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.
The accuracy of the signs and tests that clinicians use to diagnose ventilator-associated pneumonia (VAP) and initiate antibiotic treatment has not been well characterized. We sought to characterize ...and compare the accuracy of physical examination, chest radiography, endotracheal aspirate (ETA), bronchoscopic sampling cultures (protected specimen brush PSB and bronchoalveolar lavage BAL), and CPIS > 6 to diagnose VAP. We searched six databases from inception through September 2019 and selected English-language studies investigating accuracy of any of the above tests for VAP diagnosis. Reference standard was histopathological analysis. Two reviewers independently extracted data and assessed study quality. We included 25 studies (1639 patients). The pooled sensitivity and specificity of physical examination findings for VAP were poor: fever (66.4% 95% confidence interval CI: 40.7–85.0, 53.9% 95% CI 34.5–72.2) and purulent secretions (77.0% 95% CI 64.7–85.9, 39.0% 95% CI 25.8–54.0). Any infiltrate on chest radiography had a sensitivity of 88.9% (95% CI 73.9–95.8) and specificity of 26.1% (95% CI 15.1–41.4). ETA had a sensitivity of 75.7% (95% CI 51.5–90.1) and specificity of 67.9% (95% CI 40.5–86.8). Among bronchoscopic sampling methods, PSB had a sensitivity of 61.4% 95% CI 43.7–76.5 and specificity of 76.5% 95% CI 64.2–85.6; while BAL had a sensitivity of 71.1% 95% CI 49.9–85.9 and specificity of 79.6% 95% CI 66.2–85.9. CPIS > 6 had a sensitivity of 73.8% (95% CI 50.6–88.5) and specificity of 66.4% (95% CI 43.9–83.3). Classic clinical indicators had poor accuracy for diagnosis of VAP. Reliance upon these indicators in isolation may result in misdiagnosis and potentially unnecessary antimicrobial use.
There are several reports of extracorporeal membrane oxygenation (ECMO) use in patients with coronavirus disease 2019 (COVID-19) who develop severe acute respiratory distress syndrome (ARDS). We ...conducted a systematic review and meta-analysis to guide clinical decision-making and future research.
We searched MEDLINE, Embase, Cochrane and Scopus databases from 1 December 2019 to 10 January 2021 for observational studies or randomised clinical trials examining ECMO in adults with COVID-19 ARDS. We performed random-effects meta-analyses and meta-regression, assessed risk of bias using the Joanna Briggs Institute checklist and rated the certainty of evidence using the GRADE approach. Survival outcomes were presented as pooled proportions while continuous outcomes were presented as pooled means, both with corresponding 95% confidence intervals CIs. The primary outcome was in-hospital mortality. Secondary outcomes were duration of ECMO therapy and mechanical ventilation, weaning rate from ECMO and complications during ECMO.
We included twenty-two observational studies with 1896 patients in the meta-analysis. Venovenous ECMO was the predominant mode used (98.6%). The pooled in-hospital mortality in COVID-19 patients (22 studies, 1896 patients) supported with ECMO was 37.1% (95% CI 32.3-42.0%, high certainty). Pooled mortality in the venovenous ECMO group was 35.7% (95% CI 30.7-40.7%, high certainty). Meta-regression found that age and ECMO duration were associated with increased mortality. Duration of ECMO support (18 studies, 1844 patients) was 15.1 days (95% CI 13.4-18.7). Weaning from ECMO (17 studies, 1412 patients) was accomplished in 67.6% (95% CI 50.5-82.7%) of patients. There were a total of 1583 ECMO complications reported (18 studies, 1721 patients) and renal complications were the most common.
The majority of patients received venovenous ECMO support for COVID-19-related ARDS. In-hospital mortality in patients receiving ECMO support for COVID-19 was 37.1% during the first year of the pandemic, similar to those with non-COVID-19-related ARDS. Increasing age was a risk factor for death. Venovenous ECMO appears to be an effective intervention in selected patients with COVID-19-related ARDS. PROSPERO CRD42020192627.
Noninvasive mechanical ventilation (NIV) is widely used in the acute care setting for acute respiratory failure (ARF) across a variety of aetiologies. This document provides European Respiratory ...Society/American Thoracic Society recommendations for the clinical application of NIV based on the most current literature.The guideline committee was composed of clinicians, methodologists and experts in the field of NIV. The committee developed recommendations based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology for each actionable question. The GRADE Evidence to Decision framework in the guideline development tool was used to generate recommendations. A number of topics were addressed using technical summaries without recommendations and these are discussed in the supplementary material.This guideline committee developed recommendations for 11 actionable questions in a PICO (population-intervention-comparison-outcome) format, all addressing the use of NIV for various aetiologies of ARF. The specific conditions where recommendations were made include exacerbation of chronic obstructive pulmonary disease, cardiogenic pulmonary oedema,
hypoxaemic respiratory failure, immunocompromised patients, chest trauma, palliation, post-operative care, weaning and post-extubation.This document summarises the current state of knowledge regarding the role of NIV in ARF. Evidence-based recommendations provide guidance to relevant stakeholders.
AbstractObjectiveTo compare the effects of treatments for coronavirus disease 2019 (covid-19).DesignLiving systematic review and network meta-analysis.Data sourcesWHO covid-19 database, a ...comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis.Study selectionRandomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.MethodsAfter duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.Results196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low.ConclusionCorticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain.Systematic review registrationThis review was not registered. The protocol is publicly available in the supplementary material.Readers’ noteThis article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.
OBJECTIVE:To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.
DESIGN:Thirty-two international experts, four ...methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines’ development. A general content review was completed face-to-face by all panel members in January 2017.
METHODS:Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelinesPain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as “strong,” “conditional,” or “good” practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified.
RESULTS:The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation.
CONCLUSIONS:We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.
Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment ...protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs’ findings, GC plasma concentration–time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic–pituitary–adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings.
OBJECTIVE:To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock2012.”
DESIGN:A consensus committee of 55 international experts representing 25 ...international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.
METHODS:The panel consisted of five sectionshemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable.
RESULTS:The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions.
CONCLUSIONS:Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
Background
Sepsis occurs when an infection is complicated by organ failure. Sepsis may be complicated by impaired corticosteroid metabolism. Thus, providing corticosteroids may benefit patients. The ...original review was published in 2004 and was updated in 2010 and 2015 prior to this update.
Objectives
To examine the effects of corticosteroids on death in children and adults with sepsis.
Search methods
We searched CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, ISRCTN, and the WHO Clinical Trials Search Portal, on 25 July 2019. In addition, we conducted reference checking and citation searching, and contacted study authors, to identify additional studies as needed.
Selection criteria
We included randomized controlled trials (RCTs) of corticosteroids versus placebo or usual care (antimicrobials, fluid replacement, and vasopressor therapy as needed) in children and adults with sepsis. We also included RCTs of continuous infusion versus intermittent bolus of corticosteroids.
Data collection and analysis
All review authors screened and selected studies for inclusion. One review author extracted data, which was checked by the others, and by the lead author of the primary study when possible. We obtained unpublished data from the authors of some trials. We assessed the methodological quality of trials and applied GRADE to assess the certainty of evidence. Review authors did not contribute to assessment of eligibility and risk of bias, nor to data extraction, for trials they had participated in.
Main results
We included 61 trials (12,192 participants), of which six included only children, two included children and adults, and the remaining trials included only adults. Nine studies are ongoing and will be considered in future versions of this review. We judged 19 trials as being at low risk of bias.
Corticosteroids versus placebo or usual care
Compared to placebo or usual care, corticosteroids probably slightly reduce 28‐day mortality (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.84 to 0.99; 11,233 participants; 50 studies; moderate‐certainty evidence). Corticosteroids may result in little to no difference in long‐term mortality (RR 0.97, 95% CI 0.91 to 1.03; 6236 participants; 7 studies; low‐certainty evidence) and probably slightly reduce hospital mortality (RR 0.90, 95% CI 0.82 to 0.99; 8183 participants; 26 trials; moderate‐certainty evidence). Corticosteroids reduced length of intensive care unit (ICU) stay for all participants (mean difference (MD) ‐1.07 days, 95% CI ‐1.95 to ‐0.19; 7612 participants; 21 studies; high‐certainty evidence) and resulted in a large reduction in length of hospital stay for all participants (MD ‐1.63 days, 95% CI ‐2.93 to ‐0.33; 8795 participants; 22 studies; high‐certainty evidence). Corticosteroids increase the risk of muscle weakness (RR 1.21, 95% CI 1.01 to 1.44; 6145 participants; 6 studies; high‐certainty evidence). Corticosteroids probably do not increase the risk of superinfection (RR 1.06, 95% CI 0.95 to 1.19; 5356 participants; 25 studies; moderate‐certainty evidence). Corticosteroids increase the risk of hypernatraemia (high‐certainty evidence) and probably increase the risk of hyperglycaemia (moderate‐certainty evidence). Moderate‐certainty evidence shows that there is probably little or no difference in gastroduodenal bleeding, stroke, or cardiac events, and low‐certainty evidence suggests that corticosteroids may result in little to no difference in neuropsychiatric events.
Continuous infusion of corticosteroids versus intermittent bolus
We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration. Three studies reported data for this comparison, and the certainty of evidence for all outcomes was very low.
Authors' conclusions
Moderate‐certainty evidence indicates that corticosteroids probably reduce 28‐day and hospital mortality among patients with sepsis. Corticosteroids result in large reductions in ICU and hospital length of stay (high‐certainty evidence). There may be little or no difference in the risk of major complications; however, corticosteroids increase the risk of muscle weakness and hypernatraemia, and probably increase the risk of hyperglycaemia. The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.
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