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(Chest. 2005;128:3316-3321.)
© 2005 American College of Chest Physicians

The Effects of Hyperpnea on Exhaled Nitric Oxide Synthesis in Normal Subjects*

Erin West, BS; Mary Skowronski, MEd; Albert Coreno MS, MBA and E. R. McFadden, Jr, MD

* From the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, MetroHealth Medical Center and the Center for Academic Clinical Research, Case Western Reserve University School of Medicine, Cleveland, OH.

Correspondence to: E. R. McFadden, Jr, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109; e-mail: erm2{at}case.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To determine if the concentration of nitric oxide (NO) in the lungs increases with hyperpnea by contrasting calculated production (ie, the product of the fractional expired NO concentration [FeNO] and minute ventilation [VE]) [VNO] with the amount of NO in equilibrium with the conducting airways (eNOair) and the amount of NO diffusing from the alveoli (eNOalv).

Design: Observational study.

Setting: University teaching hospital.

Participants: Normal subjects.

Interventions: Measurements were made in 16 healthy people during and after 4 min of tidal breathing (10 L/min) and isocapnic hyperventilation of 60 L/min.

Measurements and results: FeNO was measured by collecting the exhaled air during the last minute of each trial and passing it through a chemiluminescence analyzer. The expired NO levels in the plateau phases of slow (30 mL/s) and fast (200 mL/s) single-breath exhalations were also obtained before and after hyperventilation. The VNO (mean ± SEM) increased from 89.8 ± 12.3 to 329.1 ± 36.2 nL/min as VE rose (p < 0.001). However, neither the quantities of eNOair nor eNOalv changed with hyperventilation (eNOair range before to after, 34.9 ± 7.7 to 30.9 ± 6.4 parts per billion [ppb], p = 0.96; eNOalv range before to after, 7.3 ± 1.5 to 6.5 ± 1.1 ppb, p = 0.97).

Conclusions: These data demonstrate that the amount of NO in equilibrium with the airway walls and alveoli are not altered by hyperpnea. Rather, the apparent augmentation in VNO in such circumstances appears to be an arithmetic artifact.

Key Words: hyperpnea • isocapnic hyperventilation • nitric oxide synthesis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The discovery of nitric oxide (NO) in the exhaled breath of humans1 has given rise to considerable interest in the role that this molecule plays in airway physiology.234 NO is generated in the airway epithelium and the endothelium of both the bronchial and pulmonary circulations, as well as the sensory nervous system during the conversion of the amino acid L-arginine to L-citrulline by constitutive and inducible NO synthesis.235 As a result, NO is strategically located throughout the lungs to influence airway and vascular function. However, the events regulating its release remain imperfectly understood, and there is controversy as to whether commonly encountered stimuli such as hyperpnea influence synthesis.

Most46789101112 but not all studies13 have suggested that the production of NO, as measured by minute ventilation (VE) times the fractional concentration of NO in the exhaled air (FeNO) [VNO], rises during exercise and hyperventilation. Since the magnitude of the increase, at least during physical exertion, correlates with carbon dioxide production, oxygen consumption, and heart rate, it has been assumed that NO augmentation is an important element in regulating these processes.46789101112 This may or may not be the case, however, for such correlations do not uniformly exist with voluntary hyperventilation.13 More importantly, it is unclear if the level of NO in the lungs actually changes whenever VE rises.13

To provide data on these issues, we made use of recently described diffusion models1415 to determine the amount of NO in equilibrium with the conducting airways (eNOair) and the amount of NO diffusing from the alveoli (eNOalv) before and after hyperpnea. We then contrasted these results with those seen when NO production is calculated in the standard manner.46789101112 Our observations form the basis of this report.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Sixteen normal nonsmoking volunteers served as our subjects. Each participant breathed air at ambient temperature and humidity at a VE of 10 L/min to standardize baseline conditions, and then performed isocapnic hyperventilation at 60 L/min using standard techniques.1617 Each period of ventilation lasted 4 min, during which time the expirate was directed into a reservoir balloon that was being constantly evacuated at a known rate through a calibrated rotameter into a dry gas meter.1617 VE was controlled at the desired value by coaching the subjects to keep the balloon filled. The level of VE was then verified directly with the dry gas meter. End-tidal carbon dioxide concentrations were monitored during hyperventilation (Nellcor N-1000; Mallinckrodt; Kansas City, MO), and sufficient carbon dioxide was added to the inspiratory port of the exchanger to maintain end-tidal carbon dioxide at eucapnic levels.

Expired air was collected during the final minute of both the resting and hyperventilation trials in nondiffusing bags. The mouthpiece of the collecting system contained a fixed resistance of 5 cm H2O to close the soft palate and exclude nasal NO.18 The FeNO was recorded off-line by passing the exhaled gas through a chemiluminescence NO analyzer designed for physiologic measurements (CLD 77 AM; ECO Physics; Ann Arbor, MI).19 The system was calibrated with NO-free gas and a standard NO concentration of 15 parts per billion (ppb) [Praxair; Bethlehem, PA] daily before use. The linearity of the analyzer was verified with analytically certified gases of 0 ppb and 200 ppb NO (Scott Specialty Gases; Plumsteadville, PA). The detection limit was 1.1 ± 0.2 ppb (coefficient of variation [CV], < 1%) [mean ± SEM]. Ambient NO levels were recorded at the start and end of each experiment. If the levels on any given day were ≥ 20 ppb, no studies were undertaken. It has been our experience and that of others20 that ambient levels ≤ 15 ppb have little impact on expired NO (eNO) values. The output of the analyzer was fed into a time-based recorder (Omega Engineering, Inc., Stamford, CT) for display. The production of NO per minute (VNO) was calculated as the product of FeNO and VE.46789101112

Prior to each period of ventilation, immediately after the collection of exhaled gas and then again 5 min later, the subjects performed single-breath exhalations from total lung capacity to residual volume at flow rates of 30 mL/s and 250 mL/s through the NO analyzer to assess the quantities of eNOair and eNOalv.1415 The desired flows were achieved by attaching calibrated resistors (Restrictor Set HTF 5019X; Sievers Instruments; Boulder, CO) to the end of the mouthpiece and coaching the subjects to maintain a constant pressure for the length of the exhalation. During the low-flow and high-flow experiments, mouth pressures were monitored continuously and kept at 8 to 9 cm H2O and 14 to 15 cm H2O, respectively. The output from the NO analyzer was digitized and stored in a personal computer. During each maneuver, the sustained steady-state eNOair and eNOalv plateau concentrations were averaged electronically and the results verified manually. All exhalations were performed in duplicate, and CVs were calculated.

The protocol was approved by the Institutional Review Board for Human Investigation at MetroHealth Medical Center, and informed consent was obtained from each volunteer before participation. The data were analyzed by paired t tests and one-factor analyses of variance. A p value < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographics of the participants, the inspired air conditions, and the resting eNO values are provided in Table 1 . Eight women and eight men (mean ± SEM age, 41 ± 3 years) served as subjects. The inspired air temperatures in the laboratory averaged 22.4 ± 1.5°C with a relative humidity of 49.5 ± 4.4%. The ambient NO levels were 2.7 ± 0.16 ppb (range, 1 to 11 ppb). The mean FeNO during baseline tidal breathing (10 L/min) was 9.0 ± 1.2 ppb, and the resting VNO equaled 89.8 ± 12.3 nL/min. The control airway and alveolar plateau concentrations were 34.9 ± 7.7 ppb and 7.1 ± 1.1 ppb, respectively.


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  		Table 1. Demographics, Inspired Air Conditions, and eNO Concentrations Prior to Breathing at 10 L/min*

 
During hyperventilation, FeNO fell significantly to 5.5 ± 0.6 ppb (p < 0.001) and VNO rose 266% to 329.1 nL/min (p < 0.001) [Fig 1 ]. Airway and alveolar NO concentrations, however, did not materially change (Fig 2 ).



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  		Figure 1. FeNO and VNO at rest and with hyperpnea. The left panel presents the FeNO values measured at ventilations (VE) of 10 L/min and 60 L/min. The right panel shows the VNO at the same VE. The data points are mean values, and the brackets are 1 SEM.

 


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  		Figure 2. Sequential observations of single-breath eNO plateau values for different flows during rest and hyperpnea. The solid circles and lines represent the eNO concentrations obtained during slow exhalations (30 mL/s) following VE of 10 L/min and 60 L/min. The concentrations so derived are thought to represent eNO in equilibrium with the airways. The open circles and broken lines indicate the eNO found with the faster expirations (250 mL/s). These levels are believed to reflect NO diffusing to and from the alveoli. The data points are mean values, and the brackets are 1 SEM. The baseline points were obtained prior to imposing a VE of 10 L/min. The resting experiments 10 L/min are shown on the left and the hyperpnea trials (60 L/min) on the right. Each data point serves as the control for the subsequent value.

 
During the control period, the eNOair value was 34.9 ± 7.7 ppb. Immediately following hyperventilation, there was an 11.5% decrement to 30.9 ± 6.4 ppb that remained constant over the next 5 min. There were no significant differences between control and intervention values by analysis of variance (p = 0.96). A similar pattern was seen with the eNOalv levels (p = 0.97). The baseline eNOalv was 7.3 ± 1.5 ppb and fell to 6.4 ± 3.8 ppb 5 min after hyperventilation. In no case did either eNOair or eNOalv rise following hyperpnea.

Representative examples of the eNO patterns during the slow and fast exhalations are presented in Figure 3 . The eNOair plateaus during the 30 mL/s trials were sustained for an average of 36.1 ± 3.2 s (between-trials mean range, 35.0 ± 3.1 to 36.8 ± 2.9 s, p = 0.99; between-subject range, 20 to 59 s). The plateaus with the 250 mL/s maneuvers lasted approximately one third as long (11.7 ± 3.1 s) and were also highly reproducible (between-trials mean range, 11.4 ± 1.0 to 12.1 ± 1.1 s, p = 0.99; individual between-subject range, 7 to 21 s).



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  		Figure 3. Representative eNO patterns during slow exhalations (top) and fast exhalations (bottom). These are duplicate studies obtained from a single subject. The tracings demonstrate the sustained duration of the plateau phase and its reproducibility. The ordinate presents NO, and the abscissa is time.

 
The CVs for repeat measures are shown in Figure 4 . The CV for eNOair averaged approximately 5%, and there were no differences between the baseline and hyperpnea trials (eNOair, p = 0.96). The eNOalv data ranged between 2% and 3% (p = 0.97).



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  		Figure 4. Reproducibility of the NO values obtained from the exhaled plateaus. The heights of the bars are mean values, and the brackets represent 1 SEM.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of the present study demonstrate that hyperpnea is not associated with up-regulation of NO synthesis in the lungs of normal subjects. Although NO generation as measured by VNO appears to rise in such circumstances, it does so for mathematical rather than physiologic reasons. As the ventilatory component of the VE-NO relationship increases, eNO actually falls. However, since the magnitude of the change in VE far exceeds the decrement in NO, the product enlarges, giving the impression that production was up-regulated. Our data show that this is clearly an epiphenomenon. While it is occurring, there are no detectable changes in the concentration of NO in equilibrium with the airways or alveoli.

The exchange dynamics of NO in the respiratory tract and its measurement in the exhaled air are complex. Unlike oxygen and carbon dioxide, NO is generated throughout the lungs as a free radical and reacts with a variety of substrates.221 As a result, the quantity exhaled represents the algebraic sum of the amounts produced minus those that are converted chemically or diffused away.1415 Both the alveoli and the conducting airways contribute to the exhaled concentrations, but do so in variable amounts. The level in the alveoli in adults is believed to be low because of the avid binding of NO with hemoglobin. In contrast, the quantities in the bronchi are considerably higher and fluctuate significantly in concert with the underlying physiologic state.221 During exhalation, the NO in the air stream leaving the alveoli is enriched by diffusion from the bronchial walls in direct proportion to the concentration gradients that exist and inversely with the velocity of the gas stream.1415 For any given gradient, the slower the flow, the higher the exhaled concentrations and the more eNO reflects the contribution from the airways. Alternatively, the faster the flow, the shorter the time for diffusion and the closer the eNO value is to alveolar levels.1415 Thus, if one is seeking to find a change in production in response to a given stimulus, it is critical that the before and after assessments be undertaken at identical flow rates. The data in Figures 2, 3 show that this requirement was readily achieved. Holding mouth pressure constant while exhaling through calibrated resistors produced highly reproducible steady-state NO elimination profiles.

The flows that we employed in the single-breath trials represent a simplification of the NO elimination model of Silkoff et al.15 The flow rates chosen to examine exhaled profiles fit nicely within the ranges thought to reflect the airway and alveolar components and were sustained sufficiently long to achieve highly reproducible steady-state values. The assumption we made was that, all else being equal, any up-regulation of NO synthesis would be manifest as an elevated plateau in the compartment in which it was generated.

We chose plateau values as representing net synthesis rather than determining flow independent parameters such as NO diffusion capacity, flux, or airway wall concentrations because of the temporal constraints imposed by our protocol. Since neither the site of any potential up-regulation nor the time course was known, we believed we needed to make serial measurements of airway and alveolar concentrations that could be completed in reasonably rapid succession from the end of hyperventilation. The use of the multiple slow flow rates required for the calculation of the above elements would have defeated our purpose. Because of the time necessary to complete such a protocol, we could never have been certain if NO synthesis was changing as we measured it.

Our data in both the multiple and single-breath analyses complement and extend previous studies.4678910111213 The VE-FeNO patterns recorded are typical of those reported in other trials with both hyperventilation11113 and exercise.67891222 High levels of VE (ie, three or more times resting levels) are typically associated with decrements in FeNO and computed increments in VNO of the magnitudes we observed. The eNO concentrations are also comparable to those in the literature. Silkoff et al15 noted steady-state eNOair concentrations between 42 ppb and 25 ppb at air flows of 21 mL/s and 38 mL/s, respectively. Similarly, St. Croix and associates13 found values between 36 ppb and 41 ppb at an exhaled flow of 46 mL/s. As can be seen in Figure 2, our data fall within the former ranges and lie quite close to the latter.

Like St. Croix and colleagues,13 we did not find that hyperpnea augmented NO synthesis. It is of interest that in their experiment, eNO did not rise with exercise or voluntary hyperventilation, but rather fell significantly. This finding suggests that production either decreased or that the before and after exhaled flow rates may not have been identical.1415 Our data do not support attenuation. We used a calibrated system with slower flow rates and lower mouth pressures to generate NO plateaus, but focused on hyperventilation. This route was chosen because isocapnic hyperventilation permits precise control over the respiratory patterns during and especially after hyperpnea. Unlike exercise, during which VE can remain elevated with short inspiratory times after exertion, particularly with high work loads because of continuing metabolic demands, hyperventilation can be stopped at will. As a result, our subjects could repeatedly perform the required flow maneuvers without being interrupted by the need to take a breath. Consequently, we could be confident that we were not inadvertently altering local events that controlled NO synthesis and elimination.

We appreciate that since we did not study all forms of hyperpnea, we cannot state with certitude that our results preclude an increase in NO production with exercise. However, we do not believe this to be the case. Others13 have examined this phenomenon by matching the ventilatory levels induced by physical exertion and voluntary hyperventilation and have not found any difference between them in the amount of NO generated in the tracheobronchial tree. Given that the thermal and mechanical effects of exercise and hyperventilation on the airways are identical when VE and the inspired air conditions are matched and carbon dioxide controlled, such findings are not surprising.16232425

In summary, hyperpnea is not associated with an increase in NO synthesis in either the conducting airways or alveoli. As a result, the suggestions in the literature that augmented NO production is linked to the cardiovascular, respiratory, and metabolic consequences of hyperpnea needs to be reevaluated.


   Footnotes
 
Abbreviations: CV = coefficient of variation; eNO = expired nitric oxide; eNOair = amount of nitric oxide in equilibrium with the conducting airways; eNOalv = amount of nitric oxide diffusing from the alveoli; FeNO = fractional expired nitric oxide concentration; NO = nitric oxide; ppb = parts per billion; VE = minute ventilation; VNO = minute ventilation times the fractional expired nitric oxide concentration

Supported in part by grants HL-33791 and HL-04140 from the National Heart, Lung, and Blood Institute and by General Clinical Research Center Grant MO1-RR00080 from the National Center for Research Resources, United States Public Health Services.

Received for publication April 25, 2005. Accepted for publication June 3, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Gustafsson, LE, Leone, AM, Persson, MG, et al (1991) Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 18,852-857
  2. Barnes, PJ, Balvisi, MG Nitric oxide and lung disease. Thorax 1993;48,1034-1043[ISI][Medline]
  3. Gaston, B, Drazen, JM, Loscalzo, J, et al The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994;149,538-551[Abstract]
  4. Hyde, RW, Geigel, EJ, Olszowka, AJ, et al Determination of production of nitric oxide by lower airways of humans: theory. J Appl Physiol 1997;82,1290-1296[Abstract/Free Full Text]
  5. DuBois, AB, Kelley, PM, Douglas, JS, et al Nitric oxide production and absorption in trachea, bronchi, bronchioles, and respiratory bronchioles of humans. J Appl Physiol 1999;86,159-167[Abstract/Free Full Text]
  6. Bauer, JA, Wald, JA, Doran, S, et al Endogenous nitric oxide in expired air: effects of acute exercise in humans. Life Sci 1994;55,1903-1909[CrossRef][ISI][Medline]
  7. Iwamoto, J, Pendergast, DR, Suzuki, H, et al Effect of graded exercise on nitric oxide in expired air in humans. Respir Physiol 1994;97,333-345[CrossRef][ISI][Medline]
  8. Maroun, MJ, Mehta, S, Turcotte, R, et al Effects of physical conditioning on endogenous nitric oxide output during exercise. J Appl Physiol 1995;79,1219-1225[Abstract/Free Full Text]
  9. Matsumoto, A, Hirata, Y, Momomura, S, et al Increased nitric oxide production during exercise. Lancet 1994;343,849-850[CrossRef][ISI][Medline]
  10. Persson, MG, Wiklund, NP, Gustafsson, LE Endogenous nitric oxide in single exhalations and the change during exercise. Am Rev Respir Dis 1993;148,1210-1214[ISI][Medline]
  11. Phillips, CR, Giraud, GD, Holden, WE Exhaled nitric oxide during exercise: site of release and modulation by ventilation and blood flow. J Appl Physiol 1996;80,1865-1871[Abstract/Free Full Text]
  12. Trolin, G, Anden, T, Hedenstierna, G Nitric oxide (NO) in expired air at rest and during exercise. Acta Physiol Scand 1994;151,159-163[ISI][Medline]
  13. St. Croix, CM, Wetter, TJ, Pegelow, DF, et al Assessment of nitric oxide formation during exercise. Am J Respir Crit Care Med 1999;159,1125-1133[Abstract/Free Full Text]
  14. George, SC, Hogman, M, Permutt, S, et al Modeling pulmonary nitric oxide exchange. J Appl Physiol 2004;96,831-839[Abstract/Free Full Text]
  15. Silkoff, PE, Sylvester, JT, Zamel, N, et al Airway nitric oxide diffusion in asthma. Am J Respir Crit Care Med 2000;161,1218-1228[Abstract/Free Full Text]
  16. Gilbert, IA, Fouke, JM, McFadden, ER, Jr Intra-airway thermodynamics during exercise and hyperventilation in asthmatics. J Appl Physiol 1988;64,2167-2174[Abstract/Free Full Text]
  17. Gilbert, IA, McFadden, ER, Jr Airway cooling and rewarming: the second reaction sequence in exercise-induced asthma. J Clin Invest 1992;90,699-704[ISI][Medline]
  18. 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]
  19. American Thoracic Society.. Recommendations for the standardized procedures for the online and offline measurement of lower respiratory nitric oxide and nasal nitric oxide in adults and children. Am J Respir Crit Care Med 1999;160,2104-2117[Free Full Text]
  20. Borland, C, Cox, Y, Higgenbottom, T Measurement of exhaled nitric oxide in man. Thorax 1993;48,1160-1162[Abstract]
  21. Massaro, AF, Drazen, JM Invited editorial on "exhaled nitric oxide during exercise: site of release and modulation by ventilation and blood flow". J Appl Physiol 1996;80,1863-1864[Free Full Text]
  22. Chirpaz-Oddou, MF, Favre-Juvin, A, Flore, P, et al Nitric oxide response in exhaled air during an incremental exhaustive exercise. J Appl Physiol 1997;82,1311-1318[Abstract/Free Full Text]
  23. Mc Fadden, ER, Jr, Pichurko, BM Intra-airway thermal profiles during exercise and hyperventilation in normal man. J Clin Invest 1985;76,1007-1010[ISI][Medline]
  24. Kotaru, C, Hejal, RB, Finigan, JH, et al Influence of hyperpnea on airway surface fluid volume and osmolarity in normal humans. J Appl Physiol 2002;93,154-160[Abstract/Free Full Text]
  25. Kotaru, C, Hejal, RB, Finigan, JH, et al Desiccation and hypertonicity of the airway surface fluid and thermally induced asthma. J Appl Physiol 2003;94,227-233[Abstract/Free Full Text]




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