The blood transfer conductance for nitric oxide: Infinite vs. finite θNO

Abstract

Whether the specific blood transfer conductance for nitric oxide (NO) with hemoglobin (θ_NO) is finite or infinite is controversial but important in the calculation of alveolar capillary membrane conductance (Dm_CO) and pulmonary capillary blood volume (V_C) from values of lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO). In this review, we discuss the background associated with θ_NO, explore the resulting values of Dm_CO and V_C when applying either assumption, and investigate the mathematical underpinnings of Dm_CO and V_C calculations. In general, both assumptions yield reasonable rest and exercise Dm_CO and V_C values. However, the finite θ_NO assumption demonstrates increasing V_C, but not Dm_CO, with submaximal exercise. At relatively high, but physiologic, DLNO/DLCO ratios both assumptions can result in asymptotic behavior for V_C values, and under the finite θ_NO assumption, Dm_CO values. In conclusion, we feel that the assumptions associated with a finite θ_NO require further in vivo validation against an established method before widespread research and clinical use.

Keywords: Alveolar capillary membrane conductance; Exercise; In vivo validation; Lung diffusing capacity; Pulmonary capillary blood volume.

Figure 1. Dm_CO and V_C values calculated from rebreathe data using both the finite and infinite θ_NO assumptions

Both assumptions yield reasonable values for Dm_CO and V_C – i.e., positive and within range of previously reported values. Outliers (red +) are defined as ± 2.7 standard deviations from the mean. Finite Dm_CO values are significantly greater that infinite Dm_CO values (p < 0.001); V_C values are not statistically different. Dm_CO, alveolar capillary membrane conductance; V_C, pulmonary capillary blood volume.

Figure 2. Dm_CO and V_C values calculated from single breath data using both the finite and infinite θ_NO assumptions

Both assumptions yield reasonable values for Dm_CO and V_C – i.e., positive and within range of previously reported values. Outliers (red +) are defined as ± 2.7 standard deviations from the mean. Finite Dm_CO values are significantly greater, and finite V_C values are significantly lower, that the infinite assumption values (both p < 0.001). Dm_CO, alveolar capillary membrane conductance; V_C, pulmonary capillary blood volume.

Figure 3. Response of Dm_CO and V_C to incremental exercise calculated from rebreathe data

A linear mixed effects model was implemented to separate the individual and group effects on either Dm_CO or V_C throughout incremental cycling exercise. The group effects for both the infinite and finite θ_NO assumptions are plotted as a function of workload. For both assumptions, Dm_CO and V_C increased significantly throughout exercise (all p < 0.001). Dm_CO, alveolar capillary membrane conductance; V_C, pulmonary capillary blood volume.

Figure 4. Effective α ratio for the conversion of DLNO to Dm_CO for the finite θ_NO assumption

The effective α ratio, which converts DLNO directly to Dm_CO for the finite θ_NO assumption, was calculated for a range for DLNO/DLCO ratios. The resulting effective α ratio is lower than the Krogh Coefficient (1.97) because the finite θ_NO assumption calculations only factor in the theoretical red blood cell resistance to the transfer of NO. The resulting effective α ratio is also lower than the α ratio used under the infinite θ_NO assumption (2.26) for DLNO/DLCO ratios below ~6.5.

Figure 5. Theoretical Dm_CO values over a range of DLNO/DLCO ratios

Dm_CO was calculated under both the infinite and finite θNO assumptions using DLCO = 20 ml/min/mmHg. The finite calculation of Dm_CO is also dependent on PO₂; values of 80, 100, and 120 mmHg are show here. While the infinite calculation of Dm_CO is stable over a large range of DLNO/DLCO ratios, the finite calculation of Dm_CO rapidly increases as the DLNO/DLCO ratio increases. DLCO, lung diffusing capacity for carbon monoxide; DLNO, lung diffusing capacity for nitric oxide; Dm_CO, alveolar capillary membrane conductance.

Figure 6. Theoretical V_C values over a range of DLNO/DLCO ratios

V_C was calculated under both the infinite and finite θ_NO assumptions using DLCO = 20 ml/min/mmHg. The infinite calculation of V_C is dependent on the technique used in our laboratory; hence, both rebreathe and single breath are shown here. Under both assumptions, calculation of V_C is increases rapidly when the DLNO/DLCO ratio is equal to the α ratio/Krogh coefficient used. DLCO, lung diffusing capacity for carbon monoxide; DLNO, lung diffusing capacity for nitric oxide; V_C, pulmonary capillary blood volume.