Cigarette Smoking Reduces Endogenous Airway Nitric Oxide Production During Cardiopulmonary Bypass in Humans

Abstract

Cytokines, including tumor necrosis factor (TNF) and interleukin-1 beta, are known to increase inducible nitric oxide synthase (iNOS) expression [1,2] with subsequent increased local production of nitric oxide (NO). TNF is among the cytokines known to be systemically released during cardiopulmonary bypass (CPB) in humans [3]. Cigarette smoking is known to reduce exhaled NO concentration in humans [4], while smokers are also known to have increased pulmonary complications after CPB [5]. Endogenous NO is known to be a bronchodilator [6], and is known to be the nonadrenergic neurotransmitter of bronchodilator nerves in human airways [7]. This study was undertaken to evaluate endogenous airway NO production during CPB in a group of currently smoking males, compared to a group who quit smoking at least 30 days but no longer than 6 mo prior to surgery, and a third group who quit smoking more than 6 mo prior to surgery. Methods After institutional review board approval and patient informed consent, 19 adult males scheduled for elective myocardial revascularization were divided into three groups determined by their smoking history: 1) those who smoked up until the time of surgery (Group A, n = 5); 2) those who stopped smoking at least 30 days but no more than 6 mo prior to surgery (Group B, n = 7); and 3) those who stopped smoking more than 6 mo prior to surgery (Group C, n = 7). A standard anesthesia consisting of fentanyl (75-100 micro gram/kg) and pancuronium (0.1-0.2 mg/kg) was used. After institution of CPB, airway NO was measured by placing a Teflon-coated catheter inside the endotracheal tube to the distal tip. Airway gas was sampled over a 60-s time period at four intervals: 1) 5 min after institution of CPB, 2) 20 min of CPB, 3) 35 min of CPB, and 4) 50 min of CPB. Upon institution of CPB, mechanical ventilation was discontinued and the lungs were left unventilated with no fresh gas inflow. Airway NO concentrations were measured with a chemiluminescence technique (NO analyzer model 270 B NOA; Sievers Instruments, Inc., Boulder, CO) at a rate of 60 mL/min. On-line recording of airway NO concentration was made on a chart recorder calibrated with a known concentration of NO (Scott Specialty Gases, Inc., Plumsteadville, PA). The amount of NO produced was calculated manually in each 60-s period and expressed as mean NO (ppb) concentration per second. A typical recording obtained in a smoker (Group A) and nonsmoker (Group C) is shown in Figure 1. A repeated-measures analysis of variance was done to distinguish within-group differences at each time period. t-Tests were done to evaluate differences at the same time periods between the groups; P values of 0.05 or less were considered significant.Figure 1: Typical tracing of airway nitric oxide (NO) concentrations (ppb) obtained by chemiluminescence in a smoker (Group A) and nonsmoker (Group C). (Time frame compressed for illustration purposes.)Results No significant differences were noted between the three groups in age, weight, or total duration of CPB Table 1. Airway NO increased significantly (P < 0.05) over time in Group C only. Group C had significantly (P < 0.05) greater airway NO concentrations at all time intervals when compared to the same time intervals of Groups A and B. No significant differences were found between Groups A and B at any of the four measurement time periods Figure 2.Table 1: Age, Weight, and Total Duration of Cardiopulmonary Bypass (CPB)Figure 2: Airway concentration of nitric oxide in parts per billion (mean +/- SE) at 5, 20, 35, and 50 min duration of cardiopulmonary bypass (CPB) in Groups A, B, and C. *P < 0.05, Group C compared to groups A and B at the same time periods. No significant differences were noted between Groups A or B at any time period.Discussion Previous reports have demonstrated an increased incidence of postoperative pulmonary complications after coronary artery bypass surgery in smokers. Patients who stopped smoking 8 wk or longer had postoperative pulmonary complications at an incidence similar to nonsmokers [5]. This study demonstrates endogenous airway NO production is reduced in smokers and requires up to 6 mo of smoking cessation to achieve airway NO levels similar to nonsmokers during CPB. The nasopharynx is the primary source of airway NO production [8], but NO is known to be produced in the lower airway [7,9]. Human bronchial epithelial cells are known to contain iNOS [1] and TNF exposure will increase iNOS expression. Asthma is characterized by increased TNF production, increased iNOS expression, and increased airway NO concentrations [10]. Similarly, human CPB is characterized by increased levels of the inflammatory mediators TNF [3] and interleukin-1 beta [11]. Airway concentrations of NO have been reported to be reduced in smokers [4,12]. Cigarette smoke extract has been shown to inhibit the ability of NO synthase to convert L-arginine to L-citrulline and NO in bronchial epithelial cells [9]. Smoke is known to contain NO and NO (2) [13] and possibly induce a negative feedback on NO synthase expression. Endogenous NO has been shown to be an important bronchodilator in animal models [6,12] and is thought to be a primary nonadrenergic bronchodilator neurotransmitter in man [7,14]. Our finding of reduced airway NO production during CPB in smokers may be a possible mechanism of increased pulmonary complications reported after CPB [5]. Concentrations of airway NO measured in Group C in this study are less than that measured in asthmatics (peak expired levels of 283 ppb) [10] but similar to values reported in normal controls (80 ppb) [4,10]. Peak airway NO values reported in exhaled air of smokers is also similar to airway concentrations found in smokers (Groups A and B) during CPB [4]. The clinical relevance of these low airway NO concentrations is not well defined at this time.