Diffusing capacity of the lung for nitric oxide (), otherwise known as the transfer factor, was first measured in 1983. This document standardises the technique and application of single-breath This panel agrees that 1) pulmonary function systems should allow for mixing and measurement of both nitric oxide (NO) and carbon monoxide (CO) gases directly from an inspiratory reservoir just before use, with expired concentrations measured from an alveolar "collection" or continuously sampled rapid gas analysers; 2) breath-hold time should be 10 s with chemiluminescence NO analysers, or 4-6 s to accommodate the smaller detection range of the NO electrochemical cell; 3) inspired NO and oxygen concentrations should be 40-60 ppm and close to 21%, respectively; 4) the alveolar oxygen tension ( ) should be measured by sampling the expired gas; 5) a finite specific conductance in the blood for NO (θNO) should be assumed as 4.5 mL·min·mmHg·mL of blood; 6) the equation for 1/θCO should be (0.0062· +1.16)·(ideal haemoglobin/measured haemoglobin) based on breath-holding and adjusted to an average haemoglobin concentration (male 14.6 g·dL, female 13.4 g·dL); 7) a membrane diffusing capacity ratio (/) should be 1.97, based on tissue diffusivity.

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10). Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 pa...

Nitric oxide (NO) has a much stronger affinity for hemoglobin than carbon monoxide (CO); therefore, the DL(NO) (diffusing capacity for NO) is less influenced by changes in capillary blood volume than the DL(CO) (diffusing capacity for CO), and represents the true membrane diffusing capacity. We measured the combined single breath DL(NO)/DL(CO) in 124 healthy subjects, and generated reference equations for the DL(NO) and K(NO). In a subset of 21 subjects the measurements were performed on different inspiratory levels. The reference equation for DL(NO) in females is 53.47*H(height)0.077*A(age)-48.28(RSD5.22) and for males 59.84*H-0.25*A-44.20(RSD6.39). Reference equations for K(NO) in females is -2.03*H-0.025*A+11.52(RSD0.48) and for males -0.15*H-0.045*A+9.47(RSD0.65). The K(CO) (DL(CO)/V(A)) increases when V(A) (alveolar volume) decreases, probably due to an increase of blood volume per unit lung volume. The DL(NO) was much stronger related to the V(A), the K(NO) was almost independent of V(A). Because of the relative independence of the K(NO) on V(A), the K(NO) appears to be a much better index for the diffusion capacity per unit lung volume (transfer coefficient) than the K(CO).

The transfer factor of the lung for nitric oxide (TL,NO) is a new test for pulmonary gas exchange. The procedure is similar to the already well-established transfer factor of the lung for carbon monoxide (TL,CO). Physiologically, TL,NO predominantly measures the diffusion pathway from the alveoli to capillary plasma. In the Roughton-Forster equation, TL,NO acts as a surrogate for the membrane diffusing capacity (DM). The red blood cell resistance to carbon monoxide uptake accounts for ,50% of the total resistance from gas to blood, but it is much less for nitric oxide.TL,NO and TL,CO can be measured simultaneously with the single breath technique, and DM and pulmonary capillary blood volume (Vc) can be estimated. TL,NO, unlike TL,CO, is independent of oxygen tension and haematocrit. The TL,NO/TL,CO ratio is weighted towards the DM/Vc ratio and to a; where a is the ratio of physical diffusivities of NO to CO (a51.97). The TL,NO/TL,CO ratio is increased in heavy smokers, with and without computed tomography evidence of emphysema, and reduced in the voluntary restriction of lung expansion; it is expected to be reduced in chronic heart failure. The TL,NO/TL,CO ratio is a new index of gas exchange that may, more than derivations from them of DM and Vc with their in-built assumptions, give additional insights into pulmonary pathology.