Confusion in reporting pulmonary diffusing capacity for nitric oxide and the alveolar-capillary membrane conductance for nitric oxide

Abstract

We read with interest the paper by Magini and colleagues on the measurement of pulmonary diffusing capacity for nitric oxide in patients with heart failure (ejection fraction<40%).1 In their study they report pulmonary diffusing capacity and the individual components of pulmonary diffusing capacity in 50 patients with heart failure (65 years of age), and 50 control subjects (61 years of age). We feel that there are two problems with this paper that warrant discussion. First, the mean values for pulmonary diffusing capacity for nitric oxide (DL NO ) for the healthy subjects are too low, and second, both their alveolar-membrane conductances (Dm NO and Dm CO ) and pulmonary capillary blood volume (Vc) calculations, and hence conclusions, are incorrect.First, the values for DL NO for the healthy volunteers appear too low. If we assume that the women's and men's mean height in the healthy volunteers was 163 and 173 cm, respectively, then the mean DLNO values should be 96-113 and 140-154 ml/min/mm Hg, for women and men, respectively.2,3 The combined average for DL NO should be then 118-133 ml/min/mm Hg. The author's mean values of 89 ml/min/mm Hg for the healthy volunteers are 25-33% lower than predicted. However, their values for pulmonary diffusing capacity for carbon monoxide (DL CO ) were correct and the healthy volunteers was close to 100% of that predicted.2,3 Thus, if the mean DL NO in the control group is under-predicted by at least 25%, then the DL NO values in the heart failure patients could be under predicted by !25% too. Since DL NO and DL CO are measured simultaneously, and DL CO values were appropriate (close to 100% of those predicted), there must be some mathematical error in the calculation of DL NO and/or their breath-hold time was too short. The breath-hold time should be 5-10 s, 4 and it seems that their breath-hold time varied between 2-4 s.Second, in the discussion they state ''Vcap was unchanged, and the DL NO /DL CO ratio was 4.1 in healthy subjects and 4.4 in heart failure patients.'' Hughes and Van der Lee 5 have elegantly illustrated how DL NO /DL CO is a proxy for Dm/Vc so the only way for the patients in this study to have an unchanged Vc and a raised DL NO /DL CO is for them to have a higher Dm than the normal controls! Clearly Magini et al.'s calculations of Vc (and Dm) are wrong. They have used the 1957 value for y CO ; Forster states that his 1957 value is incorrect and that the 1987 value should be used instead.6 Magini et al. have assumed that DL NO ¼ Dm NO i.e. that y NO is infinity, a view originally asserted by the Bordeaux group.7 Nitric oxide transfer is now known to increase with hemolysis in vitro 8 and with addition of a cell-free blood substitute in vitro and in vivo 9 indicating that y NO is finite and that DL NO < Dm NO . We and the Bordeaux group 10 recommend using the values for y NO and y CO derived from rate constants measured using the Continuous Flow Rapid Reaction apparatus at the University of Pennsylvania. 11 We have recalculated Magini et al.'s data using these ...

Standardisation and application of the single-breath determination of nitric oxide uptake in the lung

“…In liver cirrhosis with hepatopulmonary syndrome (HPS) [74], there was a greater reduction in VC and DMCO (and a lower arterial oxygen pressure) versus non-HPS patients, but both groups demonstrated a similar rise in DLNO/DLCO and DMCO/VC ratios compared to controls, consistent with microvascular disease. In heart failure, DLNO/DLCO and DMCO/VC ratios were reported to be increased [75], contrary to predictions, but there were methodological issues in the calculations of DMCO/VC [76]. As such, more studies are needed examining microvascular disease and its effects on diffusing capacity.…”

Reference equations for pulmonary diffusing capacity of carbon monoxide and nitric oxide in adult Caucasians

“…In recent years, most scientists have agreed that the most correct values for θCO are those presented by FORSTER [11] in 1987, and thereby not the 1957 values presented by ROUGHTON and FORSTER [2]. Forster himself argued that these new values were more correct, particularly since they were measured at a physiological pH of 7.4 and not pH 8.0 like the 1957 values [9,12,14]. In 2016, GUÉNARD et al [41] tested several of the available 1/θCO versus PcapO 2 equations by exposing 10 normal subjects to two different inspiratory oxygen concentrations while measuring DLNO and DLCO.…”

“…In the work of GUENARD et al [3], θNO was assumed to be infinitely great, since it had been shown earlier that the reaction rate of NO with free haemoglobin (Hb) was 250-1400 times faster than for CO [2,3,5,6]. However, in recent years the correctness of this assumption has been thoroughly debated and recent evidence points towards θNO being finite, with a value of 4.5 mLNO•mLblood −1 •min −1 •mmHg −1 [7][8][9][10]. This value is used in the present study.…”

Variability in pulmonary diffusing capacity in heart failure

“…Lung mechanics and pulmonary diffusing capacity are compromised in those with heart failure (HF) (Agostoni et al, 2006;Magini et al, 2015;Zavorsky and Borland, 2015). The former is characterized by lung restriction, while pulmonary diffusion capacity for carbon monoxide (DLCO) is impaired due to a reduction in both alveolar-capillary membrane diffusing capacity for CO (DMCO) (Puri et al, 1995) and pulmonary capillary volume (Vcap) (Magini et al, 2015;Zavorsky and Borland, 2015). Historically, DM is calculated from DLCO through the Roughton and Forster multi-step technique where 1/DLCO= 1/DM + 1/θCO•VCap), where θco is the specific conductance in the blood for CO (Roughton and Forster, 1957).…”