Protocol implementation during the COVID-19 pandemic: experiences from a randomized trial of stress ulcer prophylaxis.

BACKGROUND: During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. OBJECTIVE: To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. METHODS: REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. RESULTS: The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted. CONCLUSION: Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.

Health economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (E-PROSPECT): a cost-effectiveness analysis.

PURPOSE: We sought to compare the cost-effectiveness of probiotics and usual care with usual care without probiotics in mechanically ventilated, intensive care unit patients alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT). METHODS: We conducted a health economic evaluation alongside the PROSPECT randomized control trial (October 2013-March 2019). We adopted a public healthcare payer's perspective. Forty-four intensive care units in three countries (Canada/USA/Saudi Arabia) with adult critically ill, mechanically ventilated patients (N = 2,650) were included. Interventions were probiotics (Lactobacillus rhamnosus GG) vs placebo administered enterally twice daily. We collected healthcare resource use and estimated unit costs in 2019 United States dollars (USD) over a time horizon from randomization to hospital discharge/death. We calculated incremental cost-effectiveness ratios (ICERs) comparing probiotics vs usual care. The primary outcome was incremental cost per ventilator-associated pneumonia (VAP) event averted; secondary outcomes were costs per Clostridioides difficile-associated diarrhea (CDAD), antibiotic-associated diarrhea (AAD), and mortality averted. Uncertainty was investigated using nonparametric bootstrapping and sensitivity analyses. RESULTS: Mean (standard deviation [SD]) cost per patient was USD 66,914 (91,098) for patients randomized to probiotics, with a median [interquartile range (IQR)] of USD 42,947 [22,239 to 76,205]. By comparison, for those not receiving probiotics, mean (SD) cost per patient was USD 62,701 (78,676) (median [IQR], USD 41,102 [23,170 to 75,140]; incremental cost, USD 4,213; 95% confidence interval [CI], -2,269 to 10,708). Incremental cost-effectiveness ratios for VAP or AAD events averted, probiotics were dominated by usual care (more expensive, with similar effectiveness). The ICERs were USD 1,473,400 per CDAD event averted (95% CI, undefined) and USD 396,764 per death averted (95% CI, undefined). Cost-effectiveness acceptability curves reveal that probiotics were not cost-effective across wide ranges of plausible willingness-to-pay thresholds. Sensitivity analyses did not change the conclusions. CONCLUSIONS: Probiotics for VAP prevention among critically ill patients were not cost-effective. Study registration data www. CLINICALTRIALS: gov (NCT01782755); registered 4 February 2013.

RéSUMé: OBJECTIF: Nous avons cherché à comparer le rapport coût-efficacité d'un traitement avec probiotiques ajoutés aux soins habituels avec des soins habituels prodigués sans probiotiques chez les patients des soins intensifs sous ventilation mécanique dans le cadre de l'étude PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial). MéTHODE: Nous avons réalisé une évaluation de l'économie de la santé parallèlement à l'étude randomisée contrôlée PROSPECT (octobre 2013-mars 2019). Nous avons adopté le point de vue d'un payeur public de services de santé. Quarante-quatre unités de soins intensifs dans trois pays (Canada/États-Unis/Arabie saoudite) prenant soin de patients adultes gravement malades sous ventilation mécanique (n = 2650) ont été inclus. Les interventions ont été les suivantes : probiotiques (Lactobacillus rhamnosus GG) vs placebo administrés par voie entérale deux fois par jour. Nous avons recueilli les données concernant l'utilisation des ressources en soins de santé et estimé les coûts unitaires en dollars américains (USD) de 2019 sur un horizon temporel allant de la randomisation au congé de l'hôpital / décès. Nous avons calculé des rapports coût-efficacité différentiels (RCED) en comparant les probiotiques vs les soins habituels. Le critère d'évaluation principal était le coût différentiel par événement évité de pneumonie associée au ventilateur (PAV); les critères d'évaluation secondaires étaient les coûts par diarrhée associée au Clostridioides difficile (DACD), diarrhée associée aux antibiotiques (DAA) et mortalité évitées. L'incertitude a été étudiée à l'aide d'analyses d'amorçage et de sensibilité non paramétriques. RéSULTATS: Le coût moyen (écart type [ÉT]) par patient était de 66 914 (91 098) USD pour les patients randomisés au groupe probiotiques, avec une médiane [écart interquartile (ÉIQ)] de 42 947 USD [22 239 à 76 205]. En comparaison, pour ceux ne recevant pas de probiotiques, le coût moyen (ÉT) par patient était de 62 701 USD (78 676) (médiane [ÉIQ], 41 102 USD [23 170 à 75 140]; coût différentiel, 4213 USD; intervalle de confiance [IC] à 95%, -2269 à 10 708). En matière de rapports coût-efficacité différentiels pour les événements de PAV ou DAA évités, les probiotiques étaient dominés par les soins habituels (plus coûteux, avec une efficacité similaire). Les RCED étaient de 1 473 400 USD par événement de DACD évitée (IC 95 %, non défini) et de 396 764 USD par décès évité (IC 95 %, non défini). Les courbes d'acceptabilité coût-efficacité révèlent que les probiotiques n'étaient pas rentables dans de larges gammes de seuils plausibles de volonté de payer. Les analyses de sensibilité n'ont pas modifié les conclusions. CONCLUSION: Les probiotiques utilisés pour prévenir la PAV chez les patients gravement malades n'étaient pas rentables. Enregistrement de l'étude : www.clinicaltrials.gov (NCT01782755); enregistrée le 4 février 2013.

A Post Hoc Analysis of Osmotherapy Use in the Erythropoietin in Traumatic Brain Injury Study-Associations With Acute Kidney Injury and Mortality.

OBJECTIVES: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown. DESIGN: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use. SETTING: Twenty-nine university-affiliated teaching hospitals in seven countries. PATIENTS: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death. CONCLUSIONS: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury.

Prevention of gastrointestinal bleeding in critically ill patients.

PURPOSE OF REVIEW: This review focuses on the current literature on the epidemiology and prevention of stress-induced clinically important gastrointestinal bleeding in ICU patients. RECENT FINDINGS: The incidence of stress-induced clinically important gastrointestinal bleeding in critically ill patients seems to be decreasing. Observational studies and an exploratory randomized controlled trial suggest that early enteral nutrition may be effective in preventing gastrointestinal bleeding in patients who are not at high risk. Recent systemic reviews and meta-analyses indicate that proton pump inhibitors and H2 receptor antagonists are more effective than placebo in preventing clinically important gastrointestinal bleeding, especially in high-risk and very high-risk patients, but do not reduce mortality. Although observational data suggested an association of proton pump inhibitors and H2 receptor antagonists with Clostridium difficile infection and pneumonia, this association was not confirmed in randomized controlled trials. SUMMARY: The incidence of stress-induced clinically important gastrointestinal bleeding in critically ill patients seems to have decreased over time. Even though stress ulcer prophylaxis in critically ill patients has been a research focus for decades, many questions remain unanswered, such as which groups of patients are likely to benefit and what pharmacologic agent is associated with the best benefit-to-harm ratio.

Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02462590.

Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19).

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.

Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection.

BACKGROUND: Since September 2012, 170 confirmed infections with Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization, including 72 deaths. Data on critically ill patients with MERS-CoV infection are limited. OBJECTIVE: To describe the critical illness associated with MERS-CoV. DESIGN: Case series. SETTING: 3 intensive care units (ICUs) at 2 tertiary care hospitals in Saudi Arabia. PATIENTS: 12 patients with confirmed or probable MERS-CoV infection. MEASUREMENTS: Presenting symptoms, comorbid conditions, pulmonary and extrapulmonary manifestations, measures of severity of illness and organ failure, ICU course, and outcome are described, as are the results of surveillance of health care workers (HCWs) and patients with potential exposure. RESULTS: Between December 2012 and August 2013, 114 patients were tested for suspected MERS-CoV; of these, 11 ICU patients (10%) met the definition of confirmed or probable cases. Three of these patients were part of a health care-associated cluster that also included 3 HCWs. One HCW became critically ill and was the 12th patient in this case series. Median Acute Physiology and Chronic Health Evaluation II score was 28 (range, 16 to 36). All 12 patients had underlying comorbid conditions and presented with acute severe hypoxemic respiratory failure. Most patients (92%) had extrapulmonary manifestations, including shock, acute kidney injury, and thrombocytopenia. Five (42%) were alive at day 90. Of the 520 exposed HCWs, only 4 (1%) were positive. LIMITATION: The sample size was small. CONCLUSION: MERS-CoV causes severe acute hypoxemic respiratory failure and considerable extrapulmonary organ dysfunction and is associated with high mortality. Community-acquired and health care-associated MERS-CoV infection occurs in patients with chronic comorbid conditions. The health care-associated cluster suggests that human-to-human transmission does occur with unprotected exposure. PRIMARY FUNDING SOURCE: None.

Serum procalcitonin in cirrhotic patients with septic shock: relationship with adrenal insufficiency and clinical outcomes.

BACKGROUND: Serum procalcitonin is commonly used to differentiate systemic inflammation due to infection from non-infectious causes. Limited data exist on the value of procalcitonin in predicting relative adrenal insufficiency (RAI). This study evaluated the value of procalcitonin in predicting RAI and mortality in cirrhotic patients with septic shock. METHODS: This was a post-hoc analysis of a randomized placebo-controlled trial that evaluated low-dose hydrocortisone in cirrhotic patients with septic shock. Extracted first study-day data included serum procalcitonin, baseline serum cortisol, cortisol level after 250 microg - adrenocorticotropic hormone stimulation test and 28 - day mortality. RAI was defined as a baseline serum cortisol < 10 microg/dL or cortisol not rising by > 9 microg/dL after stimulation. Procalcitonin > 0.5 ng/mL was considered high. RESULTS: Forty-five patients had serum procalcitonin measured (mean = 2.7 +/- 3.2 ng/mL, first and third quartiles were 0.3 and 3.3 ng/mL, respectively). Most (78%) patients had high procalcitonin levels. RAI was present in 34 (76%) patients. Patients with high procalcitonin were more likely to have RAI (odds ratio, 4.8; 95% confidence interval, 1.1 - 22.1). Receiver operator characteristic curve analysis showed that the best cut-off for detecting RAI was 1.0 ng/mL (sensitivity = 79% and specificity = 55%). High serum procalcitonin was not associated with 28 -day mortality (80% for normal procalcitonin and 77% for high procalcitonin, p = 0.61). CONCLUSIONS: High serum procalcitonin was highly associated with RAI in cirrhotic patients with septic shock. Procalcitonin was not associated with 28 - day mortality in this patient population.

Protocol and statistical analysis plan for the mega randomised registry trial research program comparing conservative versus liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX).

Background: The effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in patients who require unplanned invasive mechanical ventilation in an intensive care unit (ICU) is uncertain and will be evaluated in the mega randomised registry trial research program (Mega-ROX). Objective: To summarise the protocol and statistical analysis plan for Mega-ROX. Design, setting and participants: Mega-ROX is a 40 000-patient parallel-group, registry-embedded clinical trial in which adults who require unplanned invasive mechanical ventilation in an ICU will be randomly assigned to conservative or liberal oxygen therapy. Within this overarching trial research program, three nested parallel randomised controlled trials will be conducted. These will include patients with suspected hypoxic ischaemic encephalopathy (HIE) following resuscitation from a cardiac arrest, patients with sepsis, and patients with non-HIE acute brain injuries or conditions. Main outcome measures: The primary outcome is in-hospital allcause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and proportion of patients discharged home. Results and conclusions: Mega-ROX will compare the effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in critically ill adults who receive unplanned invasive mechanical ventilation in an ICU. The protocol and a pre-specified approach to analyses are reported here to mitigate analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12620000391976).

The effect of intermittent pneumatic compression on deep-vein thrombosis and ventilation-free days in critically ill patients with heart failure.

There are contradictory data regarding the effect of intermittent pneumatic compression (IPC) on the incidence of deep-vein thrombosis (DVT) and heart failure (HF) decompensation in critically ill patients. This study evaluated the effect of adjunctive use of IPC on the rate of incident DVT and ventilation-free days among critically ill patients with HF. In this pre-specified secondary analysis of the PREVENT trial (N = 2003), we compared the effect of adjunctive IPC added to pharmacologic thromboprophylaxis (IPC group), with pharmacologic thromboprophylaxis alone (control group) in critically ill patients with HF. The presence of HF was determined by the treating teams according to local practices. Patients were stratified according to preserved (≥ 40%) versus reduced (< 40%) left ventricular ejection fraction, and by the New York Heart Association (NYHA) classification. The primary outcome was incident proximal lower-limb DVT, determined with twice weekly venous Doppler ultrasonography. As a co-primary outcome, we evaluated ventilation-free days as a surrogate for clinically important HF decompensation. Among 275 patients with HF, 18 (6.5%) patients had prevalent proximal lower-limb DVT (detected on trial day 1 to 3). Of 257 patients with no prevalent DVT, 11/125 (8.8%) patients in the IPC group developed incident proximal lower-limb DVT compared to 6/132 (4.5%) patients in the control group (relative risk, 1.94; 95% confidence interval, 0.74-5.08, p = 0.17). There was no significant difference in ventilator-free days between the IPC and control groups (median 21 days versus 25 days respectively, p = 0.17). The incidence of DVT with IPC versus control was not different across NYHA classes (p value for interaction = 0.18), nor across patients with reduced and preserved ejection fraction (p value for interaction = 0.15). Ventilator-free days with IPC versus control were also not different across NYHA classes nor across patients with reduced or preserved ejection fraction. In conclsuion, the use of adjunctive IPC compared with control was associated with similar rate of incident proximal lower-limb DVT and ventilator-free days in critically ill patients with HF.Trial registration: The PREVENT trial is registered at ClinicalTrials.gov, ID: NCT02040103 (registered on 3 November 2013, https://clinicaltrials.gov/ct2/show/study/NCT02040103 ) and Current controlled trials, ID: ISRCTN44653506 (registered on 30 October 2013).

Infection control in the intensive care unit: expert consensus statements for SARS-CoV-2 using a Delphi method.

During the current COVID-19 pandemic, health-care workers and uninfected patients in intensive care units (ICUs) are at risk of being infected with SARS-CoV-2 as a result of transmission from infected patients and health-care workers. In the absence of high-quality evidence on the transmission of SARS-CoV-2, clinical practice of infection control and prevention in ICUs varies widely. Using a Delphi process, international experts in intensive care, infectious diseases, and infection control developed consensus statements on infection control for SARS-CoV-2 in an ICU. Consensus was achieved for 31 (94%) of 33 statements, from which 25 clinical practice statements were issued. These statements include guidance on ICU design and engineering, health-care worker safety, visiting policy, personal protective equipment, patients and procedures, disinfection, and sterilisation. Consensus was not reached on optimal return to work criteria for health-care workers who were infected with SARS-CoV-2 or the acceptable disinfection strategy for heat-sensitive instruments used for airway management of patients with SARS-CoV-2 infection. Well designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) randomised clinical trial: study protocol.

INTRODUCTION: Bloodstream infections are a leading cause of mortality and morbidity; the duration of treatment for these infections is understudied. METHODS AND ANALYSIS: We will conduct an international, multicentre randomised clinical trial of shorter (7 days) versus longer (14 days) antibiotic treatment among hospitalised patients with bloodstream infections. The trial will include 3626 patients across 60 hospitals and 6 countries. We will include patients with blood cultures confirming a pathogenic bacterium after hospital admission. Exclusion criteria will include patient factors (severe immunosuppression), infection site factors (endocarditis, osteomyelitis, undrained abscesses, infected prosthetic material) and pathogen factors (Staphylococcus aureus, Staphylococcus lugdunensis, Candida and contaminant organisms). We will leave the selection of specific antibiotics, doses and route of delivery to the discretion of treating physicians; no placebo control will be used given the diversity of pathogens and sources of bacteraemia. The intervention will be assignment of treatment duration to be 7 versus 14 days. We will minimise selection bias via central randomisation with variable block sizes, with concealed allocation until day 7 of adequate antibiotic treatment. The primary outcome is 90-day survival; we will test whether 7 days is non-inferior to 14 days of treatment, with a non-inferiority margin of 4% absolute mortality. Secondary outcomes include hospital and intensive care unit (ICU) mortality, relapse rates of bacteraemia, hospital and ICU length of stay, mechanical ventilation and vasopressor duration, antibiotic-free days, Clostridium difficile infection, antibiotic allergy and adverse events and colonisation/infection with antibiotic-resistant organisms. ETHICS AND DISSEMINATION: The study has been approved by the ethics review board at each participating site. Sunnybrook Health Sciences Centre is the central ethics committee. We will disseminate study results via the Canadian Critical Care Trials Group and other collaborating networks to set the global paradigm for antibiotic treatment duration for non-staphylococcal Gram-positive, Gram-negative and anaerobic bacteraemia, among patients admitted to hospital. TRIAL REGISTRATION NUMBER: The BALANCE (Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness) trial was registered at www.clinicaltrials.gov (registration number: NCT03005145).

Managing ICU surge during the COVID-19 crisis: rapid guidelines.

Given the rapidly changing nature of COVID-19, clinicians and policy makers require urgent review and summary of the literature, and synthesis of evidence-based guidelines to inform practice. The WHO advocates for rapid reviews in these circumstances. The purpose of this rapid guideline is to provide recommendations on the organizational management of intensive care units caring for patients with COVID-19 including: planning a crisis surge response; crisis surge response strategies; triage, supporting families, and staff.

Surveillance or no surveillance ultrasonography for deep vein thrombosis and outcomes of critically ill patients: a pre-planned sub-study of the PREVENT trial.

PURPOSE: We examined the association between surveillance for deep vein thrombosis (DVT) among medical-surgical critically ill patients by twice-weekly ultrasonography and 90-day all-cause mortality. METHODS: This was a pre-planned sub-study of the Pneumatic Compression for Preventing Venous Thromboembolism (PREVENT) trial (Clinicaltrials.gov: NCT02040103) that compared addition of intermittent pneumatic compression (IPC) to pharmacologic prophylaxis versus pharmacologic prophylaxis alone. The surveillance group included enrolled patients in the trial, while the non-surveillance group included eligible non-enrolled patients. Using logistic regression and Cox proportional hazards models, we examined the association of surveillance with the primary outcome of 90-day mortality. Secondary outcomes were DVT and pulmonary embolism (PE). RESULTS: The surveillance group consisted of 1682 patients and the non-surveillance group included 383 patients. Using Cox proportional hazards model with bootstrapping, surveillance was associated with a decrease in 90-day mortality (adjusted HR 0.75; 95% CI 0.57, 0.98). Surveillance was associated with earlier diagnosis of DVT [(median 4 days (IQR 2, 10) vs. 20 days (IQR 16, 22)] and PE [median 4 days (IQR 2.5, 5) vs. 7.5 days (IQR 6.1, 28.9)]. There was an increase in diagnosis of DVT (adjusted HR 5.49; 95% CI 2.92, 13.02) with no change in frequency in diagnosis of PE (adjusted HR 0.56; 95% CI 0.19, 1.91). CONCLUSIONS: Twice-weekly surveillance ultrasonography was associated with an increase in DVT detection, reduction in diagnostic testing for non-lower limb DVT and PE, earlier diagnosis of DVT and PE, and lower 90-day mortality. TRIAL REGISTRATION: The PREVENT trial is registered at ClinicalTrials.gov, ID: NCT02040103. Registered on 3 November 2013; Current controlled trials, ID: ISRCTN44653506. Registered on 30 October 2013.

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19).

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines.

Saudi Critical Care Society clinical practice guidelines on the prevention of venous thromboembolism in adults with trauma: reviewed for evidence-based integrity and endorsed by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine

To develop evidence-based clinical practice guidelines on venous thromboembolism (VTE) prevention in adults with trauma in inpatient settings. The Saudi Critical Care Society (SCCS) sponsored guidelines development and included 22 multidisciplinary panel members who completed conflict-of-interest forms. The panel developed and answered structured guidelines questions. For each question, the literature was searched for relevant studies. To summarize treatment effects, meta-analyses were conducted or updated. Quality of evidence was assessed using the Grading Recommendations, Assessment, Development, and Evaluation (GRADE) approach, then the evidence-to-decision (EtD) framework was used to generate recommendations. Recommendations covered the following prioritized domains: timing of pharmacologic VTE prophylaxis initiation in non-operative blunt solid organ injuries; isolated blunt traumatic brain injury (TBI); isolated blunt spine trauma or fracture and/or spinal cord injury (SCI); type and dose of pharmacologic VTE prophylaxis; mechanical VTE prophylaxis; routine duplex ultrasonography (US) surveillance; and inferior vena cava filters (IVCFs). The panel issued 12 clinical practice recommendations­one, a strong recommendation, 10 weak, and one with no recommendation due to insufficient evidence. The panel suggests starting early pharmacologic VTE prophylaxis for non-operative blunt solid organ injuries, isolated blunt TBIs, and SCIs. The panel suggests using low molecular weight heparin (LMWH) over unfractionated heparin (UFH) and suggests either intermediate­high dose LMWH or conventional dosing LMWH. For adults with trauma who are not pharmacologic candidates, the panel strongly recommends using mechanical VTE prophylaxis with intermittent pneumatic compression (IPC). The panel suggests using either combined VTE prophylaxis with mechanical and pharmacologic methods or pharmacologic VTE prophylaxis alone. Additionally, the panel suggests routine bilateral lower extremity US in adults with trauma with elevated risk of VTE who are ineligible for pharmacologic VTE prophylaxis and suggests against the routine placement of prophylactic IVCFs. Because of insufficient evidence, the panel did not issue any recommendation on the use of early pharmacologic VTE prophylaxis in adults with isolated blunt TBI requiring neurosurgical intervention. The SCCS guidelines for VTE prevention in adults with trauma were based on the best available evidence and identified areas for further research. The framework may facilitate adaptation of recommendations by national/international guideline policymakers.

Introducing the Comprehensive Unit-based Safety Program for mechanically ventilated patients in Saudi Arabian Intensive Care Units.

Over the past decade, there have been major improvements to the care of mechanically ventilated patients (MVPs). Earlier initiatives used the concept of ventilator care bundles (sets of interventions), with a primary focus on reducing ventilator-associated pneumonia. However, recent evidence has led to a more comprehensive approach: The ABCDE bundle (Awakening and Breathing trial Coordination, Delirium management and Early mobilization). The approach of the Comprehensive Unit-based Safety Program (CUSP) was developed by patient safety researchers at the Johns Hopkins Hospital and is supported by the Agency for Healthcare Research and Quality to improve local safety cultures and to learn from defects by utilizing a validated structured framework. In August 2015, 17 Intensive Care Units (ICUs) (a total of 271 beds) in eight hospitals in the Kingdom of Saudi Arabia joined the CUSP for MVPs (CUSP 4 MVP) that was conducted in 235 ICUs in 169 US hospitals and led by the Johns Hopkins Armstrong Institute for Patient Safety and Quality. The CUSP 4 MVP project will set the stage for cooperation between multiple hospitals and thus strives to create a countrywide plan for the management of all MVPs in Saudi Arabia.

Preventing healthcare-associated transmission of the Middle East Respiratory Syndrome (MERS): Our Achilles heel.

Middle East Respiratory Syndrome (MERS) coronavirus is the most recent among the Coronaviridae family to jump species and infect humans. Major healthcare associated MERS outbreaks have occurred in the Middle East and Korea that affected both patients and healthcare workers. These outbreaks were characterized by intra and inter-hospital spread and were exacerbated specifically by overcrowding, delayed diagnosis and appropriate use of personal protective equipment. Recent experience with this virus emphasizes the importance of compliance with infection control practices and with other interventions addressing patient triage, placement and flow within and between healthcare facilities. Our Achilles heel remains compliance with the best infection prevention practices and their harmonization with patient flow. Both infection prevention compliance and maintenance of patient flow are critical in preventing healthcare-associated transmission of many of these emerging infectious diseases, including MERS.