Beta-agonist overuse and delay in obtaining medical review in high risk asthma: a secondary analysis of data from a randomised controlled trial

Asthma mortality surveys report delays in seeking medical review and overuse of beta-agonist therapy as factors contributing to a fatal outcome. However, the strength of these associations is limited because many asthma deaths are unwitnessed. We undertook a secondary analysis of data from a 24-week randomised controlled trial of 303 patients with high-risk asthma, randomised to combination budesonide/formoterol inhaler according to a single maintenance and reliever therapy regimen or fixed dose budesonide/formoterol with salbutamol as reliever (Standard) regimen. Medication use was measured by electronic monitors. The thresholds for high, marked and extreme beta-agonist use days were defined in the single maintenance and reliever therapy arm as: >8, >12 and >16 actuations of budesonide/formoterol in excess of four maintenance doses, respectively; and in the Standard arm as: >16, >24 and >32 actuations of salbutamol, respectively. Whether a medical review was obtained within 48 h of an overuse episode was determined by review of data collected during the study by participant report. The mean (standard deviation) proportion of days in which high, marked and extreme beta-agonist overuse occurred without medical review within 48 h was 0·94 (0·20), 0·94(0·15) and 0·94(0·17), and 0·92(0·19), 0·90(0·26) and 0·94(0·15) for single maintenance and reliever therapy and Standard regimens, respectively. In at least 90% of days, in which beta-agonist overuse occurred, patients did not obtain medical review within 48 h of beta-agonist overuse, regardless of the magnitude of overuse or the inhaled corticosteroid/long-acting beta-agonist regimen

The use of β2-agonist therapy before hospital attendance for severe asthma exacerbations: a post-hoc analysis

Background: Patterns of inhaled β2-agonist therapy use during severe asthma exacerbations before hospital attendance are poorly understood. Aims: To assess β2-agonist use prior to hospital attendance. Methods: We undertook an exploratory post hoc analysis of data from a 6-month clinical trial of 303 patients randomised to combination budesonide/formoterol inhaler according to a Single combination inhaler as Maintenance And Reliever Therapy regimen (‘SMART’) or fixed-dose budesonide/formoterol with salbutamol as reliever (‘Standard’). Patterns of β2-agonist use for 14 days before hospital attendance with a severe asthma exacerbation were determined by electronic monitoring of inhaler use. Results: There were 22 hospital attendances in 16 patients during the study. Seven and nine hospital attendances were eligible for analysis in the SMART and Standard groups, respectively. In both regimens, β2-agonist use increased before hospital attendance, with a median (range) maximum daily number of actuations of 14 (9 to 63) budesonide/formoterol in SMART and 46 (6 to 95) salbutamol in Standard with 4 (0 to 10) budesonide/formoterol actuations on the day of maximal salbutamol use. There was delay in obtaining medical review despite high β2-agonist use, in 9/16 patients. Different patterns of use were observed, including repeated days of no inhaled corticosteroid despite marked salbutamol use, which occurred in 3/9 patients in the Standard group. Conclusions: Delay in obtaining medical review in association with high β2-agonist use is common in patients before hospital presentation with severe exacerbations of asthma. The SMART regimen reduced nonadherence with inhaled corticosteroid therapy during severe exacerbations

RCT of the effect of berryfruit polyphenolic cultivar extract in mild steroid-naive asthma : a cross-over, placebo-controlled study

Objective: There is preclinical evidence that consumption of berryfruit extract may reduce chronic airways inflammation and modify airway remodelling in allergen-induced models of lung inflammation. We investigated the effect of berryfruit extract on the fractional expired nitric oxide (FeNO), a biomarker of eosinophilic airways inflammation, in adults with steroid-naïve asthma. Design: Randomised placebo-controlled cross-over double-blind trial. Setting: Single-centre community-based trial. Participants: 28 steroid-naïve mild asthmatics with FeNO >40 ppb, of whom 25 completed both study interventions. Interventions: Participants were randomised to receive, according to the cross-over design, 100 mg berryfruit polyphenolic extract (BFPE) or placebo for 4 weeks, with a 4-week washout period between the interventions. Primary outcome measure: The primary outcome variable was FeNO at 4 weeks, analysed by a mixed linear model, with a random effect for participant and baseline FeNo as a covariate. Results: The mean (SD) natural logarithm transformed (ln) FeNO after 4 weeks of treatment for the BFPE and placebo groups was 4.28 (0.47) and 4.22 (0.47), respectively. The paired change from baseline mean (SD) BFPE minus placebo ln FeNO was -0.03 (0.39), N=25. The mixed linear model estimate, with baseline covariate adjustment, difference in ln FeNO, was -0.002 (95% CI -0.15 to 0.14), p=0.98. This is equivalent to a ratio of geometric mean FeNO of 1.0 (95% CI 0.86 to 1.15). Conclusions: In steroid-naïve participants with mild asthma and elevated FeNO, there was no effect of BFPE on FeNO, a biomarker of eosinophilic airways inflammation. Caution is required in the extrapolation of apparent benefit in murine models of lung eosinophilia to clinical efficacy in patients with asthma

Metrics of salbutamol use as predictors of future adverse outcomes in asthma

Background Beta-agonist overuse is associated with adverse outcomes in asthma, however, the relationships between different metrics of salbutamol use and future risk are uncertain. Objective To investigate the relationship between metrics of salbutamol use and adverse outcome. Methods In a 24-week randomized controlled trial of 303 asthma patients at risk of severe exacerbations which compared the efficacy and safety of combination budesonide/formoterol inhaler according to a single inhaler regimen (SMART) with a fixed-dose regimen with salbutamol as reliever (‘Standard’), actual medication use was measured by electronic monitoring (Australian New Zealand Clinical Trials Registry Number ACTRN12610000515099). A nested cohort study explored the relationship between metrics of baseline salbutamol use over 2 weeks and future severe asthma exacerbations, poor asthma control (ACQ-5 ≥ 1.5) or ‘extreme’ salbutamol overuse (> 32 salbutamol actuations/24-h period). Results Higher mean daily salbutamol use (per two actuations/day) [Odds ratio (OR) (95% CI) 1.24 (1.06–1.46)], higher days of salbutamol use (per 2 days in 2 weeks) [OR 1.15 (1.00–1.31)] and higher maximal 24-h use (per two actuations/day) [OR 1.09 (1.02–1.16)] were associated with future severe exacerbations. Higher mean daily salbutamol use was associated with future poor asthma control [OR 1.13 (1.02–1.26)]. Higher mean daily salbutamol use [OR 2.73 (1.84–4.07)], number of days of use [OR 1.46 (1.24–1.71)], and maximal daily use [OR 1.57 (1.31–1.89)] were associated with an increased risk of future extreme salbutamol overuse. Conclusion and Clinical Relevance Electronically recorded frequency of current salbutamol use is a strong predictor of risk of future adverse outcomes in asthma, with average daily use performing the best. These findings provide new information for clinicians considering metrics of salbutamol as predictors of future adverse outcomes in asthma

High Concentration Oxygen and Hypercapnia in Respiratory Disease

Oxygen-induced elevations in arterial carbon dioxide tension have been demonstrated in patients with chronic obstructive pulmonary disease (COPD), asthma, pneumonia, obesity hypoventilation syndrome (OHS) and acute lung injury. A randomised controlled trial (RCT) in acute exacerbations of COPD (AECOPD) found an over two-fold increase in mortality in patients randomised to high concentration oxygen, compared to titrated oxygen. These findings support guideline recommendations for titration of oxygen therapy to a target oxygen saturation range, reducing the risks of hypoxaemia and hyperoxaemia. This thesis focuses on the potential implications of oxygen-induced elevations in carbon dioxide in the acute clinical setting. The reviews and studies in the following chapters are all aimed at addressing gaps in knowledge which may have practical implications for oxygen therapy and/or the identification of patients at risk of oxygen-induced hypercapnia in clinical practice. Numerous studies have demonstrated that high concentration oxygen continues to be administered to acutely unwell patients, despite guideline recommendations for titrated therapy. The first study in this thesis is a clinical audit evaluating the effects of a staff education program, which included face-to-face and written training for ambulance staff. The education program was associated with reduced the rates of high concentration oxygen administration to patients with AECOPD. This suggests active education may increase adherence to oxygen guidelines among clinical staff. The ability to avoid hypoxaemia and hyperoxaemia during titrated oxygen therapy relies on appropriate lower and upper target oxygen saturation limits, which may be impacted on by pulse oximeter accuracy. The second study in this thesis is a multicentre observational study in which 400 paired pulse oximeter (SpO₂) and arterial blood gas saturation (SaO₂) values were collected in the hospital setting. A SpO₂ <92% had 100% sensitivity for detecting SaO₂<90%. This indicates guideline recommended target oxygen saturations of 92-96% adequately avoid hypoxaemia. Two studies in OHS patients have investigated the effects of oxygen administration on carbon dioxide, however their designs, including recruitment of stable participants, have limited their generalisability to clinical practice. Therefore, a cross over RCT was conducted in 24 morbidly obese hospital inpatients, randomised to the order they received high concentration and titrated oxygen, each for 60 minutes. The mean change in the transcutaneous partial pressure of carbon dioxide (PtCO₂) from baseline was 3.2 mmHg higher during high concentration oxygen, compared with titrated oxygen (P=0.002). This supports guideline recommendations to titrate oxygen in patients with obesity, regardless of whether they have a diagnosis of OHS or not. The effects of oxygen in patients with bronchiectasis, neuromuscular disease or kyphoscoliosis are uncertain. Stable patients with these conditions were recruited to double-blind randomised cross over trials administering air and 50% oxygen, each for 30 minutes. A trial was also performed in stable COPD patients for comparison. There was no significant change in PtCO₂ with oxygen therapy in the neuromuscular disease/kyphoscoliosis patients. In the bronchiectasis and COPD patients, oxygen was associated with increased PtCO₂ from baseline compared to air, but the differences were not clinically significant (0.4 mmHg, P=0.012 and 1.3 mmHg, P<0.001, respectively). The lack of a clinically significant PtCO₂ increase in the COPD patients indicated the study findings were unlikely to be generalisable to the clinical setting, and highlights the potential limitations in applying data from stable participants to patients who require acute oxygen therapy. These studies support current guideline recommendations for titrated oxygen therapy, provide insight into the limits of studying the effects of oxygen in stable participants, and demonstrate the utility of an educational program to aid the translation of research findings into relevant changes in clinical practice

High Concentration Oxygen and Hypercapnia in Respiratory Disease

Oxygen-induced elevations in arterial carbon dioxide tension have been demonstrated in patients with chronic obstructive pulmonary disease (COPD), asthma, pneumonia, obesity hypoventilation syndrome (OHS) and acute lung injury. A randomised controlled trial (RCT) in acute exacerbations of COPD (AECOPD) found an over two-fold increase in mortality in patients randomised to high concentration oxygen, compared to titrated oxygen. These findings support guideline recommendations for titration of oxygen therapy to a target oxygen saturation range, reducing the risks of hypoxaemia and hyperoxaemia.   This thesis focuses on the potential implications of oxygen-induced elevations in carbon dioxide in the acute clinical setting. The reviews and studies in the following chapters are all aimed at addressing gaps in knowledge which may have practical implications for oxygen therapy and/or the identification of patients at risk of oxygen-induced hypercapnia in clinical practice.   Numerous studies have demonstrated that high concentration oxygen continues to be administered to acutely unwell patients, despite guideline recommendations for titrated therapy. The first study in this thesis is a clinical audit evaluating the effects of a staff education program, which included face-to-face and written training for ambulance staff. The education program was associated with reduced the rates of high concentration oxygen administration to patients with AECOPD. This suggests active education may increase adherence to oxygen guidelines among clinical staff.   The ability to avoid hypoxaemia and hyperoxaemia during titrated oxygen therapy relies on appropriate lower and upper target oxygen saturation limits, which may be impacted on by pulse oximeter accuracy. The second study in this thesis is a multicentre observational study in which 400 paired pulse oximeter (SpO₂) and arterial blood gas saturation (SaO₂) values were collected in the hospital setting. A SpO₂ <92% had 100% sensitivity for detecting SaO₂<90%. This indicates guideline recommended target oxygen saturations of 92-96% adequately avoid hypoxaemia.  Two studies in OHS patients have investigated the effects of oxygen administration on carbon dioxide, however their designs, including recruitment of stable participants, have limited their generalisability to clinical practice. Therefore, a cross over RCT was conducted in 24 morbidly obese hospital inpatients, randomised to the order they received high concentration and titrated oxygen, each for 60 minutes. The mean change in the transcutaneous partial pressure of carbon dioxide (PtCO₂) from baseline was 3.2 mmHg higher during high concentration oxygen, compared with titrated oxygen (P=0.002). This supports guideline recommendations to titrate oxygen in patients with obesity, regardless of whether they have a diagnosis of OHS or not.  The effects of oxygen in patients with bronchiectasis, neuromuscular disease or kyphoscoliosis are uncertain. Stable patients with these conditions were recruited to double-blind randomised cross over trials administering air and 50% oxygen, each for 30 minutes. A trial was also performed in stable COPD patients for comparison. There was no significant change in PtCO₂ with oxygen therapy in the neuromuscular disease/kyphoscoliosis patients. In the bronchiectasis and COPD patients, oxygen was associated with increased PtCO₂ from baseline compared to air, but the differences were not clinically significant (0.4 mmHg, P=0.012 and 1.3 mmHg, P<0.001, respectively). The lack of a clinically significant PtCO₂ increase in the COPD patients indicated the study findings were unlikely to be generalisable to the clinical setting, and highlights the potential limitations in applying data from stable participants to patients who require acute oxygen therapy.  These studies support current guideline recommendations for titrated oxygen therapy, provide insight into the limits of studying the effects of oxygen in stable participants, and demonstrate the utility of an educational program to aid the translation of research findings into relevant changes in clinical practice.</p

Tolerability of Nasal Delivery of Humidified and Warmed Air at Different Temperatures: A Randomised Double-Blind Pilot Study

Objectives. Delivery of warmed, humidified air via nasal high flow therapy could potentially reduce replication of temperature-sensitive viruses in the upper respiratory tract. This study investigates whether nasal high flow therapy is well tolerated by healthy adults at 37°C and 41°C. Methods. In this randomised, double-blind, controlled crossover pilot trial, nasal high flow therapy was used to deliver humidified air at 35 L/min, at either 37°C or 41°C, for three one-hour sessions of use over one day. The alternative was delivered at least 14 days later. Ten healthy, nonsmoking adults were asked, via questionnaire after each day’s use, whether they would use nasal high flow therapy while being unwell with a cold or flu if it was demonstrated to improve symptoms. Results. All participants completed both interventions. Eighty percent responded “yes” to future use of nasal high flow therapy, for both 37°C and 41°C. There was no significant change from baseline in saccharin times following either intervention or in the following morning. Conclusions. Delivering humidified air via nasal high flow therapy at both 37°C and 41°C is well tolerated by healthy adults. This supports investigation into the potential use of nasal high flow therapy as treatment in viral upper respiratory tract infections. Trial Registration. This trial is registered with ACTRN12614000183684 (tolerability study of nasal delivery of humidified & warmed air)

Oxygen versus air-driven nebulisers for exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial

Abstract Background In exacerbations of chronic obstructive pulmonary disease, administration of high concentrations of oxygen may cause hypercapnia and increase mortality compared with oxygen titrated, if required, to achieve an oxygen saturation of 88–92%. Optimally titrated oxygen regimens require two components: titrated supplemental oxygen to achieve the target oxygen saturation and, if required, bronchodilators delivered by air-driven nebulisation. The effect of repeated air vs oxygen-driven bronchodilator nebulisation in acute exacerbations of chronic obstructive pulmonary disease is unknown. We aimed to compare the effects of air versus oxygen-driven bronchodilator nebulisation on arterial carbon dioxide tension in exacerbations of chronic obstructive pulmonary disease. Methods A parallel group double-blind randomised controlled trial in 90 hospital in-patients with an acute exacerbation of COPD. Participants were randomised to receive two 2.5 mg salbutamol nebulisers, both driven by air or oxygen at 8 L/min, each delivered over 15 min with a 5 min interval in-between. The primary outcome measure was the transcutaneous partial pressure of carbon dioxide at the end of the second nebulisation (35 min). The primary analysis used a mixed linear model with fixed effects of the baseline PtCO2, time, the randomised intervention, and a time by intervention interaction term; to estimate the difference between randomised treatments at 35 min. Analysis was by intention-to-treat. Results Oxygen-driven nebulisation was terminated in one participant after 27 min when the PtCO2 rose by > 10 mmHg, a predefined safety criterion. The mean (standard deviation) change in PtCO2 at 35 min was 3.4 (1.9) mmHg and 0.1 (1.4) mmHg in the oxygen and air groups respectively, difference (95% confidence interval) 3.3 mmHg (2.7 to 3.9), p < 0.001. The proportion of patients with a PtCO2 change ≥4 mmHg during the intervention was 18/45 (40%) and 0/44 (0%) for oxygen and air groups respectively. Conclusions Oxygen-driven nebulisation leads to an increase in PtCO2 in exacerbations of COPD. We propose that air-driven bronchodilator nebulisation is preferable to oxygen-driven nebulisation in exacerbations of COPD. Trial registration Australian New Zealand Clinical Trials Registry number ACTRN12615000389505. Registration confirmed on 28/4/15