Non-invasive assessment of pulmonary blood flow using an inert gas rebreathing device in fibrotic lung disease.

BACKGROUND AND AIMS: Pulmonary hypertension (PH) is increasingly recognised in patients with diffuse lung disease, and is associated with increased mortality. Cardiac output (CO) is a prognostic marker in PH. Non-invasive assessment of pulmonary blood flow (PBF(INNOCOR)) with the inert gas rebreathing Innocor device has been validated against CO in PH, but not in PH associated with parenchymal lung disease. PBF(INNOCOR) may be less accurate in patients with lung disease because of intrapulmonary shunting and/or incomplete gas mixing. Our aim was to determine the variability of PBF(INNOCOR) in normal subjects, before evaluating PBF(INNOCOR) in diffuse lung disease against CO measured by the indirect Fick method (CO(FICK)) at right heart catheterisation (RHC). METHODS AND RESULTS: 23 normal subjects had lung volume measurements by a constant-volume body plethysmograph and three consecutive PBF(INNOCOR) measurements on the same day. 20 subjects returned for repeat assessment. PBF(INNOCOR) had good intrasession repeatability (coefficient of variation (CV)=6.57%) and intersession reproducibility (mean CO difference=0.13; single determinant SD=0.49; CV=9.7%). 28 consecutive patients with lung fibrosis referred for RHC had PBF(INNOCOR) measured within 24 h of RHC. There was good agreement between CO(FICK) and PBF(INNOCOR), with no evidence of systematic bias (mean CO(FICK) 4.3+/-1.0; PBF(INNOCOR) 4.0+/-1.2l/ min; p=0.07). Bland-Altman analysis revealed a mean difference of -0.32 and limits of agreement of -2.10 to +1.45. CONCLUSION: Non-invasive PBF measured by the inert gas rebreathing Innocor device has good intrasession repeatability and intersession reproducibility. In diffuse lung disease, CO can be accurately and non-invasively measured by the Innocor device.

Normal bronchial blood flow in COPD is unaffected by inhaled corticosteroids and correlates with exhaled nitric oxide.

BACKGROUND: In COPD patients, there is reduced vascularity and inflammation of the bronchi, which may have opposite effects on bronchial blood flow (QAW). We studied the relationship of QAW with the fraction of exhaled nitric oxide (FENO), which is a potent vasodilator. We also investigated the vascular response to budesonide and a beta(2)-agonist. METHODS: We measured QAW in 17 patients with COPD (mean [+/- SEM] age, 67 +/- 3 years; 10 male patients; mean FEV(1), 57 +/- 3% predicted; mean FEV(1)/FVC ratio, 54 +/- 4%), all of whom were ex-smokers, and in 16 age-matched nonsmoking volunteers (mean age, 64 +/- 4 years) and compared this to FENO. QAW was measured using the acetylene dilution method. RESULTS: Mean QAW was similar in patients with COPD (34.29 +/- 1.09 microL/mL/min) compared to healthy subjects (35.50 +/- 1.74 microL/mL/min; p > 0.05) and was not affected by long-term treatment (35.89 +/- 1.63 microL/mL/min) or short-term treatment (32.50 +/- 1.24 microL/mL/min; p < 0.05) with inhaled budesonide. QAW positively correlated with the diffusion of carbon monoxide (ie, carbon monoxide transfer coefficient: r = 0.74; p < 0.05). FENO levels were mildly elevated in steroid-treated patients (10.89 +/- 0.87 parts per billion [ppb]) and untreated patients (9.40 +/- 0.86 ppb) compared to the control group (8.22 +/- 0.57 ppb; p < 0.05) and were correlated with QAW (r = 0.6; p < 0.05). Ten minutes after the inhalation of 200 microg of albuterol, QAW was more elevated in healthy control subjects (59.33 +/- 2.40 microL/mL/min) compared to COPD patients (38.00 +/- 0.58 microL/mL/min; p < 0.05), indicating that COPD patients may have a reduced bronchial vascular reactivity. CONCLUSIONS: QAW is normal in COPD patients and is not affected by therapy with inhaled corticosteroids or beta(2)-agonists. In addition, QAW correlates with levels of FENO, which may have a regulatory role.

Safety and tolerability of bosentan in adults with Eisenmenger physiology.

BACKGROUND: Bosentan, a dual-endothelin receptor antagonist, is an established treatment for pulmonary arterial hypertension. We hypothesized that bosentan is safe and well tolerated in patients with Eisenmenger physiology. METHODS: In this pilot open-label study, we primarily examined safety and tolerability of oral bosentan. Patients were recruited from our adult congenital heart clinic following informed consent. Baseline and 3-month assessment included WHO functional class, resting oxygen saturations, 6-min walk test, transthoracic echocardiography and respiratory mass spectrometry. Patient clinical status and liver enzymes were closely monitored throughout. RESULTS: All 10 study patients (42+/-4 years; eight female) tolerated bosentan well. No major adverse events or significant liver enzyme elevations were observed. All but one patient felt better; none felt worse. Four patients experienced transient leg oedema. Resting oxygen saturations (83+/-5 versus 80+/-5%; P=0.011) and the distance travelled in the 6-min walk test (348+/-112 versus 249+/-117 m; P=0.004) increased relative to baseline. Changes in echocardiographic parameters (maximum aortic forward flow velocity 1.3+/-0.1 versus 1.1+/-0.2 ms, P=0.013; pulmonary arterial acceleration time 66+/-10 versus 58+/-12 m/s, P=0.02) and pulmonary blood flow (3.45+/-1.2 versus 2.58+/-1.0 L/min, P=0.008) suggested improved pulmonary haemodynamics by study end. Other echocardiographic changes suggested improved right ventricular systolic function (septal amplitude 1.0 versus 1.1 cm, P=0.048; systolic tissue Doppler velocity 4.8 versus 2.3 cm s(-1), P=0.002) by study end. CONCLUSIONS: Bosentan was safe and well tolerated in adults with Eisenmenger physiology both at initiation and after 3 months of oral therapy. Clinical status of patients and pulmonary haemodynamics appeared to improve, and this warrants further investigation.

Bronchoalveolar lavage cellular profiles in patients with systemic sclerosis-associated interstitial lung disease are not predictive of disease progression.

OBJECTIVE: To evaluate the prognostic value of bronchoalveolar lavage (BAL) cellular profiles in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: BAL cellularity was examined in relation to mortality (n = 141), serial pulmonary function findings (n = 134), and "progression-free survival" (n = 134), by proportional hazards analysis. Baseline severity was quantified according to the extent of disease on high-resolution computed tomography, the diffusing capacity for carbon monoxide, and the presence or absence of pulmonary hypertension. Mortality was subclassified into overall mortality (during 10 years of followup), early mortality (occurring within 2 years of presentation), and late mortality (occurring 2-10 years after presentation). RESULTS: Overall mortality was associated with neutrophilia on BAL (hazard ratio 2.23 [95% confidence interval 1.20-4.14], P = 0.01), but this effect was lost when disease severity was taken into account. Early mortality was associated with neutrophilia on BAL (hazard ratio 8.40 [95% confidence interval 1.91-36.95], P = 0.005), independent of disease severity. Late mortality was not associated with neutrophilia on BAL. The presence of neutrophilia on BAL was not associated with time to decline in pulmonary function or progression-free survival. Neither eosinophilia nor lymphocytosis on BAL was associated with mortality, rapidity of functional deterioration, or progression-free survival. These findings were unaltered when treatment status was taken into account. CONCLUSION: BAL findings provide only limited prognostic information in SSc-ILD. Neutrophilia on BAL is linked to early mortality, but BAL findings are not linked to long-term survival or the rapidity of progression of lung disease. The usefulness of BAL to define alveolitis in SSc is questionable.

Effect of severe isolated unilateral and bilateral diaphragm weakness on exercise performance.

Patients with isolated diaphragm paralysis depend on recruitment of extradiaphragmatic respiratory muscles to increase ventilation, but little is known about exercise performance or the response of the inspiratory muscles to loaded breathing. By convention, unilateral diaphragm paralysis is regarded as a trivial condition whereas bilateral paralysis is considered to be potentially life-threatening. In fact, no data exist concerning exercise performance under these conditions. We studied incremental treadmill exercise performed by eight patients with bilateral diaphragm paralysis, eight patients with unilateral diaphragm paralysis, and eight age-matched control subjects. Respiratory muscle endurance (RME) was also measured by an inspiratory threshold loading method. Exercise time, compared with control subjects (671 seconds), was moderately reduced in unilateral diaphragm paralysis (512 seconds, p = 0.07) and further reduced in bilateral diaphragm paralysis (456 seconds, p = 0.02). Similarly, peak minute ventilation was lower in patients with unilateral diaphragm paralysis (84 L x min(-1), p = 0.01) and in patients with bilateral diaphragm paralysis (69 L x min(-1), p = 0.001) compared with control subjects (114 L x min(-1)). However, patients with unilateral diaphragm paralysis and patients with bilateral diaphragm paralysis had increased ratios of peak oxygen consumption to peak minute ventilation compared with control subjects (p = 0.0007 and p < 0.0001, respectively). Nine patients had normal RME; exercise time was moderately increased in these patients (502 seconds) compared with seven patients with reduced RME (461 seconds). In conclusion, although exercise performance is impaired in bilateral diaphragm paralysis, these patients can sustain a reasonable exercise load, particularly if RME is preserved and compensatory mechanisms have developed. In addition, exercise tolerance is diminished in patients with unilateral diaphragm paralysis.

Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography.

In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.