GRADE pearls and pitfalls-Part 1: Systematic reviews and meta-analyses.

BACKGROUND: The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach is used to assess the certainty of evidence in systematic reviews and meta-analyses. METHODS: We describe how the GRADE approach is used in systematic reviews and meta-analyses, including key points and examples. This overview is aimed at clinicians and researchers who are, or plan to be, involved in the development or assessment of systematic reviews with meta-analyses using GRADE. RESULTS: We outline how the certainty of evidence is assessed, how the evidence is summarized using GRADE evidence profiles or summary of findings tables, how the results are communicated, and we discuss challenges, advantages, and disadvantages with using GRADE. CONCLUSIONS: This overview aims to provide an overview of how GRADE is used in systematic reviews and meta-analyses, and may be used by systematic review developers, methodologists, and evidence end-users.

GRADE pearls and pitfalls-Part 2: Clinical practice guidelines.

BACKGROUND: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach is the de facto standard framework for summarising evidence in systematic reviews and developing recommendations in clinical practice guidelines. METHODS: We describe how the GRADE approach is used in clinical practice guidelines, including key points and examples. The intended audience of this overview of GRADE is clinicians and researchers who are, or plan to be, involved in the development or assessment of clinical practice guidelines. RESULTS: We cover guideline endorsement and adaptation; guideline panels and sponsors; conflicts of interest; guideline questions and outcome prioritisation; systematic review creation, updating and re-use; rating the overall certainty of evidence; development of recommendations and implications; and peer review, publication, implementation and updating of guidelines. CONCLUSIONS: This overview aims to help developers, assessors and users of clinical practice guidelines understand how trustworthy, high-quality guidelines are developed using the GRADE approach.

Higher versus lower oxygenation targets in adult ICU patients: A rapid practice guideline.

The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) was to provide evidence-based clinical guidance about the use of higher versus lower oxygenation targets for adult patients in the intensive care unit (ICU). The guideline panel comprised 27 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines, including the use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and used the Evidence-to-Decision framework to generate recommendations. A recently published updated systematic review and meta-analysis constituted the evidence base. Through teleconferences and web-based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients' values and preferences, costs and resources, equity, feasibility, acceptability, and research priorities. The updated systematic review and meta-analysis included data from 17 randomized clinical trials with 10,248 participants. There was little to no difference between the use of higher versus lower oxygenation targets for all outcomes with available data, including all-cause mortality, serious adverse events, stroke, functional outcomes, cognition, and health-related quality of life (very low certainty of evidence). The panel felt that values and preferences, costs and resources, and equity favored the use of lower oxygenation targets. The ICM-RPG panel issued one conditional recommendation against the use of higher oxygenation targets: "We suggest against the routine use of higher oxygenation targets in adult ICU patients (conditional recommendation, very low certainty of evidence). Remark: an oxygenation target of SpO2 88%-92% or PaO2 8 kPa/60 mmHg is relevant and safe for most adult ICU patients."

Intravenous vitamin C therapy in adult patients with sepsis: A rapid practice guideline.

BACKGROUND: This Rapid Practice Guideline provides an evidence-based recommendation to address the question: in adults with sepsis or septic shock, should we recommend using or not using intravenous vitamin C therapy? METHODS: The panel included 21 experts from 16 countries and used a strict policy for potential financial and intellectual conflicts of interest. Methodological support was provided by the Guidelines in Intensive Care, Development, and Evaluation (GUIDE) group. Based on an updated systematic review, and the grading of recommendations, assessment, development, and evaluation approach, we evaluated the certainty of evidence and developed recommendations using the evidence-to-decision framework. We conducted an electronic vote, requiring >80% agreement among the panel for a recommendation to be adopted. RESULTS: At longest follow-up, 90 days, intravenous vitamin C probably does not substantially impact (relative risk 1.05, 95% confidence interval [CI] 0.94 to 1.17; absolute risk difference 1.8%, 95% CI -2.2 to 6.2; 6 trials, n = 2148, moderate certainty). Effects of vitamin C on mortality at earlier timepoints was of low or very low certainty due to risk of bias of the included studies and significant heterogeneity between study results. Few adverse events were reported with the use of vitamin C. The panel did not identify any major differences in other outcomes, including duration of mechanical ventilation, ventilator free days, hospital or intensive care unit length of stay, acute kidney injury, need for renal replacement therapy. Vitamin C may result in a slight reduction in duration of vasopressor support (MD -18.9 h, 95% CI -26.5 to -11.4; 21 trials, n = 2661, low certainty); but may not reduce sequential organ failure assessment scores (MD -0.69, 95% CI -1.55 to 0.71; 24 trials, n = 4002, low certainty). The panel judged the undesirable consequences of using IV vitamin C to probably outweigh the desirable consequences, and therefore issued a conditional recommendation against using IV vitamin C therapy in sepsis. CONCLUSIONS: The panel suggests against use of intravenous vitamin C in adult patients with sepsis, beyond that of standard nutritional supplementation. Small and single center trials on this topic should be discouraged.

Long-term outcomes of patients with COVID-19 treated with helmet noninvasive ventilation or usual respiratory support: follow-up study of the Helmet-COVID randomized clinical trial.

PURPOSE: To evaluate whether helmet noninvasive ventilation compared to usual respiratory support reduces 180-day mortality and improves health-related quality of life (HRQoL) in patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. METHODS: This is a pre-planned follow-up study of the Helmet-COVID trial. In this multicenter, randomized clinical trial, adults with acute hypoxemic respiratory failure (n = 320) due to coronavirus disease 2019 (COVID-19) were randomized to receive helmet noninvasive ventilation or usual respiratory support. The modified intention-to-treat population consisted of all enrolled patients except three who were lost at follow-up. The study outcomes were 180-day mortality, EuroQoL (EQ)-5D-5L index values, and EQ-visual analog scale (EQ-VAS). In the modified intention-to-treat analysis, non-survivors were assigned a value of 0 for EQ-5D-5L and EQ-VAS. RESULTS: Within 180 days, 63/159 patients (39.6%) died in the helmet noninvasive ventilation group compared to 65/158 patients (41.1%) in the usual respiratory support group (risk difference - 1.5% (95% confidence interval [CI] - 12.3, 9.3, p = 0.78). In the modified intention-to-treat analysis, patients in the helmet noninvasive ventilation and the usual respiratory support groups did not differ in EQ-5D-5L index values (median 0.68 [IQR 0.00, 1.00], compared to 0.67 [IQR 0.00, 1.00], median difference 0.00 [95% CI - 0.32, 0.32; p = 0.91]) or EQ-VAS scores (median 70 [IQR 0, 93], compared to 70 [IQR 0, 90], median difference 0.00 (95% CI - 31.92, 31.92; p = 0.55). CONCLUSIONS: Helmet noninvasive ventilation did not reduce 180-day mortality or improve HRQoL compared to usual respiratory support among patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia.

Treatment of multidrug-resistant Pseudomonas aeruginosa bacteremia using ceftolozane-tazobactam-based or colistin-based antibiotic regimens: A multicenter retrospective study.

BACKGROUND: Ceftolozane-tazobactam is an emerging treatment for severe infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. However, limited data support its use in bacteremia treatment. This study aimed to assess the effectiveness of the treatment of MDR P. aeruginosa bacteremia using ceftolozane- tazobactam-based or colistin-based regimens. PATIENTS AND METHODS: This retrospective, cohort, multicentre study included adult patients with MDR P. aeruginosa bacteremia treated with either ceftolozane-tazobactam or colistin, between September 2018 and August 2021, at four hospitals in Saudi Arabia. The primary endpoint was the 30-day risk-adjusted mortality. Secondary endpoints included the 14-day risk of mortality, bacterial eradication, and clinical success. Cox proportional hazards regression and relative risk estimation were used for analysis, as appropriate. RESULTS: In total, 46 patients were included; 17 patients received ceftolozane- tazobactam-based regimen, and 29 received a colistin-based regimen. There was no association with the use of ceftolozane-tazobactam compared to colistin and the 30-day risk-adjusted mortality (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.16-2.13, P = 0.42). Also, the 14-day risk of mortality and bacterial eradication were not different between the ceftolozane-tazobactam and colistin regimens, HR 2.1, 95% CI 0.42-10.48; P = 0.36; and relative risk (RR) 0.65; 95% CI 0.28-1.52; P = 0.30; respectively. On the other hand, ceftolozane-tazobactam use was associated with higher clinical success than colistin (RR 1.84, 95% CI 1.11-3.06: P = 0.021). CONCLUSION: The risk of mortality of MDR P.aeruginosa bacteremia was similar when treated with ceftolozane-tazobactam-based or colistin-based antimicrobial regimens. A higher clinical success was observed with the ceftolozane- tazobactam-based regimen compared to the colistin-based regimen. .

Effect of Helmet Noninvasive Ventilation vs Usual Respiratory Support on Mortality Among Patients With Acute Hypoxemic Respiratory Failure Due to COVID-19: The HELMET-COVID Randomized Clinical Trial.

Importance: Helmet noninvasive ventilation has been used in patients with COVID-19 with the premise that helmet interface is more effective than mask interface in delivering prolonged treatments with high positive airway pressure, but data about its effectiveness are limited. Objective: To evaluate whether helmet noninvasive ventilation compared with usual respiratory support reduces mortality in patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. Design, Setting, and Participants: This was a multicenter, pragmatic, randomized clinical trial that was conducted in 8 sites in Saudi Arabia and Kuwait between February 8, 2021, and November 16, 2021. Adult patients with acute hypoxemic respiratory failure (n = 320) due to suspected or confirmed COVID-19 were included. The final follow-up date for the primary outcome was December 14, 2021. Interventions: Patients were randomized to receive helmet noninvasive ventilation (n = 159) or usual respiratory support (n = 161), which included mask noninvasive ventilation, high-flow nasal oxygen, and standard oxygen. Main Outcomes and Measures: The primary outcome was 28-day all-cause mortality. There were 12 prespecified secondary outcomes, including endotracheal intubation, barotrauma, skin pressure injury, and serious adverse events. Results: Among 322 patients who were randomized, 320 were included in the primary analysis, all of whom completed the trial. Median age was 58 years, and 187 were men (58.4%). Within 28 days, 43 of 159 patients (27.0%) died in the helmet noninvasive ventilation group compared with 42 of 161 (26.1%) in the usual respiratory support group (risk difference, 1.0% [95% CI, -8.7% to 10.6%]; relative risk, 1.04 [95% CI, 0.72-1.49]; P = .85). Within 28 days, 75 of 159 patients (47.2%) required endotracheal intubation in the helmet noninvasive ventilation group compared with 81 of 161 (50.3%) in the usual respiratory support group (risk difference, -3.1% [95% CI, -14.1% to 7.8%]; relative risk, 0.94 [95% CI, 0.75-1.17]). There were no significant differences between the 2 groups in any of the prespecified secondary end points. Barotrauma occurred in 30 of 159 patients (18.9%) in the helmet noninvasive ventilation group and 25 of 161 (15.5%) in the usual respiratory support group. Skin pressure injury occurred in 5 of 159 patients (3.1%) in the helmet noninvasive ventilation group and 10 of 161 (6.2%) in the usual respiratory support group. There were 2 serious adverse events in the helmet noninvasive ventilation group and 1 in the usual respiratory support group. Conclusions and Relevance: Results of this study suggest that helmet noninvasive ventilation did not significantly reduce 28-day mortality compared with usual respiratory support among patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. However, interpretation of the findings is limited by imprecision in the effect estimate, which does not exclude potentially clinically important benefit or harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04477668.

Dexmedetomidine vs other sedatives in critically ill mechanically ventilated adults: a systematic review and meta-analysis of randomized trials.

Conventional gabaminergic sedatives such as benzodiazepines and propofol are commonly used in mechanically ventilated patients in the intensive care unit (ICU). Dexmedetomidine is an alternative sedative that may achieve lighter sedation, reduce delirium, and provide analgesia. Our objective was to perform a comprehensive systematic review summarizing the large body of evidence, determining if dexmedetomidine reduces delirium compared to conventional sedatives. We searched MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov and the WHO ICTRP from inception to October 2021. Independent pairs of reviewers identified randomized clinical trials comparing dexmedetomidine to other sedatives for mechanically ventilated adults in the ICU. We conducted meta-analyses using random-effects models. The results were reported as relative risks (RRs) for binary outcomes and mean differences (MDs) for continuous outcomes, with corresponding 95% confidence intervals (CIs). In total, 77 randomized trials (n = 11,997) were included. Compared to other sedatives, dexmedetomidine reduced the risk of delirium (RR 0.67, 95% CI 0.55 to 0.81; moderate certainty), the duration of mechanical ventilation (MD - 1.8 h, 95% CI - 2.89 to - 0.71; low certainty), and ICU length of stay (MD - 0.32 days, 95% CI - 0.42 to - 0.22; low certainty). Dexmedetomidine use increased the risk of bradycardia (RR 2.39, 95% CI 1.82 to 3.13; moderate certainty) and hypotension (RR 1.32, 95% CI 1.07 to 1.63; low certainty). In mechanically ventilated adults, the use of dexmedetomidine compared to other sedatives, resulted in a lower risk of delirium, and a modest reduction in duration of mechanical ventilation and ICU stay, but increased the risks of bradycardia and hypotension.

Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory Failure: A Randomized Clinical Trial.

Importance: The efficacy and safety of prone positioning is unclear in nonintubated patients with acute hypoxemia and COVID-19. Objective: To evaluate the efficacy and adverse events of prone positioning in nonintubated adult patients with acute hypoxemia and COVID-19. Design, Setting, and Participants: Pragmatic, unblinded randomized clinical trial conducted at 21 hospitals in Canada, Kuwait, Saudi Arabia, and the US. Eligible adult patients with COVID-19 were not intubated and required oxygen (≥40%) or noninvasive ventilation. A total of 400 patients were enrolled between May 19, 2020, and May 18, 2021, and final follow-up was completed in July 2021. Intervention: Patients were randomized to awake prone positioning (n = 205) or usual care without prone positioning (control; n = 195). Main Outcomes and Measures: The primary outcome was endotracheal intubation within 30 days of randomization. The secondary outcomes included mortality at 60 days, days free from invasive mechanical ventilation or noninvasive ventilation at 30 days, days free from the intensive care unit or hospital at 60 days, adverse events, and serious adverse events. Results: Among the 400 patients who were randomized (mean age, 57.6 years [SD, 12.83 years]; 117 [29.3%] were women), all (100%) completed the trial. In the first 4 days after randomization, the median duration of prone positioning was 4.8 h/d (IQR, 1.8 to 8.0 h/d) in the awake prone positioning group vs 0 h/d (IQR, 0 to 0 h/d) in the control group. By day 30, 70 of 205 patients (34.1%) in the prone positioning group were intubated vs 79 of 195 patients (40.5%) in the control group (hazard ratio, 0.81 [95% CI, 0.59 to 1.12], P = .20; absolute difference, -6.37% [95% CI, -15.83% to 3.10%]). Prone positioning did not significantly reduce mortality at 60 days (hazard ratio, 0.93 [95% CI, 0.62 to 1.40], P = .54; absolute difference, -1.15% [95% CI, -9.40% to 7.10%]) and had no significant effect on days free from invasive mechanical ventilation or noninvasive ventilation at 30 days or on days free from the intensive care unit or hospital at 60 days. There were no serious adverse events in either group. In the awake prone positioning group, 21 patients (10%) experienced adverse events and the most frequently reported were musculoskeletal pain or discomfort from prone positioning (13 of 205 patients [6.34%]) and desaturation (2 of 205 patients [0.98%]). There were no reported adverse events in the control group. Conclusions and Relevance: In patients with acute hypoxemic respiratory failure from COVID-19, prone positioning, compared with usual care without prone positioning, did not significantly reduce endotracheal intubation at 30 days. However, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT04350723.

Use of dexmedetomidine for sedation in mechanically ventilated adult ICU patients: a rapid practice guideline.

PURPOSE: The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM­RPG) was to formulate evidence­based guidance for the use of dexmedetomidine for sedation in invasively mechanically ventilated adults in the intensive care unit (ICU). METHODS: We adhered to the methodology for trustworthy clinical practice guidelines, including use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and the Evidence-to-Decision framework to generate recommendations. The guideline panel comprised 28 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. Through teleconferences and web­based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients' values and preferences, costs and resources, feasibility, acceptability, and research priorities. RESULTS: The ICM­RPG panel issued one weak recommendation (suggestion) based on overall moderate certainty of evidence: "In invasively mechanically ventilated adult ICU patients, we suggest using dexmedetomidine over other sedative agents, if the desirable effects including a reduction in delirium are valued over the undesirable effects including an increase in hypotension and bradycardia". CONCLUSION: This ICM-RPG provides updated evidence-based guidance on the use of dexmedetomidine for sedation in mechanically ventilated adults, and outlines uncertainties and research priorities.

Helmet noninvasive ventilation for COVID-19 patients (Helmet-COVID): statistical analysis plan for a randomized controlled trial.

BACKGROUND: Noninvasive respiratory support is frequently needed for patients with acute hypoxemic respiratory failure due to coronavirus disease 19 (COVID-19). Helmet noninvasive ventilation has multiple advantages over other oxygen support modalities but data about effectiveness are limited. METHODS: In this multicenter randomized trial of helmet noninvasive ventilation for COVID-19 patients, 320 adult ICU patients (aged ≥14 years or as per local standards) with suspected or confirmed COVID-19 and acute hypoxemic respiratory failure (ratio of arterial oxygen partial pressure to fraction of inspired oxygen < 200 despite supplemental oxygen with a partial/non-rebreathing mask at a flow rate of 10 L/min or higher) will be randomized to helmet noninvasive ventilation with usual care or usual care alone, which may include mask noninvasive ventilation, high-flow nasal oxygen, or standard oxygen therapy. The primary outcome is death from any cause within 28 days after randomization. The trial has 80% power to detect a 15% absolute risk reduction in 28-day mortality from 40 to 25%. The primary outcome will be compared between the helmet and usual care group in the intention-to-treat using the chi-square test. Results will be reported as relative risk  and 95% confidence interval. The first patient was enrolled on February 8, 2021. As of August 1, 2021, 252 patients have been enrolled from 7 centers in Saudi Arabia and Kuwait. DISCUSSION: We developed a detailed statistical analysis plan to guide the analysis of the Helmet-COVID trial, which is expected to conclude enrollment in November 2021. TRIAL REGISTRATION: ClinicalTrials.gov NCT04477668 . Registered on July 20, 2020.

The Saudi Critical Care Society practice guidelines on the management of COVID-19 in the ICU: Therapy section.

BACKGROUND: The rapid increase in coronavirus disease 2019 (COVID-19) cases during the subsequent waves in Saudi Arabia and other countries prompted the Saudi Critical Care Society (SCCS) to put together a panel of experts to issue evidence-based recommendations for the management of COVID-19 in the intensive care unit (ICU). METHODS: The SCCS COVID-19 panel included 51 experts with expertise in critical care, respirology, infectious disease, epidemiology, emergency medicine, clinical pharmacy, nursing, respiratory therapy, methodology, and health policy. All members completed an electronic conflict of interest disclosure form. The panel addressed 9 questions that are related to the therapy of COVID-19 in the ICU. We identified relevant systematic reviews and clinical trials, then used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach as well as the evidence-to-decision framework (EtD) to assess the quality of evidence and generate recommendations. RESULTS: The SCCS COVID-19 panel issued 12 recommendations on pharmacotherapeutic interventions (immunomodulators, antiviral agents, and anticoagulants) for severe and critical COVID-19, of which 3 were strong recommendations and 9 were weak recommendations. CONCLUSION: The SCCS COVID-19 panel used the GRADE approach to formulate recommendations on therapy for COVID-19 in the ICU. The EtD framework allows adaptation of these recommendations in different contexts. The SCCS guideline committee will update recommendations as new evidence becomes available.

Efficacy of awake prone positioning in patients with covid-19 related hypoxemic respiratory failure: systematic review and meta-analysis of randomized trials.

OBJECTIVE: To determine the efficacy and safety of awake prone positioning versus usual care in non-intubated adults with hypoxemic respiratory failure due to covid-19. DESIGN: Systematic review with frequentist and bayesian meta-analyses. STUDY ELIGIBILITY: Randomized trials comparing awake prone positioning versus usual care in adults with covid-19 related hypoxemic respiratory failure. Information sources were Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to 4 March 2022. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and assessed risk of bias. Random effects meta-analyses were performed for the primary and secondary outcomes. Bayesian meta-analyses were performed for endotracheal intubation and mortality outcomes. GRADE certainty of evidence was assessed for outcomes. MAIN OUTCOME MEASURES: The primary outcome was endotracheal intubation. Secondary outcomes were mortality, ventilator-free days, intensive care unit (ICU) and hospital length of stay, escalation of oxygen modality, change in oxygenation and respiratory rate, and adverse events. RESULTS: 17 trials (2931 patients) met the eligibility criteria. 12 trials were at low risk of bias, three had some concerns, and two were at high risk. Awake prone positioning reduced the risk of endotracheal intubation compared with usual care (crude average 24.2% v 29.8%, relative risk 0.83, 95% confidence interval 0.73 to 0.94; high certainty). This translates to 55 fewer intubations per 1000 patients (95% confidence interval 87 to 19 fewer intubations). Awake prone positioning did not significantly affect secondary outcomes, including mortality (15.6% v 17.2%, relative risk 0.90, 0.76 to 1.07; high certainty), ventilator-free days (mean difference 0.97 days, 95% confidence interval -0.5 to 3.4; low certainty), ICU length of stay (-2.1 days, -4.5 to 0.4; low certainty), hospital length of stay (-0.09 days, -0.69 to 0.51; moderate certainty), and escalation of oxygen modality (21.4% v 23.0%, relative risk 1.04, 0.74 to 1.44; low certainty). Adverse events related to awake prone positioning were uncommon. Bayesian meta-analysis showed a high probability of benefit with awake prone positioning for endotracheal intubation (non-informative prior, mean relative risk 0.83, 95% credible interval 0.70 to 0.97; posterior probability for relative risk <0.95=96%) but lower probability for mortality (0.90, 0.73 to 1.13; <0.95=68%). CONCLUSIONS: Awake prone positioning compared with usual care reduces the risk of endotracheal intubation in adults with hypoxemic respiratory failure due to covid-19 but probably has little to no effect on mortality or other outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022314856.

Helmet Non-Invasive Ventilation for COVID-19 Patients (Helmet-COVID): study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Non-invasive ventilation (NIV) delivered by helmet has been used for respiratory support of patients with acute hypoxaemic respiratory failure due to COVID-19 pneumonia. The aim of this study was to compare helmet NIV with usual care versus usual care alone to reduce mortality. METHODS AND ANALYSIS: This is a multicentre, pragmatic, parallel randomised controlled trial that compares helmet NIV with usual care to usual care alone in a 1:1 ratio. A total of 320 patients will be enrolled in this study. The primary outcome is 28-day all-cause mortality. The primary outcome will be compared between the two study groups in the intention-to-treat and per-protocol cohorts. An interim analysis will be conducted for both safety and effectiveness. ETHICS AND DISSEMINATION: Approvals are obtained from the institutional review boards of each participating institution. Our findings will be published in peer-reviewed journals and presented at relevant conferences and meetings. TRIAL REGISTRATION NUMBER: NCT04477668.

Effectiveness of ceftazidime-avibactam versus colistin in treating carbapenem-resistant Enterobacteriaceae bacteremia.

INTRODUCTION: Antimicrobial treatments for carbapenem-resistant Enterobacteriaceae (CRE) bacteremia are limited, with colistin-based regimens being a primary therapy. Ceftazidime-avibactam is an emerging treatment for various CRE infections. Our study aimed to assess ceftazidime-avibactam effectiveness compared with colistin in patients with CRE bacteremia. METHODS: This retrospective, multi-centre study included adult patients with CRE bacteremia treated with ceftazidime-avibactam or colistin, between September 1, 2017 and December 1, 2020, at two tertiary centres in Saudi Arabia. The risk of 14-day mortality was compared between recipients of ceftazidime-avibactam versus colistin, using Cox multivariable regression, adjusted for Pitt score, Charlson index score, and treatment with chemotherapy and immunosuppressive agents. RESULTS: In total, 61 patients were enrolled; 32 received ceftazidime-avibactam, and 29 received colistin. The adjusted risk for 14-day mortality was lower in the ceftazidime-avibactam group than the colistin group (hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.10-0.99; p = 0.049), while the crude 14-day mortality did not differ between the two antibiotics (HR, 0.59; 95% CI 0.21-1.66; p = 0.32). The clinical success rate was higher with the use of ceftazidime-avibactam versus colistin (46.8% versus 20.4%, respectively; p = 0.047). CONCLUSION: Ceftazidime-avibactam was associated with a lower risk of 14-day mortality than colistin in patients with CRE bacteremia.

Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

The role of eosinophils in sepsis and acute respiratory distress syndrome: a scoping review.

PURPOSE: Septic shock and acute respiratory distress syndrome (ARDS) are characterized by a dysregulated immune host response that may respond to steroid therapy. Eosinophils contribute to type 2 inflammation that often responds to steroid therapy; their role in immune dysregulation and outcomes in sepsis and ARDS is unclear. SOURCE: A systematic search of Cochrane Library, MEDLINE, and EMBASE was performed from inception to 9 September 2020. The search comprised the following terms: eosinophils, sepsis, septic shock, and ARDS. Two reviewers independently screened abstracts and texts and extracted data on disease severity and clinical outcomes. PRINCIPAL FINDINGS: Thirty-nine studies were identified: 30 evaluated serum eosinophil count in sepsis, one evaluated eosinophil activity in sepsis, three assessed bronchoalveolar lavage (BAL) eosinophil count in ARDS, four assessed eosinophil activity in ARDS, and one assessed peripheral eosinophil count in ARDS. Eleven studies showed an association between eosinopenia and sepsis, and eight studies found persistent eosinopenia at > 48 hr of intensive care unit admission to predict mortality and readmission in septic patients. Three studies found BAL eosinophil count to be low in ARDS, although one found that levels rose in late-phase ARDS. Three studies found eosinophil activity markers in BAL to be high in ARDS and correlate with ARDS severity. CONCLUSION: Persistent peripheral eosinopenia is a marker of bacterial sepsis and is independently associated with poor outcomes. Bronchoalveolar lavage eosinophil counts are low in early-phase ARDS, but increase in late-phase ARDS, while elevated markers of eosinophil activity correlate with ARDS severity. Further studies understanding the mechanisms leading to eosinopenia in sepsis and increased eosinophil activity in ARDS are needed.

RéSUMé: OBJECTIF: Le choc septique et le syndrome de détresse respiratoire aiguë (SDRA, ARDS en anglais) se caractérisent par une réponse immunitaire dérégulée chez l'hôte qui pourrait répondre à une corticothérapie. Les éosinophiles contribuent à l'inflammation de type 2, laquelle répond souvent à la corticothérapie; leur rôle dans la dérégulation immunitaire et les devenirs en cas de sepsis et de SDRA n'est pas clair. SOURCE: Une recherche systématique dans les bases de données Cochrane Library, MEDLINE et EMBASE a été réalisée de leur création au 9 septembre 2020. La recherche comprenait les termes suivants : éosinophiles, sepsis, choc septique et SDRA. Deux réviseurs ont examiné de manière indépendante les résumés et textes et ont extrait les données décrivant la gravité de la maladie et les devenirs cliniques. CONSTATATIONS PRINCIPALES: Trente-neuf études ont été identifiées : 30 études portaient sur le décompte d'éosinophiles sériques lors de sepsis, une étude examinait l'activité des éosinophiles dans un contexte de sepsis, trois ont évalué le décompte d'éosinophiles par lavage bronchoalvéolaire (LBA) dans les cas de SDRA, quatre ont examiné l'activité des éosinophiles dans le SDRA, et une a évalué le décompte d'éosinophiles périphériques dans les cas de SDRA. Onze études ont montré une association entre l'éosinopénie et le sepsis, et huit études ont remarqué qu'une éosinopédie persistante pour plus de 48 heures après l'admission à l'unité de soins intensifs était un prédicteur de mortalité et de réadmission chez les patients septiques. Trois études ont révélé que le nombre d'éosinophiles dans un LBA était faible en cas de SDRA, bien qu'une étude ait constaté que les taux augmentaient dans les SDRA de phase tardive. Trois études ont révélé que les marqueurs d'activité éosinophilique dans les LBA étaient élevés dans les cas de SDRA et étaient corrélés à la gravité du SDRA. CONCLUSION: L'éosinopénie périphérique persistante est un marqueur de sepsis bactérien et est indépendamment associée à de mauvais pronostics. Les décomptes d'éosinophiles dans les lavages bronchoalvéolaires sont bas dans les cas de SDRA en phase précoce, mais augmentent dans le SDRA en phase tardive, alors que des marqueurs élevés d'activité éosinophilique sont corrélés à la sévérité du SDRA. D'autres études visant à comprendre les mécanismes menant à l'éosinopénie dans le sepsis et à l'augmentation de l'activité éosinophilique dans le SDRA sont nécessaires.

The Use of Central Venous to Arterial Carbon Dioxide Tension Gap for Outcome Prediction in Critically Ill Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: In this systematic review and meta-analysis, we assessed whether a high CO2 gap predicts mortality in adult critically ill patients with circulatory shock. DATA SOURCES: A systematic search of MEDLINE and EMBASE electronic databases from inception to October 2019. STUDY SELECTION: Studies from adult (age ≥ 18 yr) ICU patients with shock reporting CO2 gap and outcomes of interest. Case reports and conference abstracts were excluded. DATA EXTRACTION: Data extraction and study quality assessment were performed independently in duplicate. DATA SYNTHESIS: We used the Newcastle-Ottawa Scale to assess methodological study quality. Effect sizes were pooled using a random-effects model. The primary outcome was mortality (28 d and hospital). Secondary outcomes were ICU length of stay, hospital length of stay, duration of mechanical ventilation, use of renal replacement therapy, use of vasopressors and inotropes, and association with cardiac index, lactate, and central venous oxygen saturation. CONCLUSIONS: We included 21 studies (n = 2,155 patients) from medical (n = 925), cardiovascular (n = 685), surgical (n = 483), and mixed (n = 62) ICUs. A high CO2 gap was associated with increased mortality (odds ratio, 2.22; 95% CI, 1.30-3.82; p = 0.004) in patients with shock, but only those from medical and surgical ICUs. A high CO2 gap was associated with higher lactate levels (mean difference 0.44 mmol/L; 95% CI, 0.20-0.68 mmol/L; p = 0.0004), lower cardiac index (mean difference, -0.76 L/min/m; 95% CI, -1.04 to -0.49 L/min/m; p = 0.00001), and central venous oxygen saturation (mean difference, -5.07; 95% CI, -7.78 to -2.37; p = 0.0002). A high CO2 gap was not associated with longer ICU or hospital length of stays, requirement for renal replacement therapy, longer duration of mechanical ventilation, or higher vasopressors and inotropes use. Future studies should evaluate whether resuscitation aimed at closing the CO2 gap improves mortality in shock.

Neuromuscular blocking agents in acute respiratory distress syndrome: updated systematic review and meta-analysis of randomized trials.

PURPOSE: Existing clinical practice guidelines support the use of neuromuscular blocking agents (NMBA) in acute respiratory distress syndrome (ARDS); however, a recent large randomized clinical trial (RCT) has questioned this practice. Therefore, we updated a previous systematic review to determine the efficacy and safety of NMBAs in ARDS. METHODS: We searched MEDLINE, EMBASE (October 2012 to July 2019), the Cochrane (Central) database, and clinical trial registries ( ClinicalTrials.gov , ISRCTN Register, and WHO ICTRP) for RCTs comparing the effects of NMBA as a continuous infusion versus placebo or no NMBA infusion (but allowing intermittent NMBA boluses) on patient-important outcomes for adults with ARDS. Two independent reviewers assessed the methodologic quality of the primary studies and abstracted data. RESULTS: Seven RCTs, including four new RCTs, met eligibility criteria for this review. These trials enrolled 1598 patients with moderate to severe ARDS at centers in the USA, France, and China. All trials assessed short-term continuous infusions of cisatracurium or vecuronium. The pooled estimate for mortality outcomes showed significant statistical heterogeneity, which was only explained by a subgroup analysis by depth of sedation in the control arm. A continuous NMBA infusion did not improve mortality when compared to a light sedation strategy with no NMBA infusion (relative risk [RR] 0.99; 95% CI 0.86-1.15; moderate certainty; P = 0.93). On the other hand, continuous NMBA infusion reduced mortality when compared to deep sedation with as needed NMBA boluses (RR 0.71; 95% CI 0.57-0.89; low certainty; P = 0.003). Continuous NMBA infusion reduced the rate of barotrauma (RR 0.55; 95% CI 0.35-0.85, moderate certainty; P = 0.008) across eligible trials, but the effect on ventilator-free days, duration of mechanical ventilation, and ICU-acquired weakness was uncertain. CONCLUSIONS: Inconsistency in study methods and findings precluded the pooling of all trials for mortality. In a pre-planned sensitivity analysis, the impact of NMBA infusion on mortality depends on the strategy used in the control arm, showing reduced mortality when compared to deep sedation, but no effect on mortality when compared to lighter sedation. In both situations, a continuous NMBA infusion may reduce the risk of barotrauma, but the effects on other patient-important outcomes remain unclear. Future research, including an individual patient data meta-analysis, could help clarify some of the observed findings in this updated systematic review.