Recovery following discharge from intensive care: What do patients think is helpful and what services are missing?

BACKGROUND: Recovery following critical illness is complex due to the many challenges patients face which influence their long-term outcomes. We explored patients' views about facilitators of recovery after critical illness which could be used to inform the components and timing of specific rehabilitation interventions. AIMS: To explore the views of patients after discharge from an intensive care unit (ICU) about their recovery and factors that facilitated recovery, and to determine additional services that patients felt were missing during their recovery. METHODS: Qualitative study involving individual face-to-face semi-structured interviews at six months (n = 11) and twelve months (n = 10). Written, informed consent was obtained. [Ethics approval 17/NI/0115]. Interviews were audiotaped, transcribed and analysed using template analysis. FINDINGS: Template analysis revealed four core themes: (1) Physical activity and function; (2) Recovery of cognitive and emotional function; (3) Facilitators to recovery; and (4) Gaps in healthcare services. CONCLUSION: Patient reported facilitators to recovery include support and guidance from others and self-motivation and goal setting, equipment for mobility and use of technology. Barriers include a lack of follow up services, exercise rehabilitation, peer support and personal feedback. Patients perceived that access to specific healthcare services was fragmented and where services were unavailable this contributed to slower or poorer quality of recovery. ICU patient recover could be facilitated by a comprehensive rehabilitation intervention that includes patient-directed strategies and health care services.

The predictive role of symptoms in COVID-19 diagnostic models: A longitudinal insight.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

Do critical illness survivors with multimorbidity need a different model of care?

There is currently a lack of evidence on the optimal strategy to support patient recovery after critical illness. Previous research has largely focussed on rehabilitation interventions which aimed to address physical, psychological, and cognitive functional sequelae, the majority of which have failed to demonstrate benefit for the selected outcomes in clinical trials. It is increasingly recognised that a person's existing health status, and in particular multimorbidity (usually defined as two or more medical conditions) and frailty, are strongly associated with their long-term outcomes after critical illness. Recent evidence indicates the existence of a distinct subgroup of critical illness survivors with multimorbidity and high healthcare utilisation, whose prior health trajectory is a better predictor of long-term outcomes than the severity of their acute illness. This review examines the complex relationships between multimorbidity and patient outcomes after critical illness, which are likely mediated by a range of factors including the number, severity, and modifiability of a person's medical conditions, as well as related factors including treatment burden, functional status, healthcare delivery, and social support. We explore potential strategies to optimise patient recovery after critical illness in the presence of multimorbidity. A comprehensive and individualized approach is likely necessary including close coordination among healthcare providers, medication reconciliation and management, and addressing the physical, psychological, and social aspects of recovery. Providing patient-centred care that proactively identifies critical illness survivors with multimorbidity and accounts for their unique challenges and needs is likely crucial to facilitate recovery and improve outcomes.

Unsupervised home spirometry versus supervised clinic spirometry for respiratory disease: a systematic methodology review and meta-analysis.

BACKGROUND: The number of patients completing unsupervised home spirometry has recently increased due to more widely available portable technology and the COVID-19 pandemic, despite a lack of solid evidence to support it. This systematic methodology review and meta-analysis explores quantitative differences in unsupervised spirometry compared with spirometry completed under professional supervision. METHODS: We searched four databases to find studies that directly compared unsupervised home spirometry with supervised clinic spirometry using a quantitative comparison (e.g. Bland-Altman). There were no restrictions on clinical condition. The primary outcome was measurement differences in common lung function parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC)), which were pooled to calculate overall mean differences with associated limits of agreement (LoA) and confidence intervals (CI). We used the I2 statistic to assess heterogeneity, the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool to assess risk of bias and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence certainty for the meta-analyses. The review has been registered with PROSPERO (CRD42021272816). RESULTS: 3607 records were identified and screened, with 155 full texts assessed for eligibility. We included 28 studies that quantitatively compared spirometry measurements, 17 of which reported a Bland-Altman analysis for FEV1 and FVC. Overall, unsupervised spirometry produced lower values than supervised spirometry for both FEV1 with wide variability (mean difference -107 mL; LoA= -509, 296; I2=95.8%; p<0.001; very low certainty) and FVC (mean difference -184 mL, LoA= -1028, 660; I2=96%; p<0.001; very low certainty). CONCLUSIONS: Analysis under the conditions of the included studies indicated that unsupervised spirometry is not interchangeable with supervised spirometry for individual patients owing to variability and underestimation.

Airway clearance treatments in bronchiectasis: feasibility of linking survey results to registry data and a survey of patients' and physiotherapists' practices.

Background and objective: There are limited data on airway clearance treatment (ACT) practices. This study aimed to: 1) assess the feasibility of collecting online surveys on ACTs from patients and physiotherapists and linking the patient survey data to outcome data in the Bronch-UK/EMBARC Registry; 2) assess the association between ACT practices and outcome data; and 3) ascertain the factors affecting physiotherapist ACT practices. Methods: Survey methodology was used to collect data from patients with bronchiectasis and physiotherapists in Northern Ireland. Associations between patient survey data and linked Bronch-UK/EMBARC Registry patient outcome data were explored. Results: It was feasible to conduct an online survey with patients with bronchiectasis and link the data to the Bronch-UK/EMBARC Registry. 13% of patients did not perform ACTs. ACTs were used more often by patients who were symptomatic/had more severe disease compared to those with milder symptoms/disease. Patients used ACTs when they were symptomatic rather than as a preventative management strategy. Physiotherapists generally followed the bronchiectasis guidelines, using the stepwise approach to management. Conclusion: Our survey provided information about the feasibility of linking online survey and patient registry data. This study provides up-to-date information on ACT practice throughout the course of the disease trajectory as well as insight into the implementation of bronchiectasis guidelines by physiotherapists. Future work should explore how to optimise ACT data collection to maximise the use of real-world ACT data in bronchiectasis research and inform priority ACT research questions.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial.

BACKGROUND: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. METHODS: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. RESULTS: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. CONCLUSIONS: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. CLINICAL TRIALS REGISTRATION: EudraCT, 2020-004123-16.

Clinimetric Properties of Outcome Measures in Bronchiectasis.

Rationale: There is a lack of outcome measures with robust clinimetric properties in bronchiectasis. Objectives: To determine the clinimetric properties (reliability over 1 year during clinical stability and responsiveness over the course of antibiotics for pulmonary exacerbation) of objective and patient-reported outcome measures. Methods: This multicenter cohort study included adults with bronchiectasis from seven hospitals in the United Kingdom. Participants attended four visits, 4 months apart over 1 year while clinically stable and at the beginning and end of exacerbation and completed lung function (spirometry and multiple breath washout), provided a blood sample for C-reactive protein (CRP) measurement, and completed health-related quality of life (HRQoL) questionnaires (Quality of Life-Bronchiectasis, St. George's Respiratory Questionnaire, and EuroQoL 5-Dimensions 5-Levels). Results: Participants (n = 132) had a mean (standard deviation) age of 66 (11) years, and 64% were female. Lung function parameters (forced expiratory volume in one second [FEV1], standard lung clearance index [LCI2.5]) were reliable over time [coefficient of variation (CV): <10%]). Regarding responsiveness, FEV1 demonstrated better properties than LCI2.5; therefore, a clear justification for the use of LCI2.5 in future trials is needed. CRP was less reliable (CV > 20%) over time than FEV1 and LCI2.5, and whereas CRP had a large mean change between the start and end of an exacerbation, this may have been driven by a small number of patients having a large change in CRP. Reliability of HRQoL questionnaires and questionnaire domains ranged from acceptable (CV: 20-30%) to good (CV: 10-20%), and HRQoL were responsive to treatment of exacerbations. Considering the specific questionnaire domain relevant to the intervention and its associated clinimetric properties is important. Additional statistics will support future power and/or sample size analysis. Conclusions: This information on the clinimetric properties of lung function parameters, CRP, and HRQoL parameters should be used to inform the choice of outcome measures used in future bronchiectasis trials.

The Need for Breathing Training Techniques: The Elephant in the Heart Failure Cardiac Rehabilitation Room: A Randomized Controlled Trial.

BACKGROUND: Although solid evidence has indicated that respiratory symptoms are common amongst patients with chronic heart failure (CHF), state-of-the-art cardiac rehabilitation (CR) programs do not typically include management strategies to address respiratory symptoms. This study investigated the effect of the addition of breathing exercises (BE) to the CR programs in CHF. METHODS: In a two parallel-arm randomized controlled study (RCT), 40 middle-aged patients with CHF and respiratory symptoms were recruited and randomized into two equal groups (n = 20); group (A): standard CR with BE and group (B): standard CR alone. Primary outcomes were respiratory parameters and secondary outcomes included cardiovascular and cardiopulmonary outcomes. All the participants attended a program of aerobic exercise (three sessions/week, 60-75% MHR, 45-55 min) for 12 weeks, plus educational, nutritional, and psychological counseling. Group (A) patients attended the same program together with BE using inspiratory muscle training (IMT) and breathing calisthenics (BC) (six sessions/week, 15-25 min) for the same duration. RESULTS: There was a significant improvement in the respiratory outcomes, and most of the cardiovascular and cardiopulmonary outcomes in both groups with a greater change percentage in group A (p < 0.05). CONCLUSIONS: These results indicate that the addition of BE to the CR programs in CHF is effective and is a "patient-centered" approach.

Multiple-Breath Washout Outcome Measures in Adults with Bronchiectasis.

Rationale: Lung clearance index (LCI) has good intravisit repeatability with better sensitivity in detecting lung disease on computed tomography scan compared with forced expiratory volume in 1 second (FEV1) in adults with bronchiectasis. Alternative multiple-breath washout parameters have not been systematically studied in bronchiectasis. Objectives: To determine the validity, repeatability, sensitivity, specificity, and feasibility of standard LCI (LCI2.5), shortened LCI (LCI5.0), ventilation heterogeneity arising within proximal conducting airways (ScondVT), and ventilation heterogeneity arising within the acinar airways (SacinVT) in a cross-sectional observational cohort of adults with bronchiectasis. Methods: Cross-sectional multiple-breath nitrogen washout data (Exhalyzer D; Eco Medics AG) from 132 patients with bronchiectasis across five United Kingdom centers (BronchUK Clinimetrics study) and 88 healthy control subjects were analyzed. Results: Within-test repeatability (mean coefficient of variation) was <5% for both LCI2.5 and LCI5.0 in patients with bronchiectasis, and there was no difference in mean coefficient of variation for LCI2.5 and LCI5.0 in patients with bronchiectasis compared with healthy volunteers. Moderate-strength correlations were seen between FEV1 and LCI2.5 (r = -0.54), LCI5.0 (r = -0.53), ScondVT (r = -0.35), and SacinVT (r = -0.38) z-scores. The proportion of subjects with abnormal multiple-breath washout (z-score > 2) but in normal FEV1 (z-score < -2) was 42% (LCI2.5) and 36% (LCI5.0). Overall results from the receiver operating characteristic curve analysis indicated that LCI2.5 had the greatest combined sensitivity and specificity to discriminate between bronchiectasis and control subjects, followed by LCI5.0, FEV1, and ScondVT z-scores. There was a 57% time saving with LCI5.0. Conclusions: LCI2.5 and LCI5.0 had good within-test repeatability and superior sensitivity compared with spirometry measures in differentiating between health and bronchiectasis disease. LCI5.0 is quicker and more feasible than LCI2.5. Clinical trial registered with www.clinicaltrials.gov (NCT02468271).

Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial.

Importance: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. Objective: To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. Design, Setting, and Participants: A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. Interventions: Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). Main Outcomes and Measures: The primary outcome was a composite of tracheal intubation or mortality within 30 days. Results: The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings. Trial Registration: isrctn.org Identifier: ISRCTN16912075.

Self-management intervention to reduce pulmonary exacerbations by supporting treatment adherence in adults with cystic fibrosis: a randomised controlled trial.

INTRODUCTION: Recurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether a multi-component (complex) self-management intervention to support adherence would reduce exacerbation rates over 12 months. METHODS: Between October 2017 and May 2018, adults with CF (aged ≥16 years; 19 UK centres) were randomised to the intervention (data-logging nebulisers, a digital platform and behavioural change sessions with trained clinical interventionists) or usual care (data-logging nebulisers). Outcomes included pulmonary exacerbations (primary outcome), objectively measured adherence, body mass index (BMI), lung function (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Analyses were by intent to treat over 12 months. RESULTS: Among intervention (n=304) and usual care (n=303) participants (51% female, median age 31 years), 88% completed 12-month follow-up. Mean exacerbation rate was 1.63/year with intervention and 1.77/year with usual care (adjusted ratio 0.96; 95% CI 0.83 to 1.12; p=0.64). Adjusted mean differences (95% CI) were in favour of the intervention versus usual care for objectively measured adherence (9.5% (8.6% to 10.4%)) and BMI (0.3 (0.1 to 0.6) kg/m2), with no difference for %FEV1 (1.4 (-0.2 to 3.0)). Seven CFQ-R subscales showed no between-group difference, but treatment burden reduced for the intervention (3.9 (1.2 to 6.7) points). No intervention-related serious adverse events occurred. CONCLUSIONS: While pulmonary exacerbations and FEV1 did not show statistically significant differences, the intervention achieved higher objectively measured adherence versus usual care. The adherence difference might be inadequate to influence exacerbations, though higher BMI and lower perceived CF treatment burden were observed.

BronchUK: protocol for an observational cohort study and biobank in bronchiectasis.

Bronchiectasis has been a largely overlooked disease area in respiratory medicine. This is reflected by a shortage of large-scale studies and lack of approved therapies, in turn leading to a variation of treatment across centres. BronchUK (Bronchiectasis Observational Cohort and Biobank UK) is a multicentre, prospective, observational cohort study working collaboratively with the European Multicentre Bronchiectasis Audit and Research Collaboration project. The inclusion criteria for patients entering the study are a clinical history consistent with bronchiectasis and computed tomography demonstrating bronchiectasis. Main exclusion criteria are 1) patients unable to provide informed consent, 2) bronchiectasis due to known cystic fibrosis or where bronchiectasis is not the main or co-dominant respiratory disease, 3) age <18 years, and 4) prior lung transplantation for bronchiectasis. The study is aligned to standard UK National Health Service (NHS) practice with an aim to recruit a minimum of 1500 patients from across at least nine secondary care centres. Patient data collected at baseline includes demographics, aetiology testing, comorbidities, lung function, radiology, treatments, microbiology and quality of life. Patients are followed up annually for a maximum of 5 years and, where able, blood and/or sputa samples are collected and stored in a central biobank. BronchUK aims to collect robust longitudinal data that can be used for analysis into current NHS practice and patient outcomes, and to become an integral resource to better inform future interventional studies in bronchiectasis.

Psychometrics of health-related quality of life questionnaires in bronchiectasis: a systematic review and meta-analysis.

INTRODUCTION: Understanding the psychometric properties of health-related quality of life (HRQoL) questionnaires can help inform selection in clinical trials. Our objective was to assess the psychometric properties of HRQoL questionnaires in bronchiectasis using a systematic review and meta-analysis of the literature. METHODS: A literature search was conducted. HRQoL questionnaires were assessed for psychometric properties (reliability, validity, minimal clinically important difference (MCID) and floor/ceiling effects). Meta-analyses assessed the associations of HRQoL with clinical measures and responsiveness of HRQoL in clinical trials. RESULTS: 166 studies and 12 HRQoL questionnaires were included. The Bronchiectasis Health Questionnaire (BHQ), Leicester Cough Questionnaire (LCQ), Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) had good internal consistency in all domains reported (Cronbach's α≥0.7) across all studies, and the Quality of Life-Bronchiectasis (QOL-B), St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Disease Questionnaire (CRDQ) and Seattle Obstructive Lung Disease Questionnaire (SOLQ) had good internal consistency in all domains in the majority of (but not all) studies. BHQ, SGRQ, LCQ and CAT had good test-retest reliability in all domains reported (intraclass correlation coefficient ≥0.7) across all studies, and QOL-B, CRDQ and SOLQ had good test-retest reliability in all domains in the majority of (but not all) studies. HRQoL questionnaires were able to discriminate between demographics, important markers of clinical status, disease severity, exacerbations and bacteriology. For HRQoL responsiveness, there was a difference between the treatment and placebo effect. CONCLUSIONS: SGRQ was the most widely used HRQoL questionnaire in bronchiectasis studies and it had good psychometric properties; however, good psychometric data are emerging on the bronchiectasis-specific HRQoL questionnaires QOL-B and BHQ. Future studies should focus on the medium- to long-term test-retest reliability, responsiveness and MCID in these HRQoL questionnaires which show potential in bronchiectasis.

Multiple breath washout in bronchiectasis clinical trials: is it feasible?

BACKGROUND: Evaluation of multiple breath washout (MBW) set-up including staff training, certification and central "over-reading" for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies. AIMS: To assess the outcomes of a MBW training, certification and central over-reading programme. METHODS: MBW training and certification was conducted in European sites collecting lung clearance index (LCI) data in the BronchUK Clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality. RESULTS: Thirteen training days were delivered to 56 participants from 22 sites. Of 22 sites, 18 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15 of 22 sites (68%) had completed certification with a mean (range) time since training of 6.2 (3-14) months. In the BronchUK Clinimetrics study, 468 of 589 (79%) tests met the quality criteria following central over-reading, compared with 137 of 236 (58%) tests in the i-BEST-1 study. CONCLUSIONS: LCI is feasible in a bronchiectasis multicentre clinical trial setting; however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to reduce time to certification and optimise data quality. Longer times to certification, a higher percentage of naïve sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study.

Feasibility study for supporting medication adherence for adults with cystic fibrosis: mixed-methods process evaluation.

OBJECTIVES: To undertake a process evaluation of an adherence support intervention for people with cystic fibrosis (PWCF), to assess its feasibility and acceptability. SETTING: Two UK cystic fibrosis (CF) units. PARTICIPANTS: Fourteen adult PWCF; three professionals delivering adherence support ('interventionists'); five multi-disciplinary CF team members. INTERVENTIONS: Nebuliser with data recording and transfer capability, linked to a software platform, and strategies to support adherence to nebulised treatments facilitated by interventionists over 5 months (± 1 month). PRIMARY AND SECONDARY MEASURES: Feasibility and acceptability of the intervention, assessed through semistructured interviews, questionnaires, fidelity assessments and click analytics. RESULTS: Interventionists were complimentary about the intervention and training. Key barriers to intervention feasibility and acceptability were identified. Interventionists had difficulty finding clinic space and time in normal working hours to conduct review visits. As a result, fewer than expected intervention visits were conducted and interviews indicated this may explain low adherence in some intervention arm participants. Adherence levels appeared to be >100% for some patients, due to inaccurate prescription data, particularly in patients with complex treatment regimens. Flatlines in adherence data at the start of the study were linked to device connectivity problems. Content and delivery quality fidelity were 100% and 60%-92%, respectively, indicating that interventionists needed to focus more on intervention 'active ingredients' during sessions. CONCLUSIONS: The process evaluation led to 14 key changes to intervention procedures to overcome barriers to intervention success. With the identified changes, it is feasible and acceptable to support medication adherence with this intervention. TRIAL REGISTRATION NUMBER: ISRCTN13076797; Results.

Airway clearance techniques and use of mucoactive agents for adult critically ill patients with acute respiratory failure: a qualitative study exploring UK physiotherapy practice.

OBJECTIVES: To explore and describe current UK physiotherapy practice relating to airway clearance techniques and mucoactive agents in critically ill adult patients with acute respiratory failure in the intensive care unit. DESIGN: A descriptive, qualitative study using focus group interviews. Focus groups were audio-recorded, independently transcribed, and data analysed thematically. Participants Senior, experienced physiotherapists, clinically active in critical care. RESULTS: Fifteen physiotherapists participated in four interview sessions. Five themes emerged describing airway clearance techniques: 'Repertoire of airway clearance techniques', 'Staffing and skillset', 'Commencing respiratory physiotherapy', 'Technique selection', and 'Determining effectiveness' were themes related to airway clearance techniques. Five themes were also identified in relation to mucoactive agents: 'Use in clinical practice', 'Decision to commence', 'Selection of agent', 'Stopping mucoactive agents', and 'Determining effectiveness'. A summary of key features of standard practice was developed. CONCLUSIONS: Standard UK physiotherapy practice of airway clearance techniques is variable, but patient-centred and targeted to individual need, with adjunctive use of mucoactive agents to enhance and optimise patient management if required. Based on this study, key features of airway clearance techniques have been summarised to help capture standard care, which could be used in future trials involving ACT as part of usual care.

RECOVERY- Respiratory Support: Respiratory Strategies for patients with suspected or proven COVID-19 respiratory failure; Continuous Positive Airway Pressure, High-flow Nasal Oxygen, and standard care: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVE: The trial objective is to determine if Continuous Positive Airway Pressure (CPAP) or High-Flow Nasal Oxygen (HFNO) is clinically effective compared to standard oxygen therapy in patients with confirmed or suspected COVID-19. TRIAL DESIGN: Adaptive (group-sequential), parallel group, pragmatic, superiority randomised controlled, open-label, multi-centre, effectiveness trial. PARTICIPANTS: The trial is being conducted across approximately 60 hospitals across England, Wales, Scotland, and Northern Ireland. Inpatients at participating hospitals are eligible to participate if they have respiratory failure with suspected or proven COVID-19, and meet all of the inclusion criteria and none of the exclusion criteria. INCLUSION CRITERIA: 1) Adults ≥ 18 years; 2) Admitted to hospital with suspected or proven COVID-19; 3) Receiving oxygen with fraction of inspired oxygen (FiO2) ≥0.4 and peripheral oxygen saturation (SpO2) ≤94%; and 4) Plan for escalation to tracheal intubation if needed. EXCLUSION CRITERIA: 1) Planned tracheal intubation and mechanical ventilation imminent within 1 hour; 2) Known or clinically apparent pregnancy; 3) Any absolute contraindication to CPAP or HFNO; 4) Decision not to intubate due to ceiling of treatment or withdrawal of treatment anticipated; and 5) Equipment for both CPAP and HFNO not available. INTERVENTION AND COMPARATOR: Intervention one: Continuous positive airway pressure delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention two: High-flow nasal oxygen delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Comparator group: Standard care- oxygen delivered by face mask or nasal cannula (excluding the use of continuous positive airway pressure or high-flow nasal oxygen). Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention delivery continues up to the point of death, tracheal intubation, or clinical determination that there is no ongoing need (palliation or improvement). MAIN OUTCOMES: The primary outcome is a composite outcome comprising tracheal intubation or mortality within 30 days following randomisation. Secondary outcomes include tracheal intubation rate, time to tracheal intubation, duration of invasive ventilation, mortality rate, time to mortality, length of hospital stay, and length of critical care stay. RANDOMISATION: Participants are randomised in a 1:1:1 ratio to receive either continuous positive airway pressure, high-flow nasal oxygen or standard care. Due to the challenging environment of study delivery, a specific intervention may not always be available at the hospital site. The study uses two integrated randomisation systems to allow, where required, the site to randomise between all three interventions, between CPAP and standard care, and between HFNO and standard care. System integration ensures maintenance of balance between interventions. Randomisation is performed using a telephone-based interactive voice response system to maintain allocation concealment. The randomisation sequence was computer-generated using the minimisation method. Participant randomisation is stratified by site, gender (M/F), and age (<50, >=50 years). BLINDING (MASKING): The nature of the trial interventions precludes blinding of the researcher, patient and clinical team. Primary and secondary outcomes are all objective outcomes, thereby minimising the risk of detection bias. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 4002 participants (1334 to be randomized to each of the three study arms) TRIAL STATUS: Current protocol: Version 4.0, 29th May 2020. Recruitment began on April 6, 2020 and is anticipated to be complete by April 5, 2021. The trial has been awarded Urgent Public Health status by the National Institute of Health Research on 13th April 2020. TRIAL REGISTRATION: ISRCTN, ISRCTN16912075. Registered 6th April 2020, http://www.isrctn.com/ISRCTN16912075 FULL PROTOCOL: The full protocol (version 4.0, 29th May 2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Mucoactive agents for acute respiratory failure in the critically ill: a systematic review and meta-analysis.

PURPOSE: Acute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with ARF, despite a lack of evidence to underpin clinical decision making. The aim of this systematic review was to determine if the use of mucoactive agents in patients with ARF improves clinical outcomes. METHODS: We searched electronic and grey literature (January 2020). Two reviewers independently screened, selected, extracted data and quality assessed studies. We included trials of adults receiving ventilatory support for ARF and involving at least one mucoactive agent compared with placebo or standard care. Outcomes included duration of mechanical ventilation. Meta-analysis was undertaken using random-effects modelling and certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation. RESULTS: Thirteen randomised controlled trials were included (1712 patients), investigating four different mucoactive agents. Mucoactive agents showed no effect on duration of mechanical ventilation (seven trials, mean difference (MD) -1.34, 95% CI -2.97 to 0.29, I2=82%, very low certainty) or mortality, hospital stay and ventilator-free days. There was an effect on reducing ICU length of stay in the mucoactive agent groups (10 trials, MD -3.22, 95% CI -5.49 to -0.96, I2=89%, very low certainty). CONCLUSION: Our findings do not support the use of mucoactive agents in critically ill patients with ARF. The existing evidence is of low quality. High-quality randomised controlled trials are needed to determine the role of specific mucoactive agents in critically ill patients with ARF. PROSPERO REGISTRATION NUMBER: CRD42018095408.

Mucoactive agent use in adult UK Critical Care Units: a survey of health care professionals' perception, pharmacists' description of practice, and point prevalence of mucoactive use in invasively mechanically ventilated patients.

BACKGROUND: Mechanical ventilation for acute respiratory failure is one of the most common indications for admission to intensive care units (ICUs). Airway mucus clearance is impaired in these patients medication, impaired mucociliary motility, increased mucus production etc. and mucoactive agents have the potential to improve outcomes. However, studies to date have provided inconclusive results. Despite this uncertainty, mucoactives are used in adult ICUs, although the extent of use and perceptions about place in therapy are not known. AIMS AND OBJECTIVES: We aim to describe the use of mucoactive agents in mechanically ventilated patients in UK adult critical care units. Specifically, our objectives are to describe clinicians perceptions about the use of mucoactive agents, understand the indications and anticipated benefits, and describe the prevalence and type of mucoactive agents in use. METHODS: We conducted three surveys. Firstly, a practitioner-level survey aimed at nurses, physiotherapists and doctors to elucidate individual practitioners perceptions about the use of mucoactive agents. Secondly, a critical care unit-level survey aimed at pharmacists to understand how these perceptions translate into practice. Thirdly, a point prevalence survey to describe the extent of prescribing and range of products in use. The practitioner-level survey was disseminated through the UK Intensive Care Society for completion by a multi-professional membership. The unit-level and point prevalence surveys were disseminated cthrough the UK Clinical Pharmacy Association for completion by pharmacists. RESULTS: The individual practitioners survey ranked 'thick secretions' as the main reason for commencing mucoactive agents determined using clinical assessment. The highest ranked perceived benefit for patient centred outcomes was the duration of ventilation. Of these respondents, 79% stated that further research was important and 87% expressed support for a clinical trial. The unit-level survey found that mucoactive agents were used in 83% of units. The most highly ranked indication was again 'thick secretions' and the most highly ranked expected patient centred clinical benefit being improved gas exchange and reduced ventilation time. Only five critical care units provided guidelines to direct the use of mucoactive agents (4%). In the point prevalence survey, 411/993 (41%) of mechanically ventilated patients received at least one mucoactive agent. The most commonly administered mucoactives were inhaled sodium chloride 0.9% (235/993, 24%), systemic carbocisteine (161/993, 16%) and inhaled hypertonic sodium cloride (127/993, 13%). CONCLUSIONS: Mucoactive agents are used extensively in mechanically ventilated adult patients in UK ICUs to manage 'thick secretions', with a key aim to reduce the duration of ventilation. There is widespread support for clinical trials to determine the optimal use of mucoactive agent therapy in this patient population.