Iven H. Young

Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial

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.

Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: Effect on lung function, health status and sputum

Objective:  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.

Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis

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.

Effect of mannitol and repetitive coughing on the sputum properties in bronchiectasis

UNLABELLED Mucociliary 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<0.0001) and this effect, unlike mucociliary clearance, was not dose dependent. The control produced no effect. Total mucus clearance correlated only with the percentage reduction in surface tension on 480mg mannitol and with the reduction in solids content at baseline. IN CONCLUSION Inhaled mannitol and voluntary repetitive coughing improved the sputum physical properties in bronchiectasis patients and this effect was not dose dependent. Changes in sputum properties do not predict efficacy of mucociliary and cough clearance.

Inhaled mannitol changes the sputum properties in asthmatics with mucus hypersecretion

Background and objectives:  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.

Airway closure on imaging relates to airway hyperresponsiveness and peripheral airway disease in asthma

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 S(cond) (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 S(cond) (partial R(2) = 0.22) and with AHR (partial R(2) = 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.

Pulmonary gas exchange response to exercise- and mannitol-induced bronchoconstriction in mild asthma

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 (FEV(1)), 86 +/- 8% predicted], ventilation-perfusion (Va/Q) distributions (using multiple inert gas elimination technique) were measured 5, 15, and 45 min after cycling exercise (FEV(1) fall, 35 +/- 12%) and after mannitol (33 +/- 10%), 1 wk apart. Five minutes after EIB, minute ventilation (Ve; by 123 +/- 60%), cardiac output (Qt, by 48 +/- 29%), and oxygen uptake (Vo2; by 54 +/- 25%) increased, whereas arterial Po2 (Pa(O2); by 14 +/- 11 Torr) decreased due to moderate Va/Q imbalance, assessed by increases in dispersions of pulmonary blood flow (log SD(Q); by 0.53 +/- 0.16) and alveolar ventilation (log SD(V); by 0.28 +/- 0.15) (dimensionless) (P < 0.01 each). In contrast, for an equivalent degree of bronchoconstriction and minor increases in Ve, Qt, and Vo2, mannitol decreased Pa(O2) more intensely (by 24 +/- 9 Torr) despite fewer disturbances in log SDQ (by 0.27 +/- 0.12). Notwithstanding, mannitol-induced increase in log SDV at 5 min (by 0.35 +/- 0.15) was similar to that observed during EIB, as was the slow recovery in log SD(V) and high Va/Q ratio areas, at variance with the faster recovery of log SD(Q) and low Va/Q ratio areas. In asthmatic individuals, EIB provokes more Va/Q imbalance but less hypoxemia than mannitol, primarily due to postexercise increases in Ve and Qt benefiting Pa(O2). Va/Q inequalities during both challenges most likely reflect uneven airway narrowing and blood flow redistribution generating distinctive Va/Q patterns, including the development of areas with low and high Va/Q ratios.

Exercise capacity and stroke volume are preserved late after tetralogy repair, despite severe right ventricular dilatation

Objectives 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/m2, a currently suggested threshold for pulmonary valve replacement (PVR). Design Cross-sectional study. Setting Single-centre adult congenital heart disease unit. Patients 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). Interventions Cardiovascular MRI (1.5T) and cardiopulmonary exercise test. Main outcome measures Biventricular volumes and function; exercise capacity. Results 20 patients had RVEDVi below, and 35 had RVEDVi above 150 ml/m2, at time of referral. In the >150 ml/m2 group, fractional pulmonary regurgitation was higher (41±8 vs 31±8%, p<0.001). 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/m2, p<0.001) in the >150 ml/m2 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 VO2 peak: 84±17 vs 87±12%). Conclusions 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.

Mucociliary clearance in patients with chronic asthma: effects of beta agonists.

Objective:  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).

Gas Exchange in Disease: Asthma, Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Interstitial Lung Disease

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.