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Background: Poor functional capacity has been identified as an important modifiable risk factor for postoperative complications. Cardiopulmonary exercise testing (CPET) provides objective parameters of functional capacity (e.g., oxygen consumption at peak exercise, peak VO 2 ), with significant prognostication for postoperative complications. However, sex-specific thresholds for functional capacity to predict surgical risk are yet to be established. Therefore, we performed a post hoc analysis of the international, multicentre, prospective observational METS (Measurement of Exercise Tolerance before Surgery) study to evaluate if sex-specific thresholds of peak VO 2 improve risk prediction of postoperative complications., Methods: We undertook a post hoc analysis (HREC/71824/PMCC) of the METS study, which was performed between March 2013 and March 2016. We investigated whether sex-specific differences exist for CPET-derived parameters and associated thresholds for predicting postoperative complications in this large cohort of patients that had major non-cardiac surgery (n = 1266). Logistic regression models were analyzed for the association of low peak VO 2 with moderate-to-severe in-hospital postoperative complications. Optimal sex-specific peak VO 2 thresholds were obtained by maximizing the Youden index of receiver operating characteristic (ROC) curves. Finally, multivariable logistic regression models tested the resulting sex-specific thresholds against the established non-sex-specific peak VO 2 threshold (14 mL kg -1 min -1 ) adjusted for clinically relevant features such as comorbidities and surgical complexity. Models were evaluated by bootstrapping optimism-corrected area under the ROC curve and the net reclassification improvement index (NRI)., Findings: Female patients (n = 480) had a lower mean (SD) peak VO 2 than males (16.7 (4.9) mL kg -1 min -1 versus 21.2 (6.5) mL kg -1 min -1 , p < 0.001) and a lower postoperative complication rate (10.4% versus 15.3%; p = 0.018) than males (n = 786). The optimal peak VO 2 threshold for predicting postoperative complications was 12.4 mL kg -1 min -1 for females and 22.3 mL kg -1 min -1 for males, respectively. In the multivariable regression model, low non-sex-specific peak VO 2 did not independently predict postoperative complications. In contrast, low sex-specific peak VO 2 was an independent predictor of postoperative complications (OR 2.29; 95% CI: 1.60, 3.30; p < 0.001). The optimism-corrected AUC-ROC of the sex-specific model was higher compared with the non-sex-specific model (0.73 versus 0.7; DeLong's test: p = 0.021). The sex-specific model classified 39% of the patients more correctly than the baseline model (NRI = 0.39; 95% CI: 0.24, 0.55). In contrast, the non-sex-specific model only classified 9% of the patients more correctly when compared against the baseline model (NRI = 0.09; 95% CI: -0.04, 0.22)., Interpretation: Our data report sex-specific differences in preoperative CPET-derived functional capacity parameters. Sex-specific peak VO 2 thresholds identify patients at increased risk for postoperative complications with a higher discriminatory ability than a sex-unspecific threshold. As such, sex-specific threshold values should be considered in preoperative CPET to potentially improve risk stratification and to guide surgical decision-making, including eligibility for surgery, preoperative optimization strategies (prehabilitation) or seeking non-surgical options., Funding: There was no funding for the present study. The original METS study was funded by Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University., Competing Interests: All authors declare no competing interests., (© 2023 The Authors.)

Purpose: Patients with impaired functional capacity who undergo major surgery are at increased risk of postoperative morbidity including complications and increased length of stay. These outcomes have been associated with increased hospital and health system costs. We aimed to assess whether common preoperative risk indices are associated with postoperative cost., Methods: We conducted a health economic analysis focused on the subset of Measurement of Exercise Tolerance before Surgery (METS) study participants in Ontario, Canada. Participants were scheduled for major elective noncardiac surgery and underwent several preoperative assessments of cardiac risk, including physicians' subjective assessment, Duke Activity Status Index (DASI) questionnaire, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide concentration. Using linked health administrative data, postoperative costs were calculated for both one year and in-hospital. Using multiple regression models, we tested for association between the preoperative measures of cardiac risk and postoperative costs., Results: Our study included 487 patients (mean [standard deviation] age 68 [11] yr and 47.0% female) who underwent noncardiac surgery between 13 June 2013 and 8 March 2016. Overall, the median [interquartile range] cost incurred within one year postoperatively was CAD 27,587 [13,902-32,590], of which CAD 12,928 [10,253-12,810] were incurred in-hospital and CAD 14,497 [10,917-15,017] were incurred by 30 days. None of the four preoperative measures of cardiac risk assessment were associated with costs incurred in hospital or at one year postoperatively. This lack of strong association persisted in sensitivity analyses considering type of surgical procedure, burden of preoperative cost, and when costs were categorized as quantiles., Conclusion: In patients undergoing major noncardiac surgery, common measures of functional capacity are not consistently associated with total postoperative cost. Until further data exist that differ from this analysis, clinicians and health care funders should not assume that preoperative measures of cardiac risk are associated with annual health care or hospital costs for such surgeries., (© 2023. Canadian Anesthesiologists' Society.)

Background: Sedation of critically ill patients with inhaled anaesthetics may reduce lung inflammation, time to extubation, and ICU length of stay compared with intravenous (i.v.) sedatives. However, the impact of inhaled anaesthetics on cognitive and psychiatric outcomes in this population is unclear. In this systematic review, we aimed to summarise the effect of inhaled anaesthetics on cognitive and psychiatric outcomes in critically ill adults., Methods: We searched MEDLINE, EMBASE, and PsycINFO for case series, retrospective, and prospective studies in critically ill adults sedated with inhaled anaesthetics. Outcomes included delirium, psychomotor and neurological recovery, long-term cognitive dysfunction, ICU memories, anxiety, depression, post-traumatic stress disorder (PTSD), and instruments used for assessment., Results: Thirteen studies were included in distinct populations of post-cardiac arrest survivors (n=4), postoperative noncardiac patients (n=3), postoperative cardiac patients (n=2), and mixed medical-surgical patients (n=4). Eight studies reported delirium incidence, two neurological recovery, and two ICU memories. One study reported on psychomotor recovery, long-term cognitive dysfunction, anxiety, depression, and PTSD. A meta-analysis of five trials found no difference in delirium incidence between inhaled and i.v. sedatives (relative risk 0.95 [95% confidence interval: 0.59-1.54]). Compared with i.v. sedatives, inhaled anaesthetics were associated with fewer hallucinations and faster psychomotor recovery but no differences in other outcomes. There was heterogeneity in the instruments used and timing of these assessments., Conclusions: Based on the limited evidence available, there is no difference in cognitive and psychiatric outcomes between adults exposed to volatile sedation or intravenous sedation in the ICU. Future studies should incorporate outcome assessment with validated tools during and after hospital stay., Systematic Review Protocol: PROSPERO CRD42021236455., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Stroke patients requiring mechanical ventilation often have a poor prognosis. The optimal timing of tracheostomy and its impact on mortality in stroke patients remains uncertain. We performed a systematic review and meta-analysis of tracheostomy timing and its association with reported all-cause overall mortality. Secondary outcomes were the effect of tracheostomy timing on neurological outcome (modified Rankin Scale, mRS), hospital length of stay (LOS), and intensive care unit (ICU) LOS., Methods: We searched 5 databases for entries related to acute stroke and tracheostomy from inception to 25 November 2022. We adhered to PRISMA guidance for reporting systematic reviews and meta-analyses. Selected studies included (1) ICU-admitted patients who had stroke (either acute ischaemic stroke, AIS or intracerebral haemorrhage, ICH) and received a tracheostomy (with known timing) during their stay and (2) > 20 tracheotomised. Studies primarily reporting sub-arachnoid haemorrhage (SAH) were excluded. Where this was not possible, adjusted meta-analysis and meta-regression with study-level moderators were performed. Tracheostomy timing was analysed continuously and categorically, where early (< 5 days from initiation of mechanical ventilation to tracheostomy) and late (> 10 days) timing was defined per the protocol of SETPOINT2, the largest and most recent randomised controlled trial on tracheostomy timing in stroke patients., Results: Thirteen studies involving 17,346 patients (mean age = 59.8 years, female 44%) met the inclusion criteria. ICH, AIS, and SAH comprised 83%, 12%, and 5% of known strokes, respectively. The mean time to tracheostomy was 9.7 days. Overall reported all-cause mortality (adjusted for follow-up) was 15.7%. One in five patients had good neurological outcome (mRS 0-3; median follow-up duration was 180 days). Overall, patients were ventilated for approximately 12 days and had an ICU LOS of 16 days and a hospital LOS of 28 days. A meta-regression analysis using tracheostomy time as a continuous variable showed no statistically significant association between tracheostomy timing and mortality (β = - 0.3, 95% CI = - 2.3 to 1.74, p = 0.8). Early tracheostomy conferred no mortality benefit when compared to late tracheostomy (7.8% vs. 16.4%, p = 0.7). Tracheostomy timing was not associated with secondary outcomes (good neurological outcome, ICU LOS and hospital LOS)., Conclusions: In this meta-analysis of over 17,000 critically ill stroke patients, the timing of tracheostomy was not associated with mortality, neurological outcomes, or ICU/hospital LOS., Trial Registration: PROSPERO-CRD42022351732 registered on 17th of August 2022., (© 2023. The Author(s).)

Purpose: Few quality improvement tools specific to patients with persistent or chronic critical illness exist to aid delivery of high-quality care. Using experience-based co-design methods, we sought consensus from key stakeholders on the most important actionable processes of care for inclusion in a quality improvement checklist., Methods: Item generation methods: systematic review, semi-structured interviews (ICU survivors and family) members, touchpoint video creation, and semi-structured interviews (ICU clinicians). Consensus methods: modified online Delphi and a virtual meeting using nominal group technique methods., Results: We enrolled 138 ICU interprofessional team, patients, and family members. We obtained consensus on a quality improvement checklist comprising 11 core domains: patient and family involvement in decision-making; patient communication; physical comfort and complication prevention; promoting self-care and normalcy; ventilator weaning; physical therapy; swallowing; pharmacotherapy; psychological issues; delirium; and appropriate referrals. An additional 27 actionable processes are contained within 6 core domains that provide more specific direction on the actionable process to be targeted., Conclusions: Using a highly collaborative and methodologically rigorous process, we generated a quality improvement checklist of actionable processes to improve patient and family-centred care considered important by key stakeholders. Future research is needed to understand optimal implementation strategies and impact on outcomes and experience., Competing Interests: Declaration of Competing Interest The authors have no declarations of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain., Objective: To determine whether SDD reduces in-hospital mortality in critically ill adults., Design, Setting, and Participants: A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021., Interventions: ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care., Main Outcomes and Measures: The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs., Results: Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, -1.7% [95% CI, -4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, -11.0%; 95% CI, -14.7% to -7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, -1.95%; 95% CI, -3.5% to -0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, -0.24%; 95% CI, -0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (-3.3% vs -1.59%; mean difference, -1.71% [1-sided 97.5% CI, -∞ to 4.31%] and 0.88% vs 0.55%; mean difference, -0.32% [1-sided 97.5% CI, -∞ to 5.47%]) in the first and second periods, respectively., Conclusions and Relevance: Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit., Trial Registration: ClinicalTrials.gov Identifier: NCT02389036.

Background: We performed a systematic review of mechanically ventilated patients with COVID-19, which analysed the effect of tracheostomy timing and technique (surgical vs percutaneous) on mortality. Secondary outcomes included intensive care unit (ICU) and hospital length of stay (LOS), decannulation from tracheostomy, duration of mechanical ventilation, and complications., Methods: Four databases were screened between January 1, 2020 and January 10, 2022 (PubMed, Embase, Scopus, and Cochrane). Papers were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Population or Problem, Intervention or exposure, Comparison, and Outcome (PICO) guidelines. Meta-analysis and meta-regression for main outcomes were performed., Results: The search yielded 9024 potentially relevant studies, of which 47 (n=5268 patients) were included. High levels of between-study heterogeneity were observed across study outcomes. The pooled mean tracheostomy timing was 16.5 days (95% confidence interval [CI]: 14.7-18.4; I 2 =99.6%). Pooled mortality was 22.1% (95% CI: 18.7-25.5; I 2 =89.0%). Meta-regression did not show significant associations between mortality and tracheostomy timing, mechanical ventilation duration, time to decannulation, and tracheostomy technique. Pooled mean estimates for ICU and hospital LOS were 29.6 (95% CI: 24.0-35.2; I 2 =98.6%) and 38.8 (95% CI: 32.1-45.6; I 2 =95.7%) days, both associated with mechanical ventilation duration (coefficient 0.8 [95% CI: 0.2-1.4], P=0.02 and 0.9 [95% CI: 0.4-1.4], P=0.01, respectively) but not tracheostomy timing. Data were insufficient to assess tracheostomy technique on LOS. Duration of mechanical ventilation was 23.4 days (95% CI: 19.2-27.7; I 2 =99.3%), not associated with tracheostomy timing. Data were insufficient to assess the effect of tracheostomy technique on mechanical ventilation duration. Time to decannulation was 23.8 days (95% CI: 19.7-27.8; I 2 =98.7%), not influenced by tracheostomy timing or technique. The most common complications were stoma infection, ulcers or necrosis, and bleeding., Conclusions: In patients with COVID-19 requiring tracheostomy, the timing and technique of tracheostomy did not clearly impact on patient outcomes., Systematic Review Protocol: PROSPERO CRD42021272220., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Expert recommendations propose the WHO Disability Assessment Schedule (WHODAS) 2.0 as a core outcome measure in surgical studies, yet data on its long-term measurement properties remain limited. These were evaluated in a secondary analysis of the Measurement of Exercise Tolerance before Surgery (METS) prospective cohort., Methods: Participants were adults (40 years of age or older) who underwent inpatient non-cardiac surgery. The 12-item WHODAS and EQ-5DTM-3L questionnaires were administered preoperatively (in person) and 1 year postoperatively (by telephone). Responsiveness was characterized using standardized response means (SRMs) and correlation coefficients between change scores. Construct validity was evaluated using correlation coefficients between 1-year scores and comparisons of WHODAS scores across clinically relevant subgroups., Results: The analysis included 546 patients. There was moderate correlation between changes in WHODAS and various EQ-5DTM subscales. The strongest correlation was between changes in WHODAS and changes in the functional domains of the EQ-5D-3L-for example, mobility (Spearman's rho 0.40, 95 per cent confidence interval [c.i.] 0.32 to 0.48) and usual activities (rho 0.45, 95 per cent c.i. 0.30 to 0.52). When compared across quartiles of EQ-5D index change, median WHODAS scores followed expected patterns of change. In subgroups with expected functional status changes, the WHODAS SRMs ranged from 'small' to 'large' in the expected directions of change. At 1 year, the WHODAS demonstrated convergence with the EQ-5D-3L functional domains, and good discrimination between patients with expected differences in functional status., Conclusion: The WHODAS questionnaire has construct validity and responsiveness as a measure of functional status at 1 year after major surgery., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We compared baseline characteristics and outcomes and evaluated the subgroup effects of randomised interventions by sex in males and females in large international perioperative trials., Methods: Nine randomised trials and two cohort studies recruiting adult patients, conducted between 1995 and 2020, were included. Baseline characteristics and outcomes common to six or more studies were evaluated. Regression models included terms for sex, study, and an interaction between the two. Comparing outcomes without adjustment for baseline characteristics represents the 'total effect' of sex on the outcome., Results: Of 54 626 participants, 58% were male and 42% were female. Females were less likely to have ASA physical status ≥3 (56% vs 64%), to smoke (15% vs 23%), have coronary artery disease (21% vs 32%), or undergo vascular surgery (10% vs 23%). The pooled incidence of death was 1.6% in females and 1.8% in males (risk ratio [RR] 0.92; 95% confidence interval [CI]: 0.81-1.05; P=0.20), of myocardial infarction was 4.2% vs 4.5% (RR 0.92; 95% CI: 0.81-1.03; P=0.10), of stroke was 0.5% vs 0.6% (RR 1.03; 95% CI: 0.79-1.35; P=0.81), and of surgical site infection was 8.6% vs 8.3% (RR 1.03; 95% CI: 0.79-1.35; P=0.70). Treatment effects of three interventions demonstrated statistically significant effect modification by sex., Conclusions: Females were in the minority in all included studies. They were healthier than males, but outcomes were comparable. Further research is needed to understand the reasons for this discrepancy., Clinical Trial Registration: International Registry of Meta-Research (UID: IRMR&#95;000011; 5 January 2021)., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: An accurate estimate of the average number of hand hygiene opportunities per patient hour (HHO rate) is required to implement group electronic hand hygiene monitoring systems (GEHHMSs). We sought to identify predictors of HHOs to validate and implement a GEHHMS across a network of critical care units., Design: Multicenter, observational study (10 hospitals) followed by quality improvement intervention involving 24 critical care units across 12 hospitals in Ontario, Canada., Methods: Critical care patient beds were randomized to receive 1 hour of continuous direct observation to determine the HHO rate. A Poisson regression model determined unit-level predictors of HHOs. Estimates of average HHO rates across different types of critical care units were derived and used to implement and evaluate use of GEHHMS., Results: During 2,812 hours of observation, we identified 25,417 HHOs. There was significant variability in HHO rate across critical care units. Time of day, day of the week, unit acuity, patient acuity, patient population and use of transmission-based precautions were significantly associated with HHO rate. Using unit-specific estimates of average HHO rate, aggregate HH adherence was 30.0% (1,084,329 of 3,614,908) at baseline with GEHHMS and improved to 38.5% (740,660 of 1,921,656) within 2 months of continuous feedback to units ( P < .0001)., Conclusions: Unit-specific estimates based on known predictors of HHO rate enabled broad implementation of GEHHMS. Further longitudinal quality improvement efforts using this system are required to assess the impact of GEHHMS on both HH adherence and clinical outcomes within critically ill patient populations.

Self-reported postoperative functional recovery is an important patient-centred outcome that is rarely measured or considered in research and decision-making. We conducted a secondary analysis of the measurement of exercise tolerance before surgery (METS) study for associations of peri-operative variables with functional decline after major non-cardiac surgery. Patients who were at least 40 years old, had or were at risk of, coronary artery disease and who were scheduled for non-cardiac surgery were recruited. Primary outcome was a reduction in mobility, self-care or ability to conduct usual activities (EuroQol 5 dimension) from before surgery to 30 days and 1 year after surgery. A decline in at least one function was reported by 523/1309 (40%) participants at 30 days and 320/1309 (24%) participants at 1 year. Participants who reported higher pre-operative Duke Activity Status indices more often reported functional decline 30 days after surgery and less often reported functional decline 1 year after surgery. The odds ratios (95%CI) of functional decline 30 days and 1 year after surgery with moderate or severe postoperative complications were 1.46 (1.02-2.09), p = 0.037 and 1.44 (0.98-2.13), p = 0.066. Discrimination of participants who reported functional decline 30 days and 1 year after surgery were poor (c-statistic 0.61 and 0.63, respectively). In summary, one quarter of participants reported functional decline up to one postoperative year., (© 2021 Association of Anaesthetists.)

Purpose: Oral chlorhexidine is used widely for mechanically ventilated patients to prevent pneumonia, but recent studies show an association with excess mortality. We examined whether de-adoption of chlorhexidine and parallel implementation of a standardized oral care bundle reduces intensive care unit (ICU) mortality in mechanically ventilated patients., Methods: A stepped wedge cluster-randomized controlled trial with concurrent process evaluation in 6 ICUs in Toronto, Canada. Clusters were randomized to de-adopt chlorhexidine and implement a standardized oral care bundle at 2-month intervals. The primary outcome was ICU mortality. Secondary outcomes were time to infection-related ventilator-associated complications (IVACs), oral procedural pain and oral health dysfunction. An exploratory post hoc analysis examined time to extubation in survivors., Results: A total of 3260 patients were enrolled; 1560 control, 1700 intervention. ICU mortality for the intervention and control periods were 399 (23.5%) and 330 (21.2%), respectively (adjusted odds ratio [aOR], 1.13; 95% confidence interval [CI] 0.82 to 1.54; P = 0.46). Time to IVACs (adjusted hazard ratio [aHR], 1.06; 95% CI 0.44 to 2.57; P = 0.90), time to extubation (aHR 1.03; 95% CI 0.85 to 1.23; P = 0.79) (survivors) and oral procedural pain (aOR, 0.62; 95% CI 0.34 to 1.10; P = 0.10) were similar between control and intervention periods. However, oral health dysfunction scores (- 0.96; 95% CI - 1.75 to - 0.17; P = 0.02) improved in the intervention period., Conclusion: Among mechanically ventilated ICU patients, no benefit was observed for de-adoption of chlorhexidine and implementation of an oral care bundle on ICU mortality, IVACs, oral procedural pain, or time to extubation. The intervention may improve oral health., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges., Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials., Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout., Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines., Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect., Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial., Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS., Future Work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space., Funding: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council-National Institute for Health Research Methodology Research programme.

Objective: Compared with individual-patient randomized controlled trials, cluster randomized controlled trials have unique methodological and ethical considerations. We evaluated the rationale, methodological quality, and reporting of cluster randomized controlled trials in critical care studies., Data Sources: Systematic searches of Medline, Embase, and Cochrane Central Register were performed., Study Selection: We included all cluster randomized controlled trials conducted in adult, pediatric, or neonatal critical care units from January 2005 to September 2019., Data Extraction: Two reviewers independently screened citations, reviewed full texts, protocols, and supplements of potentially eligible studies, abstracted data, and assessed methodology of included studies., Data Synthesis: From 1,902 citations, 59 cluster randomized controlled trials met criteria. Most focused on quality improvement (24, 41%), antimicrobial therapy (9, 15%), or infection control (9, 15%) interventions. Designs included parallel-group (25, 42%), crossover (21, 36%), and stepped-wedge (13, 22%). Concealment of allocation was reported in 21 studies (36%). Thirteen studies (22%) reported at least one method of blinding. The median total sample size was 1,660 patients (interquartile range, 813-4,295); the median number of clusters was 12 (interquartile range, 5-24); and the median patients per cluster was 141 (interquartile range, 54-452). Sample size calculations were reported in 90% of trials, but only 54% met Consolidated Standards of Reporting Trials guidance for sample size reporting. Twenty-seven of the studies (46%) identified a fixed number of available clusters prior to trial commencement, and only nine (15%) prespecified both the number of clusters and patients required to detect the expected effect size. Overall, 36 trials (68%) achieved the total prespecified sample size. When analyzing data, 44 studies (75%) appropriately adjusted for clustering when analyzing the primary outcome. Only 12 (20%) reported an intracluster coefficient (median 0.047 [interquartile range, 0.01-0.13])., Conclusions: Cluster randomized controlled trials in critical care typically involve a small and fixed number of relatively large clusters. The reporting of key methodological aspects of these trials is often inadequate., Competing Interests: Dr. Scales’ institution received funding from the Canadian Institutes for Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Granular data related to the likelihood of individuals of different ages accessing acute and critical care services over time is lacking., Methods: We used population-based, administrative data from Ontario to identify residents of specific ages (20, 30, 40, etc. to 100) on January 1st every year from 1995-2019. We assessed rates of emergency department (ED) visits (2003-19), hospitalizations, intensive care unit (ICU) admissions (2003-19), and mechanical ventilation., Findings: Overall the 25-year study period, ED were the most common acute healthcare encounter with 100-year-olds having the lowest rate (138.7/1,000) and 90-year-olds the highest (378.5/1,000). Rates of hospitalization ranged from 24.2/1,000 for those age 20 up to 224.9/1,000 for those age 90. Rates of ICU admission and mechanical ventilation were lowest for those age 20 (1.0 and 0.4/1,000), more than tripled by age 50 (3.3 and 1.7/1,000) and peaked at age 80 (20.3 and 10.1/1,000). Over time rates of ED visits increased (164.3 /1,000 in 2003 vs 199.1 /1,000 in 2019) as did rates of invasive mechanical ventilation (2.0/1,000 in 1995 vs 2.9/1,000 in 2019), whereas rates of ICU admission remained stable (4.8/1,000 in 2003 vs 4.9/1,000 in 2019) and hospitalization declined (66.8/1,000 in 1995 vs 51.5/1,000 in 2019). Age stratified analysis demonstrated that rates of ED presentation increased for those age 70 and younger while hospitalization decreased for all age groups; ICU admission and mechanical ventilation rates changed variably by age, with increasing rates demonstrated primarily among people under the age of 50., Interpretation: Rates of hospitalizations have decreased over time across all age groups, whereas rates of ED presentation, ICU admissions, and mechanical ventilation have increased, primarily driven by younger adults. These findings suggest that although the delivery of healthcare may be moving away from inpatient medicine, there is a growing population of young adults requiring significant healthcare resources., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The six-minute walk test (6MWT) is a simple and valid test for assessing cardiopulmonary fitness. Nevertheless, the relationship between preoperative 6MWT distance and postoperative complications is uncertain. We conducted a secondary analysis of the 6MWT nested cohort substudy of the Measurement of Exercise Tolerance before Surgery study to determine if 6MWT distance predicts postoperative complications or death., Methods: This analysis included 545 adults (≥ 40 yr) who were at elevated cardiac risk and had elective inpatient non-cardiac surgery at 15 hospitals in Canada, Australia, and New Zealand. Each participant performed a preoperative 6MWT and was followed for 30 days after surgery. The primary outcome was moderate or severe in-hospital complications. The secondary outcome was 30-day death or myocardial injury. Multivariable logistic regression modelling was used to characterize the adjusted association of 6MWT distance with these outcomes., Results: Seven participants (1%) terminated their 6MWT sessions early because of lower limb pain, dyspnea, or dizziness. Eighty-one (15%) participants experienced moderate or severe complications and 69 (13%) experienced 30-day myocardial injury or death. Decreased 6MWT distance was associated with increased odds of moderate or severe complications (adjusted odds ratio, 1.32 per 100 m decrease; 95% confidence interval, 1.01 to 1.73; P = 0.045). There was no association of 6MWT distance with myocardial injury or 30-day death (non-linear association; P = 0.49)., Conclusion: Preoperative 6MWT distance had a modest association with moderate or severe complications after inpatient non-cardiac surgery. Further studies are needed to determine the optimal role of the 6MWT as an objective exercise test for informing preoperative risk stratification.

Background: Experimental data highlight the potential benefits and health system cost savings related to surgical prehabilitation; however, adequately powered randomized controlled trial (RCT) data remain nascent. Emerging prehabilitation services may be informed by early RCT data but can be limited in informing real-world program development. Pragmatic trials emphasize external validity and generalizability to understand and advise intervention development and implementation in clinical settings. This paper presents the methodology of a pragmatic prehabilitation trial to complement emerging phase III clinical trials and inform implementation strategies., Methods: This is a pilot pragmatic clinical trial conducted in a large academic hospital in Toronto, Ontario, Canada to assess feasibility of clinical implementation and derive estimates of effectiveness. Feasibility data include program referral rates, enrolment and attrition, intervention adherence and safety, participant satisfaction, and barriers and facilitators to programming. The study aims to receive 150 eligible referrals for adult, English-speaking, preoperative oncology patients with an identified indication for prehabilitation ( e.g ., frailty, deconditioning, malnutrition, psychological distress). Study participants undergo a baseline assessment and shared-decision making regarding the intervention setting: either facility-based prehabilitation or home-based prehabilitation. In both scenarios, participants receive an individualized exercise prescription, stress-reduction psychological support, nutrition counseling, and protein supplementation, and if appropriate, smoking cessation program referrals. Secondary objectives include estimating intervention effects at the week prior to surgery and 30 and 90 days postoperatively. Outcomes include surgical complications, postoperative length of stay, mortality, hospital readmissions, physical fitness, psychological well-being, and quality of life. Data from participants who decline the intervention but consent for research-related access to health records will serve as comparators. The COVID-19 pandemic required the introduction of a 'virtual program' using only telephone or internet-based communication for screening, assessments, or intervention was introduced., Conclusion: This pragmatic trial will provide evidence on the feasibility and viability of prehabilitation services delivered under usual clinical conditions. Study amendments due to the COVID-19 pandemic are presented as strategies to maintain prehabilitation research and services to potentially mitigate the consequences of extended surgery wait times., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Santa Mina, Sellers, Au, Alibhai, Clarke, Cuthbertson, Darling, El Danab, Govindarajan, Ladha, Matthew, McCluskey, Ng, Quereshy, Karkouti and Randall.)

Background: Accurate assessment of functional capacity, a predictor of postoperative morbidity and mortality, is essential to improving surgical planning and outcomes. We assessed if all 12 items of the Duke Activity Status Index (DASI) were equally important in reflecting exercise capacity., Methods: In this secondary cross-sectional analysis of the international, multicentre Measurement of Exercise Tolerance before Surgery (METS) study, we assessed cardiopulmonary exercise testing and DASI data from 1455 participants. Multivariable regression analyses were used to revise the DASI model in predicting an anaerobic threshold (AT) >11 ml kg -1 min -1 and peak oxygen consumption (VO 2 peak) >16 ml kg -1 min -1 , cut-points that represent a reduced risk of postoperative complications., Results: Five questions were identified to have dominance in predicting AT>11 ml kg -1 min -1 and VO 2 peak>16 ml.kg -1 min -1 . These items were included in the M-DASI-5Q and retained utility in predicting AT>11 ml.kg -1 .min -1 (area under the receiver-operating-characteristic [AUROC]-AT: M-DASI-5Q=0.67 vs original 12-question DASI=0.66) and VO 2 peak (AUROC-VO2 peak: M-DASI-5Q 0.73 vs original 12-question DASI 0.71). Conversely, in a sensitivity analysis we removed one potentially sensitive question related to the ability to have sexual relations, and the ability of the remaining four questions (M-DASI-4Q) to predict an adequate functional threshold remained no worse than the original 12-question DASI model. Adding a dynamic component to the M-DASI-4Q by assessing the chronotropic response to exercise improved its ability to discriminate between those with VO 2 peak>16 ml.kg -1 .min -1 and VO 2 peak<16 ml.kg -1 .min -1 ., Conclusions: The M-DASI provides a simple screening tool for further preoperative evaluation, including with cardiopulmonary exercise testing, to guide perioperative management., (Copyright © 2020. Published by Elsevier Ltd.)

Objectives: There is conflicting evidence for the effectiveness of early rehabilitation in the intensive care and marked variation in rates of implementation in practice. We aimed to identify barriers and facilitators to early rehabilitation in mechanically ventilated patients and their relevance to practice, as perceived by key ICU clinicians across North America., Design: A Delphi study using the Theoretical Domains Framework, consisting of an initial qualitative round and subsequent quantitative rounds, was conducted to gather clinician agreement and perceived importance of barriers and facilitators to early rehabilitation. The survey included questions on the range of individual, sociocultural, and broader organizational influence on behaviors., Setting: Clinical practice in North America., Subjects: Four clinician groups (intensive care physicians, nurses, therapists, and respiratory therapists)., Interventions: A three-round Delphi study., Measurements and Main Results: Fifty of 74 (67%) of invited clinicians completed the study. Agreement and consensus with Delphi survey items were high in both rounds within and between professional groups. Agreement was highest for items related to the domain "Beliefs about Consequences" (e.g., mortality reduction) and lowest for items related to the domain "Behavioral Regulation" (e.g., team discussion of barriers). Beliefs expressed about improved mortality and improvements in a variety of other long-term outcomes were not consistent with the current evidence base. Individual agreement scores changed very little from Round 2 to Round 3 of the Delphi, suggesting stability of beliefs and existing consensus., Conclusions: This study identified a wide range of beliefs about early rehabilitation that may influence provider behavior and the success and appropriateness of further implementation. The apparent inconsistency between the optimism of stakeholders regarding mortality reductions and a low level of implementation reported elsewhere represent the most major challenge to future implementation success. Other foci for future implementation work include planning, barriers, feedback, and education of staff.

Importance: In the current setting of the coronavirus disease 2019 pandemic, there is concern for the possible need for triage criteria for ventilator allocation; to our knowledge, the implications of using specific criteria have never been assessed., Objective: To determine which and how many admissions to intensive care units are identified as having the lowest priority for ventilator allocation using 2 distinct sets of proposed triage criteria., Design, Setting, and Participants: This retrospective cohort study conducted in spring 2020 used data collected from US hospitals and reported in the Philips eICU Collaborative Research Database. Adult admissions (N = 40 439) to 291 intensive care units from 2014 to 2015 who received mechanical ventilation and were not elective surgery patients were included., Exposures: New York State triage criteria and original triage criteria proposed by White and Lo., Main Outcomes and Measures: Sequential Organ Failure Assessment (SOFA) scores were calculated for admissions. The proportion of patients who met initial criteria for the lowest level of priority for mechanical ventilation using each set of criteria and their characteristics and outcomes were assessed. Agreement was compared between the 2 sets of triage criteria, recognizing differences in stated criteria aims., Results: Among 40 439 intensive care unit admissions of patients who received mechanical ventilation, the mean (SD) age was 62.6 (16.6) years, 54.9% were male, and the mean (SD) SOFA score was 4.5 (3.7). Using the New York State triage criteria, 8.9% (95% CI, 8.7%-9.2%) were in the lowest priority category; these lowest priority admissions had a mean (SD) age of 62.9 (16.6) years, used a median (interquartile range) of 57.3 (20.1-133.5) ventilator hours each, and had a hospital survival rate of 38.6% (95% CI, 37.0%-40.2%). Using the White and Lo triage criteria, 4.3% (95% CI, 4.1%-4.5%) were in the lowest priority category; these admissions had a mean (SD) age of 68.6 (13.2) years, used a median (interquartile range) of 61.7 (24.3-142.8) ventilator hours each, and had a hospital survival rate of 56.2% (95% CI, 53.8%-58.7%). Only 655 admissions (1.6%) were in the lowest priority category for both guidelines, with the κ statistic for agreement equal to 0.20 (95% CI, 0.18-0.21)., Conclusions and Relevance: Use of 2 initially proposed ventilator triage guidelines identified approximately 1 in every 10 to 25 admissions as having the lowest priority for ventilator allocation, with little agreement. Clinical assessment of different potential criteria for triage decisions in critically ill populations is important to ensure valid and equitable allocation of resources.

Background: Elevated plasma or serum troponin, indicating perioperative myocardial injury (PMI), is common after noncardiac surgery. However, underlying mechanisms remain unclear. Acute coronary syndrome (ACS) is associated with the early appearance of circulating microRNAs, which regulate post-translational gene expression. We hypothesised that if PMI and ACS share pathophysiological mechanisms, common microRNA signatures should be evident., Methods: We performed a nested case control study of samples obtained before and after noncardiac surgery from patients enrolled in two prospective observational studies of PMI (postoperative troponin I/T>99th centile). In cohort one, serum microRNAs were compared between patients with or without PMI, matched for age, gender, and comorbidity. Real-time polymerase chain reaction quantified (qRT-PCR) relative microRNA expression (cycle quantification [Cq] threshold <37) before and after surgery for microRNA signatures associated with ACS, blinded to PMI. In cohort two, we analysed (EdgeR) microRNA from plasma extracellular vesicles using next-generation sequencing (Illumina HiSeq 500). microRNA-messenger RNA-function pathway analysis was performed (DIANA miRPath v3.0/TopGO)., Results: MicroRNAs were detectable in all 59 patients (median age 67 yr [61-75]; 42% male), who had similar clinical characteristics independent of developing PMI. In cohort one, serum microRNA expression increased after surgery (mean fold-change) hsa-miR-1-3p: 3.99 (95% confidence interval [CI: 1.95-8.19]; hsa-miR-133-3p: 5.67 [95% CI: 2.94-10.91]; P<0.001). These changes were not associated with PMI. Bioinformatic analysis of differentially expressed microRNAs from cohorts one (n=48) and two (n=11) identified pathways associated with adrenergic stress and calcium dysregulation, rather than ischaemia., Conclusions: Circulating microRNAs associated with cardiac ischaemia were universally elevated in patients after surgery, independent of development of myocardial injury., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The Duke Activity Status Index (DASI) questionnaire might help incorporate self-reported functional capacity into preoperative risk assessment. Nonetheless, prognostically important thresholds in DASI scores remain unclear. We conducted a nested cohort analysis of the Measurement of Exercise Tolerance before Surgery (METS) study to characterise the association of preoperative DASI scores with postoperative death or complications., Methods: The analysis included 1546 participants (≥40 yr of age) at an elevated cardiac risk who had inpatient noncardiac surgery. The primary outcome was 30-day death or myocardial injury. The secondary outcomes were 30-day death or myocardial infarction, in-hospital moderate-to-severe complications, and 1 yr death or new disability. Multivariable logistic regression modelling was used to characterise the adjusted association of preoperative DASI scores with outcomes., Results: The DASI score had non-linear associations with outcomes. Self-reported functional capacity better than a DASI score of 34 was associated with reduced odds of 30-day death or myocardial injury (odds ratio: 0.97 per 1 point increase above 34; 95% confidence interval [CI]: 0.96-0.99) and 1 yr death or new disability (odds ratio: 0.96 per 1 point increase above 34; 95% CI: 0.92-0.99). Self-reported functional capacity worse than a DASI score of 34 was associated with increased odds of 30-day death or myocardial infarction (odds ratio: 1.05 per 1 point decrease below 34; 95% CI: 1.00-1.09), and moderate-to-severe complications (odds ratio: 1.03 per 1 point decrease below 34; 95% CI: 1.01-1.05)., Conclusions: A DASI score of 34 represents a threshold for identifying patients at risk for myocardial injury, myocardial infarction, moderate-to-severe complications, and new disability., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Selective decontamination of the digestive tract (SDD) is an infection prevention measure for intensive care unit (ICU) patients that was proposed more than 30 years ago, and that is currently considered standard of care in the Netherlands, but only used sporadically in ICUs in other countries. In this narrative review, we first describe the rationale of the individual components of SDD and then review the evidence base for patient-centered outcomes, where we distinguish ICUs with low prevalence of antibiotic resistance from ICUs with moderate-high prevalence of resistance. In settings with low prevalence of antibiotic resistance, SDD has been associated with improved patient outcome in three cluster-randomized studies. These benefits were not confirmed in a large international cluster-randomized study in settings with moderate-to-high prevalence of antibiotic resistance. There is no evidence that SDD increases antibiotic resistance. We end with future directions for research.

Background: Routine application of chlorhexidine oral rinse is recommended to reduce risk of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Recent reappraisal of the evidence from two meta-analyses suggests chlorhexidine may cause excess mortality in non-cardiac surgery patients and does not reduce VAP. Mechanisms for possible excess mortality are unclear. The CHORAL study will evaluate the impact of de-adopting chlorhexidine and implementing an oral care bundle (excluding chlorhexidine) on mortality, infection-related ventilator-associated complications (IVACs), and oral health status., Methods: The CHORAL study is a stepped wedge, cluster randomized controlled trial in six academic intensive care units (ICUs) in Toronto, Canada. Clusters (ICU) will be randomly allocated to six sequential steps over a 14-month period to de-adopt oral chlorhexidine and implement a standardized oral care bundle (oral assessment, tooth brushing, moisturization, and secretion removal). On study commencement, all clusters begin with a control period in which the standard of care is oral chlorhexidine. Clusters then begin crossover from control to intervention every 2 months according to the randomization schedule. Participants include all mechanically ventilated adults eligible to receive the standardized oral care bundle. The primary outcome is ICU mortality; secondary outcomes are IVACs and oral health status. We will determine demographics, antibiotic usage, mortality, and IVAC rates from a validated local ICU clinical registry. With six clusters and 50 ventilated patients on average each month per cluster, we estimate that 4200 patients provide 80% power after accounting for intracluster correlation to detect an absolute reduction in mortality of 5.5%. We will analyze our primary outcome of mortality using a generalized linear mixed model adjusting for time to account for secular trends. We will conduct a process evaluation to determine intervention fidelity and to inform interpretation of the trial results., Discussion: The CHORAL study will inform understanding of the effectiveness of de-adoption of oral chlorhexidine and implementation of a standardized oral care bundle for decreasing ICU mortality and IVAC rates while improving oral health status. Our process evaluation will inform clinicians and decision makers about intervention delivery to support future de-adoption if justified by trial results., Trial Registration: ClinicalTrials.gov, NCT03382730 . Registered on December 26, 2017.

Purpose: Critical care beds are commonly described in three levels (highest level 3, lowest level 1). We aimed to describe the actual level of care for patients assigned to level 2 in a tertiary hospital with inadequate level 1 bed capacity., Materials and Methods: Prospective cohort study with daily assessment of level of care. The primary outcome was the proportion of patients who could be triaged to level 1 for the entirety of their ICU stay. Secondary outcomes included the percentage of patients who could receive level 1 care on any given day., Results: 289 patients originally classified as level 2 were assessed for the primary, and 335 for the secondary outcomes. 14.9% could be level 1 for their entire ICU stay. 20.6%, once appropriate for level 1, remained in that level for the rest of their ICU stay. 23.6% of the assessments were suitable for level 1 on any given day., Conclusion: In a single centre, 14.9% of level 2 patients could have been cared for in a lower acuity bed for the entirety of their ICU stay. We believe this methodology is reproducible and can help resource allocation with regard to the high demand for critical care beds., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Renal dysfunction predicts an increased risk of both early and long-term mortality after cardiac surgery. Cystatin C enables glomerular filtration rate (GFR) to be estimated accurately and may be superior in this regard to creatinine-based estimates. We hypothesised, therefore, that cystatin C and derived estimates of GFR would independently predict long-term survival after cardiac surgery and would be superior in this respect to traditional estimates of GFR. The current study tests this hypothesis in a large and well-characterised cohort of patients., Design: A prospective cohort study., Setting: Regional cardiothoracic centre in Northeast Scotland., Participants: 1010 patients undergoing non-emergent cardiac surgery between 2004 and 2007. Serum creatinine and cystatin C levels were measured preoperatively and demographic and clinical variables were recorded., Primary Outcome Measure: All-cause mortality, established from the National Records of Scotland., Results: The median duration of follow-up after surgery was 9.7 years (IQR 8.9-10.6 years), during which 297 participants died. Preoperative creatinine and cystatin C levels and estimates of GFR derived from these were all strong predictors of death using Cox regression and remained independently predictive after adjustment for the logistic European System for Cardiac Operative Risk Evaluation, a well-validated clinical risk score and a range of other clinical predictors. Cystatin C-based measures were superior to creatinine-based estimates of GFR., Conclusions: Cystatin C and creatinine derived eGFR are powerful and independent predictors of long-term mortality following cardiac surgery. Estimates of GFR derived from cystatin C convey superior prognostic information to conventional creatinine-based estimates, but the observed differences are modest., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Impaired cardiac vagal function, quantified preoperatively as slower heart rate recovery (HRR) after exercise, is independently associated with perioperative myocardial injury. Parasympathetic (vagal) dysfunction may also promote (extra-cardiac) multi-organ dysfunction, although perioperative data are lacking. Assuming that cardiac vagal activity, and therefore heart rate recovery response, is a marker of brainstem parasympathetic dysfunction, we hypothesized that impaired HRR would be associated with a higher incidence of morbidity after noncardiac surgery., Methods: In two prospective, blinded, observational cohort studies, we established the definition of impaired vagal function in terms of the HRR threshold that is associated with perioperative myocardial injury (HRR ≤ 12 beats min-1 (bpm), 60 seconds after cessation of cardiopulmonary exercise testing. The primary outcome of this secondary analysis was all-cause morbidity three and five days after surgery, defined using the Post-Operative Morbidity Survey. Secondary outcomes of this analysis were type of morbidity and time to become morbidity-free. Logistic regression and Cox regression tested for the association between HRR and morbidity. Results are presented as odds/hazard ratios [OR or HR; (95% confidence intervals)., Results: 882/1941 (45.4%) patients had HRR≤12bpm. All-cause morbidity within 5 days of surgery was more common in 585/822 (71.2%) patients with HRR≤12bpm, compared to 718/1119 (64.2%) patients with HRR>12bpm (OR:1.38 (1.14-1.67); p = 0.001). HRR≤12bpm was associated with more frequent episodes of pulmonary (OR:1.31 (1.05-1.62);p = 0.02)), infective (OR:1.38 (1.10-1.72); p = 0.006), renal (OR:1.91 (1.30-2.79); p = 0.02)), cardiovascular (OR:1.39 (1.15-1.69); p<0.001)), neurological (OR:1.73 (1.11-2.70); p = 0.02)) and pain morbidity (OR:1.38 (1.14-1.68); p = 0.001) within 5 days of surgery., Conclusions: Multi-organ dysfunction is more common in surgical patients with cardiac vagal dysfunction, defined as HRR ≤ 12 bpm after preoperative cardiopulmonary exercise testing., Clinical Trial Registry: ISRCTN88456378., Competing Interests: The METS Study and POM-HR funding sources had no role in the design and conduct of these studies; collection, management, analysis, and interpretation of the data; and preparation or approval of the article. RP holds research grants, and has given lectures and/or performed consultancy work for Nestle Health Sciences, BBraun, Medtronic, GlaxoSmithKline and Edwards Lifesciences, and is a member of the Associate editorial board of the British Journal of Anaesthesia; GLA is a member of the editorial advisory board for Intensive Care Medicine Experimental, is an Editor for the British Journal of Anaesthesia and has undertaken consultancy work for GlaxoSmithKline; TEFA is a committee member of the Perioperative Exercise Testing and Training Society. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Physiological measures of heart failure are common in surgical patients, despite the absence of a diagnosis. Heart rate (HR) increases during exercise are frequently blunted in heart failure (termed chronotropic incompetence), which primarily reflects beta-adrenoreceptor dysfunction. We examined whether chronotropic incompetence was associated with myocardial injury after noncardiac surgery., Methods: This was a predefined analysis of an international cohort study where participants aged ≥40 yr underwent symptom-limited cardiopulmonary exercise testing before noncardiac surgery. Chronotropic incompetence was defined as the ratio of increase in HR during exercise to age-predicted maximal increase in HR <0.6. The primary outcome was myocardial injury within 3 days after surgery, defined by high-sensitivity troponin assays >99th centile. Explanatory variables were biomarkers for heart failure (ventilatory efficiency slope [minute ventilation/carbon dioxide production] ≥34; peak oxygen consumption ≤14 ml kg -1 min -1 ; HR recovery ≤6 beats min -1 decrease 1 min post-exercise; preoperative N-terminal pro-B-type natriuretic peptide [NT pro-BNP] >300 pg ml -1 ). Myocardial injury was compared in the presence or absence of sympathetic (i.e. chronotropic incompetence) or parasympathetic (i.e. impaired HR recovery after exercise) thresholds indicative of dysfunction. Data are presented as odds ratios (ORs) (95% confidence intervals)., Results: Chronotropic incompetence occurred in 396/1325 (29.9%) participants; only 16/1325 (1.2%) had a heart failure diagnosis. Myocardial injury was sustained by 162/1325 (12.2%) patients. Raised preoperative NT pro-BNP was more common when chronotropic incompetence was <0.6 (OR: 1.57 [1.11-2.23]; P=0.011). Chronotropic incompetence was not significantly associated with myocardial injury (OR: 1.05 [0.74-1.50]; P=0.78), independent of rate-limiting therapy. HR recovery <12 beats min -1 decrease after exercise was associated with myocardial injury in the presence (OR: 1.62 [1.05-2.51]; P=0.03) or absence (OR: 1.60 [1.06-2.39]; P=0.02) of chronotropic incompetence., Conclusions: Chronotropic incompetence is common in surgical patients. In contrast to parasympathetic dysfunction which was associated with myocardial injury, preoperative chronotropic incompetence (suggestive of sympathetic dysfunction) was not associated with postoperative myocardial injury., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The aetiology of perioperative myocardial injury is poorly understood and not clearly linked to pre-existing cardiovascular disease. We hypothesised that loss of cardioprotective vagal tone [defined by impaired heart rate recovery ≤12 beats min -1 (HRR ≤12) 1 min after cessation of preoperative cardiopulmonary exercise testing] was associated with perioperative myocardial injury., Methods: We conducted a pre-defined, secondary analysis of a multi-centre prospective cohort study of preoperative cardiopulmonary exercise testing. Participants were aged ≥40 yr undergoing non-cardiac surgery. The exposure was impaired HRR (HRR≤12). The primary outcome was postoperative myocardial injury, defined by serum troponin concentration within 72 h after surgery. The analysis accounted for established markers of cardiac risk [Revised Cardiac Risk Index (RCRI), N-terminal pro-brain natriuretic peptide (NT pro-BNP)]., Results: A total of 1326 participants were included [mean age (standard deviation), 64 (10) yr], of whom 816 (61.5%) were male. HRR≤12 occurred in 548 patients (41.3%). Myocardial injury was more frequent amongst patients with HRR≤12 [85/548 (15.5%) vs HRR>12: 83/778 (10.7%); odds ratio (OR), 1.50 (1.08-2.08); P=0.016, adjusted for RCRI). HRR declined progressively in patients with increasing numbers of RCRI factors. Patients with ≥3 RCRI factors were more likely to have HRR≤12 [26/36 (72.2%) vs 0 factors: 167/419 (39.9%); OR, 3.92 (1.84-8.34); P<0.001]. NT pro-BNP greater than a standard prognostic threshold (>300 pg ml -1 ) was more frequent in patients with HRR≤12 [96/529 (18.1%) vs HRR>12 59/745 (7.9%); OR, 2.58 (1.82-3.64); P<0.001]., Conclusions: Impaired HRR is associated with an increased risk of perioperative cardiac injury. These data suggest a mechanistic role for cardiac vagal dysfunction in promoting perioperative myocardial injury., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The 6-min walk test (6MWT) is a common means of functional assessment. Its relationship to disability-free survival (DFS) is uncertain., Methods: This sub-study of the Measurement of Exercise Tolerance for Surgery study had co-primary outcome measures: correlation of the preoperative 6MWT distance with 30 day quality of recovery (15-item quality of recovery) and 12 month WHO Disability Assessment Schedule scores. The prognostic utility of the 6MWT and other risk assessment tools for 12 month DFS was assessed with logistic regression and receiver-operating-characteristic-curve analysis., Results: Of 574 patients recruited, 567 (99%) completed the 6MWT. Twelve months after surgery, 16 (2.9%) patients had died and 444 (77%) had DFS. The 6MWT correlated weakly with 30 day 15-item quality of recovery (ρ=0.14; P=0.001) and 12 month WHO Disability Assessment Schedule (ρ=-0.23; P<0.0005) scores. When the cohort was split into 6MWT distance tertiles, the adjusted odds ratio of low vs high tertiles for DFS was 3.13 [95% confidence interval (CI): 1.54-6.35]. The only independent variable predictive of DFS was the Duke Activity Status Index (DASI) score (adjusted odds ratio: 1.06; P<0.0005). The area under the receiver-operating-characteristic curve for DFS was 0.63 (95% CI: 0.57-0.70) for the 6MWT, 0.60 (95% CI: 0.53-0.67) for cardiopulmonary-exercise-testing-derived peak oxygen consumption, and 0.70 (95% CI: 0.64-0.76) for the DASI score., Conclusions: Of the risk assessment tools analysed, the DASI was the most predictive of DFS. The 6MWT was safe and comparable with cardiopulmonary exercise testing for all predictive assessments. Future research should aim to determine the optimal 6MWT distance thresholds for risk prediction., (Copyright © 2018 British Journal of Anaesthesia. All rights reserved.)

Purpose: To assess feasibility of producing intelligible and comprehensible speech with an electrolarynx; measure anxiety, communication ease, and satisfaction before/after electrolarynx training; and identify barriers/facilitators., Methods: We included tracheostomized adults from 3 units following commands, reading English, and mouthing words. On enrolment, we measured anxiety, ease, and satisfaction with communication. We gave electrolarynx instruction for ≤5 days then 2 independent raters assessed intelligibility, sentence comprehensibility (9-point difficulty scale), and Electrolarynx Effectiveness Score (EES), and re-evaluated anxiety, communication ease, and satisfaction. Interviews explored barriers/facilitators., Measurements and Main Results: We recruited 24 participants (Jan2015-Dec2016). Mean (SD) intelligibility was 45%(18%) words correct: 57%(21%) when facing. Mean comprehension difficulty was 6.4(2.0) overall, indicating moderate difficulty (5.5(2.5) scored visualizing). Mean EES was 2.9(1.0) (3 = improved lip-reading through recognizable sounds). Anxiety decreased from median 3.8 to 2.0 (P = .007). Communication was rated easier (median 15 vs 12, P = .04) whereas satisfaction remained similar (P = .06). Facilitators included device friendliness, patient independence, and word intelligibility. Barriers were patient weakness, difficulty positioning the device, and limited sentence as opposed to word intelligibility., Conclusion: The electrolarynx may aid intelligible speech for some tracheostomized patients if the communication partner can visualize the users face, and reduce anxiety and make patient perceived communication easier., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: It is uncertain whether dedicated neurocritical care units are associated with improved outcomes for critically ill neurologically injured patients in the era of collaborative protocol-driven care. We examined the association between dedicated neurocritical care units and mortality and the effects of standardized management protocols for severe traumatic brain injury., Design: We surveyed trauma medical directors from centers participating in the American College of Surgeons Trauma Quality Improvement Program to obtain information about ICU structure and processes of care. Survey data were then linked to the Trauma Quality Improvement Program registry, and random-intercept hierarchical multivariable modeling was used to evaluate the association between dedicated neurocritical care units, the presence of standardized management protocols and mortality., Setting: Trauma centers in North America participating in Trauma Quality Improvement Program., Patients: Data were analyzed from 9,773 adult patients with isolated severe traumatic brain injury admitted to 134 Trauma Quality Improvement Program centers between 2011 and 2013., Interventions: None., Measurements and Main Results: Only 50 ICUs (37%) were dedicated neurocritical care units, whereas 84 (63%) were general ICUs. Rates of standardized management protocols were similar comparing dedicated neurocritical care units and general ICUs. Among severe TBI patients admitted to trauma centers enrolled in Trauma Quality Improvement Program, care in a dedicated neurocritical care unit did not improve risk-adjusted in-hospital survival (odds ratio, 0.97; 95% CI, 0.80-1.19; p = 0.79). However, the presence of a standardized management protocol for these patients was associated with lower risk-adjusted in-hospital mortality (odds ratio, 0.77; 95% CI, 0.63-0.93; p = 0.009)., Conclusions: Compared with dedicated neurocritical care models, standardized management protocols for severe traumatic brain injured patients are process-targeted intervention strategies that may improve clinical outcomes.

Background: Functional capacity is an important component of risk assessment for major surgery. Doctors' clinical subjective assessment of patients' functional capacity has uncertain accuracy. We did a study to compare preoperative subjective assessment with alternative markers of fitness (cardiopulmonary exercise testing [CPET], scores on the Duke Activity Status Index [DASI] questionnaire, and serum N-terminal pro-B-type natriuretic peptide [NT pro-BNP] concentrations) for predicting death or complications after major elective non-cardiac surgery., Methods: We did a multicentre, international, prospective cohort study at 25 hospitals: five in Canada, seven in the UK, ten in Australia, and three in New Zealand. We recruited adults aged at least 40 years who were scheduled for major non-cardiac surgery and deemed to have one or more risk factors for cardiac complications (eg, a history of heart failure, stroke, or diabetes) or coronary artery disease. Functional capacity was subjectively assessed in units of metabolic equivalents of tasks by the responsible anaesthesiologists in the preoperative assessment clinic, graded as poor (<4), moderate (4-10), or good (>10). All participants also completed the DASI questionnaire, underwent CPET to measure peak oxygen consumption, and had blood tests for measurement of NT pro-BNP concentrations. After surgery, patients had daily electrocardiograms and blood tests to measure troponin and creatinine concentrations until the third postoperative day or hospital discharge. The primary outcome was death or myocardial infarction within 30 days after surgery, assessed in all participants who underwent both CPET and surgery. Prognostic accuracy was assessed using logistic regression, receiver-operating-characteristic curves, and net risk reclassification., Findings: Between March 1, 2013, and March 25, 2016, we included 1401 patients in the study. 28 (2%) of 1401 patients died or had a myocardial infarction within 30 days of surgery. Subjective assessment had 19·2% sensitivity (95% CI 14·2-25) and 94·7% specificity (93·2-95·9) for identifying the inability to attain four metabolic equivalents during CPET. Only DASI scores were associated with predicting the primary outcome (adjusted odds ratio 0·96, 95% CI 0·83-0·99; p=0·03)., Interpretation: Subjectively assessed functional capacity should not be used for preoperative risk evaluation. Clinicians could instead consider a measure such as DASI for cardiac risk assessment., Funding: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Despite a supportive evidence base and a push to implement, the uptake of early rehabilitation in critical care has been inconsistent. The objective of this study was to explore barriers and facilitators to early rehabilitation for critically ill patients receiving invasive mechanical ventilation., Methods: Using the Theoretical Domains Framework (TDF) of behavior change, we conducted semi-structured interviews exploring barriers and facilitators to early rehabilitation among four purposively sampled ICU clinician groups (nurses, rehabilitation professionals, respiratory therapists, and physicians). The TDF is a comprehensive framework of 14 "construct domains," synthesized from 33 theories of behavior that was developed to study determinants of behavior and to design interventions to improve evidence-based healthcare practice. A topic guide was developed and piloted based on the TDF and expert knowledge. Interviews were audio-recorded and transcribed verbatim. Transcripts were content analyzed by coding items into domains and then synthesized into more specific, over-arching themes or "beliefs." An expert consensus group used structured decision rules to classify beliefs as high, moderate, or low in importance., Results: We interviewed 40 stakeholders from the four clinician groups and identified 135 separate beliefs. Of these, 19 were classified as high, 40 as moderate, and 76 of low importance as barriers or facilitators. All beliefs classified as highly important fell within one of seven TDF domains: skills, social/professional role and identity, beliefs about capabilities, beliefs about consequences, environmental context/resources, social influences, and behavioral regulation. Beliefs of lower importance fell under the following seven domains: knowledge; optimism; reinforcement; intention; goals; memory, attention, and decision processes; and emotion. Quantitative differences in stated beliefs about early rehabilitation between professional groups were not common., Conclusions: This study identified important barriers and facilitators to early rehabilitation in critical care patients. Domains identified as important should be considered when designing interventions to increase uptake of early rehabilitation., Competing Interests: This study was reviewed and approved by the Research Ethics Board at Sunnybrook Health Sciences Centre. All participants provided explicit telephone consent.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Selective digestive decontamination of the digestive tract involves the routine administration of oral, gastric, and intravenous antibiotics to mechanically ventilated children to prevent hospital-acquired infections. It has a strong evidence base in adults, with limited pediatric evidence. Current utilization of this intervention among pediatric physicians in North America is unknown., Methods: An electronic survey administered to pediatric critical care and pediatric infectious disease providers in Canada. Participants were surveyed on current institutional practices, their current knowledge of the evidence base, and perceptions of the risks and benefits of the intervention. Descriptive statistics were utilized., Results: 50 out of 143 (35%) surveyed responded. No hospital in Canada routinely performs SDD and the majority of respondents (74%) have neutral opinions on the subject of SDD. There was concern for increasing antibiotic resistance (43%) and some disagreement with the intravenous component of SDD (46%). The majority of respondents stated a need for pediatric-specific evidence before integrating SDD into their practice, even if further, large adult RCTs were performed., Conclusion: Among surveyed providers, there is little knowledge and no use of selective digestive decontamination for the prevention of hospital-acquired infections. Before interventional studies are performed in pediatric practice, there is a need for study of facilitators, barriers and acceptability of SDD in practice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The optimal timing of tracheostomy placement in acutely brain-injured patients, who generally require endotracheal intubation for airway protection rather than respiratory failure, remains uncertain. We systematically reviewed trials comparing early tracheostomy to late tracheostomy or prolonged intubation in these patients., Methods: We searched 5 databases (from inception to April 2015) to identify randomized controlled trials comparing early tracheostomy (≤10 days of intubation) with late tracheostomy (>10 days) or prolonged intubation in acutely brain-injured patients. We contacted the principal authors of included trials to obtain subgroup data. Two reviewers extracted data and assessed risk of bias. Outcomes included long-term mortality (primary), short-term mortality, duration of mechanical ventilation, complications, and liberation from ventilation without a tracheostomy. Meta-analyses used random-effects models., Results: Ten trials (503 patients) met selection criteria; overall study quality was moderate to good. Early tracheostomy reduced long-term mortality (risk ratio [RR] 0.57. 95 % confidence interval (CI), 0.36-0.90; p = 0.02; n = 135), although in a sensitivity analysis excluding one trial, with an unclear risk of bias, the significant finding was attenuated (RR 0.61, 95 % CI, 0.32-1.16; p = 0.13; n = 95). Early tracheostomy reduced duration of mechanical ventilation (mean difference [MD] -2.72 days, 95 % CI, -1.29 to -4.15; p = 0.0002; n = 412) and ICU length of stay (MD -2.55 days, 95 % CI, -0.50 to -4.59; p = 0.01; n = 326). However, early tracheostomy did not reduce short-term mortality (RR 1.25; 95 % CI, 0.68-2.30; p = 0.47 n = 301) and increased the probability of ever receiving a tracheostomy (RR 1.58, 95 % CI, 1.24-2.02; 0 < 0.001; n = 377)., Conclusions: Performing an early tracheostomy in acutely brain-injured patients may reduce long-term mortality, duration of mechanical ventilation, and ICU length of stay. However, waiting longer leads to fewer tracheostomy procedures and similar short-term mortality. Future research to explore the optimal timing of tracheostomy in this patient population should focus on patient-centered outcomes including patient comfort, functional outcomes, and long-term mortality.

Requests for a second medical opinion (SMO) by patients or substitute decision-makers (SDMs) can arise during end-of-life disputes in critical care. Such disagreements between patients or SDMs and physicians often pertain to specific elements of the decision-making process related to withholding or withdrawing of life-sustaining treatments. When these disputes occur in the critical care setting in Canada, practicalities and policy barriers prevent an SDM from obtaining an SMO without support from healthcare providers; moreover, in a majority of these cases the SDM will require the facilitation of a physician who is often the same individual with whom they are in conflict. Institutional and a national society's policy statements propose SMOs as an important component of a conflict resolution process for end-of-life disputes (Bosslet et al. 2015; Singer et al. 2001). However, these policies do not provide specific guidance to physicians on how to fairly consider SMO requests. Given the vulnerable position of patients and their SDMs in the critical care context and in order to promote fairness, physicians should apply consistent standards in deciding whether to facilitate a request for an SMO. To guide physicians' decision-making and inform future policy development, we propose three ethical principles for considering SDM requests for an SMO in critical care at the end of life.