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Published online before print March 15, 2006, 10.1183/09031936.06.00146805
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Eur Respir J 2006; 27:1251-1257
Copyright ©ERS Journals Ltd 2006

A small amount of inhaled nitric oxide does not increase lung diffusing capacity

G. S. Zavorsky and J. M. Murias

Dept of Anesthesia, McGill University Health Center, Montreal, Canada.

CORRESPONDENCE: G. S. Zavorsky, Dept of Anesthesia, McGill University Health Center, Montreal General Hospital, 1650 Cedar Avenue, Room D10-144, Montreal, Quebec H3G 1A4, Canada. Fax: 1 5149348249. E-mail: gerald.zavorsky{at}mcgill.ca

Keywords: Diffusing capacity, nitric oxide, repeatability

Received: December 12, 2005
Accepted February 24, 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The aim of the present study was to determine: 1) whether 40–50 ppm nitric oxide (NO) increases diffusing capacity of the lung for NO (DL,NO) and carbon monoxide (DL,CO), membrane diffusing capacity for CO (Dm,CO) and pulmonary capillary blood volume (Vc); 2) the actual number of tests required to provide a reasonable estimate of DL,NO, DL,CO, Dm,CO and Vc; and 3) repeatability of these parameters using the single-breath DL,NO–DL,CO method.

In total, 31 subjects performed five single-breath hold manoeuvres at rest, inhaling 43±3 ppm NO together with a standard diffusion mixture.

DL,NO (Dm,CO) remained unchanged from the first to fifth trial. However, compared with the first trial, DL,CO and Vc had decreased by the fourth (–4±5%; 95% confidence interval (CI) = –5– –2%) and third trial (–5±7%; 95% CI = –7– –2%), respectively. Repeatability over five trials was 17, 3 and 7 mL·min–1·mmHg–1 for DL,NO, DL,CO and Dm,CO, respectively, and 13 mL for Vc when Dm,CO = DL,NO/2.42.

In conclusion, nitric oxide inhaled during sequential single-breath manoeuvres has no effect on diffusing capacity of the lung for nitric oxide and, thus, membrane diffusing capacity for carbon monoxide. Since more than two and three trials will lower pulmonary capillary blood volume and diffusing capacity of the lung for carbon monoxide, respectively, the average value of only two properly performed trials is suggested.

The equation of the diffusing capacity of the lung for carbon monoxide (DL,CO) has been classically described as:


Formula 001

(001)
where Dm,CO represents pulmonary membrane diffusing capacity for carbon monoxide (CO) and {Theta}CO is the specific blood transfer conductance for CO. Vc represents pulmonary capillary blood volume 1. Membrane resistance (1/Dm,CO) and red cell resistance (1/{Theta}CO·Vc) usually contribute equally to the overall diffusive resistance across the lung 2, although this has been debated 3. To obtain Dm,CO and Vc, DL,CO has been traditionally measured at two different levels of alveolar oxygen tension (PA,O2), ~13.3–16.0 kPa (~100–120 mmHg) and ~79.8 kPa (~600 mmHg). For each level of PA,O2, 1/DL,CO is then plotted on the y-axis and 1/{Theta}CO is plotted on the x-axis. A line is then drawn through two points and the x-intercept (1/Dm,CO) and slope (1/Vc) can be solved. This two-step method can be time consuming and uncomfortable to perform, especially during exercise.

However, over the past 15 yrs, the measurement of diffusing capacity of the lung using the transfer gases nitric oxide (NO) and CO together permits one to obtain Dm,CO and Vc in a single-breath manoeuvre, thus allowing a similar distribution of the two gases and reducing the number of measurements and testing time by half 4, 5. The velocity constant of the combination of NO with haemoglobin is about 280 times faster than that of CO 6, and thus the specific blood transfer conductance for NO ({Theta}NO) is so large that the red cell resistance to NO (1/{Theta}NO) approaches zero 7. Therefore, diffusing capacity of the lung for nitric oxide (DL,NO) equals the membrane diffusing capacity for NO (Dm,NO), and is independent of Vc and haemoglobin concentration 8. Others have made the same assumption that (1/{Theta}NO) is negligible 9–14, and it was recently determined that a nonzero 1/{Theta}NO would not be able to explain their experimental data 12. Therefore, these data suggest that DL,NO is a good measure of Dm,NO. Given that the molecular weight of CO and NO are 28 and 30 g·M–1, respectively, and solubilities (Bunsen coefficients) of CO and NO in plasma at 37°C are 0.0215 and 0.0439 15, respectively, the diffusivity of NO, which is the solubility of NO divided by the square root of the molecular weight (MW) of NO (


Formula 004

(004)
), is ~1.97 times greater than that of CO and, thus, the theoretical factor between membrane diffusing capacities for NO and CO is:


Formula 002

(002)
Indeed, the solubility of either gas will depend upon the composition of the fluid that the gas has to diffuse through. If the fluid changes composition, the relative solubilities may well be different pre- and post-exercise. Nevertheless, data obtained from sick and healthy patients performing rebreathing manoeuvres suggest that the actual ratio of DL,NO to Dm,CO is ~2.42 11, 12. The larger ratio may be due to a higher than assumed NO solubility in plasma as well as NO facilitated diffusion 12.

Several researchers have previously obtained DL,NO from single-breath 4, 5, 9, 10, 13, 14, 16–19 or rebreathing manoeuvres 11, 12, along with the simultaneous measurement of DL,CO to obtain Dm,CO and Vc. Since brief exposure to NO does not interfere with physiological function 11, 12, 20, 21, it seems pertinent to use NO as a test gas to assess lung diffusion capacity. However, there is still debate as to whether inhalations of high NO concentrations (~40–50 ppm) during sequential single-breath manoeuvres can affect the pulmonary microcirculation. At those NO concentrations, pulmonary vasodilation may occur, increasing DL,CO, Vc and perhaps DL,NO (Dm,CO) 22. Therefore, the first objective of the present study was to determine whether five sequential single breath-hold manoeuvres inhaling ~40 ppm of NO increase DL,CO, DL,NO (and thus Dm,CO) and Vc. The current hypothesis was that five repeated inhalations of 40–50 ppm of NO would not increase DL,CO, DL,NO (Dm,CO) or Vc.

Furthermore, the recent 2005 American Thoracic Society (ATS)/European Respiratory Society (ERS) task force guidelines of standardisation of the single-breath determination of CO uptake in the lung 23 mentioned that more research is needed to determine the actual number of tests required to provide a reasonable estimate of the average DL,CO. Therefore, the second objective of the current study was to determine the actual number of tests required to provide a reasonable estimate of not only DL,CO, but DL,NO (Dm,CO) and Vc for a given person. The present authors' hypothesis was that an average of three measurements would be needed to obtain a reasonable estimate of all those parameters.

The third objective was to determine the repeatability of lung diffusing capacity and its components over five trials in a given patient using the newer single-breath method of CO and NO. This would help to decide whether a change in an observation of DL,NO, DL,CO, Dm,CO and Vc represents a real clinical change in the pulmonary system or just measurement error. The current authors' hypothesis was that the repeatability for DL,NO, DL,CO and Dm,CO would be 10, 2 and 6 mL·min–1·mmHg–1, respectively, and 10 mL for Vc.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
In total, 31 healthy subjects were recruited (15 females, 16 males) and all completed the study (aged 33±9 yrs; weight 68.6±12.5 kg; height 169.9±9 cm). All subjects were nonsmokers. These subjects had normal resting spirometry function (forced expiratory volume in one second (FEV1) >80% predicted, and FEV1/forced vital capacity (FVC) >0.70) and no history of cardiopulmonary disease. Each subject was required to come into the laboratory on one occasion only.

Single-breath apparatus and technique
Volume and gas calibration of the Ergocard and the Hyp'Air lung diffusion system (Medisoft, Dinant, Belgium) were performed prior to each testing session. The subjects breathed through a three-way pneumatic valve developed by Medisoft. A dead space washout volume of 900 mL was allowed, and an expired sample volume of 900 mL was collected. The instrument dead space was measured at 140 mL (including the mouthpiece, valve and filter dead spaces). Anatomical dead space (mL) was estimated as bodyweight in kgx2.2 23. The concentrations of inspiratory gases were 0.295% CO, 9.96% He, 20.98% O2 and balance N2 for gas mixture one, and 1,000 ppm NO and balance N2 for gas mixture two. A third mixture of 77 ppm NO and balance N2 was used for calibration purposes only. For the single-breath manoeuvre, an inspiratory bag was filled with 5–8 L depending on the subject's FVC using the first two gas mixtures. Once the mixtures were injected into the inspiratory bag, the concentration of CO, He, NO, and O2 were analysed simultaneously over 30 s by gas analysers. The injection of the various gas mixtures into the inspiratory bag resulted in approximate inspired concentrations of CO, He, NO and O2 at 0.30%, 9%, 40 ppm and 20%, respectively. The types of gas analysers used for measuring inspired and expired gas mixtures have been reported elsewhere 13. Inspired volume was measured, corrected for instrument and anatomical dead space, and converted to standard temperature, pressure and dry conditions. Breath-holding time was calculated using the method of Jones and Meade 24.

Calculation of diffusion capacities, Dm and Vc
Diffusion capacities for NO and CO were calculated simultaneously from the exponential disappearance rate of each gas with respect to He using the method by Jones and Meade 24. The formulae for calculating DL,CO can be found in the 2005 ATS/ERS guidelines 23. All results were standardised to a haemoglobin (Hb) concentration of 14.6 g·dL–1 for males and 12.0 g·dL–1 for females, and a PA,O2 of 13.3 kPa (100 mmHg) by inserting these values into the following formula by Roughton and Forster 1:


Formula 003

(003)
where 1/{Theta}CO was 1.426 and {Theta}CO was 0.701 mL·min–1·mmHg–1 for males, 1/{Theta}CO was 1.594 and {Theta}CO was 0.627 mL·min–1·mmHg–1 for females and PO2 was partial pressure of oxygen. A DL,NO to Dm,CO ratio of 2.42 11, 12, 14 and 1.97 5, 9, 10, 13, 19 was used as the theoretical ratio of DL,NO to Dm,CO during single-breath manoeuvres since those ratios have both been used in the past. The ratio of 2.42 has been determined recently during rebreathing manoeuvres at rest and during exercise 11, 12, which can result in Dm,CO values that are more in line with the current normative values 25. Therefore, due to the two different DL,NO to Dm,CO ratios reported in the literature, the current authors reported two different Dm,CO values and two different Vc values.

A breath-holding time of 4–5 s was chosen because it has been shown that DL,CO values were not different with a 3- or 5-s breath hold compared with a 7- and 10-s breath hold 26 and a breath-holding time of ~9 s would result in a less than detectable amount of expired NO 4. The present authors did not account for NO back pressure in the calculations since exhaled NO concentrations at rest are negligible, ranging 11–66 ppb (0.011–0.066 ppm) 27, which tend to decrease during exercise 28. The amount of NO back pressure then would minimally affect DL,NO calculations as the measurements were carried out in the ppm range, which is ~75–500 times larger than the exhaled NO concentration at rest or during exercise after a single-breath inspiration of 40–60 ppm NO. Accounting for CO back pressure is also negligible as it has been shown that 2 min between tests virtually eliminates all the CO gas from the lungs in healthy subjects 29. As the recent ATS/ERS guidelines recommend a minimum of 4 min between DL,CO measurements 23, subjects performed the single-breath manoeuvre with a minimum of 4.5 min between tests. Five sequential diffusion capacity tests were performed.

Statistical analyses
A one-way repeated measures ANOVA was used to determine if there were significant differences in DL,CO, DL,NO, Dm,CO and Vc between the five trials. A Tukeys/Kramer post hoc comparison test was used to see where the differences in the five trials occurred. In addition, the variables height, age and weight were examined by forward stepwise multiple regression to determine which and what combination most predicted DL,NO values at rest. The measurement error for DL,NO, Dm,CO, DL,CO and Vc was calculated as the square root of the residual mean square error (which is also called the within-subject standard deviation) obtained from the one-way repeated measures ANOVA 30. The repeatability of each variable was then obtained multiplying the within-subject standard deviation by 2.77 30. A p-value of <0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 31 subjects, 29 had normal spirometry function (table 1Go) based on the fact that FEV1 was >80% pred for all subjects, and the FEV1/FVC was >0.7 for all but two subjects (FEV1/FVC 0.67 and 0.68, respectively). The single breath-hold manoeuvres, on the whole, were performed adequately (table 2Go). Breath-hold time was consistent within 0.3 s for all five trials, and the average inspired volume was always >90% of the FVC. The average alveolar volume was also maintained within 0.2 L for all trials.


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  		Table 1— Subject characteristics and resting spirometry

 

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  		Table 2— Characteristics of the five sequential single breath-hold manoeuvres in 31 subjects

 
The data show that DL,NO and, thus, Dm,CO remained unaltered from trial one to trial five (table 3Go). However, compared with the first trial, DL,CO and Vc significantly decreased by the fourth (–4±5%; 95% confidence interval (CI) –5– –2%; p<0.05) and third trial (–5±7%; 95% CI –7– –2%; p<0.05), respectively. When Dm,CO = DL,NO/2.42, the per cent predicted based on age, height and sex was 111±31% (range 62–164%; p<0.05), but when Dm,CO = DL,NO/1.97, the per cent predicted was 136±39% (72–202%; p<0.05). For Vc, when Dm,CO = DL,NO/2.42 the per cent predicted based on height and sex was 116±19% (76–155%; p<0.05), but when Dm,CO = DL,NO/1.97 the per cent predicted for Vc was 100±16% (66–131%; p>0.05). Therefore, when Dm,CO = DL,NO/2.42, the Dm,CO is reduced closer to normative values and the Vc is increased above normative values. The opposite occurs when Dm,CO = DL,NO/1.97 as the Dm,CO is largely increased above the predicted value, but Vc is reduced to 100% pred.


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  		Table 3— Lung diffusing capacity and its components over five sequential trials in 31 subjects

 
The measurement error and repeatability of five trials are presented in table 4Go. The repeatability represents the critical value in which a clinically measurable change in a given patient occurs between sessions. From the repeated measures ANOVA, a real clinical change in a patient's pulmonary diffusion capacity and its components was 17.2 and 3.2 mL·min–1·mmHg–1 for DL,NO and DL,CO, respectively. When Dm,CO = DL,NO/2.42, a real clinical change for Dm,CO and Vc were 7.1 mm·min–1·Hg–1 and 13 mL, respectively. When Dm,CO = DL,NO/1.97, a real clinical change for Dm,CO and Vc was any change >8.7 mL·min–1·mmHg–1 and 9.8 mL, respectively.


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  		Table 4— Measurement error and repeatability of lung diffusing capacity and its components for 31 subjects

 
The variables age, weight and height were examined by forward stepwise multiple regression to predict DL,NO values at rest. The only variable that appreciably affected DL,NO was height. Predicted DL,NO in mL·min–1·mmHg–1 = 2.0164xheight in cm–175.63 (r2 = 0.39; SEE = 23.3). Adding the other two variables to the equation did not increase the coefficient of determination significantly. Therefore, DL,NO at rest was best predicted by height.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study showed that repeated inhalations of 40–50 ppm NO during single breath-hold manoeuvres does not increase DL,NO, Dm,CO, DL,CO or Vc. In fact, five sequential breath-hold manoeuvres did not change DL,NO and, thus, Dm,CO. However, DL,CO significantly decreased by the fourth trial, and Vc significantly decreased by the third trial. The drop in DL,CO by the fourth trial due to progressive increase in carboxyhaemoglobin was similar to that reported elsewhere 33. As such, the data show that the actual number of tests required to provide a reasonable estimate of DL,NO, DL,CO, Dm,CO and Vc during properly performed manoeuvres is two trials. The average of the two trials should then be reported. Any more than two properly performed manoeuvres will lower Vc, and more than three will lower DL,CO. Therefore, two properly performed manoeuvres are sufficient to obtain all the components of lung diffusion capacity using the DL,NO–DL,CO method.

There has been some concern that NO may affect the pulmonary microcirculation due to its vasoactive properties 22. One study showed that there is a small nonsignificant increase in DL,CO in the presence of NO 17. However, the current authors have shown that brief exposure to NO does not interfere with physiological function. Other human 11, 12, 20, 21 and animal studies 34 are in agreement with the present study. Rebreathing 20–40 ppm NO over 16 s to 10 min resulted in no significant changes to oxygen uptake, arterial oxygen tension, alveolar–arterial oxygen tension difference, DL,CO, Dm or Vc in sick and healthy subjects at rest or during exercise 11, 12, 21. In mechanically ventilated rabbits, DL,NO values remained unchanged despite inspiratory NO concentrations varying from 10–800 ppm 34. Furthermore, the pulmonary toxicity of inhaled NO at concentrations of ~40 ppm over a prolonged period of time is minimal 35.

There is concern that different PA,O2 may slightly alter DL,NO 36. However, more recent data has shown that varying the PA,O2 in those with or without pulmonary disease does not affect DL,NO 11, 12, implying that the combined DL,NO–DL,CO method can be used in hypoxaemic patients. Therefore, taken together, there is no reason to refrain from using NO and CO concurrently as a test gas to assess lung diffusion capacity.

The clinical implication of using both NO and CO concurrently in research and medical practice is that scientists and clinicians can immediately partition and quantify the components of lung diffusing capacity in a subject from a single 4-s breath-hold manoeuvre that requires minimal effort on the part of the patient, while simultaneously being able to pinpoint which component (Vc, Dm) is causing low (or high) total lung diffusion capacities. The ability to estimate Dm,CO and Vc from one-step simultaneous measurement of DL,NO and DL,CO represents significant conceptual advantages. One conceptual advantage of the DL,NO technique is that with the standard Roughton–Forster method, cardiac output can vary between measurements of DL,CO at different O2 tensions, which then have to be interpolated to obtain DL,CO at two O2 tensions, but at the same cardiac output 12. With the DL,NO method, all measurements are obtained at the same cardiac output and O2 tension; no interpolation is necessary. Another conceptual advantage is that with the traditional method, the distribution of CO gas in the lungs may be different at two different O2 tensions, but with the DL,NO method only one inspiration is required, which results in a similar distribution of NO and CO gases. A third conceptual advantage is that with the traditional method, there is systematic underestimation of Vc and an overestimation of Dm since the inspiration at two different O2 tensions affects alveolar–capillary membrane diffusion 37. The DL,NO–DL,CO method avoids this error altogether and should improve the accuracy of estimated Dm,CO and Vc.

The ratio Dm,CO = DL,NO/2.42 gives a better estimate of Dm. When the present measured values were compared against the published norms, using the traditional two-step Roughton–Forster method 25, the predicted Dm,CO was 136% pred when Dm,CO = DL,NO/1.97, but only 111% pred when Dm,CO = DL,NO/2.42. However, the better per cent predicted values for Vc occurred when Dm,CO = DL,NO/1.97. Nonetheless, since the traditional Roughton–Forster method underestimates Vc, the current authors feel that the predicted Vc values by ZANEN et al. 25 slightly underestimate Vc. Therefore, the best compromise is to estimate Dm and Vc from a single breath using the DL,NO–DL,CO method and the formula Dm,CO = DL,NO/2.42.

It was also important to clarify the repeatability of lung diffusion capacity and its components over five trials from the single-breath DL,NO–DL,CO method. The repeatability allows clinicians to identify a true clinically meaningful change from measurement error. The difference between any two measurements for the same subject is expected to be <2.77 multiplied by the within-subject standard deviation; therefore, the repeatability was defined as 2.77 multiplied by the within-subject standard deviation obtained from the ANOVA 30. Table 4Go shows a true measurable clinical change in DL,NO and DL,CO as an absolute change of >17 and 3 mL·min–1·mmHg–1, respectively. In addition, a true clinical change in Dm,CO and Vc is an absolute change of >7 mL·min–1·mmHg–1 and 13 mL, respectively. Any change that is less than these values is considered a true measurement error. Indeed, Dm,CO equals DL,NO divided by a fixed value, and Vc is derived from the DL,NO and DL,CO; therefore the repeatability of Dm and Vc can be calculated from (or explained by) the repeatability of the DL,NO.

Based on ATS and ERS criteria, the average value of two trials whose difference in diffusing capacity is within 10% of each other is considered acceptable. The present authors looked at the average DL,NO and DL,CO for all 31 subjects over five trials, and the repeatability data of this study are in agreement with the ATS/ERS guidelines as DL,NO (and thus Dm,CO) and DL,CO are found to be 10%. However, since the variability of the parameters DL,NO and DL,CO were independent of the magnitude of the measurement, the results invalidate the use of percentage value to describe the repeatability. Using a percentage will lead to underestimation of variability in low values and overestimation for high values. Others studies have also suggested using an absolute value rather than a percentage, since the diffusing capacity was also independent of the magnitude of the measurement 38, 39. Therefore, the current authors recommend using an absolute difference rather than a percentage as alternative criteria for repeatability. It is also recommended to report the average of two trials when the absolute difference between the two measurements is within 17 mm·min–1·mmHg–1 for DL,NO, 3 mm·min–1·mmHg–1 for DL,CO, and 13 mL for Vc.

It is believed that the present paper is the first to actually quantify important measurable clinical changes in the parameters obtained from the single-breath DL,NO–DL,CO method.

Conclusion
Small amounts of nitric oxide inhaled during sequential single-breath manoeuvres have no effect on lung diffusing capacity for nitric oxide and, thus, membrane diffusing capacity for carbon monoxide. The recommended ratio is membrane diffusing capacity for carbon monoxide = lung diffusing capacity for nitric oxide/2.42. As more than two and three single-breath manoeuvres will lower pulmonary capillary blood volume and lung diffusing capacity for carbon monoxide, respectively, the average value of the first two trials are recommended to provide a reasonable estimate of lung diffusing capacity for nitric oxide, lung diffusing capacity for carbon monoxide, membrane diffusing capacity for carbon monoxide and pulmonary capillary blood volume.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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