Single-breath DLCO Research Articles

Using the phase III slope of exhaled methane during a single breath DLCO test to assess ventilation heterogeneity

BackgroundThe Phase III slope from a single breath nitrogen washout test provides information about ventilation heterogeneity (VH) in the lungs. PurposeTo determine if the Phase III slope from the exhaled tracer gas concentration during a standard, single breath DLCO test using rapid gas analysis provides similar information about VH. Basic proceduresRetrospective analysis of clinical pulmonary function laboratory data including spirometry, lung volumes, and DLCO. The normalized Phase III slope from the exhaled CH4 concentration (SnCH4) was compared among different patterns of physiologic abnormality and with VA/TLC as an indicator of VH. Main findingsSnCH4 was the steepest in the group with “Obstruction and Low DLCO”, with significant differences between this group and the “Normal”, “Obstruction with Normal DLCO”, “Mixed Obstruction and Restriction” and “Isolated Low DLCO” groups. SnCH4 was steeper in current and former smokers compared to non-smokers. Among the entire study sample, SnCH4 correlated with VA/TLC (Spearman rho = −0.56, p < 0.01) and remained a significant determinant of VA/TLC by regression modeling. Principal conclusionsThe SnCH4 derived from a standard, single breath DLCO test using rapid gas analysis varied among distinct patterns of physiologic abnormalities and was associated with VA/TLC as a measure of VH.

Phenotyping lung function disorders in respiratory Long-COVID

Dyspnea is frequently complained for several weeks in Long-COVID, still being its underlying pathophysiology poorly investigated in the clinical setting. Aim: to investigate the lung functional pattern of Long-COVID patients and healthy controls (HC). Non-smokers aged ≥18years, discharged after COVID pneumonia were investigated, were classified as low dyspnea scorers (LDS) or high dyspnea scorers (HDS) if they were not complaining or otherwise still complaining dyspnea 12-16 weeks after discharge. A group of non-smoking HC was compared. Spirometric parameters; usual DLCO; simultaneous single-breath DLNO (sDLNO) and DLCO (sDLCO); lung capillary blood volume (Vc), and expiratory nitric oxide (eNO) were assessed. Their linear association was explored by correlation analysis. Area under the curve (AUC) were used to determine the best predictors of being HC, LDS or HDS, and to establish optimal cut-off values. 40 Long-COVID patients (19 LDS; 21 HDS) and 28 HC were investigated. FEV1, VC and FEV1/VC were equal in LSD and HSD. A decreasing trend (p&lt;0.0001) for DLCO, sDLCO, sDLNO and Vc, and a corresponding increasing trend (p&lt;0.0001) for sDLNO/sDLCO and eNO were detected from HC to HDS patients. sDLNO/sDLCO and Vc resulted the best predictors of belonging to the HDS group. Optimal cut-off values were 113.5 for sDLNO/sDLCO ratio and 58.5 for Vc, respectively. Data suggest the reduction of lung capillary blood volume as the main disorder in these cases and contribute to phenotyping respiratory troubles in Long-COVID. These disorders would be otherwise neglected by usual lung function parameters, due their low specificity.

Pulmonary evaluation of post-COVID-19 patients: an Ecuadorian experience

BackgroundDespite the growing concerns related to the potential of long-term pulmonary sequelae due to COVID-19, data about intermediate and long-term changes in the respiratory function of patients who recover is relatively sparse, particularly in developing countries.ObjectivesTo assess the characteristics and pulmonary function at follow-up in a sample of Ecuadorian patients that recovered from the virus.MethodsWe conducted a cross-sectional study that included 43 patients after symptomatic COVID infection, who were evaluated by spirometry, single breath DLCO, and 6MWT. For statistical analysis we performed point biserial correlations, and chi squared tests.ResultsOverall, 30.3% of patients (n = 13) reported persistent symptoms, with fatigue being the most common (23.3%, n = 10). Around 34.9% (n = 15) of the sample had a restrictive spirometry pattern, 18.6% (n = 8) had an abnormally decreased adjusted DLCO. A restrictive spirometry pattern was associated with an abnormally low adjusted DLCO (χ2(2) = 11,979, p = 0.001).ConclusionWe found that a considerable proportion of patients presented with persistent symptoms and alterations in pulmonary function following COVID-19, mainly a restrictive respiratory pattern and abnormally low DLCO. Further studies are needed to determine which patients may benefit from the follow-up with specific pulmonary function tests.

The Correlations Between Measurement of Lung Diffusing Capacity for Carbon Monoxide and The Severity Group of Asthma Patients in Persahabatan Hospital Jakarta

Introduction: Airway remodeling in asthma which involve small airway can affect until alveoli and cause abnormalities in the lung parenchyma. This study tries to find lung parenchymal abnormalities in patients with asthma through the examination diffusion capacity with a single breath DLCO method.Methods: A cross-sectional study by dividing asthma based on the degree of severity into two major groups, namely mild asthma (intermittent and mild persistent) and severe (persistent moderate and severe). The amount of each group is 31 subjects and 29 subjects, which are taken consecutively from stable asthma patients without comorbid who are seeking treatment in Persahabatan Hospital in December 2015 - May 2016.Results: The average value of DLCO /predictions in mild asthma group is 92,74 ± 15,70% and decreased in the severe asthma group is 77,45 ± 16,78%. Some spirometry value showed significant positive correlation with the value of DLCO/prediction, namely: FVC/prediction, FEV1 /prediction and FEF25-75 % / prediction with p &lt; 0.05. Correlation analysis showed FVC/prediction could dramatically affect the diffusion capacity of asthmatic patients. There is a significant relationship between abnormalities in lung function (p=0,004) and severity of asthma (p=0.000) with a corresponding decrease DLCO / prediction (DLCO/ prediction ≤75 %).Conclusion: The severity of asthma has a relationship with the diffusion capacity of the lungs, increased severity will decrease the diffusion capacity in asthma patients. Decreasing diffusion capacity showed that abnormalities in asthma not only occur in the respiratory tract but also in the lung parenchyma.

Development of lung diffusion to adulthood following extremely preterm birth.

BackgroundGas exchange in extremely preterm (EP) infants must take place in fetal lungs. Childhood lung diffusing capacity of the lung for carbon monoxide (DLCO) is reduced; however, longitudinal development has not been investigated. We describe the growth of DLCO and its subcomponents to adulthood in EP compared with term-born subjects.MethodsTwo area-based cohorts born at gestational age ≤28 weeks or birthweight ≤1000 g in 1982–1985 (n=48) and 1991–1992 (n=35) were examined twice, at ages 18 and 25 years and 10 and 18 years, respectively, and compared with matched term-born controls. Single-breath DLCO was measured at two oxygen pressures, with subcomponents (membrane diffusion (DM) and pulmonary capillary blood volume (VC)) calculated using the Roughton–Forster equation.ResultsAge-, sex- and height-standardised transfer coefficients for carbon monoxide (KCO) and DLCO were reduced in EP compared with term-born subjects, and remained so during puberty and early adulthood (p-values for all time-points and both cohorts ≤0.04), whereas alveolar volume (VA) was similar. Development occurred in parallel to term-born controls, with no signs of pubertal catch-up growth nor decline at age 25 years (p-values for lack of parallelism within cohorts 0.99, 0.65, 0.71, 0.94 and 0.44 for z-DLCO, z-VA, z-KCO, DM and VC, respectively). Split by membrane and blood volume components, findings were less clear; however, membrane diffusion seemed most affected.ConclusionsPulmonary diffusing capacity was reduced in EP compared with term-born subjects, and development from childhood to adulthood tracked in parallel to term-born subjects, with no signs of catch-up growth nor decline at age 25 years.

Original Article: Clinical Research.

Aim:In this study, we aimed to investigate the possible role of endotrophin, a profibrotic byproduct of collagen VI, in the complex process of fibrosis development in the disease group with pulmonary fibrosis among interstitial lung diseases.Material and Method:When the patients’ participation in the study were completed, smoking or alcohol drinking conditions, and family history were recorded. Their weights and heights were recorded and body mass index (BMI) was calculated. In every patient, Spirometry with bronchodilator testing, determination of single-breath DLCO, and plethysmographic measurement of thoracic gas volume and airway resistance were performed. Blood samples were obtained for the inflammation markers such as sedimentation rate, C-reactive protein (CRP), complete blood count, liver and renal function tests, and lactate dehydrogenase levels. Serum endotrophin levels were measured in all patients.Results:Thirty-five patients with interstitial lung disease who were having pulmonary fibrosis, 35 patients with interstitial lung disease without pulmonary fibrosis, and 20 control patients without any signs or symptoms of interstitial lung disease were included in the study. Age distribution was similar between groups. The fibrotic ILD group was more commonly smoker or ex-smoker compared with the non-fibrotic ILD patients or control cases. Fibrotic ILD patients were leaner, having significantly decreased total lung capacity, diffusion capacity, and higher LDH levels. In the comparison of the 3 study groups regarding the endotrophin levels, there was a significant difference between groups. The fibrotic and non-fibrotic patient groups were compared for the Endotrophin levels and the difference was also significant. However, there was not any significant difference regarding the endotrophin levels between control cases and non-fibrotic ILD patients. Smoked cigarette pocket x year showed a significant positive correlation and DLCO % and KCO % showed a significant negative correlation with the endotrophin levels.Conclusion:Serum endotrophin levels significantly increase in fibrotic ILD patients compared with the non-fibrotic ILD patients and control cases. Endotrophin may be suggested as a diagnostic marker in fibrotic interstitial lung diseases.

Influence of Mouth Pressure on Measurement of Diffusing Capacity in the Clinical Pulmonary Function Laboratory.

Current American Thoracic Society/European Respiratory Society guidelines recommend that patients hold their breath with minimum effort at total lung capacity during measurement of the single-breath diffusing capacity of the lung for carbon monoxide (DLCO) to avoid excessively positive or negative mouth pressures. We asked to what extent do these pressures range during single-breath DLCO testing and whether mouth pressures are associated with single-breath DLCO. We analyzed mouth pressures measured during clinical single-breath DLCO testing in an academic pulmonary function laboratory over a 3-month period. We compared mouth pressures with single-breath DLCO and determined the influence of obesity, restriction, and emphysema on mouth pressures. We used multiple linear regression to evaluate whether mouth pressure was an independent determinant of single-breath DLCO. We analyzed data from 336 subjects who presented with a variety of diseases, the most common of which were unexplained dyspnea, interstitial lung disease, sarcoidosis, and emphysema. The median mouth pressure was 4.5 cm H2O, with a range of -13 to 31 cm H2O. The single-breath DLCO did not correlate with mouth pressure (P = .08). There was no difference in mouth pressures between individuals with and without obesity, with and without restriction, and with and without interstitial lung disease. Mouth pressure was lower among the subjects with emphysema. There was no difference in single-breath DLCO % predicted between individuals who were obese and individuals who were not obese. Multiple linear regression demonstrated that only age and FEV1, but not mouth pressure, were independently associated with single-breath DLCO % predicted (ß-coefficient: age, -0.35 [P = .003]; FEV1%, 0.26 [P = .004]; adjusted R2, 0.16). Mouth pressures varied widely during single-breath DLCO measurement but were not associated with the measurement of single-breath DLCO in the clinical setting of pulmonary function testing. Overall, these findings indicate that pulmonary function technologists need not discard efforts made during measurement of single-breath DLCO if only mild changes in mouth pressure occur.

Faal Paru Difusi

Diffusion capacity is useful for measuring ability of pulmonary microcirculation to transfer oxygen and carbon dioxide from alveoli to capillaries. Physiological examination of diffusion is a continuation of physiological examination of ventilation. Diffusion capacity is measured by DLCO (Diffusing capacity for Carbon Monoxide). Measurement of oxygen diffusion capacity directly is very difficult so that indirect methods are used using carbonmonoxide (DLCO). Diffusion capacity of oxygen is equivalent to DLCO multiplied by 1.23. Normal value of DLCO is 20-30 ml/minute mmHg. Some factors that affect DLCO are Hb levels, COHb in smokers, and alveolar volume. Some techniques for measuring DLCO include Steady-state, Three-equation Single-breath, Nitrogen Washout, and Intra-breath DLCO. This test is indicated in pulmonary parenchymal disease (pulmonary fibrosis, asbestosis, sarcoidosis, interstitial lung disease), cystic fibrosis, pulmonary hypertension, and pulmonary bleeding. DLCO is increased in asthma patients, obesity, polycythemia, intraalveolar bleeding, and right-left heart shunting. DLCO is decreased in emphysematous lung patients, pulmonary post resection, bronchial obstruction, multiple pulmonary embolism, anemia, idiopathic pulmonary fibrosis, asbestosis, sarcoidosis, vascular collagen disease, hypersensitive pneumonitis, and alveolar proteinosis.

The Test of DLCO Is A Valuable Predictor for Prognostic Determination of Patients with Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) is characterized by permanent and progressive air way obstruction. In terms of morbidity, this disease is the first highest pulmonary disease in the world. DLCO is used for measurement of gas transfer from alveoli to blood capillary and Hb level is one of the main factors affecting the gas transfer. The aim of this study was to examine prognosis of patients with stable COPD using lung function, DLCO and Hb tets. &#x0D; Methods: Consecutive sampling was used to recruit 33 outward patients who suffered stable COPD and visited the Lung Clinic at Public Hospital dr. Moewardi Surakarta. Classification of COPD was determined using GOLD 2016. Airway and lung functions were examined using spirometry and single breath DLCO. Hb level was measured using cyamethemoglobin method. All collected data were analyzed using student t test and p value was set up P

Reference Values for the Diffusing Capacity Determined by the Single-Breath Technique at Different Altitudes: The Latin American Single-Breath Diffusing Capacity Reference Project.

The lung diffusion capacity (DLCO) determined by the single-breath technique greatly helps in the differential diagnosis and classification of severity of common lung diseases. However, widespread use of single-breath DLCO tests in Latin America has been limited, in part, by the lack of appropriate reference values. Our objective was to derive robust reference equations for single-breath DLCO from healthy Hispanic adults, using the most recent guidelines and taking into account altitude above sea level and hemoglobin. We recruited healthy adults from Caracas (690 m), Santiago (650 m), Mexico City (2,240 m), and Bogota (2,640 m). DLCO testing was completed using an instrument that exceeds American Thoracic Society/European Respiratory Society 2005 guidelines for spirometry and single-breath DLCO and provided centralized training and a quality assurance program. We included 480 healthy Hispanic adults (58.3% women) with a mean age of 46 y (range 22-83 y). Their mean ± SD single-breath DLCO was 30.4 ± 9.2 mL/min/mm Hg. Results as a percentage of predicted by Crapo's reference values (the closest to obtained values) were 83 ± 10% (Caracas), 91 ± 10% (Santiago), 104 ± 17% (Mexico City), and 118 ± 19% (Bogota), and current suggested adjustments by hemoglobin or altitude did not correct differences, especially in Santiago and Caracas. We recommend these new single-breath DLCO reference equations to predict single-breath DLCO in Latin America performed with current instruments and procedures and including as a predictor altitude above sea level.

One hundred years of pulmonary function testing: a perspective on 'The diffusion of gases through the lungs of man' by Marie Krogh.

The single breath carbon monoxide (CO) diffusing capacity test (DLCO; or transfer factor TLCO) measures the alveolar surface area available for gas exchange from the alveolar volume and the rate of alveolar CO uptake (Hughes & Bates, 2003). It is now a test that is carried out hundreds of thousands of times a year in pulmonary function laboratories across the globe, benefiting millions of respiratory patients. The principles and application of the single breath DLCO test were first described in experiments published by Marie Krogh 100 years ago in The Journal of Physiology (Krogh, 1915). To understand the clinical and research impact of these studies it is first necessary to consider the context in which they were performed.

Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease

OBJECTIVE: Wood smoke exposure is a risk factor for COPD. For a given degree of airway obstruction, the reduction in DLCO is smaller in individuals with wood smoke-related COPD than in those with smoking-related COPD, suggesting that there is less emphysema in the former. The objective of this study was to compare HRCT findings between women with wood smoke-related COPD and women with smoking-related COPD. METHODS: Twenty-two women with severe COPD (FEV1/FVC ratio < 70% and FEV1 < 50%) were divided into two groups: those with wood smoke-related COPD (n = 12) and those with smoking-related COPD (n = 10). The two groups were compared regarding emphysema scores and airway involvement (as determined by HRCT); and functional abnormalities-spirometry results, DLCO, alveolar volume (VA), the DLCO/VA ratio, lung volumes, and specific airway resistance (sRaw). RESULTS: There were no significant differences between the two groups in terms of FEV1, sRaw, or lung hyperinflation. Decreases in DLCO and in the DLCO/VA ratio were greater in the smoking-related COPD group subjects, who also had higher emphysema scores, in comparison with the wood smoke-related COPD group subjects. In the wood smoke-related COPD group, HRCT scans showed no significant emphysema, the main findings being peribronchial thickening, bronchial dilation, and subsegmental atelectasis. CONCLUSIONS: Female patients with severe wood smoke-related COPD do not appear to develop emphysema, although they do show severe airway involvement. The reduction in DLCO and VA, with a normal DLCO/VA ratio, is probably due to severe bronchial obstruction and incomplete mixing of inspired gas during the determination of single-breath DLCO.

Prediction Equations for Single-Breath Diffusing Capacity in Subjects Aged 65 to 85 Years

In senior subjects, diffusing capacity of the lung for carbon monoxide (Dlco) is interpreted using prediction equations derived from primarily younger adult populations. Our objectives were to provide reference equations for single-breath Dlco for a cohort of healthy, never-smoking, white, European adults between 65 and 85 years of age and to compare the predicted values of this sample with those from other studies involving middle-aged adults. Reference equations were derived from a randomly selected sample from the general population of 431 healthy never smoker subjects aged 65 to 85 years (262 women and 169 men). Spirometry, lung volume determinations by plethysmography, and single-breath Dlco (corrected for hemoglobin) were performed following the American Thoracic Society/European Respiratory Society guidelines. Reference values and lower and upper limits of normal were derived using a piecewise polynomial model. In addition to age, our reference equations confirmed the height and body size dependence of Dlco and diffusing capacity for alveolar volume (Dlco/Va) in older subjects. Practically all of the reference values obtained by extrapolating reference equations of middle-aged adults underestimated the true diffusing capacity of the healthy elderly volunteers. Middle-aged reference equations underestimated Dlco by 2.1% to 22.3% in women and 2.8% to 37.8% in men. In addition, Dlco/Va was overestimated up to 18% and 39.8% in women and men, respectively, whereas other equations underestimated Dlco/Va up to 22.2% and 11.9% in women and men, respectively. These results underscore the importance of using prediction equations appropriate to the origin and age characteristics of the subjects being studied.

A comparison of single breath and re-breathe diffusing capacity in emphysema patients and controls

In emphysema patients, gas dilutional alveolar volume is underestimated by a 10s single breath maneuver at total lung capacity (TLC) compared with re-breathing at functional residual capacity (FRC); corresponding underestimation of single breath diffusing capacity (DLCO) in emphysema has not been demonstrated. The purpose of this study was to quantify the degree to which re-breathe DLCO at FRC (DLCORB) differs from single breath DLCO at TLC (DLCOSB) in emphysema.In 37 consecutively recruited patients with moderate to severe emphysema (FEV1/FVC 40%±10% predicted), DLCORB as % predicted of 91 controls without cardiopulmonary disease was 79%±24%, significantly greater than % predicted DLCOSB (44%±19%; p<0.0001). DLCORB/DLCOSB was inversely proportional to FEV1% predicted (R=−0.47, p=0.004), and FEV1/FVC (R=−0.54, p<0.001).These data indicate that a 10s single breath DLCO maneuver progressively under-represents re-breathe lung diffusing capacity in emphysema as airflow obstruction increases.

Erratum to: Impaired diffusing capacity for carbon monoxide in children with type 1 diabetes: is this the first sign of long-term complications?

We assessed the presence of lung dysfunction in children with type 1 diabetes, evaluated as reduced diffusing capacity of the lung for carbon monoxide (DLCO), and its components: membrane diffusing capacity (DM) and pulmonary capillary blood volume (Vc). A total of 42 children, aged 15.6 ± 3.8 years, with type 1 diabetes for 8.3 ± 5.5 years, and 30 healthy age and sex-matched peers were recruited for the study. Lung volumes and spirometric dynamic parameters were assessed by plethysmography. Single-breath DLCO was measured according to international recommendation. DM and Vc volume were calculated. Lung volumes were significantly reduced in young patients with type 1 diabetes when compared to controls. Moreover, DLCO was reduced in patients compared to controls (78% ± 16% vs. 120% ± 1%, P = 0.0001). However, when differentiating DM and Vc compartments, we observed a significant impairment only about Vc (34 ± 20 ml vs. 88 ± 18 ml; P = 0.0001), while no difference was observed about DM compartment (23 ± 4 vs. 26 ± 3 ml/min/mmHg, P = 0.798). Whether this might be seen as the “first” sign of microangiopathic involvement in patients with type 1 diabetes has to be confirmed on larger groups but is still fascinating. Meanwhile, we suggest to screen DLCO in all patients with type 1 diabetes.

Impaired diffusing capacity for carbon monoxide in children with type 1 diabetes: is this the first sign of long-term complications?

We assessed the presence of lung dysfunction in children with type 1 diabetes, evaluated as reduced diffusing capacity of the lung for carbon monoxide (DLCO), and its components: membrane diffusing capacity (DM) and pulmonary capillary blood volume (Vc). A total of 42 children, aged 15.6±3.8 years, with type 1 diabetes for 8.3±5.5 years, and 30 healthy age and sex-matched peers were recruited for the study. Lung volumes and spirometric dynamic parameters were assessed by plethysmography. Single-breath DLCO was measured according to international recommendation. DM and Vc volume were calculated. Lung volumes were significantly reduced in young patients with type 1 diabetes when compared to controls. Moreover, DLCO was reduced in patients compared to controls (78%±16% vs. 120%±1%, P=0.0001). However, when differentiating DM and Vc compartments, we observed a significant impairment only about Vc (34±20ml vs. 88±18ml; P=0.0001), while no difference was observed about DM compartment (23±4 vs. 26±3ml/min/mmHg, P=0.798). Whether this might be seen as the "first" sign of microangiopathic involvement in patients with type 1 diabetes has to be confirmed on larger groups but is still fascinating. Meanwhile, we suggest to screen DLCO in all patients with type 1 diabetes.

Pulmonary hypertension after ventriculoatrial shunt implantation

Ventriculoatrial (VA) shunts inserted for the treatment of hydrocephalus are known to be a risk factor for pulmonary hypertension. The aim of this study was to evaluate the incidence of pulmonary hypertension among adult patients with VA shunts. All patients who had received a VA shunt at one of two institutions between 1985 and 2000 were invited for a cardiopulmonary evaluation. The investigation included a thorough history taking, clinical examination, echocardiography, and pulmonary function testing including diffusing capacity of the lung for carbon monoxide (DLCO). Pulmonary hypertension was defined as systolic pulmonary artery pressure>35 mm Hg at rest. The study group consisted of 86 patients, of whom 38 (44%) could be examined. The patients' mean age was 47.1±18.4 years; the median interval between shunt insertion and cardiopulmonary evaluation was 15 years (range 5-20 years). Of the 38 patients, 20 (53%) had Doppler velocity profiles of tricuspid regurgitation that were adequate for the estimation of pulmonary artery systolic pressure. Doppler-defined pulmonary hypertension was observed in 3 patients (8%), 2 of whom underwent right heart catheterization. Chronic thromboembolic pulmonary hypertension was confirmed in both patients, and medical therapy, including anticoagulation, was started. The VA shunt was removed in both cases and replaced with a different type of device. Pulmonary function tests revealed a restrictive pattern in 15% and typical obstructive findings in 9% of patients. In 30% of patients the DLCO was less than 80% of predicted, and blood gas analysis showed hypoxemia in 6% of patients. No significant differences in pulmonary function tests were noted between the patients with and without echocardiographic evidence of pulmonary hypertension. However, patients with pulmonary hypertension had significantly lower DLCO values. The authors detected pulmonary hypertension by using Doppler echocardiography in a significant proportion of patients with VA shunts. It is therefore recommended that practitioners perform regular echocardiography and pulmonary function tests, including single-breath DLCO in these patients to screen for pulmonary hypertension to prevent hazardous late cardiopulmonary complications.

Simulation System for a Rebreathing Technique To Measure Multiple Cardiopulmonary Function Parameters

We developed a simple method for simulating a rebreathing maneuver to test the accuracy of the apparatus for simultaneous measurement of lung volume, diffusing capacity of the lung for carbon monoxide (Dlco), diffusing capacity of the lung for nitric oxide (Dlno), and pulmonary blood flow (Qc). A test gas mixture containing 0.3% methane, 0.3% CO, 0.8% acetylene, 30% O(2), and 40 ppm nitric oxide in balance of nitrogen was sequentially diluted with a rebreathing gas mixture containing 0.3% acetylene, 0.3% methane, and 21% O(2) in balance of nitrogen in order to simulate the in vivo end-tidal disappearance of the test gas mixture. Simulation of one rebreathing maneuver consisted of at least four serial dilution steps with a performance time of < 5 min. Using this technique, we estimated functional residual capacity, Qc, Dlco, and Dlno at various flow rates and dilution ratios (0.95 to 4.04 L, 3.54 to 6.83 L/min, 7.27 to 15.12 mL/min/mm Hg, and 6.51 to 12.00 mL/min/mm Hg, respectively) and verified simulation results against nominal values. The same apparatus also could simulate a single-breath procedure. Compared to nominal values, errors in measured values by rebreathing and single-breath Dlco simulation remained < 5% and 7%, respectively. Slopes of the correlations were close to 1.0 (within +/- 5% and +/- 6.4% in rebreathing and single-breath Dlco simulation studies, respectively). The results demonstrate the feasibility of this simulation method for standardizing the experimental measurements obtained by rebreathing and single-breath techniques. Incorporation of these simulation steps enhances the noninvasive assessment of cardiopulmonary function.

The effect of conductive ventilation heterogeneity on diffusing capacity measurement

It has long been assumed that the ventilation heterogeneity associated with lung disease could, in itself, affect the measurement of carbon monoxide transfer factor. The aim of this study was to investigate the potential estimation errors of carbon monoxide diffusing capacity (Dl(CO)) measurement that are specifically due to conductive ventilation heterogeneity, i.e., due to a combination of ventilation heterogeneity and flow asynchrony between lung units larger than acini. We induced conductive airway ventilation heterogeneity in 35 never-smoker normal subjects by histamine provocation and related the resulting changes in conductive ventilation heterogeneity (derived from the multiple-breath washout test) to corresponding changes in diffusing capacity, alveolar volume, and inspired vital capacity (derived from the single-breath Dl(CO) method). Average conductive ventilation heterogeneity doubled (P < 0.001), whereas Dl(CO) decreased by 6% (P < 0.001), with no correlation between individual data (P > 0.1). Average inspired vital capacity and alveolar volume both decreased significantly by, respectively, 6 and 3%, and the individual changes in alveolar volume and in conductive ventilation heterogeneity were correlated (r = -0.46; P = 0.006). These findings can be brought in agreement with recent modeling work, where specific ventilation heterogeneity resulting from different distributions of either inspired volume or end-expiratory lung volume have been shown to affect Dl(CO) estimation errors in opposite ways. Even in the presence of flow asynchrony, these errors appear to largely cancel out in our experimental situation of histamine-induced conductive ventilation heterogeneity. Finally, we also predicted which alternative combination of specific ventilation heterogeneity and flow asynchrony could affect Dl(CO) estimate in a more substantial fashion in diseased lungs, irrespective of any diffusion-dependent effects.

Standardization of the Single-Breath Diffusing Capacity in a Multicenter Clinical Trial

Standardization of the measurement of single-breath diffusing capacity of the lung for carbon monoxide (DLCO) is difficult to implement in multicenter trials as differences in equipment, training, and performance guidelines have led to high variability between and within centers. The safety assessment of inhalable insulin required the standardization of measurement of single-breath DLCO in multicenter clinical trials to optimize test precision. This was an open-label, 24-week, parallel-group, outpatient study of inhaled human insulin in participants with type 1 diabetes who were randomly assigned to receive treatment with daily premeal inhaled or subcutaneous (SC) insulin for 12 weeks, followed by SC insulin for 12 weeks. Monitoring of single-breath DLCO using standardized methodology was performed. Standardization included uniform instrumentation, centrally trained study coordinators, and centralized data monitoring and review of quality control. Sites received feedback within 24 h for any tests of unacceptable quality with recommendations for improvement. A total of 226 study participants at 33 sites completed 11,335 DLCO efforts during 4,797 test sessions; 3,607 (75.2%) and 4,581 (95.5%) of all testing sessions yielded two American Thoracic Society-acceptable efforts that varied by < 1 and 2 mL/min/mm Hg, respectively. Only 65 sessions produced one or fewer acceptable efforts. The root mean square intrasubject coefficient of variation in DLCO at the end of the comparative dosing phase was 6.01%. The standardized methodology employed in this study demonstrates the feasibility of collecting high-quality single-breath DLCO data in the setting of a multicenter clinical trial with reliability that is comparable to spirometry.