It has been over 100 years since Marie Krogh developed the method to measure the transfer of carbon monoxide (CO) through the alveolar wall. Since then, the single-breath CO diffusing capacity (D_LCO) has become the most clinically useful pulmonary function test after spirometry and the measurement of lung volumes. In 1957, Roughton and Forster established a model in which the two processes for explaining the transfer of CO from alveolar gas phase to hemoglobin (Hb) in erythrocytes were assumed, i.e., the membrane diffusing capacity for CO (D_MCO) and the blood diffusing capacity for CO (D_BCO). The D_MCOreflects the process of CO diffusion across the effective alveolocapillary membrane, which consists of the alveolar gas phase, the alveolocapillary tissue barrier, and the plasma layer surrounding the erythrocyte (Fig. 1). The D_BCOis defined as the product of alveolar capillary blood volume (V_C) and specific gas conductance for CO in the blood (θ_CO). The θ_COsignifies the diffusive process across the erythrocyte (membrane and its interior) and incorporates the competitive, replacement reaction of CO with oxyhemoglobin (HbO₂) in the erythrocyte. The replacement reaction between CO and HbO₂is significantly influenced by capillary PO₂.

Fig. 1. Schematic presentation of CO and NO transfer from alveolar gas to erythrocyte.

In the late 1980s, Guénard and Borland independently developed a novel method of simultaneously measuring D_LCOand D_LNO. Like D_LCO, D_LNOis composed of D_MNOand D_BNO(θ_NO×V_C). However, the transfer characteristics of NO through the alveolar wall, including the alveolocapillary membrane and the pulmonary capillary-network, differ substantially from those of CO. NO is more diffusible than CO in the aqueous media, including the alveolocapillary membrane, the plasma layer, and the inside of the erythrocyte. Furthermore, the association velocity of NO with Hb is conspicuously faster than that of CO and the affinity of NO with Hb is tremendously higher than that of CO, suggesting that the chemical reaction of NO with Hb does not impede the erythrocyte NO transfer. Thus, one can consider that the CO transfer through the alveolar wall is limited both by diffusion and reaction, but the NO transfer is primarily prescribed by diffusion. Consequently, D_LCOand D_LNOreach about 30 mL/min/mmHg and 140 mL/min/mmHg in normal adults, respectively (D_LNO/D_LCO≃4.8). Furthermore, the relative contribution of the resistance for CO imposed by the effective alveolocapillary membrane (1/D_MCO) and that by the erythrocyte (1/D_BCO) to the total resistance of CO transfer (1/D_LCO) are 23% and 77%, respectively (Fig. 2). On the other hand, the relative contribution of 1/D_MNOand that of 1/D_BNOto 1/D_LNOare 55% and 45%, respectively. These facts indicate that D_LCO-associated parameters have a high sensitivity for detecting pulmonary capillary damage, while D_LNO-associated parameters equally detect alveolocapillary membrane damage and pulmonary capillary damage. As such, the simultaneous measurement of D_LCOand D_LNOimproves the diagnostic precision of identifying pathological changes located in the alveolar wall.

Fig. 2. Relative contribution of 1/DM and 1/DB to overall resistance of 1/DL.

For estimating D_Mand V_C, two consecutive measurements at different alveolar PO₂are required when the classical D_LCOmethod is applied, but only one measurement is sufficient when D_LCOand D_LNOare simultaneously measured. This fact indicates that the simultaneous measurement of D_LCOand D_LNOis more convenient clinically and reduces the time required for determining the D_Mand V_C. The D_M/V_Cis a clinically important parameter because it changes sensitively depending on the pathological condition of the alveolocapillary membrane and that of the pulmonary capillary-network. The D_M/V_Cis expected to decrease by a lung disease predominantly affecting the alveolocapillary membrane (for instance, idiopathic pulmonary fibrosis and non-specific interstitial pneumonia) but to increase by a lung disease preferentially injuring the pulmonary microcirculation (for instance, idiopathic pulmonary arterial hypertension and microvascular angiitis).

Kazuhiro Yamaguchi
Department of Respiratory Medicine, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku,
Tokyo 160-0023, Japan

Publication

Simultaneous measurement of pulmonary diffusing capacity for carbon monoxide and nitric oxide.
Yamaguchi K, Tsuji T, Aoshiba K, Nakamura H
Respir Investig. 2018 Mar

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