M, Fofonoff D, Kingsbury K, Miller C, Budz B: Efficacy of a smoking-cessation intervention for elective-surgical patients. Res Nurs Health 2004; 27:148–61
250.
Warner DO, Sarr MG, Offord K, Dale LC: Anesthesiologists, general surgeons, and tobacco interventions in the perioperative period. Anesth Analg 2004; 99:1776–83
251.
Warner DO: Preoperative smoking cessation: The role of the primary care provider. Mayo Clin Proc 2005; 80:252–8
252.
Warner DO: Helping surgical patients quit smoking: Why, when, and how. Anesth Analg 2005; 101:481–7
253.
McBride CM, Emmons KM, Lipkus IM: Understanding the potential of teachable moments: The case of smoking cessation. Health Educ Res 2003; 18:156–70
254.
A clinical practice guideline for treating tobacco use and dependence: AUS Public Health Service report. JAMA 2000; 283:3244–54
255.
France EK, Glasgow RE, Marcus AC: Smoking cessation interventions among hospitalized patients: What have we learned? Prev Med 2001; 32:376–88