Protocol: inspiratory muscle training for promoting recovery and outcomes in ventilated patients (IMPROVe): a randomised controlled trial

Introduction: Inspiratory muscle weakness is a known consequence of mechanical ventilation and a potential contributor to difficulty in weaning from ventilatory support. Inspiratory muscle training (IMT) reduces the weaning period and increases the likelihood of successful weaning in some patients. However, it is not known how this training affects the residual inspiratory muscle fatigability following successful weaning nor patients' quality of life or functional outcomes. Methods and analysis: This dual centre study includes two concurrent randomised controlled trials of IMT in adult patients who are either currently ventilator-dependent (>7 days) (n=70) or have been recently weaned from mechanical ventilation (>7 days) in the past week (n=70). Subjects will be stable, alert and able to actively participate and provide consent. There will be concealed allocation to either treatment (IMT) or usual physiotherapy (including deep breathing exercises without a resistance device). Primary outcomes are inspiratory muscle fatigue resistance and maximum inspiratory pressures. Secondary outcomes are quality of life (Short Form-36v2, EQ-5D), functional status (Acute Care Index of Function), rate of perceived exertion (Borg Scale), intensive care length of stay (days), post intensive care length of stay (days), rate of reintubation (%) and duration of ventilation (days). Ethics and dissemination: Ethics approval has been obtained from relevant institutions, and results will be published with a view to influencing physiotherapy practice in the management of long-term ventilator-dependent patients to accelerate weaning and optimise rehabilitation outcomes

Expectations and realities: an exploration in teaching planning ethics to university students

Upon graduation, planning students move into a diverse world, ranging from development assessment to policy development and public consultation. Furthermore, students are often thrust into a darker reality of balancing conflicting interests, power struggles and the search for the multi-layered and contentious ‘public interest’ (Tait, 2011). When entering the ‘real world’ of planning practice, the need for students to be adequately prepared for a range of challenges – practical, professional and ethical – is vital (Gurran et al., 2008; Nagy, 2012). This paper presents a preliminary theoretical discussion of current state of planning ethics at tertiary, or university, level and its role in the development of the ethically aware, practising planner. It considers the role of neoliberalism in academia, stressing both the teachers' and students’ roles in understanding the highly political nature of the planning environment. Two case studies – the University of South Australia (UniSA), Australia and the University of Auckland, New Zealand are investigated. Finally, the paper provides a short overview of the need for ethics education in the current environment and its role in developing the ethically sensitive student. This includes discussion of ‘job preparedness/employability’, ‘approachability of teachers and education’, ‘approachability of moral philosophy’ and ‘the importance of self-reflexivity/reflection and positionality’. This desk-top analysis provides a valuable insight into the current state of planning ethics education at two intercontinental universities. In understanding the differences and similarities between these courses, one can begin to appreciate how the nature of assessments, assigned readings and teaching staff contribute to developing the ethically aware professional planner. Both the University of South Australia and the University of Auckland ethics courses enable students to not only begin to understand their role as part of the greater collective of planning and society, but also towards being increasingly self-aware in their own decision-making skills.Anna Marie Leditschke, Jon Kellett, Mathew W. Rofe and Rowena Butlan

Expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated critically ill adults

Introduction: The aim of this study was to develop consensus recommendations on safety parameters for mobilizing adult, mechanically ventilated, intensive care unit (ICU) patients. Methods: A systematic literature review was followed by a meeting of 23 multidisciplinary ICU experts to seek consensus regarding the safe mobilization of mechanically ventilated patients. Results: Safety considerations were summarized in four categories: respiratory, cardiovascular, neurological and other. Consensus was achieved on all criteria for safe mobilization, with the exception being levels of vasoactive agents. Intubation via an endotracheal tube was not a contraindication to early mobilization and a fraction of inspired oxygen less than 0.6 with a percutaneous oxygen saturation more than 90% and a respiratory rate less than 30 breaths/minute were considered safe criteria for in- and out-of-bed mobilization if there were no other contraindications. At an international meeting, 94 multidisciplinary ICU clinicians concurred with the proposed recommendations. Conclusion: Consensus recommendations regarding safety criteria for mobilization of adult, mechanically ventilated patients in the ICU have the potential to guide ICU rehabilitation whilst minimizing the risk of adverse events

Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression

Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study

Purpose: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation. Methods: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3 days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure. Results: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3 days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60\u20131.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14\u20131.64). Conclusion: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely

Clinical chronobiology: a timely consideration in critical care medicine

A fundamental aspect of human physiology is its cyclical nature over a 24-h period, a feature conserved across most life on Earth. Organisms compartmentalise processes with respect to time in order to promote survival, in a manner that mirrors the rotation of the planet and accompanying diurnal cycles of light and darkness. The influence of circadian rhythms can no longer be overlooked in clinical settings; this review provides intensivists with an up-to-date understanding of the burgeoning field of chronobiology, and suggests ways to incorporate these concepts into daily practice to improve patient outcomes. We outline the function of molecular clocks in remote tissues, which adjust cellular and global physiological function according to the time of day, and the potential clinical advantages to keeping in time with them. We highlight the consequences of "chronopathology", when this harmony is lost, and the risk factors for this condition in critically ill patients. We introduce the concept of "chronofitness" as a new target in the treatment of critical illness: preserving the internal synchronisation of clocks in different tissues, as well as external synchronisation with the environment. We describe methods for monitoring circadian rhythms in a clinical setting, and how this technology may be used for identifying optimal time windows for interventions, or to alert the physician to a critical deterioration of circadian rhythmicity. We suggest a chronobiological approach to critical illness, involving multicomponent strategies to promote chronofitness (chronobundles), and further investment in the development of personalised, time-based treatment for critically ill patients

Early mobilisation in intensive care units in Australia and Scotland:A prospective, observational cohort study examining mobilisation practises and barriers

Introduction: Mobilisation of patients in the intensive care unit (ICU) is an area of growing research. Currently, there is\ud little data on baseline mobilisation practises and the barriers to them for patients of all admission diagnoses.\ud Methods: The objectives of the study were to (1) quantify and benchmark baseline levels of mobilisation in Australian\ud and Scottish ICUs, (2) compare mobilisation practises between Australian and Scottish ICUs and (3) identify barriers to\ud mobilisation in Australian and Scottish ICUs. We conducted a prospective, observational, cohort study with a 4-week\ud inception period. Patients were censored for follow-up upon ICU discharge or after 28 days, whichever occurred first.\ud Patients were included if they were >18 years of age, admitted to an ICU and received mechanical ventilation in the ICU.\ud Results: Ten tertiary ICUs in Australia and nine in Scotland participated in the study. The Australian cohort had a large\ud proportion of patients admitted for cardiothoracic surgery (43.3 %), whereas the Scottish cohort had none. Therefore,\ud comparison analysis was done after exclusion of patients admitted for cardiothoracic surgery. In total, 60.2 % of the 347\ud patients across 10 Australian ICUs and 40.1 % of the 167 patients across 9 Scottish ICUs mobilised during their ICU stay\ud (p < 0.001). Patients in the Australian cohort were more likely to mobilise than patients in the Scottish cohort (hazard\ud ratio 1.83, 95 % confidence interval 1.38–2.42). However, the percentage of episodes of mobilisation where patients\ud were receiving mechanical ventilation was higher in the Scottish cohort (41.1 % vs 16.3 %, p < 0.001). Sedation was the\ud most commonly reported barrier to mobilisation in both the Australian and Scottish cohorts. Physiological instability\ud and the presence of an endotracheal tube were also frequently reported barriers.\ud Conclusions: This is the first study to benchmark baseline practise of early mobilisation internationally, and it\ud demonstrates variation in early mobilisation practises between Australia and Scotland

Factors influencing physical activity and rehabilitation in survivors of critical illness: a systematic review of quantitative and qualitative studies

PURPOSE: To identify, evaluate and synthesise studies examining the barriers and enablers for survivors of critical illness to participate in physical activity in the ICU and post-ICU settings from the perspective of patients, caregivers and healthcare providers. METHODS: Systematic review of articles using five electronic databases: MEDLINE, CINAHL, EMBASE, Cochrane Library, Scopus. Quantitative and qualitative studies that were published in English in a peer-reviewed journal and assessed barriers or enablers for survivors of critical illness to perform physical activity were included. Prospero ID: CRD42016035454. RESULTS: Eighty-nine papers were included. Five major themes and 28 sub-themes were identified, encompassing: (1) patient physical and psychological capability to perform physical activity, including delirium, sedation, illness severity, comorbidities, weakness, anxiety, confidence and motivation; (2) safety influences, including physiological stability and concern for lines, e.g. risk of dislodgement; (3) culture and team influences, including leadership, interprofessional communication, administrative buy-in, clinician expertise and knowledge; (4) motivation and beliefs regarding the benefits/risks; and (5) environmental influences, including funding, access to rehabilitation programs, staffing and equipment. CONCLUSIONS: The main barriers identified were patient physical and psychological capability to perform physical activity, safety concerns, lack of leadership and ICU culture of mobility, lack of interprofessional communication, expertise and knowledge, and lack of staffing/equipment and funding to provide rehabilitation programs. Barriers and enablers are multidimensional and span diverse factors. The majority of these barriers are modifiable and can be targeted in future clinical practice

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570