Diffusion Capacity for Nitric Oxide and Carbon Monoxide
2004; Elsevier BV; Volume: 126; Issue: 5 Linguagem: Inglês
10.1016/s0012-3692(15)31396-9
ISSN1931-3543
Autores Tópico(s)Respiratory Support and Mechanisms
ResumoI would like to express sincere thanks to Dr. Borland for commenting on our recent article.1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Dr. Borland2Roughton 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 Physiol. 1957; 11: 290-302Crossref PubMed Scopus (615) Google Scholar 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%,2Roughton 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 Physiol. 1957; 11: 290-302Crossref PubMed Scopus (615) Google Scholar allowing 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 Cox3Borland 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: 759-765Crossref Scopus (49) Google Scholar do indeed show that the Dlno/Dlco ratio rises with escalating inspired oxygen concentrations.3Borland 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: 759-765Crossref Scopus (49) Google Scholar 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.1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar 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 Forster2Roughton 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 Physiol. 1957; 11: 290-302Crossref PubMed Scopus (615) Google Scholar: 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 populations4Frans A Les valeurs normales du volume capillaire pulmonaire (Vc) et de la capacite de diffusion de la membrane alveolo-capillare.in: Arcangeli P Normal values for respiratory function in man. Panminerva Medica, Torino1970: 352-363Google Scholar (1/predicted Vc = − 0.0201 × height in meters + 0.047). However, there are several reasons for this higher value as presented our discussion.1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar First, the Dlco at rest in our study1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar was approximately 10% larger than either the predicted5Crapo RO Morris AH Standardized single breath normal values for carbon monoxide diffusing capacity.Am Rev Respir Dis. 1981; 123: 185-189PubMed Google Scholar or our measured1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar values 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,2Roughton 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 Physiol. 1957; 11: 290-302Crossref PubMed Scopus (615) Google Scholar 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,1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar the 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%,2Roughton 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 Physiol. 1957; 11: 290-302Crossref PubMed Scopus (615) Google Scholar 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 method1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar (NO/N2 mixture is absent), and use the 1/ΘCO value of 1.252, according to Roughton and Forster,2Roughton 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 Physiol. 1957; 11: 290-302Crossref PubMed Scopus (615) Google Scholar 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.4Frans A Les valeurs normales du volume capillaire pulmonaire (Vc) et de la capacite de diffusion de la membrane alveolo-capillare.in: Arcangeli P Normal values for respiratory function in man. Panminerva Medica, Torino1970: 352-363Google Scholar Their second issue is concerning the calculation of Dmco. As mentioned in our article,1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar 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 authors6Guenard 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 Physiol. 1987; 70: 113-120Crossref PubMed Scopus (162) Google Scholar7Manier G Moinard J Techoueyres P et al.Pulmonary diffusion limitation after prolonged strenuous exercise.Respir Physiol. 1991; 83: 143-153Crossref PubMed Scopus (85) Google Scholar8Manier G Moinard J Stoicheff H Pulmonary diffusing capacity after maximal exercise.J Appl Physiol. 1993; 75: 2580-2585PubMed Google Scholar9Vaida P Kays C Riviere D et al.Pulmonary diffusing capacity and pulmonary capillary blood volume during parabolic flights.J Appl Physiol. 1997; 82: 1091-1097PubMed Google Scholar 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,10Tamhane RM Johnson Jr, RL Hsia CC Pulmonary membrane diffusing capacity and capillary blood volume measured during exercise from nitric oxide uptake.Chest. 2001; 120: 1850-1856Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar11Phansalkar AR Hanson CM Shakir AR et al.Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis.Am J Respir Crit Care Med. 2004; 169: 1034-1040Crossref PubMed Google Scholar 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 studies12Borland CD Higenbottam TW A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide.Eur Respir J. 1989; 2: 56-63PubMed Google Scholar13Tsoukias NM Dabdub D Wilson AF et al.Effect of alveolar volume and sequential filling on the diffusing capacity of the lungs: II. Experiment.Respir Physiol. 2000; 120: 251-271Crossref PubMed Scopus (21) Google Scholar 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 s10Tamhane RM Johnson Jr, RL Hsia CC Pulmonary membrane diffusing capacity and capillary blood volume measured during exercise from nitric oxide uptake.Chest. 2001; 120: 1850-1856Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar11Phansalkar AR Hanson CM Shakir AR et al.Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis.Am J Respir Crit Care Med. 2004; 169: 1034-1040Crossref PubMed Google Scholar to 5 min,14Sheel 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 Physiol. 2001; 90: 926-932Crossref PubMed Scopus (21) Google Scholar so our inspiratory nitric oxide levels are not that high as van der Lee and Zanen have suggested. Nevertheless, those studies10Tamhane RM Johnson Jr, RL Hsia CC Pulmonary membrane diffusing capacity and capillary blood volume measured during exercise from nitric oxide uptake.Chest. 2001; 120: 1850-1856Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar11Phansalkar AR Hanson CM Shakir AR et al.Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis.Am J Respir Crit Care Med. 2004; 169: 1034-1040Crossref PubMed Google Scholar14Sheel 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 Physiol. 2001; 90: 926-932Crossref PubMed Scopus (21) Google Scholar 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 study1Zavorsky 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.Chest. 2004; 125: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar 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. Diffusion Capacity for Nitric Oxide and Carbon MonoxideCHESTVol. 126Issue 5PreviewWe 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. Full-Text PDF
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