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Background: The response of Canada's research community to the COVID-19 pandemic provides a unique opportunity to examine the country's clinical health research ecosystem. We sought to describe patterns of enrolment across Canadian Institutes of Health Research (CIHR)–funded studies on COVID-19. Methods: We identified COVID-19 studies funded by the CIHR and that enrolled participants from Canadian acute care hospitals between January 2020 and April 2023. We collected information on study-and site-level variables from study leads, site investigators, and public domain sources. We described and evaluated factors associated with cumulative enrolment. Results: We obtained information for 23 out of 26 (88%) eligible CIHR-funded studies (16 randomized controlled trials [RCTs] and 7 cohort studies). The 23 studies were managed by 12 Canadian and 3 international coordinating centres. Of 419 Canadian hospitals, 97 (23%) enrolled a total of 28 973 participants — 3876 in RCTs across 78 hospitals (median cumulative enrolment per hospital 30, interquartile range [IQR] 10–61), and 25 097 in cohort studies across 62 hospitals (median cumulative enrolment per hospital 158, IQR 6–348). Of 78 hospitals recruiting participants in RCTs, 13 (17%) enrolled 50% of all RCT participants, whereas 6 of 62 hospitals (9.7%) recruited 54% of participants in cohort studies. Interpretation: A minority of Canadian hospitals enrolled the majority of participants in CIHR-funded studies on COVID-19. This analysis sheds light on the Canadian health research ecosystem and provides information for multiple key partners to consider ways to realize the full research potential of Canada's health systems. [ABSTRACT FROM AUTHOR]

The HAT regimen was evaluated in the Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial ( I N i = 216) published in January 2020 [[7]]. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. 10.1001/jama.2019.11825 5 Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Vitamin C has a remarkable place in the history of medicine (Fig. [Extracted from the article]

Although hundreds of millions of dollars have been invested in coronavirus disease 2019 (COVID-19) research nationally, contributions from other countries have greatly exceeded Canada's research productivity. We discuss the limitations of the existing clinical research infrastructure in Canada, describe the mechanisms implemented to successfully embed clinical research in the UK health system and - while identifying the traps that Canadian stakeholders must avoid - provide a roadmap to a Canadian version of the UK system. The NIHR model, which takes advantage of a preexisting, longitudinally funded clinical research network funded by and embedded within the National Health Service (NHS), simultaneously solved problems related to infrastructure development, health system engagement and fragmentation in the UK context. Footnotes 1 B Competing interests: b François Lamontagne has received peer-reviewed funds from the Canadian Institutes of Health Research, the Fonds de Recherche du Québec - Santé, the National Institute for Health Research (NIHR), and the Lotte & John Hecht Memorial Foundation. [Extracted from the article]

Importance: Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.Objective: To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.Design, Setting, and Participants: A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.Interventions: Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).Main Outcome and Measures: The primary clinical outcome was all-cause mortality at 90 days.Results: Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]).Conclusions and Relevance: Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.Trial Registration: isrctn.org Identifier: ISRCTN10580502. [ABSTRACT FROM AUTHOR]

The 2013-16 Ebola virus disease outbreak in west Africa was associated with unprecedented challenges in the provision of care to patients with Ebola virus disease, including absence of pre-existing isolation and treatment facilities, patients' reluctance to present for medical care, and limitations in the provision of supportive medical care. Case fatality rates in west Africa were initially greater than 70%, but decreased with improvements in supportive care. To inform optimal care in a future outbreak of Ebola virus disease, we employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to develop evidence-based guidelines for the delivery of supportive care to patients admitted to Ebola treatment units. Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief. [ABSTRACT FROM AUTHOR]

Purpose: Guidelines for shock recommend mean arterial pressure (MAP) targets for vasopressor therapy of at least 65 mmHg and, until recently, suggested that patients with underlying chronic hypertension and atherosclerosis may benefit from higher targets. We conducted an individual patient-data meta-analysis of recent trials to determine if patient variables modify the effect of different MAP targets.Methods: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for randomized controlled trials of higher versus lower blood pressure targets for vasopressor therapy in adult patients in shock (until November 2017). After obtaining individual patient data from both eligible trials, we used a modified version of the Cochrane Collaboration's instrument to assess the risk of bias of included trials. The primary outcome was 28-day mortality.Results: Included trials enrolled 894 patients. Controlling for trial and site, the OR for 28-day mortality for the higher versus lower MAP targets was 1.15 (95% CI 0.87-1.52). Treatment effect varied by duration of vasopressors before randomization (interaction p = 0.017), but not by chronic hypertension, congestive heart failure or age. Risk of death increased in higher MAP groups among patients on vasopressors > 6 h before randomization (OR 3.00, 95% CI 1.33-6.74).Conclusions: Targeting higher blood pressure targets may increase mortality in patients who have been treated with vasopressors for more than 6 h. Lower blood pressure targets were not associated with patient-important adverse events in any subgroup, including chronically hypertensive patients. [ABSTRACT FROM AUTHOR]

Purpose: In shock, hypotension may contribute to inadequate oxygen delivery, organ failure and death. We conducted the Optimal Vasopressor Titration (OVATION) pilot trial to inform the design of a larger trial examining the effect of lower versus higher mean arterial pressure (MAP) targets for vasopressor therapy in shock.Methods: We randomly assigned critically ill patients who were presumed to suffer from vasodilatory shock regardless of admission diagnosis to a lower (60-65 mmHg) versus a higher (75-80 mmHg) MAP target. The primary objective was to measure the separation in MAP between groups. We also recorded days with protocol deviations, enrolment rate, cardiac arrhythmias and mortality for prespecified subgroups.Results: A total of 118 patients were enrolled from 11 centres (2.3 patients/site/month of screening). The between-group separation in MAP was 9 mmHg (95% CI 7-11). In the lower and higher MAP groups, we observed deviations on 12 versus 8% of all days on vasopressors (p = 0.059). Risks of cardiac arrhythmias (20 versus 36%, p = 0.07) and hospital mortality (30 versus 33%, p = 0.84) were not different between lower and higher MAP arms. Among patients aged 75 years or older, a lower MAP target was associated with reduced hospital mortality (13 versus 60%, p = 0.03) but not in younger patients.Conclusions: This pilot study supports the feasibility of a large trial comparing lower versus higher MAP targets for shock. Further research may help delineate the reasons for vasopressor dosing in excess of prescribed targets and how individual patient characteristics modify the response to vasopressor therapy. [ABSTRACT FROM AUTHOR]

Accessed 24 July 2023 13 Amstutz A, Speich B, Mentre F, Rueegg CS, Belhadi D, Assoumou L, Burdet C, Murthy S, Dodd LE, Wang Y. Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials. In less than 4 years, coronavirus disease 2019 (COVID-19) has been diagnosed in 768 million people worldwide, leading to close to 7 million deaths (https://covid19.who.int). The WHO Living guideline on COVID-19 Therapeutics and Clinical management has been a leading innovation in reviewing and synthesizing emerging evidence into timely and updated recommendations for treating patients with COVID-19 of all disease spectrum [[12]]. RCT data also demonstrated that remdesivir reduced mortality in patients hospitalized with COVID-19 who required no or conventional oxygen support but were not yet critically ill [[12]]. [Extracted from the article]

OBJECTIVES: The Lessening Organ Dysfunction with Vitamin C trial showed a harmful effect of vitamin C on 28-day death or persistent organ dysfunction. To maximize interpretation, we present a post hoc Bayesian reanalysis. DESIGN: Bayesian reanalysis of a randomized placebo-controlled trial. SETTING: Thirty-five ICUs. PATIENTS: Adults with proven or suspected infection, vasopressor support, and no more than 24 hours of ICU admission. INTERVENTIONS: Patients were allocated to receive either vitamin C (50 mg/kg of body weight) or placebo every 6 hours for up to 96 hours. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the composite of death or persistent organ dysfunction (i.e., vasopressor use, invasive mechanical ventilation, or new renal replacement therapy) at 28 days. We used Bayesian log-binomial models with random effects for hospital site and varying informative prior beliefs for the effect of vitamin C to estimate risk ratios (RRs) with 95% credible intervals (Crls) in the intention to treat population (vitamin C, 435 patients; placebo, 437 patients). Using weakly neutral priors, patients allocated to vitamin C had a higher risk of death or persistent organ dysfunction at 28 days (RR, 1.20; 95% Crl, 1.04–1.39; probability of harm, 99%). This effect was consistent when using optimistic (RR, 1.14; 95% Crl, 1.00–1.31; probability of harm, 98%) and empiric (RR, 1.09; 95% Crl, 0.97–1.22; probability of harm, 92%) priors. Patients allocated to vitamin C also had a higher risk of death at 28 days under weakly neutral (RR, 1.17; 95% Crl, 0.98–1.40; probability of harm, 96%), optimistic (RR, 1.10; 95% Crl, 0.94–1.30; probability of harm, 88%), and empiric (RR, 1.05; 95% Crl, 0.92–1.19; probability of harm, 76%) priors. CONCLUSIONS: The use of vitamin C in adult patients with proven or suspected infection and vasopressor support is associated with high probability of harm. [ABSTRACT FROM AUTHOR]

The article focuses on the efficiency of Corticosteroid therapy in the treatment of acute respiratory distress syndrome. It states that inflammatory exudates in patients having adult respiratory distress syndromes could be decreased with high doses of systemic corticosteroids. It also mentions that the experiments conducted on the animal models reveals that corticosteroids reduce lung elastance and thedeposition of collagen fibres in the extracellular matrix of the lung.

The article presents a study which systematically analyzed literature reviews of the treatments for sepsis that include animal studies. Data were obtained from EMBASE and MEDLINE. It was found that even though a large percentage of the reviews extrapolated the results to human patients, most of them failed to systematically analyze the clinical significance of preclinical studies and the risk of bias. A framework to improve such features is presented.

Background: Based on promising results from laboratory studies, we hypothesized that pneumococcal vaccination would protect patients from myocardial infarction. Methods: We conducted a hospital-based case-control study that included patients considered to be at risk of myocardial infarction. We used health databases to obtain hospital diagnoses and vaccination status. We compared patients who had been admitted for treatment of myocardial infarction with patients admitted to a surgical department in the same hospital for a reason other than myocardial infarction between 1997 and 2003. Results: We found a total of 43 209 patients who were at risk; of these, we matched 999 cases and 3996 controls according to age, sex and year of hospital admission. Cases were less likely than controls to have been vaccinated (adjusted odds ratio [OR] 0.53, 95% confidence interval [CI] 0.40-0.70). This putative protective role of the vaccine was not observed for patients who had received the vaccine up to 1 year before myocardial infarction (adjusted OR 0.85, 95% CI 0.54-1.33). In contrast, if vaccination had occurred 2 years or more before the hospital admission, the association was stronger (adjusted OR 0.33, 95% CI 0.20-0.46). Interpretation: Pneumococcal vaccination was associated with a decrease of more than 50% in the rate myocardial infarction 2 years after exposure. If confirmed, this association should generate interest in exploring the putative mechanisms and may offer another reason to promote pneumococcal vaccination. [ABSTRACT FROM AUTHOR]

The article focuses on evolution of supportive care for Ebola virus disease and proposed that aggressive supportive medical care was necessary and could coexist with infection prevention and control practices. It mentions Democratic Republic of the Congo (DRC) Ministry of Public Health, non-governmental organisations (NGOs), and others have strived to provide best care to patients. It also mentions conventional dialysis requires complex water treatment protocols.

We describe the case of an immunosuppressed transplant recipient with disseminated blastomycosis (cutaneous, central nervous system, and pulmonary infection) complicated by septic shock and severe, refractory acute respiratory distress syndrome that improved markedly and rapidly after the addition of corticosteroids to the antifungal regimen. [ABSTRACT FROM AUTHOR]

The author discusses the proposed use of quick Sequential Organ Failure Assessment (qSOFA) to identify patients with sepsis or likely to develop it by the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) task force. Topics include the qSOFA model's use of Glasgow Coma Scale score, systolic blood pressure, and respiratory rate to determine sepsis diagnosis, the 2016 redefinition of sepsis, and Freund et al.'s prospective study to determine the predictive validity of qSOFA.

The authors discuss the importance of supportive care as a specific care for Ebola virus disease which is ravaging West Africa as of October 2014. Topics include the availability of intravenous catheters, fluids, and electrolyte replacement which are being used much too sparingly, the historical bias against aggressive interventions including intravenous cannulation, and the importance of public health interventions including contact tracing and social mobilization.

Background: There is controversy regarding the optimal renal-replacement therapy (RRT) modality for critically ill patients with acute kidney injury (AKI). Methods: We conducted a secondary analysis of the STandard versus Accelerated Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial to compare outcomes among patients who initiated RRT with either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). We generated a propensity score for the likelihood of receiving CRRT and used inverse probability of treatment with overlap-weighting to address baseline inter-group differences. The primary outcome was a composite of death or RRT dependence at 90-days after randomization. Results: We identified 1590 trial participants who initially received CRRT and 606 who initially received IHD. The composite outcome of death or RRT dependence at 90-days occurred in 823 (51.8%) patients who commenced CRRT and 329 (54.3%) patients who commenced IHD (unadjusted odds ratio (OR) 0.90; 95% confidence interval (CI) 0.75–1.09). After balancing baseline characteristics with overlap weighting, initial receipt of CRRT was associated with a lower risk of death or RRT dependence at 90-days compared with initial receipt of IHD (OR 0.81; 95% CI 0.66–0.99). This association was predominantly driven by a lower risk of RRT dependence at 90-days (OR 0.61; 95% CI 0.39–0.94). Conclusions: In critically ill patients with severe AKI, initiation of CRRT, as compared to IHD, was associated with a significant reduction in the composite outcome of death or RRT dependence at 90-days. [ABSTRACT FROM AUTHOR]

Purpose: To assess whether pre-existing chronic kidney disease (CKD) modified the relationship between the strategy for renal-replacement theraphy (RRT) initiation and clinical outcomes in the STARRT-AKI trial. Methods: This was a secondary analysis of a multi-national randomized trial. We included patients who had documented pre-existing estimated glomerular filtration rate (eGFR) data prior to hospitalization, and we defined CKD as an eGFR ≤ 59 mL/min/1.73 m2. The primary outcome was all-cause mortality at 90 days. Secondary outcomes included RRT dependence and RRT-free days at 90 days. We used logistic and linear regression and interaction testing to explore the effect of RRT initiation strategy on outcomes by CKD status. Results: We studied 1121 patients who had pre-hospital measures of kidney function. Of these, 432 patients (38.5%) had CKD. The median (IQR) baseline serum creatinine was 130 (114–160) and 76 (64–90) µmol/L for those with and without CKD, respectively. Patients with CKD were older and more likely to have cardiovascular comorbidities and diabetes mellitus. Patients with CKD had higher 90-day mortality (47% vs. 40%, p < 0.001) compared to those without CKD, though this was not significant after covariate adjustment (adjusted odds ratio [aOR], 1.05; 95% CI, 0.79–1.41). Patients with CKD were more likely to remain RRT dependent at 90 days (14% vs. 8%; aOR, 1.89; 95% CI, 1.05–3.43). CKD status did not modify the effect of RRT initiation strategy on 90-day mortality. Among patients with CKD, allocation to the accelerated strategy conferred more than threefold greater odds of RRT dependence at 90 days (aOR 3.18; 95% CI, 1.41–7.91) compared with the standard strategy, whereas RRT initiation strategy had no effect on this outcome among those without CKD (aOR 0.71; 95% CI, 0.34–1.47, p value for interaction, 0.009). Conclusion: In this secondary analysis of the STARRT-AKI trial, an accelerated strategy of RRT initiation conferred a higher risk of 90-day RRT dependence among patients with pre-existing CKD; however, no effect was observed in the absence of CKD. [ABSTRACT FROM AUTHOR]

Rationale: The COVID-19 pandemic disrupted non-COVID critical care trials globally as intensive care units (ICUs) prioritized patient care and COVID-specific research. The international randomized controlled trial CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) was forced to halt recruitment at all sites in March 2020, creating immediate challenges. We applied the CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstance) statement as a framework to report the impact of the pandemic on CYCLE and describe our mitigation approaches.Methods: On March 23, 2020, the CYCLE Methods Centre distributed a standardized email to determine the number of patients still in-hospital and those requiring imminent 90-day endpoint assessments. We assessed protocol fidelity by documenting attempts to provide the in-hospital randomized intervention (cycling or routine physiotherapy) and collect the primary outcome (physical function 3-days post-ICU discharge) and 90-day outcomes. We advised sites to prioritize data for the study's primary outcome. We sought feedback on pandemic barriers related to trial procedures.Results: Our main Methods Centre mitigation strategies included identifying patients at risk for protocol deviations, communicating early and frequently with sites, developing standardized internal tools focused on high-risk points in the protocol for monitoring patient progress, data entry, and validation, and providing guidance to conduct some research activities remotely. For study sites, our strategies included determining how institutional pandemic research policies applied to CYCLE, communicating with the Methods Centre about capacity to continue any part of the research, and developing contingency plans to ensure the protocol was delivered as intended. From 15 active sites (12 Canada, 2 US, 1 Australia), 5 patients were still receiving the study intervention in ICUs, 6 required primary outcomes, and 17 required 90-day assessments. With these mitigation strategies, we attempted 100% of ICU interventions, 83% of primary outcomes, and 100% of 90-day assessments per our protocol.Conclusions: We retained all enrolled patients with minimal missing data using several time-sensitive strategies. Although CONSERVE recommends reporting only major modifications incurred by extenuating circumstances, we suggest that it also provides a helpful framework for reporting mitigation strategies with the goal of improving research transparency and trial management.Trial Registration: NCT03471247. Registered on March 20, 2018. [ABSTRACT FROM AUTHOR]

Objectives: Sepsis awareness and understanding are important aspects of prevention, recognition, and clinical management of sepsis. We conducted a scoping review to identify and map the literature related to sepsis awareness, general knowledge, and information-seeking behaviors with a goal to inform future sepsis research and knowledge translation campaigns.Design: Scoping review.Setting: Using Arksey and O'Malley's methodological framework, we conducted a systematic search on May 3, 2021, across four databases (MEDLINE, EMBASE, CINAHL, and Education Research Complete). Title/abstract and full-text screening was done in duplicate. One researcher extracted the data for each included article, and a second researcher checked data accuracy. The protocol was registered on Open Science Framework ( https://doi.org/10.17605/OSF.IO/YX7AU ).Subjects: Articles related to sepsis awareness, knowledge, and information seeking behaviors among patients, public, and healthcare professionals.Interventions: None.Measurements and Main Results: Of 5,927 unique studies, 80 reported on patient ( n = 13/80;16.3%), public ( n = 15/80;18.8%), or healthcare professional (nurses, physicians, emergency medical technicians) ( n = 48/80; 60%) awareness and knowledge of sepsis. Healthcare professional awareness and knowledge of sepsis is high compared with patients/public. The proportion of patients/public who had heard of the term sepsis ranged from 2% (Japan) to 88.6% (Germany). The proportions of patients/public who correctly identified the definition of sepsis ranged from 4.2% (Singapore) to 92% (Sweden). The results from the included studies appear to suggest that patient/public awareness of sepsis gradually improved over time. We found that the definition of sepsis was inconsistent in the literature and that few studies reported on patient, public, or healthcare professional knowledge of sepsis risk factors. Most patient/public get their sepsis information from the internet, whereas healthcare professionals get it from their role in healthcare through job training or educational training.Conclusions: Patient, public, and healthcare professional awareness and knowledge of sepsis vary globally. Future research may benefit from a consistent definition as well as country-specific data to support targeted public awareness campaigns. [ABSTRACT FROM AUTHOR]

Rhode Island Hospital: Matthew Lynch; AnnMarie O'Mara; Syed Naeem; Sairah Sharif; Joyce McKenney Goulart. Worthing Hospital, Western Sussex Hospitals NHS Foundation Trust: Luke E. Hodgson; Indra Chadbourn; Raquel Gomez; Jordi Margalef. Nottingham University Hospital-Queen's Medical Centre: Andrew Sharman; Megan Meredith; Lucy Ryan; Louise Conner; Cecilia Peters; Dan Harvey. The Miriam Hospital: Matthew Lynch; AnnMarie O'Mara; Syed Naeem; Sairah Sharif; Joyce McKenney Goulart. [Extracted from the article]

Background: There have been multiple waves in the COVID-19 pandemic in many countries. We sought to compare mortality and respiratory, cardiovascular and renal dysfunction between waves in 3 Canadian provinces. Methods: We conducted a substudy of the ARBs CORONA I study, a multicentre Canadian pragmatic observational cohort study that examined the association of pre-existing use of angiotensin receptor blockers with outcomes in adults admitted to hospital with acute COVID-19 up to April 2021 from 9 community and teaching hospitals in 3 Canadian provinces (British Columbia, Ontario and Quebec). We excluded emergency department admissions without hospital admission, readmissions and admissions for another reason. We used logistic and 0–1-inflated β regression models to compare 28-day and in-hospital mortality, and the use of invasive mechanical ventilation, vasopressors and renal replacement therapy (RRT) between the first 3 waves of the COVID-19 pandemic in these provinces. Results: A total of 520, 572 and 245 patients in waves 1, 2 and 3, respectively, were included. Patients in wave 3 were on average younger and had fewer comorbidities than those in waves 1 and 2. The unadjusted 28-day mortality rate was significantly lower in wave 3 (7.8%) than in wave 1 (18.3%) (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.24–0.78) and wave 2 (16.3%) (OR 0.46, 95% CI 0.27–0.79). After adjustment for differences in baseline characteristics, the difference in 28-day mortality remained significant (adjusted OR wave 3 v. wave 1: 0.46, 95% CI 0.26–0.81; wave 3 v. wave 2: 0.52, 95% CI 0.29–0.91). In-hospital mortality findings were similar. Use of invasive mechanical ventilation or vasopressors was less common in waves 2 and 3 than in wave 1, and use of RRT was less common in wave 3 than in wave 1. Interpretation: Severity of illness decreased (lower mortality and less use of organ support) across waves among patients admitted to hospital with acute COVID-19, possibly owing to changes in patient demographic characteristics and management, such as increased use of dexamethasone. Continued application of proven therapies may further improve outcomes. Study registration: ClinicalTrials.gov, no. NCT04510623 [ABSTRACT FROM AUTHOR]

Background: In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. Methods: For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. Results: We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). Conclusions: The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change. [ABSTRACT FROM AUTHOR]

Objectives: Low-value clinical practices have been identified as one of the most important areas of excess healthcare spending. Nevertheless, there is a knowledge gap on the scale of this problem in injury care. We aimed to identify clinical practice guideline (CPG) recommendations pertaining to low-value injury care, estimate how frequently they are used in practice, and evaluate interhospital variations in their use.Methods: We identified low-value clinical practices from internationally recognized CPGs. We conducted a retrospective cohort study using data from a Canadian trauma system (2014-2019) to calculate frequencies and assess interhospital variations.Results: We identified 29 low-value practices. Fourteen could be measured using trauma registry data. The 3 low-value clinical practices with the highest absolute and relative frequencies were computed tomography (CT) in adults with minor head injury (n = 5591, 24%), cervical spine CT (n = 2742, 31%), and whole-body CT in minor or single-system trauma (n = 530, 32%). We observed high interhospital variation for decompressive craniectomy in diffuse traumatic brain injury. Frequencies and interhospital variations were low for magnetic resonance imaging, intracranial pressure monitoring, inferior vena cava filter use, and surgical management of blunt abdominal injuries.Conclusions: We observed evidence of poor adherence to CPG recommendations on low-value CT imaging and high practice variation for decompressive craniectomy. Results suggest that adherence to recommendations for the 10 other low-value practices is high. These data can be used to advance the research agenda on low-value injury care and inform the development of interventions targeting reductions in healthcare overuse in this population. [ABSTRACT FROM AUTHOR]

Background: High-dose vitamin C is increasingly used for sepsis and more recently for coronavirus disease 2019 (COVID-19) infections. Proponents argue that the low cost and near perfect safety profile of vitamin C support its early adoption. Yet, adverse events might be underreported and underappreciated.Case Presentation: We report a 73-year-old non-diabetic white man with end-stage renal disease on peritoneal dialysis admitted to the intensive care unit with septic shock that was suspected to be due to peritonitis. The patient was enrolled in LOVIT (Lessening Organ Dysfunction with VITamin C; ClinicalTrials.gov identifier: NCT03680274), a randomized placebo-controlled trial of high-dose intravenous vitamin C. He developed factitious hyperglycemia, as measured with a point-of-care glucometer, that persisted for 6 days after discontinuation of the study drug, confirmed to be vitamin C after unblinding. He also had short-lived iatrogenic coma because of hypoglycemia secondary to insulin administration. These events triggered a protocol amendment.Conclusions: Although factitious hyperglycemia has been reported before using certain glucometers in patients treated with high-dose vitamin C, the persistence of this phenomenon for 6 days after the discontinuation of the therapy is a distinguishing feature. This case highlights the importance of monitoring glucose with a core laboratory assay for up to a week in specific populations, such as patients on peritoneal dialysis. [ABSTRACT FROM AUTHOR]

Purpose: Corticosteroids are now recommended for patients with severe COVID-19 including those with COVID-related ARDS. This has generated renewed interest regarding whether corticosteroids should be used in non-COVID ARDS as well. The objective of this study was to summarize all RCTs examining the use of corticosteroids in ARDS.Methods: The protocol of this study was pre-registered on PROSPERO (CRD42020200659). We searched online databases including MEDLINE, EMBASE, CDC library of COVID research, CINAHL, and COCHRANE. We included RCTs that compared the effect of corticosteroids to placebo or usual care in adult patients with ARDS, including patients with COVID-19. Three reviewers abstracted data independently and in duplicate using a pre-specified standardized form. We assessed individual study risk of bias using the revised Cochrane ROB-2 tool and rated certainty in outcomes using GRADE methodology. We pooled data using a random effects model. The main outcome for this review was 28-day-mortality.Results: We included 18 RCTs enrolling 2826 patients. The use of corticosteroids probably reduced mortality in patients with ARDS of any etiology (2740 patients in 16 trials, RR 0.82, 95% CI 0.72-0.95, ARR 8.0%, 95% CI 2.2-12.5%, moderate certainty). Patients who received a longer course of corticosteroids (over 7 days) had higher rates of survival compared to a shorter course.Conclusion: The use of corticosteroids probably reduces mortality in patients with ARDS. This effect was consistent between patients with COVID-19 and non-COVID-19 ARDS, corticosteroid types, and dosage. [ABSTRACT FROM AUTHOR]

Objectives: Cost utility analyses compare the costs and health outcome of interventions, with a denominator of quality-adjusted life year, a generic health utility measure combining both quality and quantity of life. Cost utility analyses are difficult to compare when methods are not standardized. It is unclear how cost utility analyses are measured/reported in critical care and what methodologic challenges cost utility analyses pose in this setting. This may lead to differences precluding cost utility analyses comparisons. Therefore, we performed a systematic review of cost utility analyses conducted in critical care. Our objectives were to understand: 1) methodologic characteristics, 2) how health-related quality-of-life was measured/reported, and 3) what costs were reported/measured.Design: Systematic review.Data Sources: We systematically searched for cost utility analyses in critical care in MEDLINE, Embase, American College of Physicians Journal Club, CENTRAL, Evidence-Based Medicine Reviews' selected subset of archived versions of UK National Health Service Economic Evaluation Database, Database of Abstracts of Reviews of Effects, and American Economic Association electronic databases from inception to April 30, 2020.Setting: Adult ICUs.Patients: Adult critically ill patients.Interventions: None.Measurements and Main Results: Of 8,926 citations, 80 cost utility analyse studies were eligible. The time horizon most commonly reported was lifetime (59%). For health utility reporting, health-related quality-of-life was infrequently measured (29% reported), with only 5% of studies reporting baseline health-related quality-of-life. Indirect utility measures (generic, preference-based health utility measurement tools) were reported in 85% of studies (majority Euro-quality-of-life-5 Domains, 52%). Methods of estimating health-related quality-of-life were seldom used when the patient was incapacitated: imputation (19%), assigning fixed utilities for incapacitation (19%), and surrogates reporting on behalf of incapacitated patients (5%). For cost utility reporting transparency, separate incremental costs and quality-adjusted life years were both reported in only 76% of studies. Disaggregated quality-adjusted life years (reporting separate health utility and life years) were described in only 34% of studies.Conclusions: We identified deficiencies which warrant recommendations (standardized measurement/reporting of resource use/unit costs/health-related quality-of-life/methodological preferences) for improved design, conduct, and reporting of future cost utility analyses in critical care. [ABSTRACT FROM AUTHOR]

Despite numerous interventions and treatment options, the outcomes of traumatic brain injury (TBI) have improved little over the last 3 decades, which raises concern about the value of care in this patient population. We aimed to synthesize the evidence on 14 potentially low-value clinical practices in TBI care. Using umbrella review methodology, we identified systematic reviews evaluating the effectiveness of 14 potentially low-value practices in adults with acute TBI. We present data on methodological quality (Assessing the Methodological Quality of Systematic Reviews), reported effect sizes, and credibility of evidence (I to IV). The only clinical practice with evidence of benefit was therapeutic hypothermia (credibility of evidence II to IV). However, the most recent meta-analysis on hypothermia based on high-quality trials suggested harm (credibility of evidence IV). Meta-analyses on platelet transfusion for patients on antiplatelet therapy were all consistent with harm but were statistically non-significant. For the following practices, effect estimates were consistently close to the null: computed tomography (CT) in adults with mild TBI who are low-risk on a validated clinical decision rule; repeat CT in adults with mild TBI on anticoagulant therapy with no clinical deterioration; antibiotic prophylaxis for external ventricular drain placement; and decompressive craniectomy for refractory intracranial hypertension. We identified five clinical practices with evidence of lack of benefit or harm. However, evidence could not be considered to be strong for any clinical practice as effect measures were imprecise and heterogeneous, systematic reviews were often of low quality, and most included studies had a high risk of bias. [ABSTRACT FROM AUTHOR]

Research to inform the care of neurologically deceased organ donors is complicated by a lack of standards for research consent. In this systematic review, we aim to describe current practices of soliciting consent for participation in prospective studies of neurologically deceased donors, including the frequency and justification for these various models of consent. Among the 74 studies included, 14 did not report on any regulatory review, and 13 did not report on the study consent procedures. Of the remaining 47 studies, 24 utilized a waiver of research consent. The most common justification for a waiver of research consent related to the fact that neurologically deceased donors are not considered human subjects. In conclusion, among studies of neurologically deceased donors, research consent models vary and are inconsistently reported. Consensus and standardization in the application of research consent models will help to advance this emerging field of research. [ABSTRACT FROM AUTHOR]

Objectives: To examine adverse events and associated factors and outcomes during transition from ICU to hospital ward (after ICU discharge).Design: Multicenter cohort study.Setting: Ten adult medical-surgical Canadian ICUs.Patients: Patients were those admitted to one of the 10 ICUs from July 2014 to January 2016.Interventions: None.Measurements and Main Results: Two ICU physicians independently reviewed progress and consultation notes documented in the medical record within 7 days of patient's ICU discharge date to identify and classify adverse events. The adverse event data were linked to patient characteristics and ICU and ward physician surveys collected during the larger prospective cohort study. Analyses were conducted using multivariable logistic regression. Of the 451 patients included in the study, 84 (19%) experienced an adverse event, the majority (62%) within 3 days of transfer from ICU to hospital ward. Most adverse events resulted only in symptoms (77%) and 36% were judged to be preventable. Patients with adverse events were more likely to be readmitted to the ICU (odds ratio, 5.5; 95% CI, 2.4-13.0), have a longer hospital stay (mean difference, 16.1 d; 95% CI, 8.4-23.7) or die in hospital (odds ratio, 4.6; 95% CI, 1.8-11.8) than those without an adverse event. ICU and ward physician predictions at the time of ICU discharge had low sensitivity and specificity for predicting adverse events, ICU readmissions, and hospital death.Conclusions: Adverse events are common after ICU discharge to hospital ward and are associated with ICU readmission, increased hospital length of stay and death and are not predicted by ICU or ward physicians. [ABSTRACT FROM AUTHOR]

The available evidence for treatment of coronavirus disease 2019 (COVID-19) is either indirect (from studies of influenza, severe acute respiratory syndrome and Middle East respiratory syndrome) or from several observational studies and randomized controlled trials in patients with COVID-19, which are limited in sample size and rigour, permitting only weak recommendations. Therefore, we have developed an evidence-based guideline that focuses on both patients with nonsevere and severe COVID-19 and, for use of corticosteroids, patients with ARDS. Best evidence suggests that about 85% of such patients will never progress to critical illness such as ARDS.[1] Because we anticipate that clinicians are unlikely to consider the use of convalescent plasma in patients with nonsevere COVID-19, for this intervention we addressed only patients with severe COVID-19. In this context, when any benefit is very uncertain, our inferences regarding patient values and preferences dictate a weak recommendation against use of corticosteroids in patients with severe COVID-19 who do not have ARDS. [Extracted from the article]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Using data from the CORONARY trial (n  = 4752), we evaluated the incidence and prognostic significance of myocardial infarction (MI) applying different definitions based on peak postoperative creatine kinase-MB isoenzyme and cardiac troponin levels. We then aimed to identify the peak cardiac troponin during the first 3 postoperative days that was independently associated with a 2-fold increase in 30-day mortality. METHODS To combine different assays, we analysed cardiac troponins in multiples of their respective upper limit of normal (ULN). We identified the lowest threshold with a hazard ratio (HR) >2 for 30-day mortality independent of EuroSCORE and on- versus off-pump surgery. RESULTS Depending on the definition used based on creatine kinase-MB, the incidence of MI after coronary artery bypass grafting (CABG) ranged from 0.6% to 19% and the associated HRs for 30-day mortality ranged from 2.7 to 6.9. Using cardiac troponin (1528 patients), the incidence of MI ranged from 1.7% to 13% depending on the definition used with HRs for 30-day mortality ranging from 5.1 to 7.2. The first cardiac troponin threshold we evaluated, 180xULN, was associated with an adjusted HR for 30-day mortality of 7.6 [95% confidence interval (CI) 3.4–17.1] when compared to <130xULN. The next independent threshold was 130xULN with an adjusted HR for 30-day mortality of 7.8 (95% CI 2.3–26.1). The next cardiac troponin tested threshold (70xULN) did not meet criteria for significance. CONCLUSIONS Our results illustrate that the incidence and prognosis of a post-CABG MI varies based on the definition used. Validated post-CABG MI diagnostic criteria formulated from their independent association with important clinical outcomes are needed. [ABSTRACT FROM AUTHOR]

Background: Most deaths in critically ill patients with severe traumatic brain injury are associated with a decision to withdraw life-sustaining treatments. We aimed to identify the behavioural determinants that influence recommendations by critical care physicians to consider the withdrawal of life-sustaining treatments in this population.Methods: We conducted a descriptive qualitative study based on the Theoretical Domains Framework of critical care physicians caring for patients with severe traumatic brain injury across Canada. We stratified critical care physicians by regions and used a purposive sampling strategy. We conducted semistructured phone interviews using a piloted and pretested interview guide. We transcribed the interviews verbatim and verified the content for accuracy. We performed the analysis using a 3-step approach: coding, generation of specific beliefs and generation of specific themes.Results: We recruited 20 critical care physicians across 4 geographic regions. After reaching saturation, we identified 7 core themes across 4 Theoretical Domains Framework domains for factors relevant to the decision to withdraw life-sustaining treatments. Four factors (i.e., clinical triggers, social triggers, interaction with families and intentions with medical decisions) were identified before the decision is made and 3 were identified during the decision-making process (i.e., considerations, priorities and knowledge needs). We identified multiple themes reflecting internal (n = 18, 8 Theoretical Domains Framework domains) and external (n = 15, 6 Theoretical Domains Framework domains) influences on the decision to withdraw life-sustaining treatments.Interpretation: We identified several core themes and domains considered by critical care physicians in Canada in the decision to withdraw life-sustaining treatments in critically ill patients with severe traumatic brain injury. Future research should aim at identifying the factors influencing surrogate decision-makers in the decision to withdraw life-sustaining treatments in these patients. [ABSTRACT FROM AUTHOR]

Objectives: Biomarkers have been suggested as potential prognostic predictors following a moderate or severe traumatic brain injury but their prognostic accuracy is still uncertain. The objective of this systematic review is to assess the ability of the glial fibrillary acidic protein to predict prognosis in patients with moderate or severe traumatic brain injury.Data Sources: MEDLINE, Embase, CENTRAL, and BIOSIS electronic databases and conference abstracts, bibliographies of selected studies, and narrative reviews were searched.Study Selection: Pairs of reviewers identified eligible studies. Cohort studies including greater than or equal to four patients with moderate or severe traumatic brain injury and reporting glial fibrillary acidic protein levels according to the outcomes of interest, namely Glasgow Outcome Scale or Extended Glasgow Outcome Scale, and mortality, were eligible.Data Extraction: Pairs of reviewers independently extracted data from the selected studies using a standardized case report form. Mean levels were log-transformed, and their differences were pooled with random effect models. Results are presented as geometric mean ratios. Methodologic quality, risk of bias, and applicability concerns of the included studies were assessed.Data Synthesis: Seven-thousand seven-hundred sixty-five citations were retrieved of which 15 studies were included in the systematic review (n = 1,070), and nine were included in the meta-analysis (n = 701). We found significant associations between glial fibrillary acidic protein serum levels and Glasgow Outcome Scale score less than or equal to 3 or Extended Glasgow Outcome Scale score less than or equal to 4 (six studies: geometric mean ratio 4.98 [95% CI, 2.19-11.13]; I = 94%) and between mortality (seven studies: geometric mean ratio 8.13 [95% CI, 3.89-17.00]; I = 99%).Conclusions: Serum glial fibrillary acidic protein levels were significantly higher in patients with an unfavorable prognosis. Glial fibrillary acidic protein has a potential for clinical bedside use in helping for prognostic assessment. Further research should focus on multimodal approaches including tissue biomarkers for prognostic evaluation in critically ill patients with traumatic brain injury. [ABSTRACT FROM AUTHOR]

Background: Perioperative corticosteroid use may reduce acute kidney injury. We sought to test whether methylprednisolone reduces the risk of acute kidney injury after cardiac surgery.Methods: We conducted a prespecified substudy of a randomized controlled trial involving patients undergoing cardiac surgery with cardiopulmonary bypass (2007-2014); patients were recruited from 79 centres in 18 countries. Eligibility criteria included a moderate-to-high risk of perioperative death based on a preoperative score of 6 or greater on the European System for Cardiac Operative Risk Evaluation I. Patients (n = 7286) were randomly assigned (1:1) to receive intravenous methylprednisolone (250 mg at anesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients, caregivers, data collectors and outcome adjudicators were unaware of the assigned intervention. The primary outcome was postoperative acute kidney injury, defined as an increase in the serum creatinine concentration (from the preoperative value) of 0.3 mg/dL or greater (≥ 26.5 μmol/L) or 50% or greater in the 14-day period after surgery, or use of dialysis within 30 days after surgery.Results: Acute kidney injury occurred in 1479/3647 patients (40.6%) in the methylprednisolone group and in 1426/3639 patients (39.2%) in the placebo group (adjusted relative risk 1.04, 95% confidence interval 0.96 to 1.11). Results were consistent across several definitions of acute kidney injury and in patients with preoperative chronic kidney disease.Interpretation: Intraoperative corticosteroid use did not reduce the risk of acute kidney injury in patients with a moderate-to-high risk of perioperative death who had cardiac surgery with cardiopulmonary bypass. Our results do not support the prophylactic use of steroids during cardiopulmonary bypass surgery. Trial registration: ClinicalTrials.gov, no. NCT00427388. [ABSTRACT FROM AUTHOR]

The acute respiratory distress syndrome (ARDS) may encompass sub-populations that respond differently to treatments [[1]]. The hypothesized effect modifier (risk of RV failure) was defined by the acute cor pulmonale (ACP) score measured at baseline (pre-randomization) [[5]]. [Extracted from the article]

Objectives: Mechanisms underlying sepsis-associated encephalopathy remain unclear, but reduced cerebral blood flow, alone or in conjunction with altered autoregulation, is reported as a potential contributor. We compared cerebral blood flow of control subjects and vasopressor-dependent septic patients.Design: Randomized crossover study.Setting: MRI with arterial spin labeling.Patients: Ten sedated septic patients on mechanical ventilation (four with controlled chronic hypertension) and 12 control subjects (six with controlled chronic hypertension) were enrolled. Mean ± SD ages were 61.4 ± 10.2 and 44.2 ± 12.8 years, respectively (p = 0.003). Mean Acute Physiology and Chronic Health Evaluation II score of septic patients at ICU admission was 27.7 ± 6.6.Interventions: To assess the potential confounding effects of sedation and mean arterial pressure, we measured cerebral blood flow with and without sedation with propofol in control subjects and at a target mean arterial pressure of 65 mm Hg and greater than or equal to 75 mm Hg in septic patients. The sequence of sedation versus no sedation and mean arterial pressure targets were randomized.Measurements and Main Results: In septic patients, cerebral blood flow measured at a mean arterial pressure target of 65 mm Hg (40.4 ± 10.9 mL/100 g/min) was not different from cerebral blood flow measured at a mean arterial pressure target of greater than or equal to 75 mm Hg (41.3 ± 9.8 mL/100 g/min; p = 0.65). In control subjects, we observed no difference in cerebral blood flow measured without and with sedation (24.8 ± 4.2 vs 24.9 ± 5.9 mL/100 g/min; p = 0.93). We found no interaction between chronic hypertension and the effect of sedation or mean arterial pressure targets. Cerebral blood flow measured in sedated septic patients (mean arterial pressure target 65 mm Hg) was 62% higher than in sedated control subjects (p = 0.001).Conclusions: In septic patients, cerebral blood flow was higher than in sedated control subjects and did not vary with mean arterial pressure targets. Further research is required to understand the clinical significance of cerebral hyperperfusion in septic patients on vasopressors and to reassess the neurologic effects of current mean arterial pressure targets in sepsis. [ABSTRACT FROM AUTHOR]

Background: During the 2013–2016 West Africa Ebola outbreak, supportive care was the only non-experimental treatment option for patients with Ebola virus disease (EVD). However, providing care that would otherwise be routine for most clinical settings in the context of a highly contagious and lethal pathogen is much more challenging. The objective of this study was to document and deepen understanding of barriers to provision of supportive care in Ebola treatment units (ETUs) as perceived by those involved in care delivery during the outbreak. Methods: This qualitative study consisted of 29 in-depth semi-structured interviews with stakeholders (decision-makers, physicians, nurses) involved in patient care delivery during the outbreak. Analysis consisted of interview debriefing and team-based transcript coding in NVivo10 software using thematic analysis. Findings: Participants emphasized three interconnected barriers to providing high-quality supportive care during the outbreak: 1) lack of material and human resources in ETUs; 2) ETU organizational structure limiting the provision of supportive clinical care; and 3) delayed and poorly coordinated policies limiting the effectiveness of global and national responses. Participants also noted the ethical complexities of defining and enacting best clinical practices in low-income countries. They noted tension between, on one hand, scaling up minimal care and investing in clinical care preparedness to a level sustainable in West Africa and, on the other, providing a higher level of supportive care, which in low-resource health systems would require important investments. Conclusion: Our findings identified potentially modifiable barriers to the delivery of supportive care to patients with EVD in West Africa. Addressing these in the inter-outbreak period will be useful to improve patient care and outcomes during inevitable future outbreaks. Promoting community trust and engagement through long-term capacity building of the healthcare workforce and infrastructure would increase both health system resilience and ability to handle other outbreaks of emerging diseases. [ABSTRACT FROM AUTHOR]

Background: Informed consent is a hallmark of ethical clinical research. An inherent challenge in critical care research is obtaining consent when patients lack decision-making capacity. One solution is deferred consent, which is often used for studies that are low risk or involve emergency interventions. Our objective was to describe a deferred consent model in a low-risk critical care study. Methods: Prognostic Value of Elevated Troponins in Critical Illness Study was a prospective, pilot observational study of critically ill patients in 3 intensive care units, involving serial electrocardiograms and cardiac biomarkers. Newly admitted patients were enrolled over 1 month. When possible, informed consent was obtained a priori from the patient or substitute decision maker (SDM); otherwise, consent was deferred until the patient regained consent capacity or until their SDM was available. Logistic regression analysis was used to determine the association between patient’s sex, Acute Physiology and Chronic Health Evaluation II score, study center, person providing consent (patient vs SDM), method of consent (telephone vs in person), and the provision or not of informed consent. Results: The overall consent rate was 80.1% (213 of 266 persons approached). Of the 53 persons declining consent, 37 (69.8%) agreed to the use of data collected up until that point. Over half of all consent encounters were with patients rather than SDMs. Median interval delay between enrollment and the consent encounter was 1 day. On multivariate analysis, the only variable associated with consent was male sex of the patient (odds ratio for males 2.59, confidence interval: 1.19-5.63). Conclusion: Deferred consent facilitates implementation of time-sensitive research protocols until a consent encounter is possible. As a feasible alternative to exclusive a priori consent, the deferred consent model can be useful in low-risk studies in critically ill patients. [ABSTRACT FROM AUTHOR]

Importance: Vasopressin is an alternative to catecholamine vasopressors for patients with distributive shock-a condition due to excessive vasodilation, most frequently from severe infection. Blood pressure support with a noncatecholamine vasopressor may reduce stimulation of adrenergic receptors and decrease myocardial oxygen demand. Atrial fibrillation is common with catecholamines and is associated with adverse events, including mortality and increased length of stay (LOS).Objectives: To determine whether treatment with vasopressin + catecholamine vasopressors compared with catecholamine vasopressors alone was associated with reductions in the risk of adverse events.Data Sources: MEDLINE, EMBASE, and CENTRAL were searched from inception to February 2018. Experts were asked and meta-registries searched to identify ongoing trials.Study Selection: Pairs of reviewers identified randomized clinical trials comparing vasopressin in combination with catecholamine vasopressors to catecholamines alone for patients with distributive shock.Data Extraction and Synthesis: Two reviewers abstracted data independently. A random-effects model was used to combine data.Main Outcomes and Measures: The primary outcome was atrial fibrillation. Other outcomes included mortality, requirement for renal replacement therapy (RRT), myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit and hospital. Measures of association are reported as risk ratios (RRs) for clinical outcomes and mean differences for LOS.Results: Twenty-three randomized clinical trials were identified (3088 patients; mean age, 61.1 years [14.2]; women, 45.3%). High-quality evidence supported a lower risk of atrial fibrillation associated with vasopressin treatment (RR, 0.77 [95% CI, 0.67 to 0.88]; risk difference [RD], -0.06 [95% CI, -0.13 to 0.01]). For mortality, the overall RR estimate was 0.89 (95% CI, 0.82 to 0.97; RD, -0.04 [95% CI, -0.07 to 0.00]); however, when limited to trials at low risk of bias, the RR estimate was 0.96 (95% CI, 0.84 to 1.11). The overall RR estimate for RRT was 0.74 (95% CI, 0.51 to 1.08; RD, -0.07 [95% CI, -0.12 to -0.01]). However, in an analysis limited to trials at low risk of bias, RR was 0.70 (95% CI, 0.53 to 0.92, P for interaction = .77). There were no significant differences in the pooled risks for other outcomes.Conclusions and Relevance: In this systematic review and meta-analysis, the addition of vasopressin to catecholamine vasopressors compared with catecholamines alone was associated with a lower risk of atrial fibrillation. Findings for secondary outcomes varied. [ABSTRACT FROM AUTHOR]

Objectives: Vasopressors are not recommended by current trauma guidelines, but recent reports indicate that they are commonly used. We aimed to describe the early hemodynamic management of trauma patients outside densely populated urban centers. Methods: We conducted a single-center retrospective cohort study in a Canadian regional trauma center. All adult patients treated for traumatic injury in 2013 who died within 24 hours of admission or were transferred to the intensive care unit were included. A systolic blood pressure <90 mmHg, a mean arterial pressure <60 mmHg, the use of vasopressors or ≥2 L of intravenous fluids defined hemodynamic instability. Main outcome measures were use of intravenous fluids and vasopressors prior to surgical or endovascular management. Results: Of 111 eligible patients, 63 met our criteria for hemodynamic instability. Of these, 60 (95%) had sustained blunt injury and 22 (35%) had concomitant severe traumatic brain injury. The subgroup of patients referred from a primary or secondary hospital (20 of 63, 32%) had significantly longer transport times (243 vs. 61 min, p<0.01). Vasopressors, used in 26 patients (41%), were independently associated with severe traumatic brain injury (odds ratio 10.2, 95% CI 2.7–38.5). Conclusions: In this cohort, most trauma patients had suffered multiple blunt injuries. Patients were likely to receive vasopressors during the early phase of trauma care, particularly if they exhibited signs of neurologic injury. While these results may be context-specific, determining the risk-benefit trade-offs of fluid resuscitation, vasopressors and permissive hypotension in specific patients subgroups constitutes a priority for trauma research going forwards. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a worldwide leading cause of mortality and disability. Among TBI complications, agitation is a frequent behavioural problem. Agitation causes potential harm to patients and caregivers, interferes with treatments, leads to unnecessary chemical and physical restraints, increases hospital length of stay, delays rehabilitation, and impedes functional independence. Pharmacological treatments are often considered for agitation management following TBI. Several types of agents have been proposed for the treatment of agitation. However, the benefit and safety of these agents in TBI patients as well as their differential effects and interactions are uncertain. In addition, animal studies and observational studies have suggested impaired cognitive function with the use of certain antipsychotics and benzodiazepines. Hence, a safe and effective treatment for agitation, which does not interfere with neurological recovery, remains to be identified. Methods/design: With the help of Health Sciences librarian, we will design a search strategy in the following databases: PubMed, Ovid MEDLINE®, EMBASE, CINAHL, PsycINFO, Cochrane Library, Google Scholar, Directory of Open Access Journals, LILACS, Web of Science, and Prospero. A grey literature search will be performed using the resources suggested in CADTH’s Grey Matters. We will include all randomized controlled, quasi-experimental, and observational studies with control groups. The population of interest is all patients, including children and adults, who have suffered a TBI. We will include studies in which agitation, not further defined, was the presenting symptom or one of the presenting symptoms. We will also include studies where agitation was not the presenting symptom but was measured as an outcome variable and studies assessing the safety of these pharmacological interventions in TBI patients. We will include studies evaluating all pharmacological interventions including betaadrenergic blockers, typical and atypical antipsychotics, anticonvulsants, dopamine agonists, psychostimulants, antidepressants, alpha-2-adrenergic agonists, hypnotics, and anxiolytics. Discussion: Although agitation is frequent following TBI and pharmacological agents that are often used, there is no consensus on the most efficacious and safest strategy to treat these complications. There is a need for an updated systematic review to summarize the evidence in order to inform practice and future research. [ABSTRACT FROM AUTHOR]

Background: Surveillance of antimicrobial resistance is vital to guiding empirical treatment of infections. Collating and reporting routine data on clinical isolate testing may offer more timely information about resistance patterns than traditional surveillance network methods. Methods: Using routine microbiology testing data collected from the Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness retrospective cohort study, we conducted a descriptive secondary analysis among critically ill patients in whom bloodstream infections had been diagnosed in 14 intensive care units (ICUs) in Canada. The participating sites were located within tertiary care teaching hospitals and represented 6 provinces and 10 cities. More than 80% of the study population was accrued from 2011-2013. We assessed the epidemiologic features of the infections and corresponding antimicrobial susceptibility profiles. Susceptibility testing was done according to Clinical Laboratory Standards Institute guidelines at accredited laboratories. Results: A total of 1416 pathogens were isolated from 1202 patients. The most common organisms were Escherichia coli (217 isolates [15.3%]), Staphylococcus aureus (175 [12.4%]), coagulase-negative staphylococci (117 [8.3%]), Klebsiella pneumoniae (86 [6.1%]) and Streptococcus pneumoniae (85 [6.0%]). The contribution of individual pathogens varied by site. For 13 ICUs, gram-negative susceptibility rates were high for carbapenems (95.4%), tobramycin (91.2%) and piperacillin--tazobactam (90.0%); however, the proportion of specimens susceptible to these agents ranged from 75.0%-100%, 66.7%-100% and 75.0%-100%, respectively, across sites. Fewer gram-negative bacteria were susceptible to fluoroquinolones (84.5% [range 64.1%-97.2%]). A total of 145 patients (12.1%) had infections caused by highly resistant microorganisms, with significant intersite variation (range 2.6%-24.0%, א² = 57.50, p < 0.001). Interpretation: We assessed the epidemiologic features of bloodstream infections in a geographically diverse cohort of critically ill Canadian patients using routine pathogen and susceptibility data extracted from readily available microbiology testing databases. Expanding data sharing across more ICUs, with serial measurement and prompt reporting, could provide much-needed guidance for empiric treatment for patients as well as system-wide prevention methods to limit antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Background: The promotion of early mobilization following critical illness is tempered by national reports of patient and institutional barriers to this approach. We carried out a survey to assess current knowledge, perceptions and practices of Canadian physicians and physiotherapists with respect to acquired weakness and early mobilization in adults in the intensive care unit (ICU). Methods: We conducted a cross-sectional, self-administered postal survey among critical care physicians and physiotherapists in all 46 academic ICUs in Canada in 2011-2012. To identify all physicians and physiotherapists working in the ICUs, we contacted division heads and senior physiotherapists by telephone or email. We designed, tested and administered a questionnaire with the following domains: knowledge of ICU-acquired weakness and early mobilization; personal views of, perceived barriers to and adequacy of technical skills for early mobilization; assessments for initiation of early mobilization and permissible activity levels by patient physiologic characteristics, diagnoses and therapies; staffing issues; and sedation practices. Results: The overall response rate was 71.3% (311/436); it was 64.2% (194/302) among physicians and 87.3% (117/134) among physiotherapists. A total of 214 respondents (68.8%) underestimated the incidence of ICU-acquired weakness in the general medical-surgical ICU population, and 186 (59.8%) stated they had insufficient knowledge or skills to mobilize patients receiving mechanical ventilation. Excessive sedation, medical instability, limited staffing, safety concerns, insufficient guidelines and insufficient equipment were common perceived barriers to early mobilization. Interpretation: Physicians and physiotherapists in the ICU underestimated the incidence of ICU-acquired weakness and felt inadequately trained to mobilize patients receiving mechanical ventilation. We identified multiple modifiable barriers to early mobilization at the institutional, health care provider and patient levels that need to be addressed when designing mobilization programs for critically ill adults. [ABSTRACT FROM AUTHOR]

Background: Prognosis is difficult to establish early after moderate or severe traumatic brain injury despite representing an important concern for patients, families and medical teams. Biomarkers, such as neuron-specific enolase, have been proposed as potential early prognostic indicators. Our objective was to determine the association between neuron-specific enolase and clinical outcomes, and the prognostic value of neuron-specific enolase after a moderate or severe traumatic brain injury. Methods: We searched MEDLINE, Embase, The Cochrane Library and Biosis Previews, and reviewed reference lists of eligible articles to identify studies. We included cohort studies and randomized controlled trials that evaluated the prognostic value of neuron-specific enolase to predict mortality or Glasgow Outcome Scale score in patients with moderate or severe traumatic brain injury. Two reviewers independently collected data. The pooled mean differences were analyzed using random-effects models. We assessed risk of bias using a customized Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Subgroup and sensitivity analyses were performed based on a priori hypotheses. Results: We screened 5026 citations from which 30 studies (involving 1321 participants) met our eligibility criteria. We found a significant positive association between neuron-specific enolase serum levels and mortality (10 studies, n = 474; mean difference [MD] 18.46 µg/L, 95% confidence interval [CI] 10.81 to 26.11 µg/L; I2 = 83%) and a Glasgow Outcome Scale ≤ 3 (14 studies, n = 603; MD 17.25 µg/L, 95% CI 11.42 to 23.07 µg/L; I2 = 82%). We were unable to determine a clinical threshold value using the available patient data. Interpretation: In patients with moderate or severe traumatic brain injury, increased neuron-specific enolase serum levels are associated with unfavourable outcomes. The optimal neuron-specific enolase threshold value to predict unfavourable prognosis remains unknown and clinical decision-making is currently not recommended until additional studies are made available. [ABSTRACT FROM AUTHOR]