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Summary Background In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting β-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting β-agonist (SABA) reliever therapy. We investigated the efficacy of combination budesonide–formoterol reliever therapy compared with maintenance budesonide plus as-needed terbutaline. Methods We did a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial at 15 primary care or hospital-based clinical trials units and primary care practices in New Zealand. Participants were adults aged 18–75 years with a self-reported doctor's diagnosis of asthma who were using SABA for symptom relief with or without maintenance low to moderate doses of inhaled corticosteroids in the previous 12 weeks. We randomly assigned participants (1:1) to either reliever therapy with budesonide 200 μg–formoterol 6 μg Turbuhaler (one inhalation as needed for relief of symptoms) or maintenance budesonide 200 μg Turbuhaler (one inhalation twice daily) plus terbutaline 250 μg Turbuhaler (two inhalations as needed). Participants and investigators were not masked to group assignment; the statistician was masked for analysis of the primary outcome. Six study visits were scheduled: randomisation, and weeks 4, 16, 28, 40, and 52. The primary outcome was the number of severe exacerbations per patient per year analysed by intention to treat (severe exacerbations defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids). Safety analyses included all participants who had received at least one dose of study treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616000377437. Findings Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment and included 885 eligible participants in the analysis: 437 assigned to budesonide–formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. Severe exacerbations per patient per year were lower with as-needed budesonide–formoterol than with maintenance budesonide plus terbutaline as needed (absolute rate per patient per year 0·119 vs 0·172; relative rate 0·69, 95% CI 0·48–1·00; p=0·049). Nasopharyngitis was the most common adverse event in both groups, occurring in 154 (35%) of 440 patients receiving as-needed budesonide–formoterol and 144 (32%) of 448 receiving maintenance budesonide plus terbutaline as needed. Interpretation In adults with mild to moderate asthma, budesonide–formoterol used as needed for symptom relief was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline. The findings support the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid–formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma. Funding Health Research Council of New Zealand.

Recognition that there are risks associated with hyperoxaemia, as well as hypoxaemia, with the use of oxygen therapy in critically ill patients, has led to a paradigm shift in clinical practice, from the traditional approach of liberal administration to titration within a target oxygen saturation range.1 This paradigm shift, colloquially referred to as ‘swimming between the flags’,2 particularly applies to the use of oxygen in severe exacerbations of chronic obstructive pulmonary disease (COPD), in which guidelines now recommend that oxygen is titrated to a target oxygen saturation range of 88%–92%.2–4 This recommendation is based on the landmark randomised controlled trial in patients with acute exacerbations of COPD, in which oxygen therapy titrated to maintain oxygen saturations between 88% and 92% in the prehospital setting reduced the risk of mortality by 58%, when compared with high concentration oxygen therapy.5 While this randomised controlled trial provides the evidence base for the recommended 88%–92% target range, it raises the important question as to whether a ‘physiologically normal’ target of 93%–96%, that also avoids hyperoxaemia, may result in better outcomes than the 88%–92% target. A 93%–96% range is attractive, as it would achieve a modest increase in the arterial partial …

Background and objective Hypercapnia is associated with worse clinical outcomes in exacerbations of COPD. The present study aimed to determine the effects of nasal high flow (NHF) therapy on transcutaneous partial pressure of carbon dioxide (PtCO2) in stable COPD patients. Methods In a single-blind randomized controlled cross-over trial, 48 participants with COPD were allocated in random order to all of four 20 min interventions: NHF at 15 L/min, 30 L/min and 45 L/min or breathing room air with each intervention followed by a washout period of 15 min. The primary outcome measure was PtCO2 at 20 min, adjusted for baseline PtCO2. Secondary outcomes included respiratory rate at 20 min, adjusted for baseline. Results The mean (95% CI) change in PtCO2 at 20 min was −0.6 mm Hg (−1.1 to 0.0), P = 0.06; −1.3 mm Hg (−1.9 to 0.8), P

Background and objective Increased arterial carbon dioxide tension (PaCO2 ) is an important complication of acute exacerbations of COPD. The effects of nasal high-flow cannulae (NHF) on PaCO2 in patients with COPD exacerbations, and whether this therapy should be used in this clinical situation, are less certain. We aimed to investigate the effect of NHF on PaCO2 in patients admitted to hospital with a COPD exacerbation. Methods We performed a single-centre randomized controlled cross-over trial in 24 hospital inpatients with acute exacerbations of COPD receiving oxygen via standard nasal prongs (SNPs). Patients received both supplemental oxygen via NHF (35 L/min) and SNP for 30 min each, with oxygen titrated to maintain the patient's baseline oxygen saturation, measured by pulse oximetry (SpO2 ). Interventions were administered in random order with a minimum 15-min washout between interventions. The primary outcome was difference in transcutaneous carbon dioxide tension (PtCO2 ) at 30 min adjusted for time zero. Results The difference in PtCO2 adjusted for time zero was lower after 30 min for NHF compared with SNP (−1.4 mm Hg (95% CI: −2.2 to −0.6), P = 0.001). There was no difference in SpO2 at 30 min (−0.02% (95% CI: −0.8 to 0.7), P = 0.96). The reduction in respiratory rate for NHF at 30 min was not statistically significant (−2.0 breaths/min (95% CI: −4.5 to 0.4), P = 0.099). Conclusion Short-term use of NHF results in a small reduction in PtCO2 compared with SNP in patients with acute exacerbations of COPD, but whether this is clinically significant is uncertain.

Background High-concentration oxygen therapy causes increased arterial partial pressure of carbon dioxide (PaCO2) in patients with COPD, asthma, pneumonia, obesity and acute lung injury. The objective of these studies was to investigate whether this physiological response to oxygen therapy occurs in stable patients with neuromuscular disease or kyphoscoliosis, and bronchiectasis. Methods Three randomised cross-over trials recruited stable patients with neuromuscular disease or kyphoscoliosis (n = 20), bronchiectasis (n = 24), and COPD (n = 24). Participants were randomised to receive 50% oxygen and 21% oxygen (air), each for 30 min, in randomly assigned order. The primary outcome was transcutaneous partial pressure of carbon dioxide (PtCO2) at 30 min. The primary analysis was a mixed linear model. Results Sixty six of the 68 participants had baseline PtCO2 values

Summary Background Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysis of a previously published open-label clinical trial, we aimed to assess associations between blood eosinophil counts and FeNO with outcomes and response to asthma treatment. Methods In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only β agonist reliever inhalers were enrolled at one of 16 clinical trials units in New Zealand, the UK, Italy, or Australia. Eligible participants were randomly assigned (1:1:1, stratified by country), to receive inhalers to take as-needed salbutamol (two inhalations of 100 μg in a pressurised metered dose inhaler), maintenance budesonide (200 μg twice per day by inhaler) plus as-needed salbutamol (two inhalations of 100 μg), or as-needed budesonide–formoterol (one inhalation of 200 μg budesonide and 6μg formoterol by inhaler). The primary outcome was the annual rates of asthma exacerbations per patient, and in this prespecified subgroup analysis, we assessed whether annual exacerbation rates in each treatment group were significantly different depending on levels of blood eosinophil count, FeNO, or a composite score of both. Analyses were done for patients with available biomarker measurements The study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000999538. Findings 675 participants were enrolled between March 17, 2016, and Aug 29, 2017, of whom 656 had results for blood eosinophil analysis and 668 had results for FeNO. Of the patients who received as-needed salbutamol, the proportion of patients having a severe exacerbation increased progressively with increasing blood eosinophil count (two [4%] of 49 participants with Interpretation In patients with mild asthma, the effects of as-needed budesonide–formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts than in patients with low counts. Funding AstraZeneca, Health Research Council of New Zealand.

The influence of variables that might affect the accuracy of pulse oximetry (SpO2) recordings in critically ill patients is not well established. We sought to describe the relationship between paired SpO2/SaO2 (oxygen saturation via arterial blood gas analysis) in adult intensive care unit (ICU) patients and to describe the diagnostic performance of SpO2 in detecting low SaO2 and PaO2. A paired SpO2/SaO2 measurement was obtained from 404 adults in ICU. Measurements were used to calculate bias, precision, and limits of agreement. Associations between bias and variables including vasopressor and inotrope use, capillary refill time, hand temperature, pulse pressure, body temperature, oximeter model, and skin colour were estimated. There was no overall statistically significant bias in paired SpO2/SaO2 measurements; observed limits of agreement were +/-4.4%. However, body temperature, oximeter model, and skin colour, were statistically significantly associated with the degree of bias. SpO2 2 2/SaO2 in adult ICU patients provides support for the use of pulse oximetry to titrate oxygen therapy. However, SpO2 recordings alone should be used cautiously when SaO2 recordings of 4.4% higher or lower than the observed SpO2 would be of concern. A range of variables relevant to the critically ill had little or no effect on bias.

Background and objective: The optimal management of people with asthma with a significant smoking history is uncertain. The aim of this study was to determine whether the efficacy/safety profile of single combination inhaled corticosteroid (ICS)/long acting beta-agonist (LABA) inhaler maintenance and reliever therapy is influenced by smoking status. Methods: We undertook secondary analyses from an open-label 24-week randomized study of 303 high risk adult asthma patients randomized to budesonide/formoterol 200/6-µg-metred dose inhaler for maintenance (two actuations twice daily) and either budesonide/formoterol 200/6-µg-metred dose inhaler one actuation (‘single ICS/LABA maintenance and reliever therapy (SMART)’ regimen) or salbutamol 100 µg 1–2 actuations for symptom relief (‘Standard’ regimen). Smoking status was classified in to three groups, as ‘current’, ‘ex’ or ‘never’, and a smoking/treatment interaction term tested for each outcome variable. The primary outcome variable was number of participants with at least one severe exacerbation. Results: There were 59 current, 97 ex and 147 never smokers included in the analyses. The smoking status/treatment interaction term was not statistically significant for any of the outcome measures. With adjustment for smoking status, the number of participants with severe exacerbations was lower with the SMART regimen (OR 0.45, 95% CI: 0.26–0.77, P = 0.004; P value for interaction between smoking status and treatment 0.29). Conclusion: We conclude that the favourable safety/efficacy profile of the SMART regimen applies to patients with high risk asthma, irrespective of smoking status.

The purpose of the Thoracic Society of Australia and New Zealand guidelines is to provide simple, practical evidence-based recommendations for the acute use of oxygen in adults in clinical practice. The intended users are all health professionals responsible for the administration and/or monitoring of oxygen therapy in the management of acute medical patients in the community and hospital settings (excluding perioperative and intensive care patients), those responsible for the training of such health professionals, and both public and private health care organizations that deliver oxygen therapy.

During the last decade, there have been major advances in knowledge of the effects of oxygen therapy in patients with acute exacerbations of chronic obstructive pulmonary disease. This includes a randomised controlled trial of oxygen therapy in the pre-hospital setting, which showed that high concentration oxygen therapy leads to a 2.4-fold increased risk of mortality compared with titrated oxygen therapy to maintain oxygen saturations (SpO2) within a target range of 88-92%. Professional guidelines now recommend the use of supplementary oxygen in acute exacerbations of chronic obstructive pulmonary disease only if the SpO2 is less than 88%, with titration to achieve an SpO2 of 88-92%, and the delivery of bronchodilators by air-driven nebulisation or metered dose inhaler with a spacer. The aim of this review is to provide an overview of the evidence base that underpins these recommendations. We suggest that their implementation will require important changes to current clinical practice in which there is an entrenched culture of the use of high concentration oxygen therapy.

Background: Despite guidelines recommending avoidance of oxygen-driven nebulisation in patients with COPD, many still receive this method of bronchodilator delivery. In the absence of compressed air, the BTS suggests limiting oxygen-driven nebulisation to 6 minutes (Level D evidence). Aims: This study compared the effects of oxygen versus air-driven nebulisers on PaCO 2 and pH in acute exacerbations of COPD (AECOPD). Methods: A parallel group double-blind RCT was performed in 90 in-patients with AECOPD. Patients receiving non-invasive ventilation or ≥4L/min of oxygen to maintain SpO 2 88-92% were excluded. Participants were randomised to receive two 2.5mg salbutamol nebulisers driven by air or oxygen at 8L/min, each delivered over 15 minutes with a 5 minute interval in-between. Participants had continuous transcutaneous carbon dioxide (PtCO 2 ) monitoring and capillary blood gas samples obtained at baseline and at 35 minutes. Results: The mean difference in PtCO 2 at 35 minutes was 3.3mmHg (95%CI 2.6 to 4.0, p 2 rose by >10mmHg, a predefined safety criterion. 18/45 (40%) participants in the oxygen group experienced a rise in PtCO 2 ≥4mmHg at any time point compared to 0/44 (0%) driven by air. Six minutes into the second nebulisation, the difference in PtCO 2 was 2.9mmHg (95%CI 2.3 to 3.5, p Conclusion: Oxygen-driven nebulisation leads to an increase in PtCO 2 in AECOPD. Limiting oxygen-driven nebulisers to 6 minutes would not substantially ameliorate this risk.

Hypercapnia is associated with worse clinical outcomes in exacerbations of COPD. The present study aimed to determine the effects of nasal high flow (NHF) therapy on transcutaneous partial pressure of carbon dioxide (PtCOIn a single-blind randomized controlled cross-over trial, 48 participants with COPD were allocated in random order to all of four 20 min interventions: NHF at 15 L/min, 30 L/min and 45 L/min or breathing room air with each intervention followed by a washout period of 15 min. The primary outcome measure was PtCOThe mean (95% CI) change in PtCONHF results in a small flow-dependent reduction in PtCO

OBJECTIVE To compare the effects on transcutaneous carbon dioxide tension (Ptco2) of high concentration and titrated oxygen therapy in medical inpatients with morbid obesity who were not selected for a pre-existing diagnosis of obesity hypoventilation syndrome. DESIGN A randomised, crossover trial undertaken between February and September 2015. SETTING Internal medicine service, Wellington Regional Hospital, New Zealand. PARTICIPANTS 22 adult inpatients, aged 16 years or more, with a body mass index exceeding 40 kg/m2. INTERVENTIONS Participants received in random order two 60-minute interventions, with a minimum 30-minute washout period between treatments: titrated oxygen therapy (oxygen delivered, if required, via nasal prongs to achieve peripheral oxygen saturation [Spo2] of 88-92%), and high concentration oxygen therapy (delivered via Hudson mask at 8 L/min, without regard to Spo2). Ptco2 and Spo2 were recorded at 10-minute intervals. MAIN OUTCOME MEASURE Ptco2 at 60 minutes, adjusted for baseline. RESULTS Baseline Ptco2 was 45 mmHg or lower for 16 participants with full data (73%). The mean difference in Ptco2 between high concentration and titrated oxygen therapy at 60 minutes was 3.2 mmHg (95% CI, 1.3-5.2 mmHg; P = 0.002). CONCLUSION High concentration oxygen therapy increases Ptco2 in morbidly obese patients. Our findings support guidelines that advocate oxygen therapy, if required in patients with morbid obesity, be titrated to achieve a target Spo2 of 88-92%. CLINICAL TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry, ACTRN12610000522011.

Background and objective There are significant health disparities between Māori and non-Māori with asthma, a pattern seen between other ethnic populations. This study investigates outcomes for Māori in a randomized controlled trial (RCT) of combination budesonide/formoterol inhaler therapy in asthma. Methods This 24-week multicentre RCT recruited 303 adult asthma patients, 44 of whom were Māori. Participants were randomized to the single combination budesonide/formoterol inhaler as maintenance and reliever therapy (‘SMART’) regimen or ‘standard’ regimen (combination budesonide/formoterol inhaler for maintenance and salbutamol as reliever). Outcomes included patterns of beta-agonist inhaler use including ‘high use’ of reliever therapy (>8 actuations of budesonide/formoterol in excess of four maintenance doses per day for SMART and >16 actuations per day of salbutamol for standard). Differences in outcomes for Māori versus non-Māori were assessed using an interaction term between ethnicity and treatment. Results With adjustment for ethnicity, the SMART group had fewer days of high use (relative rate (RR) 0.57 (95% confidence interval (CI): 0.38–0.85)), days of high use without medical review within 48 h (RR 0.49 (95% CI: 0.32–0.75)) and severe exacerbations (RR 0.54 (95% CI: 0.36–0.81)) compared with standard. The magnitude of the benefit from the SMART regimen was similar in Māori and non-Māori. Regardless of treatment regimen, Māori demonstrated more days of high use, high use without medical review and underuse of maintenance therapy. Conclusions The SMART regimen has a favourable risk/benefit profile in Māori. Days of high use, days of high use without medical review and underuse of maintenance treatment were greater in Māori, regardless of treatment regimen.

Background In 2009 the Wellington Free Ambulance implemented an education programme to reduce high concentration oxygen delivery to patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The aim of this audit was to compare pre-hospital oxygen delivery to patients with AECOPD before and after the programme. Methods An audit of patients who presented to Wellington Regional Hospital by ambulance with an AECOPD in 2005 and then in 2010, after implementation of the education programme. Oxygen therapy was categorised as: HIGH, supplemental high concentration oxygen therapy ≥3 L/min and/or delivery via high concentration mask; NEB, high concentration oxygen only during nebuliser use; or LOW, neither of these. Results In 2005 those in the HIGH, NEB and LOW categories were 81 (75.0%), 18 (16.7%) and 9 (8.3%) of 108 identified patients. In 2010 those in the HIGH, NEB and LOW categories were 80 (44.0%), 61 (33.5%) and 41 (22.5%) of 182 identified patients. The proportions of patients in the three oxygen groups were significantly different between 2005 and 2010 (p

a b s t r a c t Background: Arterial carbon dioxide tension (PaCO2) affects neuronal function and cerebral blood flow. However, its association with outcome in patients admitted to intensive care unit (ICU) after cardiac arrest (CA) has not been evaluated. Methods and results: Observational cohort study using data from the Australian New Zealand (ANZ) Inten- sive Care Society Adult-Patient-Database (ANZICS-APD). Outcomes analyses were adjusted for illness severity, co-morbidities, hypothermia, treatment limitations, age, year of admission, glucose, source of admission, PaO2 and propensity score. We studied 16,542 consecutive patients admitted to 125 ANZ ICUs after CA between 2000 and 2011. Using the APD-PaCO2 (obtained within 24 h of ICU admission), 3010 (18.2%) were classified into the hypo- (PaCO2 45 mmHg) group. The hypocapnia group, compared with the normocapnia group, had a trend toward higher in-hospital mortality (OR 1.12 (95% CI 1.00-1.24, p = 0.04)), lower rate of discharge home (OR 0.81 (0.70-0.94, p < 0.01)) and higher likelihood of fulfilling composite adverse outcome of death and no discharge home (OR 1.23 (1.10-1.37, p < 0.001)). In contrast, the hypercapnia group had similar in- hospital mortality (OR 1.06 (0.97-1.15, p = 0.19)) but higher rate of discharge home among survivors (OR 1.16 (1.03-1.32, p = 0.01)) and similar likelihood of fulfilling the composite outcome (OR 0.97 (0.89-1.06, p = 0.52)). Cox-proportional hazards modelling supported these findings. Conclusions: Hypo- and hypercapnia are common after ICU admission post-CA. Compared with normocap- nia, hypocapnia was independently associated with worse clinical outcomes and hypercapnia a greater likelihood of discharge home among survivors.

Summary Background The Single combination budesonide–formoterol inhaler Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations in patients, but whether the high doses of corticosteroid and β agonist increase the risk of adverse effects with both short-term and cumulative exposure is not certain. Our aim was to investigate whether the SMART regimen would reduce the risk of overuse of β agonist, reduce the likelihood of patients to seek medical review when such episodes occurred, and if any reduction in severe asthma exacerbations would be at the cost of a higher burden of systemic corticosteroid. Methods In this 24-week trial undertaken at four primary health-care practices and one hospital in New Zealand, patients (aged 16–65 years) with a recent asthma exacerbation were randomly assigned in a 1:1 ratio to the SMART or standard fixed-dose regimen. Treatment in the SMART group consisted of two actuations of budesonide–formoterol (200 μg and 6 μg, respectively, per actuation) twice daily, delivered through a combination metered dose inhaler (MDI), with one extra actuation as needed for relief of symptoms; treatment in the standard group consisted of two actuations of budesonide–formoterol (200 μg and 6 μg, respectively, per actuation) twice daily through a combination MDI with one to two actuations of salbutamol (100 μg per actuation) by MDI as needed for relief of symptoms. MDIs were monitored electronically to measure actual use of medication. The allocation sequence for randomisation was computer generated, with a block size of eight per site. Participants, investigators, and the statistician were not masked to group assignment. The primary outcome was the proportion of participants with at least one high-use episode of β agonist (more than eight actuations per day of budesonide–formoterol in addition to the four maintenance doses in the SMART group or more than 16 actuations per day of salbutamol in the standard group). Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000515099. Findings 303 patients were randomly assigned to the SMART (n=151) or standard group (n=152). No significant difference was noted between the SMART and standard groups in the proportion of participants with at least one high-use episode of β agonist (84 [56%] vs 68 [45%], respectively, relative risk 1·24 [95% CI 0·99–1·56]; p=0·058). There were fewer days of high use in the SMART group (mean 5·1 days [SD 14·3] vs 8·9 days [20·9], relative rate 0·58 [0·39–0·88]; p=0·01). Of the patients who had at least one high-use episode, those in the SMART group had fewer days of high use without medical review (8·5 days [17·8] vs 18·3 days [24·8], 0·49 [0·31–0·75]; p=0·001). The SMART regimen resulted in higher inhaled corticosteroid exposure (943·5 μg budesonide per day [1502·5] vs 684·3 μg budesonide per day [390·5], respectively; ratio of means 1·22 [1·06–1·41]; p=0·006), but reduced oral corticosteroid exposure (77·5 mg prednisone [240·5] vs 126·6 mg prednisone [382·1], respectively; p=0·011), with no significant difference in composite systemic corticosteroid exposure (793·7 mg prednisone equivalent per year [893·1] vs 772·1 mg prednisone equivalent per year [1062·7], respectively; 1·03 [0·86–1·22]; p=0·76). Participants in the SMART group had fewer severe asthma exacerbations (35 [weighted mean rate per year 0·53] vs 66 [0·97]; relative rate 0·54 [0·36–0·82]; p=0·004). Interpretation The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations. Funding Health Research Council of New Zealand.

Background Electronic monitoring of inhaled asthma medications is one method to measure medication adherence and patterns of use. Information on the performance of monitors in a randomized controlled trial allows researchers and clinicians to understand their utility and limitations. The Smartinhaler Tracker is an electronic monitor for metered-dose inhalers (MDIs) that records the date, time, and number of actuations. Objective To determine the performance of the Smartinhaler monitors used in a 24-week randomized controlled trial of 303 patients with asthma in a real-world setting. Methods Prestudy use checks involved 2 actuations of the MDI, with a further 2 performed 2 hours later. Within-study monitor checks, performed before dispensing at clinic visits 2 to 4, included a computerized check of monitor clock function, actuation accuracy, and battery life. Within-study data checks involved computerized checks of monitor clock function before data upload. Results Two thousand six hundred seventy-eight of 2728 monitors (98.2%) passed prestudy use checks. Seventy-six of 2642 monitors (2.9%) dispensed to participants failed within-study monitor checks. Fifty-one of 2642 monitors (1.9%) malfunctioned before data upload, mostly as a result of fluid immersion. Ninety-three of 2642 monitors (3.5%) were lost or thrown away by participants. Complete data was available from 2498 of 2642 dispensed monitors (94.5%) and 2498 of 2549 returned monitors (98.0%). Conclusions The Smartinhaler Tracker is a reliable monitor for measuring MDI use in a real-world setting. Use of extensive monitor and data-checking protocols reduces data loss. In a research or clinical setting, the use of a validated and reliable electronic monitor represents the reference standard for assessing patterns of medication use.

The purpose of the Asthma and Respiratory Foundation NZ Adult Asthma Guidelines is to provide simple, practical and evidence-based recommendations for the diagnosis, assessment and management of asthma in adults (aged 16 and over) in a quick reference format. The intended users are health professionals responsible for delivering asthma care in the community and hospital Emergency Department settings, and those responsible for the training of such health professionals.

Increased arterial carbon dioxide tension (PaCOWe performed a single-centre randomized controlled cross-over trial in 24 hospital inpatients with acute exacerbations of COPD receiving oxygen via standard nasal prongs (SNPs). Patients received both supplemental oxygen via NHF (35 L/min) and SNP for 30 min each, with oxygen titrated to maintain the patient's baseline oxygen saturation, measured by pulse oximetry (SpOThe difference in PtCOShort-term use of NHF results in a small reduction in PtCO

Objective To investigate the cardioprotective efficacy of remote ischaemic preconditioning (RIPC) in cardiac surgery. Design We have performed a systematic search of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify randomized controlled trials involving RIPC. Setting Randomized controlled trials of RIPC in open cardiac surgery patients. Main outcome measures Meta-analysis was performed with the primary outcome the standardized mean difference between intervention and control groups in 12 hour postoperative troponin concentration. Heterogeneity was examined by fixed effects meta-regression. Results Ten studies with a total of 693 participants were included in the meta-analysis. RIPC reduced troponin levels 12 hours after surgery compared with control. The fixed and random effects differences were 0.35 (95% CI 0.19 to 0.51) and 0.53 (95% CI 0.18-0.88) respectively. However, important heterogeneity was present. Fixed effects meta-regression partially accounted for heterogeneity based on whether studies had full blinding, comprising blinding of patients, surgeons, anaesthetists and investigators. Studies with incomplete or no blinding demonstrated a larger estimate of effect, 0.74 (95% CI 0.47 to 1.00) compared to those with full blinding, 0.13 (95% CI - 0.07 to 0.33). Conclusions Although our analysis suggests RIPC may result in cardiac protection during cardiac surgery, the effect was most marked in studies without full blinding, with a smaller and statistically non-significant effect in fully blinded studies. We propose that further double blind randomized controlled trials investigating the cardioprotective effects of RIPC in cardiac surgery are required to resolve the current clinical uncertainty.

Background Prehospital high concentration oxygen therapy leads to worse clinical outcomes in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Less is known about the risks of hypoxaemia despite oxygen treatment. Current respiratory and ambulance guidelines recommend titration of supplemental oxygen to a target oxygen saturation range of 88%–92%. Aim To explore the association between PaO2 and risk of serious adverse clinical outcomes in AECOPD. Methods A retrospective review of consecutive patients presenting via ambulance to the Wellington Regional Hospital Emergency Department with AECOPD between June 2005 and January 2008. Patients with an arterial blood gas taken within 4 h of triage were included in the study and were categorised as hypoxaemic (PaO2100 mm Hg). Serious adverse outcome was defined as a composite of hypercapnic respiratory failure, assisted ventilation or inpatient death. Multivariate logistic regression analysis examined the association between PaO2 category and the composite outcome. Results Of the 680 patients presenting with AECOPD in the review period, 254 presentations in 180 patients had data suitable for analysis. Hyperoxaemia occurred in 61/254 (24%) presentations and was strongly associated with serious adverse outcome compared with normoxaemia (OR 9.17, 95% CI 4.08 to 20.6). Hypoxaemia was also associated with an increased risk of serious adverse outcome compared with normoxaemia (OR 2.16, 95% CI 1.11 to 4.20). Compared with the recommended target oxygen saturation range of 88%–92%, the risk of a serious adverse outcome was increased in both the 96% group (OR 2.37, 95% CI 1.34 to 4.20). Conclusions In patients presenting via ambulance to the Emergency Department with AECOPD, serious adverse clinical outcomes are associated with both hypoxaemia and hyperoxaemia. These data provide further support for the principle of titrating supplemental oxygen therapy to target oxygen saturations.

This scientific letter considers the rationale for the target oxygen saturation measured by pulse oximetry (SpO

Background Electronic monitoring of inhaled asthma therapy is suggested as the 'gold standard' for measuring patterns of medication use in clinical trials. The SmartTurbo (Adherium (NZ) Ltd, Auckland, New Zealand) is an electronic monitor for use with a turbuhaler device (AstraZeneca, UK). The aim of this study was to determine the accuracy of the SmartTurbo in recording Symbicort actuations over a 12-week period of use. Methods Twenty SmartTurbo monitors were attached to the base of 20 Symbicort turbuhalers. Bench testing in a research facility was undertaken on days 0, 5, 6, 7, 8, 9, 14, 21, 28, 56 and 84. Patterns of 'low-use' (2 sets of 2 actuations on the same day) and 'high-use' (2 sets of 8 actuations on the same day) were performed. The date and time of actuations were recorded in a paper diary and compared with data uploaded from the SmartTurbo monitors. Results 2800 actuations were performed. Monitor sensitivity was 99.9% with a lower 97.5% confidence bound of 99.6%. The positive predictive value was 99.9% with a 97.5% lower confidence bound of 99.7%. Accuracy was not affected by whether the pattern of inhaler use was low or high, or whether there was a delay in uploading the actuation data. Conclusions The SmartTurbo monitor is highly accurate in recording and retaining electronic data in this 12-week bench study. It can be recommended for use in clinical trial settings, in which quality control systems are incorporated into study protocols to ensure accurate data acquisition.

The purpose of the Thoracic Society of Australia and New Zealand guidelines is to provide simple, practical evidence-based recommendations for the acute use of oxygen in adults in clinical practice. The intended users are all health professionals responsible for the administration and/or monitoring of oxygen therapy in the management of acute medical patients in the community and hospital settings (excluding perioperative and intensive care patients), those responsible for the training of such health professionals, and both public and private health care organizations that deliver oxygen therapy.

Introduction In adult asthma, combination inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) used solely as reliever therapy may represent an effective and safe alternative to ICS maintenance and short-acting beta agonist (SABA) reliever therapy. Objective To compare the efficacy and safety of ICS/fast-onset LABA reliever therapy with ICS maintenance and SABA reliever therapy in adults with asthma. Methods and analysis A 52-week, open-label, parallel group, multicentre, phase III randomised controlled trial with 1:1 randomisation to either budesonide/formoterol Turbuhaler 200/6 µg, one actuation as required for symptom relief, or budesonide Turbuhaler 200 µg, one actuation twice daily and terbutaline Turbuhaler 250 µg, two actuations as required for symptom relief. 890 adults aged 18–75 years with asthma for whom maintenance ICS and SABA reliever therapy is indicated by current guidelines will be recruited in New Zealand. The primary outcome variable is the rate of severe exacerbations per patient per year. This study will investigate a novel treatment regimen that might lead to a paradigm shift in asthma management for adults for whom guidelines currently recommend maintenance ICS and SABA reliever therapy. Ethics and dissemination Ethical approval has been granted (15/NTB/178). Study findings will be published according to Iinternational Committee of Medical Journal Editors9 recommendations. Trial registration number ACTRN12616000377437; Pre-results.

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-naive asthma. Design Randomised placebo-controlled cross-over double-blind trial. Setting Single-centre community-based trial. Participants 28 steroid-naive 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-naive 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. Trial registration number ANZCTR: 12613000451707; Results.

There are significant health disparities between Māori and non-Māori with asthma, a pattern seen between other ethnic populations. This study investigates outcomes for Māori in a randomized controlled trial (RCT) of combination budesonide/formoterol inhaler therapy in asthma.This 24-week multicentre RCT recruited 303 adult asthma patients, 44 of whom were Māori. Participants were randomized to the single combination budesonide/formoterol inhaler as maintenance and reliever therapy ('SMART') regimen or 'standard' regimen (combination budesonide/formoterol inhaler for maintenance and salbutamol as reliever). Outcomes included patterns of beta-agonist inhaler use including 'high use' of reliever therapy (8 actuations of budesonide/formoterol in excess of four maintenance doses per day for SMART and16 actuations per day of salbutamol for standard). Differences in outcomes for Māori versus non-Māori were assessed using an interaction term between ethnicity and treatment.With adjustment for ethnicity, the SMART group had fewer days of high use (relative rate (RR) 0.57 (95% confidence interval (CI): 0.38-0.85)), days of high use without medical review within 48 h (RR 0.49 (95% CI: 0.32-0.75)) and severe exacerbations (RR 0.54 (95% CI: 0.36-0.81)) compared with standard. The magnitude of the benefit from the SMART regimen was similar in Māori and non-Māori. Regardless of treatment regimen, Māori demonstrated more days of high use, high use without medical review and underuse of maintenance therapy.The SMART regimen has a favourable risk/benefit profile in Māori. Days of high use, days of high use without medical review and underuse of maintenance treatment were greater in Māori, regardless of treatment regimen.

Background: Predictors of asthma exacerbations, poor asthma control, or extreme β-agonist overuse may be of clinical utility in the management of asthma. Objective: To investigate characteristics that predict subsequent adverse outcomes in asthma. Methods: An independent 24-week, randomized controlled trial of 303 adult patients with asthma who are at risk, which compared the efficacy of SMART (single budesonide-formoterol inhaler as maintenance and reliever therapy) with a fixed-dose regimen with salbutamol as reliever (“Standard”). Inhaled medication use was measured by electronic monitoring. Baseline characteristics that were predictors of subsequent severe asthma exacerbations, poor asthma control (Asthma Control Questionnaire –5 score ≥1.5), and “extreme” β-agonist overuse (>16 budesonide-formoterol actuations/d in SMART and >32 salbutamol actuations/d in Standard) were assessed by multivariate analyses. Results: FEV1 % predicted (rate ratio [RR] 1.14 [95% CI, 1.03-1.27] per 10% lower), more previous exacerbations (RR 1.15 [95% CI, 1.01-1.31]), Standard therapy (RR 1.62 [95% CI, 1.07-2.47]), and female sex (RR 2.18 [95% CI, 1.29-3.67]) were associated with future severe exacerbations. Asthma Control Questionnaire–5 (regression coefficient 0.20 [95% CI, 0.13-0.27] per 0.5 points higher) and age (regression coefficient 0.09 [95% CI, 0.01-0.17] per decade older) were associated with future poorly controlled asthma. Higher reliever use (RR 1.63 [95% CI, 1.36-1.95] per categorical score in Asthma Control Questionnaire question no. 6), Māori ethnicity (RR 2.20 [95% CI, 1.43-3.38]) and FEV1 % predicted (RR 1.16 [95% CI, 1.03-1.31] per 10% lower) were associated with future extreme β-agonist overuse. Conclusion: Future severe asthma exacerbations, poor asthma control, and extreme β-agonist overuse are predicted by different baseline clinical and demographic characteristics and management approaches in at-risk asthma.

In the Single combination inhaler as Maintenance And Reliever Therapy (SMART) regimen, asthma patients use a corticosteroid/fast-onset long-acting beta-agonist inhaler as both regular maintenance and reliever therapy. In this multicenter, double-blind randomized controlled trial, Papi et al. have demonstrated that treatment with the combination beclometasone/formoterol hydrofluoroalkane (HFA)-MDI when used as both maintenance and reliever therapy significantly prolongs the time to the first severe asthma exacerbation and reduces severe exacerbations compared with the same fixed dose of maintenance beclometasone/formoterol HFA-MDI with salbutamol MDI for relief. These findings are consistent with those of the prior studies of the SMART regimen with the budesonide/formoterol DPI and extend the evidence for use of the SMART regimen to the extrafine beclometasone/formoterol HFA-MDI, to patients with high baseline reliever use, and to patients in whom the SMART regimen results in a step up, step down or no change in baseline inhaled corticosteroid dose.

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.

Background The SmartTouch Ventolin monitor (Adherium, Auckland, New Zealand) is an electronic monitor for use with a Ventolin metered dose inhaler, which records the date and time of inhaler actuations. This technology has the potential to allow in-depth analysis of patterns of inhaler use in clinical trial settings. The aim of this study was to determine the accuracy of the SmartTouch Ventolin monitor in recording Ventolin actuations. Methods 20 SmartTouch Ventolin monitors were attached to Ventolin metered dose inhalers. Bench testing was performed over a 10-week period, to reflect the potential time frame between visits in a clinical trial. Inhaler actuations were recorded in a paper diary, which was compared with data uploaded from the monitors. Results 2560 actuations were performed during the 10-week study period. Monitor sensitivity for diary-recorded actuations was 99.9% with a lower 97.5% confidence bound of 99.7%. The positive predictive value for diary-recorded actuations was 100% with a 97.5% lower confidence bound of 99.9%. Conclusions The SmartTouch Ventolin monitor is highly accurate in recording and retaining electronic data. It can be recommended for use in clinical trial settings in which training and quality control systems are incorporated into study protocols to ensure accurate data acquisition.

Aim To investigate whether titration of inspired oxygen can be achieved through adjustment of oxygen flow into a self-inflating resuscitation bag with a reservoir of a type used in standard ambulance practice. Methods In a series of bench experiments, oxygen was delivered via a flow metre to a 1500ml self-inflating resuscitation bag with a 2500ml reservoir bag and connected to a test lung. The oxygen concentration delivered to the test lung by manual inflation of the resuscitation bag was measured using an anaesthetic machine while the delivered tidal volume was measured using a respirometer. The delivered oxygen concentration was measured at flows of 0.5, 2, 6, 12 and 15lmin −1 for tidal volumes of 300, 600, and 900ml with bag inflation rates of 10, 20 and 30min −1 . Results A wide range of delivered oxygen concentrations ranging between 24% and 99.5% were achieved with different oxygen flows, tidal volumes, and inflation rates. Overall, the mean delivered oxygen concentration increased significantly with each of the increments of oxygen flow tested ( p Conclusions Effective titration of oxygen delivery can be achieved using adjustment of oxygen flow with a standard self-inflating resuscitation bag and reservoir.

Rationale Remote ischaemic preconditioning (RIPC) is a novel cardioprotective strategy that uses brief intermittent limb ischaemia to protect the myocardium and other organs from perioperative ischaemic damage. The precise mechanism through which this protective effect occurs is unknown, but potentially could be related to changes in blood-borne mediators such as cytokines. Objective To determine whether RIPC alters inflammatory cytokine expression in a double-blind, randomised, controlled trial of patients undergoing high-risk cardiac surgery. Methods and results Serum interleukin (IL)-6, IL-8, and IL-10 levels from 95 patients randomised to RIPC (n=47) or control treatment (n=48) were measured preoperatively, and 1, 2, 3, 6 and 12 h after cross-clamp removal. Systemic concentrations of all cytokines were increased from baseline following surgery, and, compared with simple procedures, complex surgeries were associated with significantly higher release of IL-6 (ratio of mean area under the curves 1.54 (95% CI 1.02 to 2.34), p=0.04) and IL-10 (1.97 (1.16 to 3.35), p=0.012). No significant difference in mean cytokine levels between the RIPC and control groups was detected at any time point, irrespective of the type of surgery undergone. Conclusions High levels of IL-6, IL-8 and IL-10 are produced during high-risk cardiac surgery, and RIPC does not alter these elevated perioperative cytokine concentrations. Identification of factors that influence the ability to induce RIPC-mediated cardioprotection should be the priority of future research. Trial registration is in the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au; ACTRN12609000965202)

The efficacy of remote ischemic preconditioning (RIPC) in high-risk cardiac surgery is uncertain. In this study, 96 adults undergoing high-risk cardiac surgery were randomised to RIPC (3 cycles of 5 min of upper-limb ischemia induced by inflating a blood pressure cuff to 200 mmHg with 5 min of reperfusion) or control. Main endpoints were plasma high-sensitivity troponin T (hsTNT) levels at 6 and 12 h, worst post-operative acute kidney injury (AKI) based on RIFLE criteria, and noradrenaline duration. hsTNT levels were log-normally distributed and higher with RIPC than control at 6-h post cross-clamp removal [810 ng/ml (IQR 527–1,724) vs. 634 ng/ml (429–1,012); ratio of means 1.41 (99.17% CI 0.92–2.17); P=0.04] and 12 h [742 ng/ml (IQR 427–1,700) vs. 514 ng/ml (IQR 356–833); ratio of means 1.56 (99.17% CI 0.97–2.53); P=0.01]. After adjustment for baseline confounders, the ratio of means of hsTNT at 6 h was 1.23 (99.17% CI 0.88–1.72; P=0.10) and at 12 h was 1.30 (99.17% CI 0.92–1.84; P=0.05). In the RIPC group, 35/48 (72.9%) had no AKI, 5/48 (10.4%) had AKI risk, and 8/48 (16.7%) had either renal injury or failure compared to the control group where 34/48 (70.8%) had no AKI, 7/48 (14.6%) had AKI risk, and 7/48 (14.6%) had renal injury or failure (Chi-squared 0.41; two degrees of freedom; P = 0.82). RIPC increased post-operative duration of noradrenaline support [21 h (IQR 7–45) vs. 9 h (IQR 3–19); ratio of means 1.70 (99.17% CI 0.86–3.34); P=0.04]. RIPC does not reduce hsTNT, AKI, or ICU-support requirements in high-risk cardiac surgery.

Aim There are conflicting findings from observational studies regarding the nature of the association between hyperoxia and risk of mortality in patients admitted to intensive care following cardiac arrest. This systematic review and meta-analysis evaluates animal data investigating the effect of administration of high concentrations of oxygen following cardiac arrest on neurological outcome and the clinical applicability of this data. Methods A systematic search of Medline and Embase identified controlled animal studies modelling cardiac arrest with subsequent cardiopulmonary resuscitation that compared ventilation with 100% oxygen to lower concentrations following return of spontaneous circulation. Eligible studies were included in a meta-analysis in which the inverse variance weighted differences were calculated for the standardised mean difference of the primary outcome measure, the neurological deficit score. Results Ten studies met the criteria for inclusion in the systematic review. In a meta-analysis of six studies, with 95 animals, treatment with 100% oxygen resulted in a significantly worse neurological deficit score than oxygen administered at lower concentrations, with a standardised mean difference of −0.64 (95% CI −1.06 to −0.22). In four of five studies, histological evidence of increased neuronal damage was present in animals that received 100% oxygen therapy. Conclusions The administration of 100% oxygen therapy is associated with worse neurological outcome than lower oxygen concentrations in animal models of cardiac arrest. However, due to limitations in study design and poor generalisability of the animal models to the situation of post cardiac arrest resuscitation in humans, the clinical applicability of this data is uncertain.

Patterns of inhaled β2-agonist therapy use during severe asthma exacerbations before hospital attendance are poorly understood. To assess β2-agonist use prior to hospital attendance. 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. 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. 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. New data show that prior to attending hospital with severe asthma, most patients overuse their beta-agonist inhalers for prolonged periods. Beta-agonists relax muscles in the lungs to widen the airways and ease breathing. However, patients may overuse when symptoms worsen and delay seeking medical assistance. Mitesh Patel at the Medical Research Institute of New Zealand, and colleagues, examined the patterns of beta-agonist use in 303 patients by electronically monitoring inhaler use. Over the course of six months, there were 22 hospital attendances. In 90% of occasions when patients overused their beta-agonist, medical review was not obtained within the subsequent 48 hours. Such periods of overuse represent key opportunities for patients to seek medical review and reduce the risk of a life-threatening attack.

Introduction The Single budesonide/formoterol inhaler Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations, but it is uncertain whether it increases the risk of adverse effects due to high beta-agonist and corticosteroid doses with both short-term and cumulative exposure. Objectives Our hypothesis was that treatment with the SMART regimen would reduce the risk of beta-agonist overuse but that when such episodes occurred, patients were less likely to seek medical review and, that any reduction in severe exacerbations would be at the cost of a higher systemic corticosteroid burden. Methods This was a 24-week, open-label, parallel group trial in 303 asthma patients with a recent exacerbation, conducted at four primary healthcare practices and one secondary care hospital. Participants were randomised to 200/6µg budesonide/formoterol metered dose inhaler according to the SMART regimen (two actuations twice daily maintenance with one extra actuation as-needed) or a fixed-dose regimen (two actuations twice daily maintenance) with one to two actuations of 100µg salbutamol as-needed (‘Standard’), with electronic monitoring of actual inhaler use. The primary outcome was the proportion of participants with at least one high beta-agonist use episode (>12 budesonide/formoterol actuations/day in SMART or >16 salbutamol actuations/day in Standard). Results There was no significant difference between groups in the proportion of participants with at least one high use episode: SMART 84/151 (56%) vs Standard 68/152 (45%) participants; relative risk (95% CI) 1.24 (0.99–1.56), p = 0.058. There were fewer days of high use [mean (SD) 5.1 days (14.3) vs 8.9 days (20.9), relative rate (RR) (95% CI) 0.58 (0.39–0.88), p = 0.01] and days of high use without medical review [8.5 days (17.8) vs 18.3 days (24.8) per high use patient, RR 0.49 (0.31–0.75), p = 0.001] in the SMART group. The SMART regimen resulted in higher average daily inhaled corticosteroid exposure, but reduced oral corticosteroid exposure, with no difference in composite systemic corticosteroid exposure [ratio of means (95% CI) 1.03 (0.86–1.22), p = 0.76]. SMART participants had fewer severe asthma exacerbations [35 vs 66, RR 0.54 (0.36–0.82), p = 0.004]. Conclusions The SMART regimen has a favourable risk/benefit profile in patients at risk of severe asthma exacerbations.

Introduction Electronic monitoring is one method to measure the use of inhaled therapy in asthma patients in clinical trials, though the reliability of these devices has been variable. Implementation of trial quality control processes and reporting on the performance of electronic monitors during patient use may help to better understand their utility and limitations. The Smartinhaler Tracker is an electronic monitor for metered dose inhalers (MDIs) that records the date, time and number of actuations to the nearest second. Objectives In a recently completed 24-week real-world randomised controlled trial of 303 asthma patients at risk of severe exacerbations, Smartinhaler Tracker electronic monitors were used to measure actual use of budesonide/formoterol and salbutamol MDI therapy with two treatment regimens. Our aim is to report on the performance of these monitors, based on the implementation of extensive pre-trial and within-trial validation protocols for their use. Methods Pre-study use checks involved two actuations of the MDI, with a further two actuations performed at least two hours later. Within-study monitor checks, performed prior to dispensing at follow-up clinic visits, included a computerised check of monitor clock function, actuation accuracy and battery life. Within-study data checks, performed after use of MDIs by participants during the trial, involved computerised checks of monitor clock function prior to data upload. Results 2678/2728 (98.2%) monitors passed pre-study use checks; 46/50 monitors failed pre-study checks either because they did not record actuations that were performed, or erroneously recorded extra actuations. 76/2642 (2.9%) monitors dispensed to participants failed within-study monitor checks; 33/76 monitors failed because the battery was not fully charged. 51/2642 (1.9%) monitors failed data upload checks, mostly as a result of fluid immersion during participant use. 93/2642 (3.5%) monitors were lost or thrown away by participants. Complete data was available from 2498/2642 (94.5%) of dispensed monitors and 2498/2549 (98.0%) of returned monitors. Conclusions The Smartinhaler Tracker is a reliable monitor for measuring MDI use in a real-world asthma clinical trial. Implementation of extensive monitor and data-checking protocols reduces data loss. The use of validated and reliable electronic monitors is the optimal method to assess patterns of inhaled medication use.

Introduction Observational studies have reported that the overuse of inhaled beta-agonists during severe asthma is a common feature associated with a fatal outcome. However, patterns of actual use of beta-agonists prior to hospital attendance for severe exacerbations are poorly understood. Objectives We have recently reported that in 303 adult asthma patients randomised to receive either combination budesonide/formoterol metered dose inhaler (MDI) as part of a single maintenance and reliever therapy regimen (‘SMART’) or as fixed-dose maintenance treatment with salbutamol MDI for relief (‘Standard’), overuse of beta-agonists without subsequent medical review occurred commonly in both groups. We now report on the use of beta-agonists by patients who attended hospital with a severe exacerbation of asthma. Our hypothesis was that extremely high beta-agonist doses would be used by patients in both groups and that inhaled corticosteroid (ICS) non-adherence may occur in the Standard group during severe asthma. Methods Data on MDI use, as measured by electronic monitoring, were extracted for each patient for the 14 24-hour periods before the attendance time at hospital for a severe exacerbation. Results Electronic data were available for 7/7 and 9/11 hospital attendances in the SMART and Standard groups respectively. The median (range) daily number of actuations 14 days before hospital attendance was 4 (2 to 12) budesonide/formoterol in SMART and 4 (0 to 26) salbutamol and 2 (0 to 8) budesonide/formoterol in Standard. This increased to 11 (6 to 39) budesonide/formoterol in SMART and 25 (3 to 86) salbutamol and 4 (0 to 39) budesonide/formoterol in Standard, in the 24-hours before attendance. The median (range) maximum daily number of actuations was 14 (9 to 63) budesonide/formoterol in SMART and 46 (6 to 95) salbutamol in Standard. Repeated days of no ICS use occurred in 3/9 patients in the Standard group, despite concomitant salbutamol overuse. Conclusions Very high doses of beta-agonists are commonly self-administered by patients for prolonged periods prior to hospital presentation with severe asthma. The opportunity exists for clinical review and appropriate medical intervention during this period, which may reduce the risk of a life-threatening attack.

Case based discussion JP: A 25-year-old gentleman with asthma attended for routine out-patient review. As part of this consultation, his current symptoms and recent inhaler use were discussed, including whether he ever left home without his reliever inhaler. Though his asthma was well controlled, he reported that he always carried his reliever inhaler with him for use as a bottle opener for the treatment of acute beverage thirst attacks. MP: Asthma patients traditionally use reliever inhalers for symptoms of chest tightness, wheeze and cough,1 and are generally advised to always keep these inhalers with …

A major change is needed in the entrenched culture of routinely administering high-concentration oxygen to acutely ill patients regardless of need. Oxygen is a drug that should be prescribed for specific indications. There should be a documented target range for oxygen saturation, and regular monitoring of the patient's response. There are risks from unrelieved hypoxaemia due to insufficient oxygen therapy, and from provoked hyperoxaemia due to excessive oxygen therapy. Oxygen therapy should therefore be titrated so that the saturation is within a range that avoids these risks. If oxygen requirements are increasing, the clinician should review the patient and consider transfer to a higher level of care. If oxygen requirements are decreasing, consider reducing or discontinuing oxygen therapy.