Published ahead of print on March 4, 2004, doi:10.1164/rccm.200310-1473OC
© 2004 American Thoracic Society Effect of Caffeine Ingestion on Exhaled Nitric Oxide Measurements in Patients with AsthmaOtago Respiratory Research Unit, Dunedin School of Medicine, University of Otago Medical School, Dunedin, New Zealand Correspondence and requests for reprints should be addressed to D. Robin Taylor, M.D., F.R.C.P.C., Department of Medical and Surgical Sciences, Dunedin School of Medicine, P.O. Box 913, Dunedin, New Zealand. E-mail: robin.taylor{at}stonebow.otago.ac.nz
Exhaled nitric oxide (FENO) measurements may be influenced by a number of confounding factors. Reports have offered conflicting evidence as to whether caffeine consumption increases or decreases FENO. In this study we aimed to confirm whether caffeine ingestion affects FENO in patients with asthma. On two separate days, 20 patients with asthma (10 steroid-naive and 10 steroid-treated) received a standard cup of either caffeinated or noncaffeinated coffee (15 g) (control) in a randomized, double-blind, cross-over manner. FENO measurements were obtained at baseline, and 30, 60, 120, and 180 minutes after ingestion. Serum caffeine levels were also measured at 0 and 60 minutes. No significant changes in FENO occurred after caffeine compared with the control. We conclude that caffeinated foods and beverages are unlikely to acutely influence FENO in subjects with asthma, and protocols for laboratory measurement do not need to take this factor into account.
Key Words: asthma • caffeine • exhaled nitric oxide • measurement Measurement of exhaled nitric oxide (FENO) is becoming increasingly important as a tool in the diagnosis and assessment of airway inflammation in asthma (1, 2). The test is easy to perform and results are highly reproducible (3). Recommendations regarding the appropriate methods for FENO measurement have been published (4, 5). A number of factors that may affect FENO levels acutely have been identified, including inhalation of tobacco smoke, alcohol ingestion, strenuous exercise, menstruation, and recent respiratory tract infection (1). There are theoretical reasons why caffeine ingestion might also influence FENO measurements. Caffeine inhibits phosphodiesterase, and in turn this has the potential to alter cyclic AMP regulation of nitric oxide synthase. To date the results of limited studies to investigate this issue have been conflicting (6, 7), and have not provided adequate guidance as to whether recent caffeine ingestion should be taken into account when measuring FENO. Both of the two previous studies were performed in healthy subjects with no evidence of asthma and normal baseline FENO measurements. In one study (6), a 20% reduction in FENO levels over a 4-hour interval after caffeine consumption was reported. In the other (7), the opposite effect was found, with FENO levels increasing significantly after drinking caffeine-containing coffee. Our aim in the present study was to establish definitively whether recent caffeine ingestion might contribute to variation in FENO measurements in patients with asthma, so that this might be controlled for during FENO testing. We therefore examined the effect of caffeine consumption in patients with asthma whose baseline FENO levels were raised. Because inducible nitric oxide synthase activity is inhibited by corticosteroid treatment (8), both steroid-naive and steroid-treated subjects were included. Our data have previously been presented as an abstract (9).
Twenty nonsmoking, asthmatic, adult volunteers with FENO levels greater than 10 ppb (flow rate, 250 ml/second) at screening, and who were regular coffee drinkers were enrolled into a randomized, double-blind, placebo-controlled, cross-over study. Ten patients were steroid naive and 10 patients were taking regular inhaled corticosteroid therapy (mean dose, 980 µg/day; range, 200–2,000 µg/day of beclomethasone or equivalent). No patient had used oral prednisone, oral theophylline, or inhaled long-acting ß-agonist for at least 1 month before the study. All caffeine-containing foods and beverages were withheld for at least 24 hours, and inhaled bronchodilators were withheld for a minimum of 6 hours before each study visit. Patients attended the research laboratory on two separate occasions at the same time of day. After obtaining baseline measurements, patients were instructed to drink a 200-ml cup of coffee within 10 minutes. A standard quantity (15 g) of either caffeine-containing coffee (Illy Espresso Caffe Macinato) or decaffeinated coffee (Illy Espresso Decaffeinated Macinato) was prepared in an espresso coffee maker. The order of administration was randomized. FENO measurements were performed at baseline, and 30, 60, 120, and 180 minutes after each subject began drinking the coffee. Measurements were obtained online, using a calibrated chemiluminescence analyzer in accordance with published guidelines and with an exhalation flow rate of 250 ml/second (5). Spirometry was measured at the end of the first study visit, using a rolling seal spirometer (SpiroTech/VIASYS Healthcare, Marietta, GA). Venous blood samples were obtained at baseline and 1 hour after coffee ingestion for the measurement of serum caffeine levels. These were analyzed by high-performance liquid chromatography (Agilent Series 1100; Hewlett-Packard, Palo Alto, CA). The study was approved by the Otago Ethics Committee and each participant gave written informed consent.
Statistical Analysis
Demographic details for the 20 study volunteers are shown in Table 1 . Serum caffeine levels increased significantly from baseline with caffeinated coffee (0.3 ± 0.4 to 3.9 ± 1.2 mg/ml; p < 0.0001) at 60 minutes but not with decaffeinated coffee (0.3 ± 0.4 to 0.4 ± 0.3 mg/ml, p = 0.8).
There were no significant differences in baseline FENO between the two study days (see Table 1). Changes in FENO with time are shown in Figures 1 and 2 . Mean FENO levels did not vary by more than 1 ppb at any time point from baseline. Mean AUC0–180 FENO values determined with and without caffeine were 2,950 ± 1,334 and 2,853 ± 1,158 ppb, respectively. There were no significant differences with caffeinated coffee compared with decaffeinated coffee (p = 0.38). Likewise, subgroup analyses based on inhaled corticosteroid treatment did not reveal any significant differences between steroid-naive and steroid-treated subjects.
The results of the present study show that recent caffeine consumption does not affect exhaled nitric oxide levels in patients with asthma. This outcome contrasts with the results of two previous investigations (6, 7). In the first of these, Bruce and coworkers reported that FENO levels decreased significantly with caffeine. However, in that study the changes in FENO (about 20%) were reported as percentage values rather than as absolute changes. Given that these authors studied healthy volunteers who had low FENO levels at baseline (12.3 ppb at an exhalation flow rate of 83 ml/second; comparable to about 5.4 ppb at the exhalation flow rate used in this study [2]), this implied an absolute change of about 2.5 ppb. The magnitude of this effect is just outside the range of reproducibility for repeated measurements of FENO (3) and hence its clinical significance is doubtful. It may also be that because the baseline FENO levels in that study were higher (12.3 ppb) before caffeine consumption compared with placebo (9.9 ppb) the apparent fall in FENO with caffeine represents regression toward the mean. In the second study (7), an increase in FENO occurred 30 minutes after caffeine ingestion and levels returned to baseline at 1 hour. However, this was an open-label, uncontrolled investigation in healthy subjects, which makes interpretation difficult. In our study we included both steroid-naive and steroid-treated patients. This was to explore the possibility that caffeine ingestion might selectively influence those patients whose inducible nitric oxide synthase activity was not suppressed by prior inhaled corticosteroid exposure. It is theoretically possible that, via a cyclic AMP-mediated mechanism, the effects of caffeine might be more apparent in steroid-naive subjects. Although the numbers were small, subgroup analyses did not suggest that this might be the case. In clinical practice, the control of factors that may influence a test measurement is important, particularly when the result may determine either the diagnosis or a change in treatment. A number of factors that might potentially alter FENO levels have been identified. Examples include recent tobacco smoking and alcohol consumption, both of which reduce FENO measurements acutely, possibly by inhibition of nitric oxide synthase activity (1). Obviously, the fewer confounding factors that affect the results of a test, the more reliable the results will be. The present results indicate that caffeine consumption does not have any significant effect on FENO measurements in patients with asthma, and that it is unnecessary to advise patients to withhold caffeinated foods or beverages before testing.
Supported by the Otago Medical Research Foundation and the Otago Respiratory Research Trust. Supported in part by a summer studentship awarded to E.T. by the Asthma and Respiratory Foundation of New Zealand. GlaxoSmithKline provided a personal educational grant to A.D.S. as GSK Research Fellow. Conflict of Interest Statement: E.S.T. has no declared conflict of interest; A.D.S. has no declared conflict of interest; J.O.C. has no declared conflict of interest; G.P.H. has no declared conflict of interest; D.R.T. has no declared conflict of interest. Received in original form October 29, 2003; accepted in final form March 2, 2004
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