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Clips, Spirometry, and Submaximal Inhalation for Exhaled Nitric Oxide

I wish to thank Drs. Tee and Hui for their letter regarding the 2005 ATS/ERS revised statement on exhaled and nasal NO measurement, which was the output from two ATS workshops on this subject (1). I served as cochair for the workshops and committees that assembled this document, but am writing this letter as an individual. Tee and coworkers recently published a study on the effects of the inspiratory maneuver, nasal clipping, and spirometry on exhaled NO values (2). Of note, the 2005 statement was completed and ratified by the ATS and ERS in 2004 before their article appeared. I will address the issues one by one.

Inspiration maneuver. The 2005 exhaled NO statement relaxed the requirement to inhale to TLC (total lung capacity) and changed this to near TLC (if TLC is difficult for the patient) in contrast to the 1999 ATS statement, which strictly recommended TLC (3). It is known that levels of exhaled NO (FE_NO) are lower when exhaling from FRC compared with TLC (4), perhaps due to reductions in mucosal surface available for NO diffusion from airway wall to lumen. This could also apply to near TLC compared with TLC. At the ATS workshop on exhaled NO in 2002, several investigators, who were contributors to the revised statement, reported that their subjects could not always inhale to TLC, and recommended this change. It was thought that this modification would have minimal effect on FE_NO values, but there were no confirmatory data at that time (2004). However, if an individual couldn't inhale to TLC, there really was no other option. It is now gratifying to learn from these authors that near TLC and TLC are equivalent as regards FE_NO values (2). I will endeavor to reference their study in any future revisions of the statement.

Use of a nasal clip. In the same study, Tee and coworkers showed that the application of a nasal clip during online measurement or the performance of prior spirometric maneuver did not significantly affect FE_NO levels. In general, nasal clips are used in pulmonary function testing to prevent nasal exhalation, or loss of gas from a closed system, e.g., DL_CO measurement. The application of a nasal clip is not necessary for FE_NO online measurement as it has been demonstrated that exhalation against resistance with a positive mouth pressure closes the soft palate, excluding nasal NO (4, 5). It is encouraging to hear Tee and coworkers confirm that a nasal clip is unnecessary. I will also endeavor to reference their study on this point in any future revisions of the statement.

The effect of spirometry before exhaled NO. Previous reports in 10 and 18 subjects (6, 7) support the concept of small declines in FE_NO levels after a forced vital capacity exhalation. This is the basis behind previous and current societal recommendations for avoiding spirometry before FE_NO measurement. In their study, Tee and coworkers report no significant effect of spirometry on FE_NO in 30 subjects. Therefore, the jury is still out as to whether it is important to avoid spirometry. I still recommend doing so where possible especially in research protocols where measurement accuracy is essential. As regards clinical measurement, which may require less rigorous methodology, it may be unnecessary to avoid spirometry beforehand, but studies are required.

Finally, I agree that the use of FE_NO in research and clinical practice warrants regular reviews to fine tune measurement techniques, and we will continue to examine all the evidence, including the article by Tee and colleagues, when we revise the measurement recommendations in the future.

Philip Silkoff

Narberth, Pennsylvania

FOOTNOTES

Conflict of Interest Statement: P.S. is currently a full-time employee of AstraZeneca LP but this letter is not connected to his work for AstraZeneca. He has served as a consultant in the past for Aerocrine and Ionics Instruments, who manufacture exhaled NO monitors, and is the owner of a patent currently licensed to Ionics Instruments for which he received royalties.

REFERENCES

1. American Thoracic Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005;171:912–930.[Free Full Text]
2. Tee AK, Hui KP. Effect of spirometric maneuver, nasal clip, and submaximal inspiratory effort on measurement of exhaled nitric oxide levels in asthmatic patients. Chest 2005;127:131–134.[Abstract/Free Full Text]
3. American Thoracic Society. Recommendations for standardized procedures for the online and offline 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]
4. Silkoff PE, McClean PA, Slutsky AS, Furlott HG, Hoffstein E, Wakita S, Chapman KR, Szalai JP, Zamel N. 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]
5. Kharitonov SA, Barnes PJ. Nasal contribution to exhaled nitric oxide during exhalation against resistance or during breath holding. Thorax 1997;52:540–544.[Abstract]
6. Deykin A, Massaro AF, Coulston E, Drazen JM, Israel E. Exhaled nitric oxide following repeated spirometry or repeated plethysmography in healthy individuals. Am J Respir Crit Care Med 2000;161:1237–1240.[Abstract/Free Full Text]
7. Silkoff PE, Wakita S, Chatkin J, Ansarin K, Gutierrez C, Caramori M, McClean P, Slutsky AS, Zamel N, Chapman KR. Exhaled nitric oxide after beta2-agonist inhalation and spirometry in asthma. Am J Respir Crit Care Med 1999;159:940–944.[Abstract/Free Full Text]

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