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The recently published Global Lung Function Initiative (GLI) carbon monoxide transfer factor ( T LCO ) reference equations provide an opportunity to adopt a current, all-age, widely applicable reference set. The aim of this study was to document the effect of changing to GLI from commonly utilised reference equations on the interpretation of T LCO results.33 863 T LCO results (48% female, 88% Caucasian, n=930 aged <18 years) from clinical pulmonary function laboratories within three Australian teaching hospitals were analysed. The lower limit of normal (LLN) and proportion of patients with a T LCO below this value were calculated using GLI and other commonly used reference equations.The average T LCO LLN for GLI was similar or lower than the other equations, with the largest difference seen for Crapo equations (median: -1.25, IQR: -1.64, -0.86 mmol·min -1 ·kPa -1 ). These differences resulted in altered rates of reduced T LCO for GLI particularly for adults (+1.9% versus Miller to -27.6% versus Crapo), more so than for children (-0.8% versus Kim to -14.2% versus Cotes). For adults, the highest raw agreement for GLI was with Miller equations (94.7%), while for children it was with Kim equations (98.1%). Results were reclassified from abnormal to normal more frequently for younger adults, and for adult females, particularly when moving from Roca to GLI equations (30% of females versus 16% of males).The adoption of GLI T LCO reference equations in adults will result in altered interpretation depending on the equations previously used and to a greater extent in adult females. The effect on interpretation in children is less significant., Competing Interests: Conflict of interest: D.J. Brazzale has nothing to disclose. Conflict of interest: L.M. Seccombe has nothing to disclose. Conflict of interest: L. Welsh has nothing to disclose. Conflict of interest: C.J. Lanteri has nothing to disclose. Conflict of interest: C.S. Farah has nothing to disclose. Conflict of interest: W.R. Ruehland has nothing to disclose., (Copyright ©ERS 2020.)

Background: We examine the ability of pre-existing measures of Forced Expiratory Volume in 1 s (FEV1), and Diffusion Capacity for Carbon Monoxide (DLCO) to determine the subsequent 30-day mortality outcome following unselected acute medical admission., Methods: Between 2002 and 2017, we studied all emergency medical admissions (106,586 episodes in 54,928 patients) of whom 8071 were classified as respiratory. We employed logisitic multiple variable regression models to evaluate the ability of FEV1 or DLCO to predict the 30-day hospital mortality outcome., Results: The 30-day hospital episode mortality outcome demonstrated curvilinear relationships to the underlying FEV1 or DLCO values; adjusted for major outcome predictors, a higher FEV1 - OR 0.85 (95% CI: 0.82, 0.89) or DLCO OR 0.76 (95% CI: 0.73, 0.79) values predicted survival. The range of predicted mortalities was from 3.3% (95% CI: 2.5, 4.0) to 23.5% (95% CI: 20.8, 26.2); the FEV1 (Model1) and DLCO (Model2) outcome prediction was essentially equivalent (Chi2 = 2.9: p = 0.08)., Conclusion: The 30-day mortality outcome was clearly related to the pre-admission FEV1 and DLCO value. The outcome relationship was curvilinear. Either parameter appears a useful tool to explore hospital outcomes. Previously suggested cut-points are likely an artefact and not supported by these data., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

The study aims to analyze the effects of induction treatment with cyclophosphamide (CYC) pulse therapy followed by maintenance treatment with other mild immunosuppressive agents on lung function in scleroderma (SSc) patients. Thirty patients with SSc (mean age 52 years, mean disease duration < 2 years) with forced vital capacity (FVC) ≤ 80% and/or diffusing capacity of carbon monoxide (DLco) ≤ 70% were included. Monthly CYC pulses were given for 6 months (induction treatment), followed by 3-monthly maintenance pulses for the next 18 months, and during the next 5 years patients received other mild immunosupressive therapy brought by the competent rheumatologist. The efficacy was evaluated by comparing FVC% and DLco% after 6, 24, and 84 months from the baseline. All patients completed induction and maintenance treatment with CYC. Three patients were lost to follow-up. The rest of 27 patients, during the next 5 years, received other immunosupressive agents (14 azathioprine, 9 methotrexate, and 4 mycophenolate mofetil). Three patients died in the 4 years of follow-up. By 6, 24, and 84 months, the mean FVC and DLco changes were + 0.47 and + 2.10, + 3.30 and - 2.49, and + 1.53 and - 3.76%, respectively. These changes were not significantly different from the baseline values. CYC does not appear to result in clinically significant improvement of pulmonary function but fulfilled criteria of stable disease. Maintenance treatment with other mild immunosupressive agents preserves the benefits achieved during CYC treatment.

The value of rates of change in forced expiratory volume in 1 s (FEV 1 ) and diffusing capacity of the lung for carbon monoxide ( D LCO ) to predict disease progression, and initiation of mTOR (mechanistic target of rapamycin) inhibitor therapy has not been evaluated.In 84 premenopausal lymphangioleiomyomatosis patients, individual rates of change in FEV 1 and D LCO and their 95% confidence intervals were used to derive subsequent lowest values of FEV 1 and D LCO that would prompt initiation of sirolimus therapy. These treatment criteria were compared with a criterion based on FEV 1 or D LCO ≤70% predicted. In 12 patients undergoing sirolimus therapy both methods for determining the optimal point for initiation of therapy were evaluated.27 and 35 patients who experienced greater than expected rates of change in FEV 1 and D LCO , respectively, would have been excluded from therapy based on an FEV 1 or D LCO >70% pred. 25 of the 84 patients were eventually treated, but only when FEV 1 or D LCO were ≤70% pred. Applying such treatment criteria to 12 patients undergoing sirolimus therapy would have delayed treatment for many years.Premenopausal females in whom FEV 1 or D LCO are declining at rates above the expected based on their individual rates of decline, should be considered for sirolimus therapy before the FEV 1 or D LCO falls to ≤70% pred., Competing Interests: Conflict of interest: None declared., (The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2018.)

There are numerous reference equations available for the single-breath transfer factor of the lung for carbon monoxide ( T ); however, it is not always clear which reference set should be used in clinical practice. The aim of the study was to develop the Global Lung Function Initiative (GLI) all-age reference values for  LCO ); however, it is not always clear which reference set should be used in clinical practice. The aim of the study was to develop the Global Lung Function Initiative (GLI) all-age reference values for T  LCO Data from 19 centres in 14 countries were collected to define T , transfer coefficient of the lung for carbon monoxide and alveolar volume.This is the largest collection of normative  LCO reference values. Similar to the GLI spirometry project, reference values were derived using the LMS (lambda, mu, sigma) method and the GAMLSS (generalised additive models for location, scale and shape) programme in R.12 660 T  LCO measurements from asymptomatic, lifetime nonsmokers were submitted; 85% of the submitted data were from Caucasians. All data were uncorrected for haemoglobin concentration. Following adjustments for elevation above sea level, gas concentration and assumptions used for calculating the anatomic dead space volume, there was a high degree of overlap between the datasets. Reference values for Caucasians aged 5-85 years were derived for T  LCO , transfer coefficient of the lung for carbon monoxide and alveolar volume.This is the largest collection of normative T  LCO data, and the first global reference values available for T  LCO ., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2017.)

Rationale: Exploration of FVC as it relates to mortality in idiopathic pulmonary fibrosis (IPF), a chronic, progressive, and ultimately fatal parenchymal lung disease, is important both clinically and to the current drug development paradigm. We evaluated the association between FVC decline and mortality in what is to our knowledge the largest well-characterized placebo cohort to date. Additionally, we sought to explore the risk of death caused by acute exacerbations and to further validate previously identified baseline predictors of mortality., Objectives: To validate and further characterize FVC decline, acute exacerbations, and previously identified baseline predictors as they relate to risk of death., Methods: A total of 1,132 placebo subjects from six studies used for the clinical development of nintedanib and pirfenidone for the treatment of IPF were included in the present analysis. Deaths were captured as all-cause mortality. A stratified Cox proportional hazards model was used to test the association between baseline predictors, decline in FVC % predicted from baseline, acute exacerbations, and death. Decline in FVC % predicted and exacerbations were treated as time-varying covariates., Results: Subjects were followed for a mean of 60 weeks. At baseline, age, smoking status, lower FVC % predicted, and lower diffusing capacity of the lung for carbon monoxide % predicted were associated with an increased risk of death. The risk of death was also increased for subjects having one or more exacerbations with a hazard ratio (HR) of 10.3 (95% confidence interval [CI], 5.7-18.7). Compared with an FVC % predicted absolute decline from baseline at any time during the study of less than 5%, a decline greater than or equal to 10% to less than 15% was associated with an increased risk of death, with an HR of 2.2 (95% CI, 1.1-4.4), as was a decline greater than or equal to 15%, which was estimated with an HR of 6.1 (95% CI, 3.1-11.8). A decline ranging from greater than or equal to 5% to less than 10% was not associated with increased mortality., Conclusions: Our analyses validate the importance of baseline FVC, diffusing capacity of the lung for carbon monoxide, age, and smoking status as predictors of mortality and strengthen the association between decline in FVC and exacerbations with death, verifying a decline in FVC as an appropriate endpoint in IPF drug development. Clinical trial registered with www.clinicaltrials.gov (NCT00514683, NCT01335464, NCT01335477, NCT00287729, NCT00287716, and NCT01366209).

Background: Lung diffusing capacity for carbon monoxide (DLCO) gives an overall assessment of functional lung surface area for gas exchange and can be assessed using various methods. DLCO is an important factor in exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). We investigated if the intra-breath (IBDLCO) method may give a more sensitive measure of available gas exchange surface area than the more typical single breath (SBDLCO) method and if COPD subjects with the largest resting DLCO relative to pulmonary blood flow (Qc) would have a more preserved exercise capacity., Methods: Informed consent, hemoglobin, spirometry, SBDLCO, IBDLCO, and Qc during IBDLCO were performed in moderate to severe COPD patients, followed by progressive cycle ergometry to exhaustion with measures of oxygen saturation (SaO 2 ) and expired gases., Results: Thirty two subjects (47% female, age 66 ± 9 yrs., BMI 30.4 ± 6.3 kg/m 2 , smoking hx 35 ± 29 pkyrs, 2.3 ± 0.8 on the 0-4 GOLD classification scale) participated. The majority used multiple inhaled medications and 20% were on oral steroids. Averages were: FEV 1 /FVC 58 ± 10%Pred, peak VO 2 11.4 ± 3.1 ml/kg/min, and IBDLCO 72% of the SBDLCO (r = 0.88, SB vs IB methods). Using univariate regression, both the SB and IBDLCO (% predicted but not absolute) were predictive of VO 2 peak in ml/kg/min; SBDLCO/Qc (r = 0.63, p < 0.001) was the best predictor of VO 2 peak; maximal expiratory flows over the mid to lower lung volumes were the most significantly predictive spirometric measure (r = 0.49, p < 0.01). However, in multivariate models only BMI added additional predictive value to the SBDLCO/Qc for predicting aerobic capacity (r = 0.73). Adjusting for current smoking status and gender did not significantly change the primary results., Conclusion: In patients with moderate to severe COPD, preservation of lung gas exchange surface area as assessed using the resting SBDLCO/Qc appears to be a better predictor of exercise capacity than more classic measures of lung mechanics.

This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis.Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide ( D ), transfer coefficient of the lung for carbon monoxide ( LCO ), transfer coefficient of the lung for carbon monoxide ( K , and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p<0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p<0.0001) reduced gas transfer ( CO ), composite physiologic index (CPI)) and mortality.The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using D LCO , and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p<0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p<0.0001) reduced gas transfer ( D LCO ).There is no prognostic impact of emphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Background: The existing screening modalities for pulmonary embolism (PE), such as D-dimer and clinical prediction rules, have low positive predictive values. With its capability to indicate pulmonary vascular abnormalities, the ratio of the transfer factor of the lungs for nitric oxide and the transfer factor of the lungs for carbon monoxide (T L,NO /T L,CO ) might be an additional discriminating parameter., Methods: Carbon monoxide/Nitric oxide diffusion measurements were performed on unselected patients seen on the emergency department for which due to suspected PE a computed tomography pulmonary angiogram (CTPA) was ordered., Results: A total of 28 patients were included, PE was found in 12 on CTPA. Median T L,NO /T L,CO ratio was 4·09 (interquartile range (IQR) 3·83-4·40) in the no PE group versus 4·00 (IQR 3·78-4·32) in the PE group (P = 0·959). Median alveolar volume was 77·1% of predicted in the no PE group versus 71·0% of predicted in the PE group (P = 0·353). Median T L,CO was 75·8% of predicted in the no PE group versus 68·8% of predicted in the PE group (P = 0·120). Median T L,NO was 69·3% of predicted in the no PE group versus 60·5% of predicted in the PE group (P = 0·078)., Conclusion: The presented data indicate that the T L,NO /T L,CO ratio cannot be used to exclude PE., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Just a few clinicians routinely measure the subcomponents of the lung diffusing capacity for Carbone monoxide (DL CO ). This is because the measurement of membrane and blood conductances for CO (Dm CO and Db CO  = θ CO  × V c , respectively) by the classic Roughton and Forster method is complicated and time consuming. In addition, it mistakenly assumes a close relationship between alveolar oxygen partial pressure (PAO 2 ) and mean intracapillary oxygen partial pressure (PcapO 2 ) which is the true determinant of specific conductance of haemoglobin for CO (θ CO ). Besides that, the critical multistep oxygenation method along with different linear equations relating 1/θ CO to PcapO 2 gave highly scattered Dm CO and V c values. The Dm and V c can also be derived from a simultaneous measurement of DL NO and DL CO with the blood resistance for NO assumed to be negligible. However, recent in vitro and in vivo experiments point towards a finite value of θ NO (about 4·5 ml NO  × ml blood -1  × min -1  × mmHg -1 ). Putting together the arguments and our clinical data allows us to report here the state of the art in partitioning the CO diffusing capacity into its constitutive components, with the goal to encourage further studies examining the sensitivity of Dm CO and V c to alterations observed in parenchymal diseases., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

7The prevalence of idiopathic pulmonary fibrosis (IPF), a fatal and progressive lung disease, is estimated at 1.25-63 out of 100 000, making large population studies difficult. Recently, the need for large longitudinal registries to study IPF has been recognised.The Australian IPF Registry (AIPFR) is a national registry collating comprehensive longitudinal data of IPF patients across Australia. We explored the characteristics of this IPF cohort and the effect of demographic and physiological parameters and specific management on mortality.Participants in the AIPFR (n=647, mean age 70.9±8.5 years, 67.7% male, median follow up 2 years, range 6 months-4.5 years) displayed a wide range of age, disease severity and co-morbidities that is not present in clinical trial cohorts. The cumulative mortality rate in year one, two, three and four was 5%, 24%, 37% and 44% respectively. Baseline lung function (forced vital capacity, diffusing capacity of the lung for carbon monoxide, composite physiological index) and GAP (gender, age, physiology) stage (hazard ratio 4.64, 95% CI 3.33-6.47, p<0.001) were strong predictors of mortality. Patients receiving anti-fibrotic medications had better survival (hazard ratio 0.56, 95% CI 0.34-0.92, p=0.022) than those not on anti-fibrotic medications, independent of underlying disease severity.The AIPFR provides important insights into the understanding of the natural history and clinical management of IPF., (Copyright ©ERS 2017.)

This document provides an update to the European Respiratory Society (ERS)/American Thoracic Society (ATS) technical standards for single-breath carbon monoxide uptake in the lung that was last updated in 2005. Although both D LCO (diffusing capacity) and T LCO (transfer factor) are valid terms to describe the uptake of carbon monoxide in the lung, the term D LCO is used in this document. A joint taskforce appointed by the ERS and ATS reviewed the recent literature on the measurement of D LCO and surveyed the current technical capabilities of instrumentation being manufactured around the world. The recommendations in this document represent the consensus of the taskforce members in regard to the evidence available for various aspects of D LCO measurement. Furthermore, it reflects the expert opinion of the taskforce members on areas in which peer-reviewed evidence was either not available or was incomplete. The major changes in these technical standards relate to D LCO measurement with systems using rapidly responding gas analysers for carbon monoxide and the tracer gas, which are now the most common type of D LCO instrumentation being manufactured. Technical improvements and the increased capability afforded by these new systems permit enhanced measurement of D LCO and the opportunity to include other optional measures of lung function., (Copyright ©ERS 2017.)

Membrane conductance (Dm) and capillary lung volume (Vc) derived from NO and CO lung transfer measurements in humans depend on the blood conductance (θ) values of both gases. Many θ values have been proposed in the literature. In the present study, measurements of CO and NO transfer while breathing 15% or 21% O2 allowed the estimation of θNO and the calculation of the optimal equation relating 1/θCO to pulmonary capillary oxygen pressure (PcapO2). In 10 healthy subjects, the mean calculated θNO value was similar to the θNO value previously reported in the literature (4.5mmHgmin(-1)) provided that one among three θCO equations from the literature was chosen. Setting 1/θCO=a·PcapO2+b, optimal values of a and b could be chosen using two methods: 1) by minimizing the difference between Dm/Vc ratios for any PcapO2, 2) by establishing a linear equation relating a and b. Using these methods, we are proposing the equation 1/θCO=0.0062·PcapO2+1.16, which is similar to two equations previously reported in the literature. With this set of θ values, DmCO reached the morphometric range., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Lung function abnormalities occur in children with sickle cell disease (SCD) and may be associated with elevated pulmonary blood volume. To investigate that association, we determined whether blood transfusion in SCD children acutely increased pulmonary capillary blood volume (PCBV) and increased respiratory system resistance (Rrs5). Measurements of Rrs5 and spirometry were made before and after blood transfusion in 18 children, median age 14.2 (6.6-18.5) years. Diffusing capacity for carbon monoxide and nitric oxide were assessed to calculate the PCBV. Post transfusion, the median Rrs5 had increased from 127.4 to 141.3% predicted (p<0.0001) and pulmonary capillary blood volume from 39.7 to 64.1 ml/m2 (p<0.0001); forced expiratory volume in one second (p=0.0056) and vital capacity (p=0.0008) decreased. The increase in Rrs5 correlated with the increase in PCBV (r=0.50, p=0.0493). Increased pulmonary capillary blood volume may at least partially explain the lung function abnormalities in SCD children., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: Lung diffusing capacity for carbon monoxide (DLCO) is impaired in interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) associated to systemic sclerosis (SSc), but the mechanism of DLCO reduction remains controversial. We hypothesised that the determinants of DLCO impairment differ in interstitial or vascular involvement of the lung of SSc patients., Methods: DLCO was partitioned into alveolar-capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) using combined single-breath DLNO and DLCO measurements. Seventeen SSc patients without pulmonary involvement (SSc), 20 SSc patients with ILD (SSc-ILD), with and without PAH, and 21 healthy controls were included., Results: DLNO and Dm were reduced in SSc patients as compared with controls, whereas Vc was not significantly different. SSc-ILD patients showed a highly significant decrease in Dm and Vc as compared with SSc patients and controls. Vc tended to be more reduced than Dm in SSc-ILD patients with PAH. Dm and Vc were negatively correlated with PAPs and HCRT scores, but the relationship with the HRCT score was stronger., Conclusions: DLNO is more sensitive than DLCO in detecting functional impairment in SSc without radiologic or haemodynamic alterations. A disproportional reduction of Dm relative to Vc suggests a thickening of the blood-gas diffusion barrier in these patients. In SSc patients with detectable ILD, the gas exchange impairment is due to both components of lung diffusing capacity, and partitioning of DLCO in Dm and Vc is of little use in distinguishing the patients with only ILD from those with ILD complicated by PAH.

Objectives: To identify factors indicating exercise-induced oxygen desaturation during the 6-minute walk test (6MWT) in patients with diffuse systemic sclerosis (SSc) and initial interstitial lung disease (ILD)., Methods: The study involved 121 consecutive adult anti-Scl 70 autoantibody-positive SSc patients with initial ILD, 93 of whom were followed up for five years. Before enrolment and then annually, the patients underwent high-resolution computed tomography (HRCT), functional lung tests, with carbon monoxide diffusion capacity of the lung (DLCO) and its components (alveolar-capillary membrane [Dm] and pulmonary blood volume [Vc]), the evaluation of dyspnea before and after the 6MWT using the Borg scale, and transthoracic echocardiography. A decrease in peripheral capillary oxygen saturation (SpO2) of ≥4% during the 6MWT was used to define desaturation, the appearance of which led to the patient being withdrawn from follow-up., Results: There were no significant differences in HRCT score during the follow-up, but 32 patients (35%) desaturated during the 6MWT, including 12 (37%) who experienced a severe decrease SpO2 to ≤88%, indicating a high risk of mortality. At baseline, there was no statistically significant difference in any considered clinical characteristics between the desaturating and non-desaturating patients but, at the time of desaturation, the desaturators had lower minimum SpO2% levels during the 6MWT (p<0.0001), and lower DLCO (p<0.0001) and Dm (p<0.0001). Comparison of the desaturators defined on the basis of a reduction in SpO2 to ≤88% and those defined on the basis of a decrease in SpO2 of ≥4% showed that, at baseline, the former had lower minimum SpO2% levels during 6MWT (p<0.001), lower DLCO (p=0.01), a lower DLCO/VA ratio (p=0.05), lower Dm (p<0.005) and Vc values (p<0.5), and higher RVsystP (p=0.01). At the time of desaturation, the desaturators' minimum SpO2 levels during the 6MWT correlated with their DLCO (r=0.78; p<0.001), Dm (r=0.65; p<0.01), Vc (r=0.52;p<0.05) and RV-systP values (r = -0.53; p<0.05)., Conclusions: Our data seem to confirm the close interdependence between pulmonary diffusion and oxygen desaturation during exercise. In SSc combined 6MWT, DLCO and its components may indicate patients at increased risk of developing pulmonary hypertension.

Introduction: To prevent extensive pulmonary lesions in submerged oxygen divers lung function like the forced vital capacity (FVC) or the diffusing capacity for carbon monoxide (DL,co) are used to monitor pulmonary oxygen toxicity (POT). As the diffusing capacity for nitric oxide (DL,no) measures more accurately the membrane diffusing capacity compared to DL,co we hypothesized that DL,no is superior in monitoring the onset of physiological changes indicative of POT as compared to DL,co or FVC., Method: 26 healthy divers (mean age 30.7 ± 6.2 years) made two submerged dives to 190 kPa for 1 h on two randomized separate days, whilst breathing 100% oxygen or compressed air. FVC, DL,no, DL,co and alveolar volume (VA ) were measured 6 times during a 26-h period., Results: Up to 8 h no significant differences in outcomes were found between the oxygen and air dives. However, at 8 h after the oxygen dives there was a significant reduction in DL,no, DL,co and VA as compared with air dives. In contrast, the reduction in FVC was significantly greater after the air dive. At 22 h there were no longer differences in outcomes between the dives., Conclusions: These data show that DL,no and DL,co are significantly reduced 8 h after submerged oxygen dives as compared to similar air dives. Together with the reduction in VA this may be indicative of interstitial edema as an early sign of POT. Our data warrant validation of the superiority of DL,no and DL,co over FVC in the practical monitoring of divers., (© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Background: Previous studies have demonstrated an important role for beta-2 adrenergic receptors (β(2)AR) in lung fluid clearance. The purpose of this investigation was to examine the relationship between β(2)AR density on lymphocytes and indices of lung water in healthy humans exposed to ≈ 17 h of hypoxia (FIO2 = 12.5% in a hypoxia tent)., Methods: Thirteen adults (mean ± SEM; age=31 ± 3 years, BMI=24 ± 1 kg/m(2), VO2 Peak = 40 ± 2 ml/kg/min ) participated. Pulmonary function, CT derived lung tissue volume (V(tis)-tissue, blood and water), lung diffusing capacity for carbon monoxide (D(CO)) and nitric oxide (D(NO)), alveolar-capillary conductance (D(M)), pulmonary capillary blood volume (V(c)) and lung water (CT V(tis)-V(c)) were assessed before and after ≈ 17 h normobaric hypoxia (FIO2 = 12.5%). β(2)AR density on lymphocytes was measured via radioligand binding. Arterial oxygen saturation (SaO2), cardiac output (Q), right ventricular systolic pressure (RVSP) and blood pressure (BP) were also assessed., Results: After 17 h hypoxia, SaO2 decreased from 97 ± 1 (normoxia) to 82 ± 4% and RVSP increased from 14 ± 3 (normoxia) to 29 ± 2 mmHg (p<0.05) with little change in Q or BP. V(c) and D(M) both increased with hypoxia with a small increase in D(M)/V(c) ratio (p>0.05). CT V(tis) decreased and lung water was estimated to decline 7 ± 13%, respectively. β(2)AR density averaged 1497 ± 187 receptors/lymphocyte and increased 21 ± 34% with hypoxia (range -31 to +86%). The post-hypoxia increase in β(2)AR density was significantly related to the reduction in lung water (r=-0.64, p<0.05), with the subjects with the greatest increase in density demonstrating the largest decline in lung water., Conclusions: Lung water decreases with 17 h normobaric hypoxia are associated with changes in beta adrenergic receptor density on lymphocytes in healthy adults., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Lung diffusing capacity for nitric oxide (DLNO) is used to measure alveolar membrane conductance (DMNO), but disagreement remains as to whether DMNO=DLNO, and whether blood conductance (thetaNO)=infinity. Our previous in vitro and in vivo studies suggested that thetaNO

The purpose of the study was to evaluate serum concentrations of selected growth factors and the diffusing capacity of the lung for carbon monoxide (DLCO) in 21 females treated for systemic lupus erythematosus. The control group consisted of 24 healthy women. Based on the high-resolution computed tomography (HRCT), patients were allocated to a subgroup of 11 subjects (HRCT-negative) and a subgroup of 10 with pulmonary abnormalities (HRCT-positive). In HRCT-negative patients a significantly higher level of TNF-α as compared with the control was observed and positive correlation between TNF-α and bFGF was revealed in this subgroup and in the total group of patients. DLCO was below the predicted value in 13 patients. No correlations between DLCO and growth factors concentrations were observed. DLCO reduction in asymptomatic, with respect to the respiratory system, SLE patients suggests a need for long-term monitoring of this parameter. The role of TNF-α in these patients requires further investigations.

Background: 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)., Methods: 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., Results: 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)., Conclusion: 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 test for the diffusing capacity of the lung for carbon monoxide (DLCO) has been available for nearly 100 years for research and clinical purposes. The single-breath method is used almost exclusively in the United States It has been available in clinical pulmonary function laboratories for > 50 years. DLCO has great value in evaluating patients with lung diseases. Guidelines to standardize DLCO have been published by the American Thoracic Society and European Respiratory Society to reduce the interlaboratory variability that has existed. One code, 94720, should be reported for the billing for DLCO. Another code, 94725, the membrane diffusing capacity, exists for the measurement of the membrane and blood components of the DLCO. Currently, no clinical indications exist for the use of the membrane diffusing capacity. The finding that the number of tests in the Medicare population coded with 94725 has increased by > 1,000% from 2000 to 2005 is quite surprising. This rate is 14-times higher than the rate of increase in the utilization of 94720 over the same period. The possible reasons for these increases are discussed, but the most likely explanation is the financial gain derived from coding 94725. It is proposed that coding and billing of 94725 be stopped until the clinical indications for membrane diffusing capacity have been established. Those who code and bill for 94725 must be prepared to justify the use of this code to Medicare and third-party payers.

The spleen acts as an erythrocyte reservoir in highly aerobic species such as the dog and horse. Sympathetic-mediated splenic contraction during exercise reversibly enhances convective O2 transport by increasing hematocrit, blood volume, and O2-carrying capacity. Based on theoretical interactions between erythrocytes and capillary membrane (Hsia CCW, Johnson RL Jr, and Shah D. J Appl Physiol 86: 1460-1467, 1999) and experimental findings in horses of a postsplenectomy reduction in peripheral O2-diffusing capacity (Wagner PD, Erickson BK, Kubo K, Hiraga A, Kai M, Yamaya Y, Richardson R, and Seaman J. Equine Vet J 18, Suppl: 82-89, 1995), we hypothesized that splenic contraction also augments diffusive O2 transport in the lung. Therefore, we have measured lung diffusing capacity (DL(CO)) and its components during exercise by a rebreathing technique in six adult foxhounds before and after splenectomy. Splenectomy eliminated exercise-induced polycythemia, associated with a 30% reduction in maximal O2 uptake. At any given pulmonary blood flow, DL(CO) was significantly lower after splenectomy owing to a lower membrane diffusing capacity, whereas pulmonary capillary blood volume changed variably; microvascular recruitment, indicated by the slope of the increase in DL(CO) with respect to pulmonary blood flow, was also reduced. We conclude that splenic contraction enhances both convective and diffusive O2 transport and provides another compensatory mechanism for maintaining alveolar O2 transport in the presence of restrictive lung disease or ambient hypoxia.

Extrathoracic airways obstruction and scuba diving may induce pulmonary edema, probably because of increased hydrostatic transmural capillary pressure in the lung. This study was designed to examine the subacute pulmonary effects of the combined exposure to inspiratory resistive loading and immersion, as in scuba diving. Two groups each of eight healthy men were exposed to head-out water immersion in thermoneutral water for 40 min with or without an added inspiratory resistive load. At flows of 0.5 and 1.0 liter x s, the measured resistances were 4.4 and 9.0 hPa x s(-1) x liter(-1), respectively. Pulmonary function, including a flow-volume loop and transfer factor of the lung for carbon monoxide (Tlco, was measured before and 60 min after the end of the exposures. Body fluid balance was restored in the first 15 min after exposure, and Tlco was always corrected to a hemoglobin concentration of 146 g x liter(-1). There was a significant reduction in Tlco of 7.3+/-5.5% (P < 0.01) after the combined exposure to head-out water immersion and inspiratory resistive load. No changes in pulmonary function were seen after exposure to head-out water immersion or inspiratory resistive loading alone. The change in Tlco was normalized within 24 h. Submersion and resistance in breathing apparatus may contribute to the changes in pulmonary function seen immediately after dives. The nature of the exposure in these experiments and the time for recovery indicate that these changes are mechanically induced, and may not contribute to the long-term effects of diving on the lung.

The contribution of reaction resistance to overall resistance to pulmonary carbon monoxide (CO) uptake [DLCO/(ThetaCO . Vc), where DLCO is lung CO diffusing capacity, ThetaCO is CO uptake conductance of erythrocytes, and Vc is pulmonary capillary blood volume] was determined in 10 anesthetized, paralyzed, and artificially ventilated rabbits. On the basis of the classical double-reciprocal equation of F. G. W. Roughton and R. E. Forster (J. Appl. Physiol. 11: 290-302, 1957), DLCO/(ThetaCO . Vc) was obtained by solving the relation DLCO/(ThetaCO . Vc) = 1 - 2/(DLNO/DLCO), where DLNO/DLCO represents the ratio between the respective single-breath diffusing capacities (DL) of nitric oxide (NO) and CO pulmonary capillary blood. The lungs of eight rabbits were inflated, starting from residual volume, by using 55 ml of indicator gas mixture (0.2% CO and 0.05% NO in nitrogen). DL values were calculated by taking the end-tidal partial pressures of CO and NO as analyzed by using a respiratory mass spectrometer. The overall value was DLCO/(ThetaCO . Vc) = 0.4 +/- 0.025 (mean +/- SD). Because of the use of O2-free indicator gas mixtures, the end-tidal O2 partial pressures were approximately 21 Torr. In one other rabbit, the application of 0.2% CO and 0.001% NO yielded DLCO/(ThetaCO . Vc) = 0.39; in the tenth rabbit, however, inspiratory volume was varied, and an identical value was found at functional residual capacity. We conclude that the contribution of reaction resistance to overall resistance to pulmonary CO uptake is independent of the inspiratory NO concentration used, including, with respect to the pertinent literature, the conclusion that in rabbits, dogs, and humans this contribution amounts to 40% when determined at functional residual capacity.

Carbon monoxide is hypothesized to be produced by the enzyme heme oxygenase predominantly in liver and spleen, bound to hemoglobin, and excreted by the lungs. Thus, venous carboxyhemoglobin is expected to be higher or equal to arterial carboxyhemoglobin. Unspecific inflammatory stimuli have been shown to induce heme oxygenase in lung tissue possibly leading to pulmonary carbon monoxide production. Arterial and central venous carboxyhemoglobin levels were measured in critically ill patients on the third day of ICU stay (n = 59) as well as in otherwise healthy humans prior to orthopedic surgery (n = 29). Arterial and central venous carboxyhemoglobin were higher in ICU patients than in healthy humans, respectively. In both groups, arterial carboxyhemoglobin was significantly higher than central venous carboxyhemoglobin. The arteriovenous carboxyhemoglobin differences were similar in both groups. The data suggest (a) increased CO-generation in critical illness and (b) pulmonary CO-production in healthy and critically ill humans.

Two experimental types of cigarette sidestream smoke (SS) were compared in a subchronic inhalation study on rats. Fresh SS (FSS) was generated continuously from the reference cigarette 2R1. Room-aged SS (RASS) was generated by aging FSS for 1.5 h in a room with noninert surfaces with materials typically found in residences or offices. Male Sprague-Dawley rats were head-only exposed to three dose levels of each SS type and to filtered, conditioned fresh air (sham-exposure) for 6 h/day, 7 days/week, for 90 days. Room-aging resulted in decreased concentrations of various SS components, e.g., total particulate matter (TPM) and nicotine, while other components, such as carbon monoxide (CO), were not affected. The CO concentrations were 6, 13, and 28 ppm for both SS types. TPM concentrations were between 0.6 and 8.7 micrograms/liter and thus up to 100-fold above the maximum of average concentrations of respiratory suspended particles reported for environmental tobacco smoke. Slight reserve cell hyperplasia in the anterior part of the nose as well as hyperplastic and metaplastic epithelial changes in the larynx were the only observed dose-dependent findings. The metabolism of benzo(a)-pyrene--as a proxy for polycyclic aromatic hydrocarbon metabolism--was induced in the nasal respiratory epithelium and in the lungs while no effect was seen in the nasal olfactory epithelium. The lowest-observed effect level was 6 ppm CO or 0.6 microgram TPM/liter. Most of the effects seen were less expressed in RASS-than in FSS-exposed rats when compared on the basis of the CO concentrations. When compared on the basis of TPM, these effects were equally pronounced for both SS types, suggesting a major role of particulate matter-associated compounds. All findings reverted to sham control levels following a 42-day postinhalation period.

We studied retrospectively 286 cases of fire deaths from a 10 year period. The victims were classified according to the type of fire. Among the victims of smouldering fire, 80% had lethal HbCO saturations, whereas only 30% had such saturations when an accelerant had been used. The third group consisted of victims of fires in which the type of fire was, for various reasons, undetermined. HbCO saturations were not influenced by sex, age, concomitant disease or blood alcohol concentration. In eight cases neither respiratory soot nor HbCO was detected in spite of evidence that the deceased was alive as the fire broke out. The material included nine cases of homicide and 22 cases of suicide.

It may be possible to design an intravascular membrane lung with gas transfer properties augmented by the natural flow oscillations in the venous and pulmonary circulation caused by the beating heart and ventilatory movements. The authors used a simple dye visualization technique, the Pierce-Donachy assist pump, and mass spectrometry to investigate these effects on membrane lungs made with tethered, blind-ended, microporous, polypropylene fibers using in vitro tests in water saturated with O2, CO2, and He. Prototypes were constructed on a 7.5 Fr pulmonary artery catheter. The fibers had an outer diameter (OD) of 380 microns and a wall thickness of 50 microns and were mounted on 4.8 mm OD sleeves. Control measurements were taken over a range of steady water flows from 0.4 l/min to 3 l/min. While pumping the same water flow rates with a roller pump, the Pierce-Donachy pump generated pulsatile flow at a rate of 45 beats/min and a systolic duration of 300 msec. This produced a phasic flow with an instantaneous average flow velocity varying from 0 to as high as 46 cm/sec. O2 and CO2 transfer increased by as much as 91% and 59%, respectively. The largest effects were seen at the lower water flow rates.

Pulmonary function was measured before and after a 28-day saturation dive to a pressure of 0.25 MPa in eight subjects. PO2 was 40 kPa, with periods of 75 kPa for 2 h every 2nd day during the first 14 days, 50 kPa for the next 12 days, and a gradual fall to 21 kPa over the last 2 days in decompression. A 28-day saturation dive with six subjects to a pressure of 0.15 MPa and a PO2 of 21 kPa was used as control. The measurements included static and dynamic lung volumes and flows, transfer factor for carbon monoxide (TLCO), and a cycle ergometer exercise test. There was a significant reduction in TLCO of 9.8 +/- 6.0% (P < 0.001) after the dive when values were corrected for hemoglobin concentration changes. Effective alveolar volume was unchanged. There was a reduction in forced midexpiratory flow rate of 9.8 +/- 7.0% (P < 0.01), but forced vital capacity and forced expired volume in 1 s were unchanged. Peak oxygen uptake was reduced by 10.1 +/- 5.3% (P < 0.001). There were no significant changes in any of the lung function variables after the control dive. Exposure to raised PO2 contributes significantly to the changes in pulmonary function that have been reported after deep saturation dives to pressures of 3.1-4.6 MPa with a similar profile of oxygen exposure. TLCO is apparently a more sensitive index than vital capacity for oxygen toxicity.

Background: Lung function often deteriorates after bone marrow transplantation for haematological malignancies. Whether pulmonary function measurements are useful for monitoring patients' progress after transplantation and for alerting clinicians to the development of pneumonitis is uncertain., Methods: Serial pulmonary function measurements were made in 39 patients with a haematological malignancy, and the values from 18 recipients of T cell depleted allogeneic (n = 17) or autologous (n = 1) bone marrow transplants who developed interstitial pneumonitis were compared retrospectively with values from 21 recipients of allogeneic (n = 17) or autologous (n = 4) transplants who did not develop pneumonitis. Lung function was measured at the onset of a further 18 episodes of pneumonitis., Results: Measurements made before transplantation showed no difference in forced expiratory volume in one second (FEV1), transfer factor for carbon monoxide (TLCO), or total lung capacity between the two groups, but the forced vital capacity (FVC) was slightly higher in those who developed pneumonitis (mean (SD)% predicted 104 (12)) than in those who did not (93 (17%)). Six weeks and three months after transplantation all pulmonary function measurements had fallen slightly in both groups but TLCO had fallen considerably more in those who later developed pneumonitis, being 71% (SD 11%) and 77% (7%) of pretransplant values in patients who later developed pneumonitis compared with 109% (38%) and 96% (26%) in those who did not. All lung function measurements were significantly lower at the onset of pneumonitis than three months after transplantation, even in patients with no abnormal signs and a normal chest radiograph., Conclusions: Serial measurements of gas transfer before and after bone marrow transplantation may be useful for predicting which patients will be at risk of developing pneumonitis and may help to diagnose pneumonitis in breathless patients with no abnormal signs.

In a series of 34 lung transplant patients, donor lung dysfunction occurred on 7 occasions. One patient underwent retransplantation and the remaining 6 were treated conservatively. Survival was 100% in the donor lung dysfunction group. Percent predicted forced expiratory volume in 1 second, carbon monoxide diffusion, room air oxygen tension, and distance walked in 6 minutes were all lower (p less than 0.05) at 1 month after transplantation in those patients with donor lung dysfunction as compared with those without. These differences were not significant at 3 months after transplantation. We conclude that donor lung dysfunction can usually be managed conservatively with satisfactory results. Longer follow-up of this group of patients will be necessary to determine the long-term consequences of early graft injury.

Standard methods of measuring the diffusing capacity of the lung for CO are susceptible to inhomogeneity and to errors in the performance of a breathing maneuver by the subject. A mathematical model of CO uptake from a single alveolar lung is developed and used as the basis for an estimation procedure to measure both lung volume and diffusing capacity during a rebreathing maneuver. Because this estimator-model uses the exact flow generated by the subject, errors in such factors as breath-hold times or depth of inspiration do not result. The estimator-model was tested using simulated data from uniformly and nonuniformly ventilated models and was found to be insensitive to noise and inhomogeneity, in contrast to the diffusing capacity of the lungs for CO (exhaled). The estimator-model makes greater use of the available data than traditional methods by utilizing both the slope of the alveolar plateaus for CO and the relative heights of such plateaus in a rebreathing experiment.

A mathematical model of CO uptake from a single alveolus is modified to include stationary pulmonary blood arising from a pulmonary vascular obstruction. From this model an estimator model is developed that produces simultaneous estimations of the diffusing capacity of the lung for CO and the fraction of the pulmonary capillary blood that is stationary. The estimator model was tested using simulated data from uniform and non-uniform simulators and found to be only mildly sensitive to noise and incorrect values for the pulmonary capillary blood volume. Both the estimator model and breath-to-breath changes in the diffusing capacity of the lung for CO (exhaled) were found to be greatly affected by inhomogeneity of diffusing capacity and ventilation. At times both returned false positive results that limit their use as a screening test for stationary pulmonary blood. Although changes in CO uptake may at times indicate the presence of stationary pulmonary blood, the confounding effects of inhomogeneity of ventilation and diffusing capacity make the use of such changes impractical under most circumstances.

During our earlier saralasin infusion study in hypertensive patients, we found a drug-induced rise in arterial oxygen tension (PaO2) associated with unchanged mixed venous PO2 or the PaCO2 and unrelated to cardiopulmonary hemodynamic changes. To test the hypothesis that saralasin improved pulmonary mechanics, blood gases, lung mechanics, lung volumes, diffusing capacity, and distribution of ventilation were analyzed and cardiac output (CO) measured in 12 normotensive men with chronic pulmonary disease before and during a 2 1/2 hour infusion of Saralasin (5 micrograms/kg/min). The PaO2 increased from a mean of 63 +/- 3 (SEM) to 70 +/- 3 mm Hg (p less than 0.001), while the CO decreased from 6.81 +/- 0.52 L/min to 6.18 +/- 0.48 L/min (p less than 0.005). The change in (delta)CO correlated with delta PaO2 (r = -0.67, p less than 0.05). Total systemic vascular resistance rose from 1,201 +/- 134 to 1,353 +/- 147 dynes X sec X cm5 (p less than 0.001). The PaCO2 and other measurements remained unchanged. We conclude that saralasin raised the PaO2 not by changing pulmonary function or mechanics, but by redistributing pulmonary blood flow and improving the ventilation-perfusion relationship.

The action of high doses of cigarette smoke alone or combined with coal dust or acrolein was investigated in noninbred Sprague-Dawley rats. Inhalation occurred up to six sessions per day (Hamburg machine), the animals being subjected to a treatment with oxygen after each inhalation session to reduce the carbon monoxide level in the blood. The amount of tar found in the lungs depended on the number of inhalation sessions per day rather than on the total number of inhalations. Smoke inhalation caused emphysematous lesions, the extent of which depended on the total dose of smoke inhaled. No lung tumors were observed. Only a hyperplasia of the alveolar lining involving type II alveolar cells and, at a later stage, areas of metaplasia generally limited to the bronchial area were found. The association of coal dust with cigarette smoke did not alter the specific effects of smoke and resulted in effects peculiar to the action of dust: alveolitis of the macrophage type, fibrosis of the reticulin type, limited hyperplasia, and ciliated metaplasia. When smoke was combined with acrolein, the effects due to smoke were not appreciably altered.