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St. Antonius Hospital, Nieuwegein, The Netherlands
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{at}tiscali.nl
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 (
CO) is essential in calculating the product 1/
CO x VC. In the past years, different equations23 have been used to calculate the CO, 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 research23 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 CO 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.
References
Concordia University, Montreal, QU, Canada
Correspondence to: Gerald S. Zavorsky, PhD, Assistant Professor, Department of Exercise Science, Concordia University, 165.21 Science Pavilion, 7141 Sherbrooke St West, Montreal, QU, Canada, H4B-1R6; e-mail: zavorsky{at}alcor.concordia.ca
To the Editor:
I would like to express sincere thanks to Dr. Borland for commenting on our recent article.1 Dr. 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 (CO) by approximately 14%,2 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 (NO), unlike CO, 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 CO. We used the following formula by Roughton and Forster2: 1/CO = 0.73 + 0.0058 x (PO2). The alveolar PO2 and hemoglobin concentration were standardized to 120 mm Hg and 146 g/L, respectively, and therefore 1/CO 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 populations4 (1/predicted VC = – 0.0201 x 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 study1 was approximately 10% larger than either the predicted5 or our measured1 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,2 which follows: 1/DLCO = 1/DMCO + 1/CO x 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,1 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 CO 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 method1 (NO/N2 mixture is absent), and use the 1/CO 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 authors6789 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,1011 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 studies101114 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
This article has been cited by other articles:
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  G. S. Zavorsky and J. M. Murias A small amount of inhaled nitric oxide does not increase lung diffusing capacity Eur. Respir. J., June 1, 2006; 27(6): 1251 - 1257. [Abstract] [Full Text] [PDF]
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