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BACKGROUND AND OBJECTIVE Sleep-disordered breathing (SDB) has been reported as highly prevalent in idiopathic pulmonary fibrosis (IPF) and other interstitial lung disease (ILD) populations. Nocturnal oxygen desaturation (NOD), or the total sleep time spent with SpoO2 < 90% (TST

Exercise limitation is a common feature in idiopathic interstitial pneumonia (IIP). There are multiple contributing pathophysiological mechanisms, including ventilatory mechanical limitation, impaired gas exchange, pulmonary vascular insufficiency and peripheral muscle dysfunction. Progressive exertional dyspnoea and functional incapacity impact significantly on quality of life. Exercise-induced desaturation is frequently observed and is predictive of poorer outcomes. Tests to assess the cardiorespiratory system under stress (e.g. cardiopulmonary exercise testing and the 6-min walk test) can provide important physiologic and prognostic information as adjuncts to resting measurements of lung function. Despite many advances in understanding disease mechanisms, therapies to improve exercise capacity, symptom burden and quality of life are lacking. Exercise training and supplemental oxygen are two potential interventions that require closer evaluation in patients with IIP.

Background Pulmonary arterial hypertension (PAH) is an increasingly recognised serious illness with insidious onset, delayed diagnosis, complex diagnostic algorithms and poor prognosis, but with recently available effective treatments. Aims To efficiently diagnose and to offer treatment for PAH, we established a multidisciplinary service in 2005, where patients attend a clinic staffed by specialists in cardiology, respiratory medicine, rheumatology and immunology in a tertiary referral hospital setting. Methods We studied the first 200 patients referred. Serology, echocardiography, lung function tests, high-resolution computed tomography, World Health Organisation Class determination and 6-min walk tests and/or right heart catheterisation were performed, as clinically indicated. Results Of the 200 patients seen, 66 had confirmed pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg) diagnosed on echocardiography ± right heart catheterisation. Of these patients, 58 had catheter-proven PAH (mean pulmonary artery pressure > 25 mmHg with mean wedge pressure < 15 mmHg). Underlying diagnoses for the confirmed PAH patients were idiopathic (32), scleroderma-associated (14), other connective tissue disease (4) and associated with congenital heart disease (8). Patients with confirmed PAH were commenced on PAH-specific therapy – initially bosentan in the majority but sildenafil, and iloprost were occasionally used initially for patient-specific reasons. Median time from when the patient first called the clinic to prescription of therapy was 16 days (interquartile range; 0–31 days). All surviving patients with PAH have attended for regular 6-monthly follow-up visits with a 100% retention rate up to 4 years. Conclusion A multidisciplinary clinic can provide efficient diagnosis and rapid triage to PAH-specific therapy, if appropriate. Retention rates remain high, at follow up.

The regional pattern and extent of airway closure measured by three-dimensional ventilation imaging may relate to airway hyperresponsiveness (AHR) and peripheral airways disease in asthmatic subjects. We hypothesized that asthmatic airways are predisposed to closure during bronchoconstriction in the presence of ventilation heterogeneity and AHR. Fourteen asthmatic subjects (6 women) underwent combined ventilation single photon emission computed tomography/computed tomography scans before and after methacholine challenge. Regional airway closure was determined by complete loss of ventilation following methacholine challenge. Peripheral airway disease was measured by multiple-breath nitrogen washout from which Scond (index of peripheral conductive airway abnormality) was derived. Relationships between airway closure and lung function were examined by multiple-linear regression. Forced expiratory volume in 1 s was 87.5 ± 15.8% predicted, and seven subjects had AHR. Methacholine challenge decreased forced expiratory volume in 1 s by 23 ± 5% and increased nonventilated volume from 16 ± 4 to 29 ± 13% of computed tomography lung volume. The increase in airway closure measured by nonventilated volume correlated independently with both Scond (partial R2 = 0.22) and with AHR (partial R2 = 0.38). The extent of airway closure induced by methacholine inhalation in asthmatic subjects is greater with increasing peripheral airways disease, as measured by ventilation heterogeneity, and with worse AHR.

Background: Globally, cardiovascular disease (CVD) is the leading cause of death. Beta-blocker medications have well-established survival benefit for myocardial infarction and heart failure. However, CVD frequently coexists with chronic obstructive airways disease (COPD), a disease in which beta-blockers are traditionally avoided. We sought to investigate the adverse respiratory effects associated with long term beta-blocker treatment in patients with cardiac disease, and presumed high risk of COPD. Methods: In this prospective cohort study, patients admitted with acute cardiac disease were recruited from the cardiology unit of a tertiary referral hospital. The treating cardiologist determined beta-blocker treatment, independent of the study. Repeated measures of spirometry and respiratory symptom scores were assessed over 12 months. Respiratory exacerbations, cardiac events and survival were recorded over six years. Outcomes were compared according to beta-blocker exposure. Results: Sixty-four subjects participated, 30 of whom received beta-blockers. Beta-blockers did not adversely affect spirometry, respiratory symptoms or survival. However, considering two categories of respiratory exacerbations (symptom-based versus treated) subjects taking beta-blockers accumulated increased annual risk (RR 1.30, 95% CI 1.11 - 1.53, P = 0.001 and RR 1.37, 95% CI 1.09 - 1.72, P = 0.008) and concluded with overall increased risk (RR 3.67, 95% CI 1.65 - 8.18, P = 0.001 and RR 4.03, 95% CI 1.26 - 12.9, p = 0.019), when compared with the group not taking beta-blockers. Conclusions: Long term beta-blocker treatment did not adversely affect lung function, respiratory symptom scores or survival, but was associated with increased risk of respiratory exacerbations.

Background and objective: Dry powder mannitol has the potential to be used to enhance clearance of mucus in subjects with bronchiectasis. A reduction in FEV1 has been recorded in some subjects with bronchiectasis after inhaling mannitol. The aim of this study was to investigate if pre-medicating with either sodium cromoglycate (SCG) or eformoterol could inhibit this reduction in FEV1. Methods: A double-blind, placebo-controlled, randomized cross-over study was conducted. Lung function and airway response to mannitol was assessed on a control day and then re-assessed after pre-medication with placebo, SCG and eformoterol in nine subjects. Sensitivity to mannitol, expressed as the dose required to induce a 15% fall in FEV1 (PD15), and reactivity to mannitol, expressed as the % fall in FEV1 per mg of mannitol (response–dose ratio, RDR), are reported. Results: Subjects had an FEV1 of 68 ± 14% predicted, FVC of 97 ± 15% predicted and FEV1/FVC of 71 ± 8%. They were mildly hypoxemic and the SpO2 was 95 ± 2%.They had a PD15 to mannitol of 235 mg (95% CI: 150–368 mg) and a RDR of 0.057% fall in FEV1 per mg (95% CI: 0.038–0.085). After pre-medication with SCG, PD15 increased (773 mg, P

SummaryAsthmatics with overproduction of mucus that is viscous and sticky have impaired mucociliary clearance (MCC) leading to mucus plugs, and airway obstruction. Inhaled mannitol improves mucus clearance in other hypersecretory diseases. This study investigated the effect of mannitol and cough in asthmatics with mucociliary dysfunction.Seven stable asthmatics, age 52 ± 20 yr, lifelong non-smokers, without the diagnosis of bronchiectasis, with chronic cough and sputum production, treated with inhaled corticosteroids participated in the study. MCC and cough clearance (CC) was measured on 4 visits: at baseline (no cough or mannitol), with mannitol (240 and 480 mg) and cough control (no mannitol) over total 90 min using a radioaerosol technique and imaging with a gamma camera. Cough clearance was assessed after MCC by asking subjects to cough 100 times over 30 min. Premedication with eformoterol (12 μg) on all visits protected all subjects from bronchoconstriction (fall in FEV1 > 15%) in response to mannitol.Mean (±SD) clearance over 60 min increased from 5.5 ± 5.6% at baseline and 7.3 ± 6.6% with cough control to 19.5 ± 14.6% and 26.4 ± 11.5% with 240 mg (p 0.05). Mannitol improved clearance in all lung regions (p

Summary Background Palliative oxygen therapy is widely used for treatment of dyspnoea in individuals with life-limiting illness who are ineligible for long-term oxygen therapy. We assessed the effectiveness of oxygen compared with room air delivered by nasal cannula for relief of breathlessness in this population of patients. Methods Adults from outpatient clinics at nine sites in Australia, the USA, and the UK were eligible for enrolment in this double-blind, randomised controlled trial if they had life-limiting illness, refractory dyspnoea, and partial pressure of oxygen in arterial blood (PaO 2 ) more than 7·3 kPa. Participants were randomly assigned in a 1:1 ratio by a central computer-generated system to receive oxygen or room air via a concentrator through a nasal cannula at 2 L per min for 7 days. Participants were instructed to use the concentrator for at least 15 h per day. The randomisation sequence was stratified by baseline PaO 2 with balanced blocks of four patients. The primary outcome measure was breathlessness (0–10 numerical rating scale [NRS]), measured twice a day (morning and evening). All randomised patients who completed an assessment were included in the primary analysis for that data point (no data were imputed). This study is registered, numbers NCT00327873 and ISRCTN67448752. Findings 239 participants were randomly assigned to treatment (oxygen, n=120; room air, n=119). 112 (93%) patients assigned to receive oxygen and 99 (83%) assigned to receive room air completed all 7 days of assessments. From baseline to day 6, mean morning breathlessness changed by −0·9 points (95% CI −1·3 to −0·5) in patients assigned to receive oxygen and by −0·7 points (−1·2 to −0·2) in patients assigned to receive room air (p=0·504). Mean evening breathlessness changed by −0·3 points (−0·7 to 0·1) in the oxygen group and by −0·5 (−0·9 to −0·1) in the room air group (p=0·554). The frequency of side-effects did not differ between groups. Extreme drowsiness was reported by 12 (10%) of 116 patients assigned to receive oxygen compared with 14 (13%) of 108 patients assigned to receive room air. Two (2%) patients in the oxygen group reported extreme symptoms of nasal irritation compared with seven (6%) in the room air group. One patient reported an extremely troublesome nose bleed (oxygen group). Interpretation Since oxygen delivered by a nasal cannula provides no additional symptomatic benefit for relief of refractory dyspnoea in patients with life-limiting illness compared with room air, less burdensome strategies should be considered after brief assessment of the effect of oxygen therapy on the individual patient. Funding US National Institutes of Health, Australian National Health and Medical Research Council, Duke Institute for Care at the End of Life, and Doris Duke Charitable Foundation.

SummaryMucociliary clearance increases with increasing doses of mannitol and clearance is enhanced when mannitol inhalation is followed by repetitive voluntary coughing.The aim of the study was to investigate: 1) the effect of increasing doses of mannitol and repetitive coughing on the sputum physical properties; 2) if the changes in sputum properties can predict the efficacy of mucus clearance measured by radioaerosol technique in bronchiectasis patients.Sputum was collected from 14 patients, age: 63±6yr, who participated on the mucociliary and cough clearance studies at baseline, with mannitol (160, 320 and 480mg) and control (Daviskas et al. ERJ 2008; 31:765-772). Sputum was collected: 1) on the screening visit before and after mannitol challenge (635mg); 2) at the start and end of each clearance study after 100 repetitive voluntary coughs except on the control study (no mannitol or repetitive coughing). The sputum solids content, surface tension, contact angle and rheology were measured.Mannitol in association with coughing and coughing alone reduced the solids content, surface tension, contact angle and viscoelastic sputum properties (p

Summary This study examined the influence of electroencephalographic (EEG) arousal on the magnitude and morphology of the pressor response to Cheyne–Stokes respiration (CSR) in subjects with congestive heart failure (CHF). Thirteen subjects with stable CHF (left ventricular ejection fraction, 26 ± 7%) and CSR (apnea–hypopnea index 52 ± 15 h−1) underwent overnight polysomnography with beat-to-beat measurement of systemic arterial blood pressure (BP). CSR events were divided into those with or without an EEG arousal defined according to the criteria of the American Sleep Disorders Association. The pressor response was quantified in terms of the delta BP change (difference between the minimum BP during apnea and maximum BP during hyperpnea). Changes in the morphology of the pressor response were assessed by subdividing individual respiratory events into six periods (three during apnea: A1, A2, A3; and three during hyperpnea: H1, H2, H3). Considerable fluctuations in BP and heart rate (HR) were observed across the CSR cycle (delta mean BP 20.2 ± 6.5 mmHg). The presence of an EEG arousal did not alter the amplitude of fluctuations in BP. Mean blood pressure (MBP) increased 21.0 ± 7.5 mmHg with arousal versus 19.3 ± 5.8 mmHg without arousal (NS). A repeated measures ANOVA showed no significant interaction between the presence of arousal and the proportional change in mean BP across the six periods, indicating that an EEG arousal had no effect on the morphology of MBP change during CSR [F(5,60) = 1.44, P = 0.22]. This study showed that EEG-defined arousal does not amplify the pressor response to CSR in CHF.

Background To simulate the short-term dynamics of soluble gas exchange (e.g. CO2 rebreathing), model structure, ventilation–perfusion ( V ˙ A / Q ˙ ) and ventilation–volume ( V ˙ A / V A ) parameters must be selected correctly. Some diseases affect mainly the V ˙ A / Q ˙ distribution while others affect both V ˙ A / Q ˙ and V ˙ A / V A distributions. Results from the multiple inert gas elimination technique (MIGET) and multiple breath nitrogen washout (MBNW) can be used to select V ˙ A / Q ˙ and V ˙ A / V A parameters, but no method exists for combining V ˙ A / Q ˙ and V ˙ A / V A parameters in a multicompartment lung model. Methods We define a tidally breathing lung model containing shunt and up to eight alveolar compartments. Quantitative and qualitative understanding of the diseases is used to reduce the number of model compartments to achieve a unique solution. The reduced model is fitted simultaneously to inert gas retentions calculated from published V ˙ A / Q ˙ distributions and normalized MBNWs obtained from similar subjects. Normal lungs and representative cases of emphysema and embolism are studied. Results The normal, emphysematous and embolism models simplify to one, three and two alveolar compartments, respectively. Conclusions The models reproduce their respective MIGET and MBNW patient results well, and predict disease-specific steady-state and dynamic soluble and insoluble gas responses.

This document attempts to provide a broad consensus statement about common practice in respiratory function testing and the use of its results in assessing respiratory disease and disability. It is written for respiratory and general clinicians. General principles only are provided and the source documents are referenced but detail is not exhaustive and technically the document does not attempt to provide best practice guidelines. It is meant to reflect usual practice and in some individual patients use of respiratory function tests outside these guidelines may clearly be appropriate in particular clinical circumstances. General statements about quality assurance and cost benefit will be given at the end of the document but for each individual test there are sections on description, indications, interpretation, normal values, specific quality assurance and cost benefit. The scope of the document will cover tests of mechanical function, gas exchange and exercise assessment.

Chronic asthma is characterized by airway inflammation, mucus hypersecretion and impaired mucociliary clearance (MCC). We investigated baseline MCC and the acute effect of terbutaline in chronic asthmatics with sputum production while on long-term treatment with salmeterol in combination with inhaled corticosteroids (ICS). MCC was measured at baseline and in response to 1 mg terbutaline (or placebo) on three visits over 80 min in 16 asthmatics (52 +/- 13 years of age). Subjects who had greater than 10% absolute increase in MCC above baseline and placebo, after terbutaline, were categorized in group A and subjects who had less than 10% in group B. In group A subjects (n = 6), MCC increased from 23.7 +/- 4.0% at baseline to 43.7 +/- 4.9% with terbutaline (P 0.05). Group B subjects withdrew from all beta(2) agonists for a week and MCC was remeasured. After withdrawal, baseline MCC (7.0 +/- 1.8%) was similar to the initial baseline value (P > 0.1) and MCC with terbutaline (15.8 +/- 4.9%) was greater than baseline (P < 0.005) but remained abnormal in most subjects. Baseline percentage predicted FEV1 and FEF25-75% were 77.3 +/- 7.2 and 41.7 +/- 5.6 in group A and 59.9 +/- 8.1 and 29.5 +/- 8.4 in group B subjects, respectively. MCC was impaired in most of these asthmatics with persistent airway obstruction and sputum production, despite regular treatment with ICS and salmeterol. In addition, there was little or no stimulation of MCC acutely after terbutaline in most of these asthmatics.

Patients with chronic obstructive pulmonary disease and a stable daytime PaO2 of 55 mmHg (7.3kPa) live longer and have a better quality of life if provided with long-term continuous oxygen therapy. • It is reasonable to offer continuous oxygen therapy also to patients with other lung diseases that cause chronic hypoxaemia. • Indications for supplemental oxygen therapy during exercise (ambulatory oxygen therapy) and sleep (nocturnal oxygen MJA 2005; 182: 621-626 therapy) are less clear. This position statement is a consensus statement based on evidence from English-language publications up to 2004 obtained by searching MEDLINE and EMBASE with the keywords domiciliary, home, long term and oxygen. We retrieved and reviewed 417 articles. We prepared the position statement, which was then reviewed and revised in consultation with the Clinical Care and Resources Subcommittee and the executive of the Thoracic Society of Australia and New Zealand (TSANZ). It was endorsed in December 2004 by the executive of the TSANZ. We made minor modifications after independent peer review via the Medical Journal of Australia. These changes were once again endorsed by the Clinical Care and Resources Subcommittee of the TSANZ. This is an update of the position statement published in the Journal in 1998 1 and has a currency of 5 years from the date of publication (unless superseded). We used the National Health and Medical Research Council's four levels of evidence (Levels I-IV, designated here E1-E4). 2

Inhaled mannitol increases mucus clearance in patients with bronchiectasis by an unclear mechanism. The effect of mannitol on lung function, health status and sputum properties was investigated.Nine patients with bronchiectasis inhaled 400 mg of mannitol once daily for 12 days. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ). Sputum was analysed for viscosity, elasticity, spinnability, surface tension, contact angle, solids, mucociliary transportability (MCTR) on a frog palate, and cough transportability (CTR) on a simulated cough machine.Lung function was unchanged with treatment (baseline FEV1 82.0 +/- 16.2%) apart from an improvement in FEF from 85.4 +/- 13% (baseline) to 90.7 +/- 14.4% (P0.05; 12th treatment; visit 7). The total SGRQ score (mean +/- SD) of 49.3 +/- 13.8 at baseline, decreased by 12.4 +/- 10.2 (P0.01; visit 7) and 10.1 +/- 9.4 units (P0.02) 6-10 days after treatment cessation. The baseline subscores for symptoms (72.9 +/- 11.8), activity (44.7 +/- 20.9) and impact (44.4 +/- 14.3) were reduced by 0.8 +/- 9.1 (P0.7), 8.4 +/- 16.0 (P0.1) and 19.2 +/- 13.7 (P0.005) units, respectively (visit 7). Mannitol reduced the baseline (mean +/- SE) surface tension from 94.5 +/- 1.4 to 84.7 +/- 2.1 mN/m (P0.0001), contact angle from 51.1 +/- 2.8 to 33.2 +/- 2.4 degrees (P0.0001), spinnability from 11.6 +/- 0.4 to 10.0 +/- 0.2 mm (P0.005), and solids from 5.7 +/- 0.4 to 4.3 +/- 0.7% (P0.02), acutely (visit 7). Viscosity, elasticity and MCTR did not change significantly, while CTR was increased from 25.8 +/- 1.0 to 34.1 +/- 2.7 mm (P0.003).Mannitol significantly improved the health status over 12 days and this improvement was maintained for 6-10 days after cessation of treatment. In addition, mannitol reduced the tenacity, increased the hydration of mucus acutely and improved cough clearability in patients with bronchiectasis.

Beta2-agonists and osmotic agents stimulate mucociliary clearance (MCC) via different mechanisms which could potentially interact. The effects of inhaling terbutaline in combination with mannitol on MCC were investigated in nine healthy (aged 19+/-1 yrs) and 11 mild (aged 21+/-4 yrs) asthmatic subjects. Using 99mTc-sulphur colloid radioaerosol and a gamma camera, MCC was studied on four separate days with each of the following interventions: 1) terbutaline or its placebo inhaled 10 min before mannitol (in random, double blind); 2) terbutaline inhaled 5 min after mannitol; and 3) terbutaline inhaled 10 min before the control for mannitol. Lung images were collected over a period of 120 min postintervention and over 150 min in total. The mannitol-induced increase in clearance was transiently inhibited by terbutaline pretreatment and transiently enhanced when terbutaline was administered after mannitol both in asthmatic and healthy subjects. The order of administration of mannitol and terbutaline did not affect the total clearance of radioactive mucus over 140 min from the start of intervention in both groups. The pathways through which terbutaline and mannitol increase mucociliary clearance may transiently interact in an inhibitory or synergistic way, depending on the order of administration. However, this did not affect the overall increase in mucociliary clearance over 140 min.

Exercise limitation is a common feature in idiopathic interstitial pneumonia (IIP). There are multiple contributing pathophysiological mechanisms, including ventilatory mechanical limitation, impaired gas exchange, pulmonary vascular insufficiency and peripheral muscle dysfunction. Progressive exertional dyspnoea and functional incapacity impact significantly on quality of life. Exercise-induced desaturation is frequently observed and is predictive of poorer outcomes. Tests to assess the cardiorespiratory system under stress (e.g. cardiopulmonary exercise testing and the 6-min walk test) can provide important physiologic and prognostic information as adjuncts to resting measurements of lung function. Despite many advances in understanding disease mechanisms, therapies to improve exercise capacity, symptom burden and quality of life are lacking. Exercise training and supplemental oxygen are two potential interventions that require closer evaluation in patients with IIP.

Deposition of technetium-99m diethylene triamine penta-acetic acid aqueous radioaerosols generated by a novel aerosol delivery system (AERx) was studied in six healthy subjects using both planar and single-photon emission tomography (SPET) imaging. AERx is a microprocessor-controlled, bolus inhalation device that is actuated at pre-programmed values of inspiratory flow rate and volume. The aims of the study were to determine the effects of posture and inhaled volume upon deposition of the aerosol in the lungs. Each subject inhaled the radioaerosol in two positions (supine vs sitting) and with two inspiratory manoeuvres [vital capacity (VC) vs "fixed volume" of 1 l above functional residual capacity]. Simultaneous transmission-emission planar and tomographic images were acquired. The results showed diffuse deposition of the aerosol in the lung. Neither the breathing manoeuvre nor the posture was found to affect the distribution of the aerosol as measured by the ratio of the activity (counts per pixel) in the peripheral:central (penetration index, PI) or in the apex:base regions of the planar lung images (P0.1). A small, albeit statistically significant, difference in PI (P0.03) was found between VC and fixed volume sitting manoeuvres with SPET only. The PI values themselves indicate that the radioaerosol was well distributed in the lung, with the periphery having 45%-64% of the activity of the central region. Superposition of transmission SPET lung outline on emission SPET visually confirmed the excellent peripheral deposition of the aerosol. The AERx system showed high efficiency of delivery, with approximately 50% of the extruded dose in the device depositing in the lung. The uniformity of radioactivity distributed throughout the lung is attributed to the fine particle size (mass median aerodynamic diameter of 2 microm) of the aerosol and the electronic control of aerosol inhalation by the device. In conclusion, the AERx system can be ideal for diffuse aerosol deposition of therapeutic or diagnostic agents and is largely unaffected by inhaled volume and posture. The efficiency of the device device can limit the total radiation exposure of patients and staff administering the radioaerosols, and can make it suitable for delivery of expensive drugs.

The absence of a maximal dose-response plateau as well as gas trapping and increases in closing capacity (CC) suggest that increased airway closure is an important mechanical abnormality of asthmatic airways. We compared the extent and distribution of airway closure in 13 normal and in 23 asthmatic subjects. Airway closure (LVclosed) was measured with single-photon emission computed tomography (SPECT) and an inhaled Technegas bolus as the percentage of lung volume without Technegas (LVtrans), and with CC, using nitrogen washout. LVclosed was compared in the apical, middle and lower zones, each being of equal vertical height. Values of mean LVclosed +/- 95% confidence interval (CI) were similar in normal (30 +/- 6.0% LVtrans) and asthmatic subjects (30 +/- 7.8% LVtrans). In normal subjects, LVclosed correlated with both age (r = 0.89, p < 0. 01) and CC (r = 0.86, p < 0.01), was more extensive in the lower zone (58 +/- 18.8% LVtrans, p < 0.01) than in the middle and upper zones (17 +/- 8.7% and 26 +/- 8.2 LVtrans, respectively), and increased with age in both the middle and lower zones (r = 0.94 and r = 0.90, respectively, p < 0.01). In asthmatic subjects, LVclosed did not correlate with age; was greatest in the lower zone, intermediate in the middle zone, and lowest in the apical zone (59 +/- 13.2%, 22 +/- 5.8%, and 12 +/- 4.4% LVtrans, respectively, p < 0. 01); and correlated weakly with age in the middle zone only (r = 0. 46, p < 0.05). We conclude that there is a predictable pattern of airway closure in normal subjects and that it is primarily influenced by pulmonary elastic recoil. This pattern is lost in asthmatic subjects. This may be explained by an increased range of closing pressures and a patchy distribution of airway closure, probably secondary to allergic inflammation.

Ventilation-perfusion (VA/Q) inequality is the underlying abnormality determining hypoxemia and hypercapnia in lung diseases. Hypoxemia in asthma is characterized by the presence of low VA/Q units, which persist despite improvement in airway function after an attack. This hypoxemia is generally attenuated by compensatory redistribution of blood flow mediated by hypoxic vasoconstriction and changes in cardiac output, however, mediator release and bronchodilator therapy may cause deterioration. Patients with chronic obstructive pulmonary disease have more complex patterns of VA/Q inequality, which appear more fixed, and changes in blood flow and ventilation have less benefit in improving gas exchange efficiency. The inability of ventilation to match increasing cardiac output limits exercise capacity as the disease progresses. Deteriorating hypoxemia during exacerbations reflects the falling mixed venous oxygen tension from increased respiratory muscle activity, which is not compensated by any redistribution of VA/Q ratios. Shunt is not a feature of any of these diseases. Patients with cystic fibrosis (CF) have no substantial shunt when managed according to modern treatment regimens. Interstitial lung diseases demonstrate impaired oxygen diffusion across the alveolar-capillary barrier, particularly during exercise, although VA/Q inequality still accounts for most of the gas exchange abnormality. Hypoxemia may limit exercise capacity in these diseases and in CF. Persistent hypercapnic respiratory failure is a feature of advancing chronic obstructive pulmonary disease and CF, closely associated with sleep disordered breathing, which is not a prominent feature of the other diseases. Better understanding of the mechanisms of hypercapnic respiratory failure, and of the detailed mechanisms controlling the distribution of ventilation and blood flow in the lung, are high priorities for future research.

To assess if exercise capacity and resting stroke volume are different in tetralogy of Fallot (TOF) repair survivors with indexed RV (right ventricle) end-diastolic volume (RVEDVi) more versus less than 150 ml/m(2), a currently suggested threshold for pulmonary valve replacement (PVR).Cross-sectional study.Single-centre adult congenital heart disease unit.55 consecutively eligible patients with repaired TOF (age at repair 2.3±1.9 years; age at evaluation 26.2±8.8 years; NYHA Class I or II).Cardiovascular MRI (1.5T) and cardiopulmonary exercise test.Biventricular volumes and function; exercise capacity.20 patients had RVEDVi below, and 35 had RVEDVi above 150 ml/m(2), at time of referral. In the150 ml/m(2) group, fractional pulmonary regurgitation was higher (41±8 vs 31±8%, p0.001). Although RV ejection fraction (EF) was lower (47±7 vs 54±6%, p=0.007), indexed RV stroke volume was higher (87±14 vs 64±10 ml/m(2), p0.001) in the150 ml/m(2) group. There were no significant differences in LVEF, indexed LV stroke volume or exercise capacity (% predicted peak work: 90±17 vs 89±11% and; % predicted VO(2) peak: 84±17 vs 87±12%).Exercise capacity and stroke volume are maintained with RVEDVi above compared with below a commonly used cut-off for PVR surgery. Optimal timing for PVR, thus, remains unclear.

Dry powder mannitol has the potential to be used to enhance clearance of mucus in subjects with bronchiectasis. A reduction in FEV1 has been recorded in some subjects with bronchiectasis after inhaling mannitol. The aim of this study was to investigate if pre-medicating with either sodium cromoglycate (SCG) or eformoterol could inhibit this reduction in FEV1.A double-blind, placebo-controlled, randomized cross-over study was conducted. Lung function and airway response to mannitol was assessed on a control day and then re-assessed after pre-medication with placebo, SCG and eformoterol in nine subjects. Sensitivity to mannitol, expressed as the dose required to induce a 15% fall in FEV1 (PD15), and reactivity to mannitol, expressed as the % fall in FEV1 per mg of mannitol (response-dose ratio, RDR), are reported.Subjects had an FEV1 of 68 ± 14% predicted, FVC of 97 ± 15% predicted and FEV1 /FVC of 71 ± 8%. They were mildly hypoxemic and the SpO2 was 95 ± 2%.They had a PD15 to mannitol of 235 mg (95% CI: 150-368 mg) and a RDR of 0.057% fall in FEV1 per mg (95% CI: 0.038-0.085). After pre-medication with SCG, PD15 increased (773 mg, P 0.05) and RDR was reduced (0.013, P 0.05). Pre-medication with eformoterol also resulted in an increased PD15 (1141 mg, P 0.01) and a reduced RDR (0.009, P 0.01). A small but significant decrease in SpO2 from baseline was noted after mannitol in the presence of SCG (P 0.05). Pre-medication with either SCG or eformoterol protects patients with bronchiectasis from developing a significant reduction in FEV1 after inhaling mannitol.

Background Studies using the multiple inert gas elimination technique (MIGET) to characterise the mechanisms of impaired gas exchange in CF, provide conflicting results on the importance of ventilation–perfusion ( V A / Q ) inequality over shunt. We hypothesise that the mechanisms of gas exchange abnormality have changed with changing CF management over the last two decades. Methods Detailed gas exchange was evaluated by MIGET with venous sampling in stable patients, age>20 years, FEV 1 % predicted ≤50. Results Fifteen (14 male) subjects were studied with a mean±SD age 28.1±8.4 years, FEV 1 % 32.6±10.3, TLC% 111.5±12.9, PaO 2 9.3±1.3 kPa, (69.5±9.6 mm Hg), and PaCO 2 6.2±0.7 kPa, (45.9±5.3 mm Hg). The predominant gas exchange abnormality was V A / Q inequality with a log SD of the distributions of perfusion 0.91±0.30 and of ventilation 0.60±0.14. Unimodal distributions were seen in nine subjects, a low V A / Q mode in five and one subject had a bimodal distribution, mean intrapulmonary shunt was negligible. Conclusions Subjects had a lower FEV 1 % by comparison with previously published studies and demonstrated severe V A / Q inequality and negligible shunt. This suggests a low degree of complete obstruction of airways in adults with CF and severe stable pulmonary disease. The primary mechanism of hypoxaemia in CF subjects reaching adulthood today appears to have changed with modern management over the last two decades.

Both exercise (EIB) and mannitol challenges were performed in asthmatic patients to assess and compare their pulmonary gas exchange responses for an equivalent degree of bronchoconstriction. In 11 subjects with EIB [27 ± 4 (SD) yr; forced expiratory volume in 1 s (FEV1), 86 ± 8% predicted], ventilation-perfusion (V̇a/Q̇) distributions (using multiple inert gas elimination technique) were measured 5, 15, and 45 min after cycling exercise (FEV1fall, 35 ± 12%) and after mannitol (33 ± 10%), 1 wk apart. Five minutes after EIB, minute ventilation (V̇e; by 123 ± 60%), cardiac output (Q̇t, by 48 ± 29%), and oxygen uptake (V̇o2; by 54 ± 25%) increased, whereas arterial Po2(PaO2; by 14 ± 11 Torr) decreased due to moderate V̇a/Q̇ imbalance, assessed by increases in dispersions of pulmonary blood flow (log SDQ̇; by 0.53 ± 0.16) and alveolar ventilation (log SDV̇; by 0.28 ± 0.15) (dimensionless) ( P < 0.01 each). In contrast, for an equivalent degree of bronchoconstriction and minor increases in V̇e, Q̇t, and V̇o2, mannitol decreased PaO2more intensely (by 24 ± 9 Torr) despite fewer disturbances in log SDQ̇ (by 0.27 ± 0.12). Notwithstanding, mannitol-induced increase in log SDV̇ at 5 min (by 0.35 ± 0.15) was similar to that observed during EIB, as was the slow recovery in log SDV̇and high V̇a/Q̇ ratio areas, at variance with the faster recovery of log SDQ̇and low V̇a/Q̇ ratio areas. In asthmatic individuals, EIB provokes more V̇a/Q̇ imbalance but less hypoxemia than mannitol, primarily due to postexercise increases in V̇e and Q̇t benefiting PaO2. V̇a/Q̇ inequalities during both challenges most likely reflect uneven airway narrowing and blood flow redistribution generating distinctive V̇a/Q̇ patterns, including the development of areas with low and high V̇a/Q̇ ratios.

Bronchiectasis is characterised by hypersecretion and impaired clearance of mucus. A 400-mg dose of inhaled mannitol improves mucus clearance however, the effect of other doses is unknown. A total of 14 patients, aged 63.3+/-5.7 yrs, were studied on five visits. Mucus clearance at baseline and with mannitol (160, 320 and 480 mg) was measured using technetium-99m-sulphur colloid and imaging with a gamma camera over 45 min, followed by a further 30 min involving 100 voluntary coughs. A control study assessed the effect of cough provoked by mannitol during the intervention. Whole right lung clearance over 45 min was 4.7+/-1.2 and 10.6+/-2.6% on baseline and control days, respectively, and increased to 16.7+/-4.2, 22.8+/-4.2 and 31+/-4.7% with 160, 320 and 480 mg mannitol, respectively. Clearance over 45 min with 480 mg mannitol was greater than clearance with 320 and 160 mg. Total clearance over 75 min, after mannitol administration and voluntary coughs, was 36.1+/-5.5, 40.9+/-5.6 and 46.0+/-5.2% with 160, 320 and 480 mg mannitol, respectively, all significantly different from baseline (24.1+/-6.0%) and control (13.1+/-3.0%). Total clearance over 75 min with 480 mg mannitol was greater compared with 160 mg. In conclusion, mucus clearance increases with increasing doses of mannitol and can be further increased by cough in patients with bronchiectasis.

Most asthmatics with mucus hypersecretion have difficulty in clearing their secretions so that mucus plugs and airway obstruction are commonly present. Inhaled mannitol facilitates clearance of mucus. This study investigated the changes in the physical properties of sputum in response to mannitol in asthmatics with chronic cough and sputum production.Sputum was collected from 12 asthmatics (26-73 year), lifelong non-smokers, at baseline, after eformoterol (24 mug) and after mannitol on each of four visits. Inhaled mannitol doses were: 635 mg (Visit 1), 240 mg (Visit 2), 360 mg (Visit 3) and 360 mg in the presence of montelukast (Visit 4). Eformoterol was inhaled before mannitol on each visit to prevent bronchoconstiction. Sputum measurements included viscosity, elasticity, surface tension, contact angle-glass and percentage solids.There were no significant differences between the sputum properties at baseline and after eformoterol. Mannitol (360 mg) reduced the baseline (mean +/- SEM) elasticity from 29.9 +/- 4.5 to 15.1 +/- 1.4 Pa (P0.0001), viscosity from 18.4 +/- 3.2 to 8.1 +/- 1.2 Pa (P0.0001) at 1 rad/ s, surface tension from 92.1 +/- 2.2 to 81.9 +/- 2.5 mN/m (P0.0001), contact angle-glass from 57.5 +/- 3.2 to 49.6 +/- 2.0 degrees (P0.0001), and percentage solids from 6.9 +/- 0.7 to 5.7 +/- 0.4% (P0.0001). All doses of mannitol reduced the sputum properties similarly and no property was further reduced by montelukast (P0.4).Inhaled mannitol reduced the viscoelasticity, surface tension, contact angle and the solids content of sputum in asthmatics with chronic cough and sputum production, consistent with the osmotic effect of mannitol causing water efflux in the airway lumen.

Chronic asthma is characterized by airway inflammation, mucus hypersecretion and impaired mucociliary clearance (MCC). We investigated baseline MCC and the acute effect of terbutaline in chronic asthmatics with sputum production while on long-term treatment with salmeterol in combination with inhaled corticosteroids (ICS).MCC was measured at baseline and in response to 1 mg terbutaline (or placebo) on three visits over 80 min in 16 asthmatics (52+/-13 years of age). Subjects who had greater than 10% absolute increase in MCC above baseline and placebo, after terbutaline, were categorized in group A and subjects who had less than 10% in group B.In group A subjects (n=6), MCC increased from 23.7+/-4.0% at baseline to 43.7+/-4.9% with terbutaline (P0.0001) and to 34.4+/-5.7% with placebo (P0.01). In group B subjects (n=10), MCC remained similar: 11.3+/-3.2% at initial baseline, 12.0+/-3.2% with terbutaline and 7.3+/-3.0% with placebo (P0.05). Group B subjects withdrew from all beta(2) agonists for a week and MCC was remeasured. After withdrawal, baseline MCC (7.0+/-1.8%) was similar to the initial baseline value (P0.1) and MCC with terbutaline (15.8+/-4.9%) was greater than baseline (P0.005) but remained abnormal in most subjects. Baseline percentage predicted FEV(1) and FEF(25--75%) were 77.3+/-7.2 and 41.7+/-5.6 in group A and 59.9+/-8.1 and 29.5+/-8.4 in group B subjects, respectively.MCC was impaired in most of these asthmatics with persistent airway obstruction and sputum production, despite regular treatment with ICS and salmeterol. In addition, there was little or no stimulation of MCC acutely after terbutaline in most of these asthmatics.

This study evaluates the physiological responses to giant bullectomy. A 42-year-old female with bilateral giant bullae presented with dyspnoea and exercise limitation. At baseline and 3 months after bullectomy she had tests of lung function; exercise capacity via a symptom-limited cycle test and a 6-min walk test (6MWT). Quality of life (QoL) and gas exchange using the multiple inert gas elimination technique (MIGET) were also assessed. There were significant improvements in pulmonary function following surgery with the FEF25–75% predicted increasing from 16 to 96. The 6MWT increased by 10% and the peak leg work capacity by 48%. A MIGET measure of the distribution of perfusion (Log SDQ) fell from 0.52 to 0.36. There was also radiological improvement in hyperinflation and diaphragmatic configuration. The QoL total score decreased from 56 to 25. This patient demonstrated significant improvements in exercise tolerance, gas exchange and QoL following bullectomy.

Planar gamma camera scintigraphy is a well-established technique for characterising the deposition and clearance of radiolabelled aerosols. While single-photon emission tomography (SPET) can offer superior assessment of radioaerosol deposition and better differentiation between peripheral and central deposition, the long acquisition times of single-headed SPET have largely prevented its use for measuring clearance or deposition of fast-clearing radioaerosols. This study investigated the feasibility of fast dynamic SPET imaging (1 min/frame) using a three-headed gamma camera to assess the regional and total deposition and clearance of different radioaerosols over a period of 26 min. Six subjects inhaled nebulised technetium-99m diethylene triamine penta-acetic acid radiolabelled aerosols with small and large droplet sizes [mass median aerodynamic diameter (MMAD) 3.2 +/- 0.2 and 6.5 +/- 0.2 microm, span 1.8 and 1.7, respectively] and in normal (0.9%) or hypertonic (7%) saline with controlled breathing on four separate occasions. The penetration indices (PIs) calculated from the SPET data for normal saline were 0.50 +/- 0.04 and 0.36 +/- 0.02 for the small and large droplet sizes, respectively. Consistent with the hygroscopic growth of the hypertonic aerosols, the PIs for hypertonic saline were lower, at 0.43 +/- 0.02 and 0.34 +/- 0.02 for the small and large droplet sizes, respectively. PIs calculated from the planar data showed similar trends, but failed to detect the significant difference seen with SPET between small normal and small hypertonic saline radioaerosols. In conclusion, the feasibility of using fast dynamic SPET for imaging radioaerosol deposition and associated radiolabel clearance in the lung has been successfully demonstrated. The fast SPET was able to reveal important differences in aerosol deposition that were not detected by planar imaging.

To investigate the acute effect of mannitol on the clearance of mucus, and (1) the 24-h mucus retention, and (2) the mucus clearance rate and lung function 24 h after inhalation of a single dose of mannitol.Clearance of mucus was measured on 3 consecutive days using (99m)Tc-sulfur colloid radioaerosol and a gamma camera.Mannitol, 330 +/- 68 mg (mean+/- SD), was inhaled using a dry powder inhaler only on day 2.Eight patients with bronchiectasis (age range, 29 to 70 years).On each day, lung images were collected over 2 h and at 24 h. Key findings of the study are as follows: (1) the 24-h retention of mucus was reduced the day after mannitol had been inhaled, compared to the day without mannitol (day 1) in the whole right lung (57.6 +/- 6.2% vs 68.1 +/- 5.9%), central (47.5 +/- 6.7% vs 56.9 +/- 6.5%), intermediate (61.7 +/- 5.6% vs 73.8 +/- 5.5%), and peripheral regions (70.9 +/- 4.3% vs 86.6 +/- 4.6%)(p0.02); and (2) mannitol helped patients clear mucus within 2 h that might otherwise take up to 24 h, from the whole right lung and defined regions. However, clearance over 60 min measured 24 h after mannitol inhalation was not significantly different to baseline clearance without mannitol (8.7 +/- 1.9% on day 1 vs 9.7 +/- 3.7% 24 h after mannitol; p0.8). The patients maintained the same lung function the day before and after mannitol had been inhaled: FEV(1) (percent predicted), 79 +/- 5 on day 1 vs 80 +/- 5 on day 3; and forced expiratory flow, midexpiratory phase (percent predicted), 50 +/- 6 on day 1 vs 51 +/- 6 on day 3; p0.6).Mannitol inhalation acutely increases clearance of mucus, and this effect extends beyond the acute study period, resulting in decreased mucus retention at 24 h.

The detailed mechanisms of oxygen-induced hypercapnia were examined in 22 patients during an acute exacerbation of chronic obstructive pulmonary disease. Ventilation, cardiac output, and the distribution of ventilation-perfusion (V A/Q ) ratios were measured using the multiple inert gas elimination technique breathing air and then 100% oxygen through a nose mask. Twelve patients were classified as retainers (R) when Pa(CO(2)) rose by more than 3 mm Hg (8.3 +/- 5.6; mean +/- SD) after breathing 100% oxygen for at least 20 min. The other 10 patients showed a change in Pa(CO(2)) of -1.3 +/- 2.2 mm Hg breathing oxygen and were classified as nonretainers (NR). Ventilation fell significantly from 9.0 +/- 1.5 to 7.2 +/- 1.2 L/min in the R group breathing oxygen (p = 0.007), whereas there was no change in ventilation in the NR group (9.8 +/- 1.8 to 9.9 +/- 1.8 L/min). The dispersion of V A/Q ratios as measured by log SD of blood flow (log SD Q) increased significantly in both R (0.96 +/- 0. 17 to 1.13 +/- 0.17) and NR (0.77 +/- 0.20 to 1.04 +/- 0.23, p0.05) groups breathing oxygen, whereas log SD of ventilation (log SD Q ) increased only in the R group (0.97 +/- 0.24 to 1.20 +/- 0.46, p0.05). This study suggests that an overall reduction in ventilation characterizes oxygen-induced hypercapnia, as an increased dispersion of blood flow from release of hypoxic vasoconstriction occurred to a significant and similar degree in both groups. The significant increase in wasted ventilation (alveolar dead space) in the R group only may be secondary to the higher carbon dioxide tension, perhaps related to bronchodilatation.

An elderly woman presented with unexplained, intermittent hypoxaemia unrelated to posture. Subsequent investigations revealed intermittent and variable right-to-left interatrial shunting through a patent foramen ovale in the presence of normal pulmonary arterial and intracardiac pressures, caused by right atrial compression from a horizontal, elongated ascending aorta. Surgical closure of the foramen resulted in marked clinical improvement.

Chlamydia psittaci infection typically causes a mild respiratory illness in humans. Severe respiratory failure requiring mechanical ventilation or intensive care therapy is an uncommon development. The aetiological agents causing severe community acquired pneumonia often remain undetermined. Serological tests may aid in diagnosis. We present two cases of fulminant psittacosis, one demonstrating early cross-reactivity with Legionella longbeachae.

To test the hypothesis that diffusion-limitation for oxygen is due to abnormal vascular dilatation and significantly contributes to the arterial hypoxaemia of liver cirrhosis requires an experimental approach that detects both diffusion-limitation for oxygen and the presence of abnormal dilatation of pulmonary vessels exposed to alveolar gas. We therefore studied the gas exchange of a 64 year old man with alcoholic liver cirrhosis and severe resting arterial hypoxaemia (arterial oxygen tension (Pa,O2) 7.5 kPa) whilst breathing air and 100% O2 using conventional blood gas (CBG) analysis, the multiple inert gas elimination technique (MIGET) and whole body scintigraphy (WBS) following the i.v. administration of radiolabelled boli of macroaggregates with a minimum diameter of 15 microM. During air breathing, there was a consistently positive difference between the arterial oxygen tension predicted by MIGET and that actually measured (P-M Pa,O2, average 0.9 kPa). During O2 breathing, P-M Pa,O2 became negative, (average -12.2 kPa), and shunt estimated by the O2 method (% of Q') was consistently less than that measured by MIGET. Whereas both O2 method and MIGET estimates of shunt never exceeded 25%, the WBS shunt was 40%, indicating that a substantial fraction of cardiac output flowed through abnormally dilated pulmonary vessels, some of which were exposed to alveolar gas and, hence, participated in gas exchange. Although our observations pertain to one subject, we believe they provide the most convincing in vivo evidence to date that abnormal dilatation of interalveolar vessels may, per se, result in a significant diffusion impairment for O2. Furthermore, in view of the consistently negative P-M Pa,O2 observed during oxygen breathing, we speculate that such abnormal vascular dilatation may also have produced a significant diffusive impairment of one or more of the less soluble inert gases used in the MIGET analysis.

A 37-yr-old man with pulmonary alveolar microlithiasis (PAM) presented with respiratory failure and cor pulmonale. The FEV1/FVC was 1.4/1.8 L with total lung capacity of 3.2 L using the helium dilution method (54% predicted) and 6.1 L using body plethysmography (102% predicted), indicating large noncommunicating regions. The KCO (transfer factor per liter lung volume) was 3.05 ml/min/mm Hg/L (47% predicted). Despite home oxygen (3 L/min) and diuretic therapy, the patient remained hypoxic (PaO2, 55 mm Hg) and incapacitated with dyspnea. Nasal continuous positive airway pressure (nCPAP) at 12 cm H2O and oxygen at 1 L/min improved his oxygenation (PaO2, 93 mm Hg), and introduction of this regimen at night resulted in subjective improvement in daytime function. A Grandjean right heart catheter was introduced at the bedside, and the multiple inert gas elimination technique (MIGET) was used to measure ventilation and blood flow distributions at ambient pressure and with the addition of 10 cm H2O nCPAP. The patient had severe pulmonary hypertension (mean Ppa, 57 mm Hg) and severe hypoxemia (PaO2 37 mm Hg), which was mainly due to shunt (16% of cardiac output) and a broadening of the main mode of the ventilation-perfusion (VA/Q) distribution (log SD Q, 0.94). There was a significant reduction in shunt during nCPAP to 6% of cardiac output without increasing Ppa, and this effect appeared to extend past the period of application. We conclude that nCPAP reduces intrapulmonary shunt in this rare condition and allows for correction of hypoxemia with a smaller oxygen flow rate.

Beta-adrenoceptor agonists such as albuterol are very effective in preventing exercise-induced asthma (EIA) when they are given as an aerosol immediately before exercise. However, their duration of protection against EIA is usually less than 2 h. This may be due partly to their rapid clearance from the airways. Salmeterol is a highly lipophylic compound that is thought to bind to an exoreceptor near the beta-receptor. The objective of this study was to compare the protective effect of salmeterol with albuterol against EIA. Exercise was performed 0.5, 2.5, 4.5, and 6.5 hours after administration of the active drugs. Subjects attended the laboratory on four days within six weeks and cycled for 8 min breathing dry compressed air. We studied 17 asthmatic subjects (aged 19 to 49 years) with moderate to severe EIA. Salmeterol (50 micrograms) or albuterol (200 micrograms) was given from a metered dose inhaler via a spacer (Volumatic). On the control day, the mean work load +/- 1 SD was 174 +/- 47 W, ventilation (VE) was 77.9 percent +/- 11.2 percent of the target ventilation (60 percent maximum voluntary ventilation [MVV]), and heart rate was 170 +/- 14 beats per minute. This intensity was maintained for all tests. FEV1 was measured before and after exercise and was expressed as percent predicted and as percentage of the preexercise value (percentage of fall). Thirty minutes after treatment, both drugs were effective in inhibiting EIA--percentage of fall in FEV1, 17 +/- 12 after salmeterol; percentage of fall in FEV1, 15 +/- 15 after albuterol. At 2.5, 4.5, and 6.5 hours, the reduction in FEV1 was significantly less (p less than 0.01) after salmeterol compared with albuterol. At 6.5 hours, the percentage of fall in FEV1 was 20 +/- 10 after salmeterol and 36 +/- 12 after albuterol. Salmeterol also had a more prolonged action as a bronchodilator and values for FEV1 were significantly higher compared with those on albuterol at 4.5 and 6.5 hours. At 6.5 hours, the FEV1 percent predicted was 96 +/- 10 after salmeterol and 84 +/- 12 after albuterol (p less than 0.01). We conclude that the extent of protection against EIA and the bronchodilation induced by both drugs was similar, but that salmeterol has a longer duration of action compared with albuterol. The reason for its superior duration of action may be due to a slower clearance of the drug from the airways.

is a timely reminder of the importance of avoiding the induction of hyperoxic hypercapnia in patients with acute-on-chronic respiratory failure. The complica-tion of acute hypercapnic respiratory failure precipitated by giving oxygen has long been recognised; most resident medical and nursing staff are aware of this problem. The natural intervention in patients presenting with acute-on-chronic respiratory failure is to relieve any hypoxia with supplemental oxygen, but this can be associated with carbon dioxide retention, narcosis, respiratory acidosis, and death. That the use of controlled oxygen flow rates could avoid this complication (and the need, in those days, for tracheostomy and invasive ventilation) was first recognised in the 1940s and 1950s.

The detailed mechanisms of oxygen-induced hypercapnia were examined in 22 patients during an acute exacerbation of chronic obstructive pulmonary disease. Ventilation, cardiac output, and the distribution of ventilation-perfusion (V A/Q ) ratios were measured using the multiple inert gas elimination technique breathing air and then 100% oxygen through a nose mask. Twelve patients were classified as retainers (R) when Pa(CO(2)) rose by more than 3 mm Hg (8.3 +/- 5.6; mean +/- SD) after breathing 100% oxygen for at least 20 min. The other 10 patients showed a change in Pa(CO(2)) of -1.3 +/- 2.2 mm Hg breathing oxygen and were classified as nonretainers (NR). Ventilation fell significantly from 9.0 +/- 1.5 to 7.2 +/- 1.2 L/min in the R group breathing oxygen (p = 0.007), whereas there was no change in ventilation in the NR group (9.8 +/- 1.8 to 9.9 +/- 1.8 L/min). The dispersion of V A/Q ratios as measured by log SD of blood flow (log SD Q) increased significantly in both R (0.96 +/- 0. 17 to 1.13 +/- 0.17) and NR (0.77 +/- 0.20 to 1.04 +/- 0.23, p < 0.05) groups breathing oxygen, whereas log SD of ventilation (log SD Q ) increased only in the R group (0.97 +/- 0.24 to 1.20 +/- 0.46, p < 0.05). This study suggests that an overall reduction in ventilation characterizes oxygen-induced hypercapnia, as an increased dispersion of blood flow from release of hypoxic vasoconstriction occurred to a significant and similar degree in both groups. The significant increase in wasted ventilation (alveolar dead space) in the R group only may be secondary to the higher carbon dioxide tension, perhaps related to bronchodilatation.

Continuous distributions of ventilation-perfusion (VA/Q) ratios were measured in ten subjects with moderately severe symptomatic asthma. Six of the subjects had only minimal VA/Q inequality (mean log SD of bloodflow 0.5) despite having airways obstruction similar to that in the four subjects with marked VA/Q inequality (mean log SD of bloodflow 1.0). The six patients with minimal VA/Q inequality developed marked widening of their VA/Q distributions while breathing 100 percent oxygen (mean log SD bloodflow 1.1), and four of these patients maintained more modest widening after receiving an intravenous antihistamine, clemastine (mean log SD bloodflow 0.75). The four subjects with a wide control VA/Q distribution showed smaller changes while breathing pure oxygen and no change after receiving clemastine. FEV1 improved with clemastine treatment in the first four patients only. The results suggest that the majority of patients with moderately severe asthma have compensatory pulmonary vasoconstriction, causing better VA/Q matching which is responsive to hypoxia and, possibly, histamine. The data demonstrate a relationship between active compensatory vasoconstriction and airway sensitivity to antihistamine.