Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tee, A. K. H.
Right arrow Articles by Hui, K. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tee, A. K. H.
Right arrow Articles by Hui, K. P.
(Chest. 2005;127:131-134.)
© 2005 American College of Chest Physicians

Effect of Spirometric Maneuver, Nasal Clip, and Submaximal Inspiratory Effort on Measurement of Exhaled Nitric Oxide Levels in Asthmatic Patients*

Augustine K. H. Tee, MMed and Kok P. Hui, MD, FCCP

* From the Department of Medicine, Changi General Hospital, Singapore.

Correspondence to: Augustine K. H. Tee, MMed; Department of Medicine, Changi General Hospital, 2 Simei St 3, Singapore 529889; e-mail: augustine_tee{at}cgh.com.sg


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Study objectives: The measurement of exhaled nitric oxide (eNO) in asthmatic patients is increasingly being used to aid diagnosis and management. To standardize the measurement techniques, the American Thoracic Society and European Respiratory Society guidelines were published, but these were based mainly on expert opinions without strong clinical evidence on many aspects. We investigated the effect of three different factors on the on-line measurement of eNO. In a clinical setting, we evaluated the effect of prior spirometry, the use of nasal clips, and the influence of submaximal inspiratory effort on on-line eNO readings. Recommended guidelines on these factors have been published but have been supported by scanty research data.

Methods: Three groups of stable asthmatic patients (30 patients in each group) had eNO measurements made on-line (NIOX; Aerocrine AB; Solna, Sweden) before and 5 min after performing spirometric maneuvers, without and with a nasal clip, or with maximal and then submaximal inspiratory efforts.

Results: There were no significant differences in mean eNO levels among all three groups, before and after spirometry (68.2 vs 66.0 parts per billion [ppb], respectively; mean difference, 2.2 ppb; 95% confidence interval [CI], –0.4 to 4.9; p = 0.090), without use of a nasal clip compared with its use (46.7 vs 45.6 ppb, respectively; mean difference, 1.1 ppb; 95% CI, –0.7 to 2.8; p = 0.234), and maximal or submaximal inspiratory effort (52.6 vs 51.2 ppb, respectively; mean difference, 1.4 ppb; 95% CI, –0.3 to 3.0; p = 0.096).

Conclusion: We conclude that on-line eNO measurements in clinical practice are not significantly affected by prior spirometry maneuver, use of a nasal clip, or submaximal inspiratory effort.

Key Words: asthma • breath tests • nitric oxide • spirometry


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
High levels of lower respiratory tract exhaled nitric oxide (eNO) have been well-documented in asthmatic patients as a marker of airway inflammation.1234 The use of eNO measurements has recently been approved by the US Food and Drug Administration as a noninvasive test for monitoring asthma in adults and children ≥ 4 years of age. However, the technique of measuring eNO has been variable among investigators.56 Two major factors that may affect the measurement of lower respiratory eNO levels include nasal nitric oxide (NO) contamination and the performance of premeasurement spirometric maneuvers, causing unexpected elevated and decreased eNO levels, respectively. As such, both the European Respiratory Society (ERS) Task Force 19977 and the American Thoracic Society (ATS) 19998 have published recommendations to standardize the testing methodology. Both guidelines discouraged the use of nasal clips because accumulated nasal NO is thought to leak via the posterior nasopharynx and contribute to high eNO readings. The guidelines recommended avoiding the performance of spirometry before eNO measurements are made, as it has been shown to transiently reduce eNO levels.910 Full inhalation to total lung capacity was also a requirement, although this was based more on familiar spirometric practice than on evidence.

The purpose of this study was to evaluate the effect of three procedures on eNO levels measured with a single-breath on-line technique in stable asthmatic patients. These three procedures were the use of a nasal clip, spirometric maneuvers performed before measurement, and full vs submaximal inspiratory effort.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Three groups of stable asthmatic patients underwent eNO measurement during routine outpatient visits to a clinic specializing in asthma. Prior approval by the institutional review board and a waiver of informed written consent were granted. On-line eNO measurements were performed using an NO monitoring system (NIOX; Aerocrine AB; Solna, Sweden) that utilized biofeedback guidance to maintain a constant standard expiratory flow rate of 0.05 L/s at each measurement. The monitoring system measures eNO with specifications in accordance with ATS guidelines. Patients were seated for at least 5 min before commencing the measurement and throughout the procedure. They were required to inspire to full vital capacity, except those in the third group, before breathing out into the mouthpiece of the monitoring system. The eNO reading displayed on the monitoring system is the mean eNO level during each eNO plateau, which is between 5 s and 8 s of exhalation. The mean of three acceptable readings was taken, with at least 30 s of relaxed tidal breathing between maneuvers, according to ATS guidelines.

Group 1 consisted of 30 patients with sequential measurements of eNO, without a nose clip, before a spirometric maneuver and 5 min after a spirometric maneuver. FVC was the standard spirometry used, with each patient performing at least three maneuvers. A full inspiratory effort was used.

Group 2 consisted of 30 patients who had nasal clips randomly applied, during the same visit, with at least a 2-min interval between measurements made with a nose clip (clip) or without a nose clip (unclip). No chronologic testing method was adopted.

Group 3 included 30 patients performing eNO measurements without a nose clip. This group used random submaximal and maximal inspiration to full vital capacity before recording an eNO level. With submaximal effort, patients were instructed on expiring before full inspiratory vital capacity to trigger an eNO measurement. No prior spirometry was performed in this group.

Statistical analysis was performed with a statistical software package (SPSS, version 9.0 for Windows; SPSS; Chicago, IL). A p value of < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Asthmatic patients were recruited randomly during outpatient visits. These were Singaporeans of Chinese, Malay, or Indian descent. All patients completed at least three eNO readings for each analysis. Their ages ranged from 14 to 80 years, with the mean age and mean FEV1 percentage of predicted being similar across all three groups (Table 1 ).


View this table:
[in this window]
[in a new window]

  		Table 1. Demographic Data of the Three Groups of Patients

 
There was no difference in eNO level whether a spirometry maneuver was performed before or after the measurement, with mean eNO levels of 68.2 vs 66.0 parts per billion (ppb), respectively (mean difference, 2.2 ppb; 95% confidence interval [CI], –0.4 to 4.9; p = 0.090).

The use of nasal clip did not appear to significantly affect eNO levels (eNO levels: clip, 45.6 ppb; no clip, 46.7 ppb; mean difference, 1.1 ppb; 95% CI, –0.7 to 2.8; p = 0.234). Submaximal inspiratory effort had no significant effect on eNO levels (maximal effort, 52.6 ppb; submaximal effort, 51.2 ppb; mean difference, 1.4 ppb; 95% CI, –0.3 to 3.0; p = 0.096). Results are summarized in Table 2 .


View this table:
[in this window]
[in a new window]

  		Table 2. eNO Levels for the Three Groups*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
Since the availability of on-line eNO analyzers that simplified the measurement of eNO, many centers have embraced this new technology for research into the diagnosis and monitoring of airway diseases, particularly asthma. Off-line eNO measurement is widely used in research, but does not provide the clinician with a readily available result for management. The interest in the use of eNO in asthma patients has led to the release of recommendations by both the ATS and ERS task force, in an effort to standardize measurement techniques. Although procedural sources of variation in eNO measurements are recognized, some of these aspects of on-line eNO measurement are based on expert opinion, while other recommendations rely on laboratory studies in healthy individuals. Thus, we embarked on the assessment of three aspects of these guidelines in an actual clinical scenario.

A difference in online eNO levels with nasal clip usage was expected, but the lack of such a difference in our study was in contrast with the published guidelines, which were largely drawn from extrapolations of studies on off-line nasal NO measurements.11121314 To our knowledge, there are no studies addressing this practical comparison among asthmatic patients. The actual effect of occluding the nasal passage outflow and its effect on the dynamic movement of the soft palate in isolating the oropharynx from the nasal cavity may vary with expiratory pressure. Such postulated nasal NO back-leakage may not be clinically significant, as shown by our data. Nasal occlusion as a procedural source of eNO variation was implied indirectly from studies on nasal NO sampling.13 Kharitonov and Barnes13 studied seven healthy adults using a nasally delivered tracer gas to detect nasal contamination by expired air. No communication between the nasopharynx and the rest of the respiratory tract was shown when exhaling slowly against a resistance. Kimberly et al12 reported a significant nasal contribution to eNO levels in healthy subjects while performing tidal breathing with nose clips in place. In practice, although the use of nasal clips can add to patient discomfort, some patients cannot avoid nasal inspiration or expiration, thus necessitating the use of a nasal clip.

Two previous studies have addressed the effect of spirometry on eNO; however, one study10 was performed in healthy individuals, while the other9 consisted of 11 patients with mild asthma. Nevertheless, both studies showed an immediate fall in eNO level (ie, 1 to 5 min) to a delayed fall in eNO level (30 min) after spirometry. Silkoff et al9 showed that postspirometric eNO levels fell approximately 10% in 11 asthmatic patients to the lowest point at 1 min, started to increase at the 5-min mark, and subsequently returned to baseline levels at > 1 h. All of these asthmatic patients had eNO levels that were at least 40 ppb higher than those obtained in healthy control subjects. Our data involving larger numbers of asthmatic patients showed the lack of influence of spirometric maneuvers on eNO levels at 5 min. In our population of patients with predominantly mild asthma, an interval of 5 min seemed sufficient to revert eNO levels to prespirometric levels. This lack of difference between eNO levels measured before and after spirometry is of practical relevance. Asthmatic patients often have measurements of peak expiratory flow rate or other FVC maneuvers to gauge disease severity during a clinic visit. Current guidelines, however, do not encourage spirometry or other taxing respiratory maneuvers before an eNO measurement. Our results showed that avoiding spirometry before measuring eNO levels is unnecessary. Therefore, patients can have both spirometry and eNO readings performed at a single clinic visit, which greatly helps in the overall management of asthma.

Although total lung capacity is a constant point in the respiratory cycle, and asthmatic patients may be familiar with inhaling in this manner, no studies to date have investigated whether full inspiratory efforts are required in online eNO measurements. Furthermore, ERS guidelines require a rapid inspiratory time to total lung capacity, which may be beyond the recommended time of 4 s in patients with severe airway obstruction.7 Our results showed that submaximal inspiration does not affect eNO readings. The effect of submaximal inspiratory effort on eNO measurement is difficult to predict and may depend on several factors, such as nasal NO contamination and airway gas admixture. Therefore, other definitive studies may be required to investigate the effect of varying inspiratory efforts on eNO measurements. Nonetheless, as long as inspiratory effort can maintain adequate exhalation for eNO to be analyzed, a full tidal capacity inhalation does not seem to be a prerequisite for an acceptable eNO reading. The measurement of eNO levels in patients who may not be able to make full inspiratory efforts (eg, the elderly and children) or in those who require a long inspiratory time (eg, patients with severe persistent asthma) are therefore still valid in this regard.

Finally, we acknowledge a limitation of sample size due to logistical reasons, and we accept that the power of the statistical analysis may have been improved with a larger cohort. Future studies would require a sample size of at least 82 patients for an 80% power to detect a 10% difference in mean eNO levels at a 5% significance level. Despite this, we believe that the results of our study will provide valuable information to those conducting eNO measurements. Further studies are warranted not only with a larger number of subjects, but also with different gender and ethnic groups, or to determine whether similar effects are seen with off-line eNO measurements.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
Our results showed that there were no statistically significant differences between eNO measurements for the three different groups. We concluded that in clinical practice eNO measurements obtained in asthmatic patients with a NO monitoring system are not significantly affected by prior spirometry maneuvers, the use of a nasal clip, or submaximal inspiratory effort.


   Footnotes
 
Abbreviations: ATS = American Thoracic Society; CI = confidence interval; eNO = exhaled nitric oxide; ERS = European Respiratory Society; NO = nitric oxide; ppb = parts per billion

Support for the NIOX consumables used in the study was provided by Astra-Zeneca Singapore Pte Ltd.

Received for publication January 30, 2004. Accepted for publication August 11, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

  1. Stuart, LJ, Kittelson, J, Cowan, JO, et al (2001) The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 164,738-743[Abstract/Free Full Text]
  2. Alving, K, Weitzberg, E, Lundberg, JM Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993;6,1368-1370[Abstract]
  3. Kharitonov, SA, Yates, D, Robbins, RA, et al Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994;343,133-135[CrossRef][ISI][Medline]
  4. Kharitonov, SA, Yates, D, Springall, DR, et al Exhaled nitric oxide is increased in asthma. Chest 1995;107(suppl),156S-157S
  5. Robbins, RA, Floreani, AA, Von Essen, SG, et al Measurement of exhaled nitric oxide by three different techniques. Am J Respir Crit Care Med 1996;153,1631-1635[Abstract]
  6. Silkoff, PE, McClean, PA, Slutsky, AS, et al Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide. Am J Respir Crit Care Med 1997;155,260-267[Abstract]
  7. Kharitonov, S, Alving, K, Barnes, PJ Exhaled and nasal nitric oxide measurements: recommendations: the European Respiratory Society Task Force. Eur Respir J 1997;10,1683-1693[CrossRef][ISI][Medline]
  8. Slikoff, PE Recommendations for standardized procedures for the on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children-1999. Am J Respir Crit Care Med 1999;160,2104-2117[Free Full Text]
  9. Silkoff, PE, Wakita, S, Chatkin, J, et al Exhaled nitric oxide after ß2-agonist inhalation and spirometry in asthma. Am J Respir Crit Care Med 1999;159,940-944[Abstract/Free Full Text]
  10. Deykin, A, Halpern, O, Massaro, AF, et al Expired nitric oxide after bronchoprovocation and repeated spirometry in patients with asthma. Am J Respir Crit Care Med 1998;157,769-775[Abstract/Free Full Text]
  11. Gerlach, H, Rossaint, R, Pappert, D, et al Autoinhalation of nitric oxide after endogenous synthesis in nasopharynx. Lancet 1994;343,518-519[CrossRef][ISI][Medline]
  12. Kimberly, B, Nejadnik, B, Giraud, GD, et al Nasal contribution to exhaled nitric oxide at rest and during breathholding in humans. Am J Respir Crit Care Med 1996;153,829-836[Abstract]
  13. Kharitonov, SA, Barnes, PJ Nasal contribution to exhaled nitric oxide during exhalation against resistance or during breath holding. Thorax 1997;52,540-544[Abstract]
  14. Schedin, U, Frostell, C, Persson, MG, et al Contribution from upper and lower airways to exhaled endogenous nitric oxide in humans. Acta Anaesthesiol Scand 1995;39,327-332[ISI][Medline]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
H.-W. Shin, C. D. Schwindt, A. S. Aledia, C. M. Rose-Gottron, J. K. Larson, R. L. Newcomb, D. M. Cooper, and S. C. George
Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry
Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1741 - R1748.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
K. H. A. Tee and K. P. Hui
Clips, Spirometry, and Submaximal Inhalation for Exhaled Nitric Oxide
Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 931 - 931.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
P. Silkoff
Clips, Spirometry, and Submaximal Inhalation for Exhaled Nitric Oxide
Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 931 - 932.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tee, A. K. H.
Right arrow Articles by Hui, K. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tee, A. K. H.
Right arrow Articles by Hui, K. P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS