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Communications to the Editor |

Diffusion Capacity for Nitric Oxide and Carbon Monoxide FREE TO VIEW

Ivo van der Lee, MD; Pieter Zanen, MD, PhD
Author and Funding Information

Affiliations: St. Antonius Hospital, Nieuwegein, The Netherlands,  Concordia University, Montreal, QU, Canada

Correspondence to: Ivo van der Lee, MD, Department of Pulmonary Disease, St. Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, The Netherlands; e-mail: vdlee@tiscali.nl



Chest. 2004;126(5):1708-1710. doi:10.1378/chest.126.5.1708
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To the Editor:

We read with interest the article by Zavorsky et al1 about the relationship between the diffusion capacity of the lung for nitric oxide (Dlno) and exercise. Their study was well performed, but leaves some serious matters concerning the methods and results.

First, after reading the section concerning the calculation of diffusion capacities and pulmonary capillary blood flow (Vc), it still is unclear to us how the investigators determined the Vc. The determination of the specific blood transfer conductance for carbon monoxide (ΘCO) is essential in calculating the product 1/θCO × Vc. In the past years, different equations23 have been used to calculate the ΘCO, as Borland et al stated in their reply to Heller et al.4 Zavorsky et al1 do not describe which equation they used. As the results of the Vc are higher than expected, as much as 134% higher than in previous studies,,5 we think a clearer description of methodology is necessary. As the authors state in their discussion, a probable cause for the high Vc lies in the high Dlno values they determined.

A second issue is the calculation of membrane diffusing capacity for carbon monoxide (Dmco), defined as Dlno/1.94, which is solely based on the theoretical relationship between the Dlno and diffusion capacity of the lung for carbon monoxide (Dlco). A recent study6 revealed a higher Dlno/Dmco ratio of 2.42. Other research,23 constantly shows a higher Dlno/Dmco ratio than the expected 1.94.

A third concern is the extremely high inspiratory nitric oxide levels used. The most obvious reason for this is the use of the electrochemical cell, because the cell is less sensitive than the chemiluminescence analyzers other investigators have used. Zavorsky et al1 state that the nitric oxide backpressure varies between 11 ppb and 66 ppb. This estimate is much too high; Pietropaoli et al7 showed values of 2 to 3 ppb in healthy subjects at high exhalation flows. The use of the very high nitric oxide levels can lead to vasodilation, what can explain the significantly higher Dlco obtained with the simultaneous Dlno measurements.

We think the overall findings of the investigators holds up, namely the dependence of Dlno on alveolar volume, and the linear increment of Dlco and Dlno with increasing workload, but the absolute values of pulmonary membrane diffusing capacity and Vc are to be interpreted with caution. Because of the fact there are still no exact values of ΘCO and specific blood transfer conductance for nitric oxide, we would like to propose the recommendation to publish and interpret the values of Dlco and Dlno, in which the latter gives more insight to the true function of the alveolocapillary membrane than the first, instead of publishing pulmonary membrane diffusing capacity and Vc values, which are difficult to interpret.

Zavorsky, GS, Quiron, KB, Massarelli, PS, et al (2004) The relationship between single-breath diffusion capacity of the lung for nitric oxide and carbon monoxide during various exercise intensities.Chest125,1019-1027. [CrossRef] [PubMed]
 
Guenard, H, Varene, N, Vaida, P Determination of lung capillary blood volume and membrane diffusing capacity in man by the measurements of NO and CO transfer.Respir Physiol1987;70,113-120. [CrossRef] [PubMed]
 
Borland, CD, Cox, Y Effect of varying alveolar oxygen partial pressure on diffusing capacity for nitric oxide and carbon monoxide, membrane diffusing capacity and lung capillary blood volume.Clin Sci (Lond)1991;81,759-765. [PubMed]
 
Heller, H, Brandt, S, Schuster, KD, et al Pulmonary nitric oxide uptake reflects the entire diffusive properties of the alveolar capillary membrane.J Appl Physiol2002;92,1772-1773. [PubMed]
 
Zanen, P, van der Lee, I, van der Mark, T, et al Reference values for alveolar membrane diffusion capacity and pulmonary capillary blood volume.Eur Respir J2001;18,764-769. [CrossRef] [PubMed]
 
Phansalkar, AR, Hanson, CM, Shakir, AR, et al Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis.Am J Respir Crit Care Med2004;169,1039-1040
 
Pietropaoli, AP, Perillo, IB, Torres, A, et al Simultaneous measurement of nitric oxide production by conducting and alveolar airways of humans.J Appl Physiol1999;87,1532-1542. [PubMed]
 
To the Editor:

I would like to express sincere thanks to Dr. Borland for commenting on our recent article.1Dr. Borland2 previously investigated the diffusion capacity of the lung for carbon monoxide (Dlco) and diffusion capacity of the lung for nitric oxide (Dlno) in three subjects at various exercise levels and increased levels of inspired oxygen, which was missing from our discussion. In the present study, we looked at higher workloads and the effect of hypoxia (15% inspired oxygen). The hypoxic inspiratory gas should have resulted in an alveolar Po2 of approximately 90 mm Hg in our subjects. We hypothesized that the reduced inspiratory oxygen concentrations may have increased the blood transfer conductance for carbon monoxide (ΘCO) by approximately 14%,,2allowing for the 6% overestimation of Dlco that we observed. As such, the Dlno/Dlco ratio of 4.52 that we report may actually be slightly higher in normoxia since the blood transfer conductance for nitric oxide (ΘNO), unlike ΘCO, is not affected by hypoxia. The data by Borland and Cox3 do indeed show that the Dlno/Dlco ratio rises with escalating inspired oxygen concentrations.,3 We have since corrected the problem of inspiring low oxygen concentrations during a Dlno maneuver by using a higher concentration of nitric oxide (900 ppm) in a NO/N2 tank, and thus the dilution in the inspiratory bag is minimal (the oxygen concentration is now approximately 20%). We have also added an oxygen analyzer that directly measures the inspiratory oxygen concentrations prior to inhalation to verify normal oxygen delivery to the alveolus. Nevertheless, this does not change the fact that inspired oxygen concentrations were the same at rest and throughout all levels of exercise, and thus the Dlno/Dlco ratios were maintained.,1

We also appreciate Drs. van der Lee and Zanen for their comments on the methodology chosen. We would like to clarify some of their concerns. In determining pulmonary capillary blood volume (Vc), a main factor is the specific ΘCO. We used the following formula by Roughton and Forster2: 1/ΘCO = 0.73 + 0.0058 × (Po2). The alveolar Po2 and hemoglobin concentration were standardized to 120 mm Hg and 146 g/L, respectively, and therefore 1/ΘCO was 1.426. We acknowledge that the Vc at rest was approximately 25% larger than the expected 92.4-mL predicted values for healthy male populations,4 (1/predicted Vc = − 0.0201 × height in meters + 0.047). However, there are several reasons for this higher value as presented our discussion.,1 First, the Dlco at rest in our study,1 was approximately 10% larger than either the predicted5 or our measured1values when 232 ppm of nitric oxide (balance N2) gases were added to the CO/He/O2 diffusion mixture. The addition of NO/N2 gases from a 232 ppm NO tank (balance N2) most likely diluted the inspiratory bag of oxygen, and consequently resulted in a higher overall Dlco. We have performed some calculations, and if we reduced the overall exaggerated resting Dlco by 10% in our study from 46 to 42 mL/min/mm Hg, the Vc would have been reduced from 116 mL to approximately 99 mL according to the formula by Roughton and Forster,2 which follows: 1/Dlco = 1/Dmco + 1/ΘCO × Vc, where Dmco is membrane diffusion capacity for carbon monoxide. A value of 99 mL is closer to the predicted value of 92.4 mL. This brings us to a second and related reason why the Dlcos at rest and during exercise may have been slightly elevated. As reported in our discussion,,1the alveolar Po2 was reported as 120 mm Hg. However, due to the dilution of CO/He/O2 diffusion mixture with the 232 ppm NO (balance N2), the oxygen concentrations in the inspiratory bag may have been approximately 15%. As such, the alveolar Po2 during inspiration would have decreased to approximately 90 mm Hg, and therefore that would increase ΘCO by 14%,2 resulting in an overall increase in Dlco. Therefore, if we take the Dlco value of 42 mL/min/mm Hg that was obtained from the Dlco method,1(NO/N2 mixture is absent), and use the 1/ΘCO value of 1.252, according to Roughton and Forster,2 the Vc will have further decreased to 86.8 mL and would be much closer to the predicted value of 92.4 mL. We have since corrected the problem of having the subjects inspire low oxygen concentrations during a Dlno maneuver by using a higher concentration of nitric oxide (900 ppm) in a NO/N2 tank, and thus the dilution in the inspiratory bag is minimal (the oxygen concentration is now approximately 20%). We have verified the modifications in our laboratory by looking at a groups of male subjects (mean height, 181.4 ± 6.8 cm; weight, 86.4 ± 9.5 kg [± SD]), and the average Vc at rest was 84 ± 21 mL calculated from simultaneous measurement of nitric oxide and carbon monoxide gases from the single-breath method. This is quite close to the predicted value.,4

Their second issue is concerning the calculation of Dmco. As mentioned in our article,1 we decided to use the theoretical ratio of 1.97 since the diffusivity of nitric oxide is approximately 1.97 times greater than carbon monoxide. Other authors69 have used 1.97 as the theoretical ratio of Dlno to Dmco during single-breath maneuvers. The ratio of 2.42 has been determined during rebreathing maneuvers,11 not single breath as was the case in the present study. Interestingly, a ratio of 2.42 results in a resting Dmco of 86.9 mL/min/mm Hg, a value more in line with the current normative values. Obviously, more research is required to determine the true Dlno to Dmco in humans.

Their third concern is that we used high levels of nitric oxide gas (mean concentration on inspiration, 67 ppm). Previous studies1213 have used 40 to 50 ppm of NO during a single-breath maneuver, while other studies have had subjects rebreathe between 20 ppm and 40 ppm for least 16 s1011 to 5 min,14 so our inspiratory nitric oxide levels are not that high as van der Lee and Zanen have suggested. Nevertheless, those studies1011,14 demonstrated that there is no effect of either repeated single-breath maneuvers or rebreathing maneuvers on pulmonary gas exchange and lung diffusion capacity, so we are confident that the inspiratory levels of nitric oxide from our study did not cause vasodilation of the pulmonary capillaries leading to the high Dlco levels. In fact, data in our laboratory have shown that even four repeated single-breathhold maneuvers interspersed with 5 min rest does not increase Dlno or Dlco.

Despite the concerns with the methods, the overall findings of our study1 holds up, namely the dependence of Dlno on alveolar volume and workload, and that the relationship between Dlno vs workload, and Dlco vs workload is linear. We appreciate the comments by Drs. van der Lee and Zanen.

References
Zavorsky, GS, Quiron, KB, Massarelli, PS, et al The relationship between single-breath diffusion capacity of the lung for nitric oxide and carbon monoxide during various exercise intensities.Chest2004;125,1019-1027. [CrossRef] [PubMed]
 
Roughton, FJW, Forster, RE Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries.J Appl Physiol1957;11,290-302. [PubMed]
 
Borland, CD, Cox, Y Effect of varying alveolar oxygen partial pressure on diffusing capacity for nitric oxide and carbon monoxide, membrane diffusing capacity and lung capillary blood volume.Clin Sci (Colch)1991;81,759-765
 
Frans, A Les valeurs normales du volume capillaire pulmonaire (Vc) et de la capacite de diffusion de la membrane alveolo-capillare. Arcangeli, P eds.Normal values for respiratory function in man1970,352-363 Panminerva Medica. Torino:
 
Crapo, RO, Morris, AH Standardized single breath normal values for carbon monoxide diffusing capacity.Am Rev Respir Dis1981;123,185-189. [PubMed]
 
Guenard, H, Varene, N, Vaida, P Determination of lung capillary blood volume and membrane diffusing capacity in man by the measurements of NO and CO transfer.Respir Physiol1987;70,113-120. [CrossRef] [PubMed]
 
Manier, G, Moinard, J, Techoueyres, P, et al Pulmonary diffusion limitation after prolonged strenuous exercise.Respir Physiol1991;83,143-153. [CrossRef] [PubMed]
 
Manier, G, Moinard, J, Stoicheff, H Pulmonary diffusing capacity after maximal exercise.J Appl Physiol1993;75,2580-2585. [PubMed]
 
Vaida, P, Kays, C, Riviere, D, et al Pulmonary diffusing capacity and pulmonary capillary blood volume during parabolic flights.J Appl Physiol1997;82,1091-1097. [PubMed]
 
Tamhane, RM, Johnson, RL, Jr, Hsia, CC Pulmonary membrane diffusing capacity and capillary blood volume measured during exercise from nitric oxide uptake.Chest2001;120,1850-1856. [CrossRef] [PubMed]
 
Phansalkar, AR, Hanson, CM, Shakir, AR, et al Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis.Am J Respir Crit Care Med2004;169,1034-1040. [CrossRef] [PubMed]
 
Borland, CD, Higenbottam, TW A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide.Eur Respir J1989;2,56-63. [PubMed]
 
Tsoukias, NM, Dabdub, D, Wilson, AF, et al Effect of alveolar volume and sequential filling on the diffusing capacity of the lungs: II. Experiment.Respir Physiol2000;120,251-271. [CrossRef] [PubMed]
 
Sheel, AW, Edwards, MR, Hunte, GS, et al Influence of inhaled nitric oxide on gas exchange during normoxic and hypoxic exercise in highly trained cyclists.J Appl Physiol2001;90,926-932. [PubMed]
 

Figures

Tables

References

Zavorsky, GS, Quiron, KB, Massarelli, PS, et al (2004) The relationship between single-breath diffusion capacity of the lung for nitric oxide and carbon monoxide during various exercise intensities.Chest125,1019-1027. [CrossRef] [PubMed]
 
Guenard, H, Varene, N, Vaida, P Determination of lung capillary blood volume and membrane diffusing capacity in man by the measurements of NO and CO transfer.Respir Physiol1987;70,113-120. [CrossRef] [PubMed]
 
Borland, CD, Cox, Y Effect of varying alveolar oxygen partial pressure on diffusing capacity for nitric oxide and carbon monoxide, membrane diffusing capacity and lung capillary blood volume.Clin Sci (Lond)1991;81,759-765. [PubMed]
 
Heller, H, Brandt, S, Schuster, KD, et al Pulmonary nitric oxide uptake reflects the entire diffusive properties of the alveolar capillary membrane.J Appl Physiol2002;92,1772-1773. [PubMed]
 
Zanen, P, van der Lee, I, van der Mark, T, et al Reference values for alveolar membrane diffusion capacity and pulmonary capillary blood volume.Eur Respir J2001;18,764-769. [CrossRef] [PubMed]
 
Phansalkar, AR, Hanson, CM, Shakir, AR, et al Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis.Am J Respir Crit Care Med2004;169,1039-1040
 
Pietropaoli, AP, Perillo, IB, Torres, A, et al Simultaneous measurement of nitric oxide production by conducting and alveolar airways of humans.J Appl Physiol1999;87,1532-1542. [PubMed]
 
Zavorsky, GS, Quiron, KB, Massarelli, PS, et al The relationship between single-breath diffusion capacity of the lung for nitric oxide and carbon monoxide during various exercise intensities.Chest2004;125,1019-1027. [CrossRef] [PubMed]
 
Roughton, FJW, Forster, RE Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries.J Appl Physiol1957;11,290-302. [PubMed]
 
Borland, CD, Cox, Y Effect of varying alveolar oxygen partial pressure on diffusing capacity for nitric oxide and carbon monoxide, membrane diffusing capacity and lung capillary blood volume.Clin Sci (Colch)1991;81,759-765
 
Frans, A Les valeurs normales du volume capillaire pulmonaire (Vc) et de la capacite de diffusion de la membrane alveolo-capillare. Arcangeli, P eds.Normal values for respiratory function in man1970,352-363 Panminerva Medica. Torino:
 
Crapo, RO, Morris, AH Standardized single breath normal values for carbon monoxide diffusing capacity.Am Rev Respir Dis1981;123,185-189. [PubMed]
 
Guenard, H, Varene, N, Vaida, P Determination of lung capillary blood volume and membrane diffusing capacity in man by the measurements of NO and CO transfer.Respir Physiol1987;70,113-120. [CrossRef] [PubMed]
 
Manier, G, Moinard, J, Techoueyres, P, et al Pulmonary diffusion limitation after prolonged strenuous exercise.Respir Physiol1991;83,143-153. [CrossRef] [PubMed]
 
Manier, G, Moinard, J, Stoicheff, H Pulmonary diffusing capacity after maximal exercise.J Appl Physiol1993;75,2580-2585. [PubMed]
 
Vaida, P, Kays, C, Riviere, D, et al Pulmonary diffusing capacity and pulmonary capillary blood volume during parabolic flights.J Appl Physiol1997;82,1091-1097. [PubMed]
 
Tamhane, RM, Johnson, RL, Jr, Hsia, CC Pulmonary membrane diffusing capacity and capillary blood volume measured during exercise from nitric oxide uptake.Chest2001;120,1850-1856. [CrossRef] [PubMed]
 
Phansalkar, AR, Hanson, CM, Shakir, AR, et al Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis.Am J Respir Crit Care Med2004;169,1034-1040. [CrossRef] [PubMed]
 
Borland, CD, Higenbottam, TW A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide.Eur Respir J1989;2,56-63. [PubMed]
 
Tsoukias, NM, Dabdub, D, Wilson, AF, et al Effect of alveolar volume and sequential filling on the diffusing capacity of the lungs: II. Experiment.Respir Physiol2000;120,251-271. [CrossRef] [PubMed]
 
Sheel, AW, Edwards, MR, Hunte, GS, et al Influence of inhaled nitric oxide on gas exchange during normoxic and hypoxic exercise in highly trained cyclists.J Appl Physiol2001;90,926-932. [PubMed]
 
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