Automated oxygen titration with non-invasive ventilation in hypoxaemic adults with cardiorespiratory disease: a randomised cross-over trial.

BACKGROUND: Closed-loop oxygen control systems automatically adjust the fraction of inspired oxygen (FiO2) to maintain oxygen saturation (SpO2) within a predetermined target range. Their performance with low and high-flow oxygen therapies, but not with non-invasive ventilation, has been established. We compared the effect of automated oxygen on achieving and maintaining a target SpO2 range with nasal high flow (NHF), bilevel positive airway pressure (bilevel) and continuous positive airway pressure (CPAP), in stable hypoxaemic patients with chronic cardiorespiratory disease. METHODS: In this open-label, three-way cross-over trial, participants with resting hypoxaemia (n=12) received each of NHF, bilevel and CPAP treatments, in random order, with automated oxygen titrated for 10 min, followed by 36 min of standardised manual oxygen adjustments. The primary outcome was the time taken to reach target SpO2 range (92%-96%). Secondary outcomes included time spent within target range and physiological responses to automated and manual oxygen adjustments. RESULTS: Two participants were randomised to each of six possible treatment orders. During automated oxygen control (n=12), the mean (±SD) time to reach target range was 114.8 (±87.9), 56.6 (±47.7) and 67.3 (±61) seconds for NHF, bilevel and CPAP, respectively, mean difference 58.3 (95% CI 25.0 to 91.5; p=0.002) and 47.5 (95% CI 14.3 to 80.7; p=0.007) seconds for bilevel and CPAP versus NHF, respectively. Proportions of time spent within target range were 68.5% (±16.3), 65.6% (±28.7) and 74.7% (±22.6) for NHF, bilevel and CPAP, respectively.Manually increasing, then decreasing, the FiO2 resulted in similar increases and then decreases in SpO2 and transcutaneous carbon dioxide (PtCO2) with NHF, bilevel and CPAP. CONCLUSION: The target SpO2 range was achieved more quickly when automated oxygen control was initiated with bilevel and CPAP compared with NHF while time spent within the range across the three therapies was similar. Manually changing the FiO2 had similar effects on SpO2 and PtCO2 across each of the three therapies. TRIAL REGISTRATION NUMBER: ACTRN12622000433707.

Patterns of asthma medication use and hospital discharges in New Zealand.

Background: In New Zealand a progressive increase in budesonide/formoterol dispensing, accompanied by a reduction in dispensing of short-acting ß2-agonists (SABAs), inhaled corticosteroids (ICSs), and other ICS/long-acting ß2-agonists (ICSs/LABAs), occurred in the 18-month period following publication of the 2020 New Zealand asthma guidelines, which recommended budesonide/formoterol anti-inflammatory reliever therapy. Objective: Our aim was to investigate more recent trends in asthma medication use and asthma hospital discharges in New Zealand. Methods: New Zealand national dispensing data for inhalers for the period from January 2010 to December 2022 were reviewed for patients aged 12 years and older. Monthly rates of dispensing of budesonide/formoterol, ICSs, other ICS/LABAs, and SABAs were displayed graphically by locally weighted scatterplot smoother plots. The rates of dispensing and hospital discharge for asthma were compared between the past 6 months for which dispensing data were available (July-December 2022) and the corresponding period from July to December 2019. Results: There has been a progressive increase in dispensing of budesonide/formoterol since 2019, with a 108% increase between the period from July to December 2019 and the period from July to December 2022 in adolescents and adults. In contrast, there was a reduction in rates of dispensing of other ICS/LABAs, ICSs, and SABAs by 3%, 18%, and 5%, respectively. During this period, there was a 17% reduction in hospital discharges for asthma. Conclusion: There has been a further widespread uptake of ICS/formoterol reliever and/or maintenance therapy in adolescents and adults with asthma in New Zealand. The changes in prescribing practice have been temporally associated with a reduction in hospital admissions for asthma.

Albuterol-budesonide fixed-dose combination rescue inhaler for asthma: a plain language summary of the MANDALA study.

What is this summary about?This summary describes the results of a clinical study called MANDALA that was published in the New England Journal of Medicine in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both albuterol and budesonide in a single inhaler (known as albuterol-budesonide, AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

The carbon footprint of as-needed budesonide/formoterol in mild asthma: a post hoc analysis.

INTRODUCTION: The use of pressurised metered-dose inhalers (pMDIs) and asthma exacerbations necessitating healthcare reviews contribute substantially to the global carbon footprint of healthcare. It is possible that a reduction in carbon footprint could be achieved by switching patients with mild asthma from salbutamol pMDI reliever-based therapy to inhaled corticosteroid-formoterol dry powder inhaler (DPI) reliever therapy, as recommended by the Global Initiative for Asthma. METHODS: This post hoc analysis included all 668 adult participants in the Novel START trial, who were randomised 1:1:1 to treatment with as-needed budesonide/formoterol DPI, as-needed salbutamol pMDI or maintenance budesonide DPI plus as-needed salbutamol pMDI. The primary outcome was carbon footprint of asthma management, expressed as kilograms of carbon dioxide equivalent emissions (kgCO2e) per person-year. Secondary outcomes explored the effect of baseline symptom control and adherence (maintenance budesonide DPI arm only) on carbon footprint. RESULTS: As-needed budesonide/formoterol DPI was associated with 95.8% and 93.6% lower carbon footprint compared with as-needed salbutamol pMDI (least-squares mean 1.1 versus 26.2 kgCO2e; difference -25.0, 95% CI -29.7 to -20.4; p<0.001) and maintenance budesonide DPI plus as-needed salbutamol pMDI (least-squares mean 1.1 versus 17.3 kgCO2e; difference -16.2, 95% CI -20.9 to -11.6; p<0.001), respectively. There was no statistically significant evidence that treatment differences in carbon footprint depended on baseline symptom control or adherence in the maintenance budesonide DPI arm. CONCLUSIONS: The as-needed budesonide/formoterol DPI treatment option was associated with a markedly lower carbon footprint than as-needed salbutamol pMDI and maintenance budesonide DPI plus as-needed salbutamol pMDI.

START CARE: a protocol for a randomised controlled trial of step-wise budesonide-formoterol reliever-based treatment in children.

Background: Asthma is the most common chronic childhood respiratory condition globally. Inhaled corticosteroid (ICS)-formoterol reliever-based regimens reduce the risk of asthma exacerbations compared with conventional short-acting ß2-agonist (SABA) reliever-based regimens in adults and adolescents. The current limited evidence for anti-inflammatory reliever therapy in children means it is unknown whether these findings are also applicable to children. High-quality randomised controlled trials (RCTs) are needed. Objective: The study aim is to determine the efficacy and safety of budesonide-formoterol reliever alone or maintenance and reliever therapy (MART) compared with standard therapy: budesonide or budesonide-formoterol maintenance, both with terbutaline reliever, in children aged 5 to 11 years with mild, moderate and severe asthma. Methods: A 52-week, multicentre, open-label, parallel group, phase III, two-sided superiority RCT will recruit 400 children aged 5 to 11 years with asthma. Participants will be randomised 1:1 to either budesonide-formoterol 100/6 µg Turbuhaler reliever alone or MART; or budesonide or budesonide-formoterol Turbuhaler maintenance, with terbutaline Turbuhaler reliever. The primary outcome is moderate and severe asthma exacerbations as rate per participant per year. Secondary outcomes are asthma control, lung function, exhaled nitric oxide and treatment step change. Assessment of Turbuhaler technique and cost-effectiveness analysis are also planned. Conclusion: This will be the first RCT to compare the efficacy and safety of a step-wise budesonide-formoterol reliever alone or MART regimen with conventional inhaled ICS or ICS-long-acting ß-agonist maintenance plus SABA reliever in children. The results will provide a much-needed evidence base for the treatment of asthma in children.

Effect of a lower target oxygen saturation range on the risk of hypoxaemia and elevated NEWS2 scores at a university hospital: a retrospective study.

BACKGROUND: The optimal target oxygen saturation (SpO2) range for hospital inpatients not at risk of hypercapnia is unknown. The objective of this study was to assess the impact on oxygen usage and National Early Warning Score 2 (NEWS2) of changing the standard SpO2 target range from 94-98% to 92-96%. METHODS: In a metropolitan UK hospital, a database of electronic bedside SpO2 measurements, oxygen prescriptions and NEWS2 records was reviewed. Logistic regression was used to compare the proportion of hypoxaemic SpO2 values (<90%) and NEWS2 records ≥5 in 2019, when the target SpO2 range was 94-98%; with 2022, when the target range was 92-96%. RESULTS: In 2019, 218 of 224 936 (0.10%) observations on room air and 162 of 11 328 (1.43%) on oxygen recorded an SpO2 <90%, and in 2022, 251 of 225 970 (0.11%) and 233 of 12 845 (1.81%), respectively (risk difference 0.04%, 95% CI 0.02% to 0.07%). NEWS2 ≥5 was observed in 3009 of 236 264 (1.27%) observations in 2019 and 4061 of 238 815 (1.70%) in 2022 (risk difference 0.43%, 0.36% to 0.50%; p<0.001). The proportion of patients using supplemental oxygen with hyperoxaemia (SpO2 100%) was 5.4% in 2019 and 3.9% in 2022 (OR 0.71, 0.63 to 0.81; p<0.001). DISCUSSION: The proportion of observations with SpO2 <90% or NEWS2 ≥5 was greater with the 92-96% range; however, absolute differences were very small and of doubtful clinical relevance, in contrast to hyperoxaemia for which the proportion was markedly less in 2022. These findings support proposals that the British Thoracic Society oxygen guidelines could recommend a lower target SpO2 range.

Associations between the intraoperative fraction of inspired intraoperative oxygen administration and days alive and out of hospital after surgery.

Background: There is limited knowledge about the effect of liberal intraoperative oxygen on non-infectious complications and overall recovery from surgery. Methods: In this retrospective cohort study, we investigated associations between mean intraoperative fraction of inspired oxygen (FiO2), and outcome in adults undergoing elective surgery lasting more than 2 h at a large metropolitan New Zealand hospital from 2012 to 2020. Patients were divided into low, medium, and high oxygen groups (FiO2 ≤ 0.4, 0.41-0.59, ≥0.6). The primary outcome was days alive and out of hospital at 90 days (DAOH90). The secondary outcomes were post-operative complications and admission to the ICU. Results: We identified 15,449 patients who met the inclusion criteria. There was no association between FiO2 and DAOH90 when high FiO2 was analysed according to three groups. Using high FiO2 as the reference group there was an adjusted mean (95% confidence interval [CI]) difference of 0.09 (-0.06 to 0.25) days (P = 0.25) and 0.28 (-0.05 to 0.62) days (P = 0.2) in the intermediate and low oxygen groups, respectively. Low FiO2 was associated with increased surgical site infection: the adjusted odds ratio (OR) for low compared with high FiO2 was 1.53 (95% CI 1.12-2.10). Increasing FiO2 was associated with respiratory complications: the adjusted OR associated with each 10% point increase in FiO2 was 1.17 (95% CI 1.08-1.26) and the incidence of being admitted to an ICU had an adjusted OR of 1.1 (95% CI 1.03-1.18). Conclusions: We found potential benefits, and risks, associated with liberal intraoperative oxygen administration indicating that randomised controlled trials are warranted.

The Role of ICS-Containing Rescue Therapy Versus SABA Alone in Asthma Management Today.

The Global Initiative for Asthma (GINA) recommends that short-acting ß2-agonist (SABA) monotherapy should no longer be prescribed, and that as-needed combination inhaled corticosteroids (ICS)-formoterol is the preferred reliever therapy in adults and adolescents with mild asthma. These recommendations are based on the risks of SABA monotherapy, the evidence that ICS-formoterol reliever therapy markedly decreases the occurrence of severe asthma exacerbations compared with SABA reliever therapy alone, and because ICS-formoterol reliever therapy has a favorable risk/benefit profile compared with maintenance ICS plus SABA reliever therapy. Data supporting the use of combination ICS-albuterol reliever therapy in mild asthma are more limited, but there are studies that inform its use in this population. In this review, we compare, using a pros and cons format, the (1) long-term safety and efficacy of ICS-formoterol reliever therapy versus SABA reliever therapy alone, (2) long-term safety and efficacy of ICS-albuterol reliever therapy versus SABA reliever therapy alone, (3) immediate bronchodilator effects of ICS-formoterol versus SABA alone, and (4) clinical and regulatory factors that may inform reliever therapy prescription decisions. By presenting the evidence of these reliever inhaler options, we hope to inform the reader while also calling for necessary future effectiveness and implementation research.

Prevalence, Diagnostic Utility and Associated Characteristics of Bronchodilator Responsiveness.

Rationale: The prevalence and diagnostic utility of bronchodilator responsiveness (BDR) in a real-life setting is unclear. Objective: To explore this uncertainty in patients aged ⩾12 years with physician-assigned diagnoses of asthma, asthma and chronic obstructive pulmonary disease (COPD), or COPD in NOVELTY, a prospective cohort study in primary and secondary care in 18 countries. Methods: The proportion of patients with a positive BDR test in each diagnostic category was calculated using 2005 (ΔFEV1 or ΔFVC ⩾12% and ⩾200 ml) and 2021 (ΔFEV1 or ΔFVC >10% predicted) European Respiratory Society/American Thoracic Society criteria. Measurements and Main Results: We studied 3,519 patients with a physician-assigned diagnosis of asthma, 833 with a diagnosis of asthma + COPD, and 2,436 with a diagnosis of COPD. The prevalence of BDR was 19.7% (asthma), 29.6% (asthma + COPD), and 24.7% (COPD) using 2005 criteria and 18.1%, 23.3%, and 18.0%, respectively, using 2021 criteria. Using 2021 criteria in patients diagnosed with asthma, BDR was associated with higher fractional exhaled nitric oxide; lower lung function; higher symptom burden; more frequent hospital admissions; and greater use of triple therapy, oral corticosteroids, or biologics. In patients diagnosed with COPD, BDR (2021) was associated with lower lung function and higher symptom burden. Conclusions: BDR prevalence in patients with chronic airway diseases receiving treatment ranges from 18% to 30%, being modestly lower with the 2021 than with the 2005 European Respiratory Society/American Thoracic Society criteria, and it is associated with lower lung function and greater symptom burden. These observations question the validity of BDR as a key diagnostic tool for asthma managed in clinical practice or as a standard inclusion criterion for clinical trials of asthma and instead suggest that BDR be considered a treatable trait for chronic airway disease.

Protocol summary and statistical analysis plan for the low oxygen intervention for cardiac arrest injury limitation (LOGICAL) trial.

Background: The effect of conservative vs. liberal oxygen therapy on outcomes of intensive care unit (ICU) patients with hypoxic ischaemic encephalopathy (HIE) is uncertain and will be evaluated in the Low Oxygen Intervention for Cardiac Arrest injury Limitation (LOGICAL) trial. Objective: The objective of this study was to summarise the protocol and statistical analysis plans for the LOGICAL trial. Design setting and participants: LOGICAL is a randomised clinical trial in adults in the ICU who are comatose with suspected HIE (i.e., those who have not obeyed commands following return of spontaneous circulation after a cardiac arrest where there is clinical concern about possible brain damage). The LOGICAL trial will include 1400 participants and is being conducted as a substudy of the Mega Randomised registry trial comparing conservative vs. liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX). Main outcome measures: The primary outcome is survival with favourable neurological function at 180 days after randomisation as measured with the Extended Glasgow Outcome Scale (GOS-E). A favourable neurological outcome will be defined as a GOS-E score of lower moderate disability or better (i.e. a GOS-E score of 5-8). Secondary outcomes include survival time, day 180 mortality, duration of invasive mechanical ventilation, ICU length of stay, hospital length of stay, the proportion of patients discharged home, quality of life assessed at day 180 using the EQ-5D-5L, and cognitive function assessed at day 180 using the Montreal Cognitive Assessment (MoCA-blind). Conclusions: The LOGICAL trial will provide reliable data on the impact of conservative vs. liberal oxygen therapy in ICU patients with suspected HIE following resuscitation from a cardiac arrest. Prepublication of the LOGICAL protocol and statistical analysis plan prior to trial conclusion will reduce the potential for outcome-reporting or analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN12621000518864).