Pharmacological agents for procedural sedation and analgesia in the emergency department and intensive care unit: a systematic review and network meta-analysis of randomised trials.

BACKGROUND: We aimed to evaluate the comparative effectiveness and safety of various i.v. pharmacologic agents used for procedural sedation and analgesia (PSA) in the emergency department (ED) and ICU. We performed a systematic review and network meta-analysis to enable direct and indirect comparisons between available medications. METHODS: We searched Medline, EMBASE, Cochrane, and PubMed from inception to 2 March 2023 for RCTs comparing two or more procedural sedation and analgesia medications in all patients (adults and children >30 days of age) requiring emergent procedures in the ED or ICU. We focused on the outcomes of sedation recovery time, patient satisfaction, and adverse events (AEs). We performed frequentist random-effects model network meta-analysis and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty in estimates. RESULTS: We included 82 RCTs (8105 patients, 78 conducted in the ED and four in the ICU) of which 52 studies included adults, 23 included children, and seven included both. Compared with midazolam-opioids, recovery time was shorter with propofol (mean difference 16.3 min, 95% confidence interval [CI] 8.4-24.3 fewer minutes; high certainty), and patient satisfaction was better with ketamine-propofol (mean difference 1.5 points, 95% CI 0.3-2.6 points, high certainty). Regarding AEs, compared with midazolam-opioids, respiratory AEs were less frequent with ketamine (relative risk [RR] 0.55, 95% CI 0.32-0.96; high certainty), gastrointestinal AEs were more common with ketamine-midazolam (RR 3.08, 95% CI 1.15-8.27; high certainty), and neurological AEs were more common with ketamine-propofol (RR 3.68, 95% CI 1.08-12.53; high certainty). CONCLUSION: When considering procedural sedation and analgesia in the ED and ICU, compared with midazolam-opioids, sedation recovery time is shorter with propofol, patient satisfaction is better with ketamine-propofol, and respiratory adverse events are less common with ketamine.

Ketamine sedation in the intensive care unit: a survey of Canadian intensivists.

PURPOSE: We sought to understand the beliefs and practices of Canadian intensivists regarding their use of ketamine as a sedative in critically ill patients and to gauge their interest in a randomized controlled trial (RCT) examining its use in the intensive care unit (ICU). METHODS: We designed and validated an electronic self-administered survey examining the use of ketamine as a sedative infusion for ICU patients. We surveyed 400 physician members of the Canadian Critical Care Society (CCCS) via email between February and April 2022 and sent three reminders at two-week intervals. The survey was redistributed in January 2023 to improve the response rate. RESULTS: We received 87/400 (22%) completed questionnaires. Most respondents reported they rarely use ketamine as a continuous infusion for sedation or analgesia in the ICU (52/87, 58%). Physicians reported the following conditions would make them more likely to use ketamine: asthma exacerbation (73/87, 82%), tolerance to opioids (68/87, 77%), status epilepticus (44/87, 50%), and severe acute respiratory distress syndrome (33/87, 38%). Concern for side-effects that limited respondents' use of ketamine include adverse psychotropic effects (61/87, 69%) and delirium (47/87, 53%). The majority of respondents agreed there is need for an RCT to evaluate ketamine as a sedative infusion in the ICU (62/87, 71%). CONCLUSION: This survey of Canadian intensivists illustrates that use of ketamine as a continuous infusion for sedation is limited, and is at least partly driven by concerns of adverse psychotropic effects. Canadian physicians endorse the need for a trial investigating the safety and efficacy of ketamine as a sedative for critically ill patients.

RéSUMé: OBJECTIF: Nous avons cherché à comprendre les croyances et les pratiques des intensivistes pratiquant au Canada concernant leur utilisation de la kétamine comme sédatif chez la patientèle gravement malade et à évaluer leur intérêt pour une étude randomisée contrôlée (ERC) examinant son utilisation à l'unité de soins intensifs (USI). MéTHODE: Nous avons mis au point et validé un sondage électronique auto-administré examinant l'utilisation de la kétamine comme perfusion sédative pour les patient·es aux soins intensifs. Nous avons envoyé le sondage à 400 médecins membres de la Société canadienne de soins intensifs (SCCC) par courriel entre février et avril 2022 et envoyé trois rappels à intervalles de deux semaines. Le sondage a été redistribué en janvier 2023 afin d'améliorer le taux de réponse. RéSULTATS: Nous avons reçu 87 questionnaires remplis sur 400 (22 %). La plupart des personnes répondantes ont déclaré qu'elles utilisaient rarement la kétamine en perfusion continue pour la sédation ou l'analgésie à l'USI (52/87, 58 %). Les médecins ont déclaré que les conditions suivantes les rendraient plus susceptibles d'utiliser de la kétamine : une exacerbation de l'asthme (73/87, 82 %), une tolérance aux opioïdes (68/87, 77 %), un état de mal épileptique (44/87, 50 %) et un syndrome de détresse respiratoire aigu (33/87, 38 %). Les inquiétudes quant aux effets secondaires qui ont limité l'utilisation de la kétamine par les répondant·es comprennent les effets psychotropes indésirables (61/87, 69 %) et le delirium (47/87, 53 %). La majorité des personnes répondantes étaient d'accord qu'une ERC est nécessaire pour évaluer la kétamine en tant que perfusion sédative à l'USI (62/87, 71 %). CONCLUSION: Cette enquête menée auprès d'intensivistes au Canada montre que l'utilisation de la kétamine comme perfusion continue pour la sédation est limitée, au moins en partie en raison d'inquiétudes liées aux effets psychotropes indésirables. Les médecins pratiquant au Canada reconnaissent la nécessité d'une étude sur l'innocuité et l'efficacité de la kétamine comme sédatif pour la patientèle gravement malade.

Prognostic value of natriuretic peptides in heart failure: systematic review and meta-analysis.

Risk models, informing optimal long-term medical management, seldom use natriuretic peptides (NP) in ascertaining the absolute risk of outcomes for HF patients. Individual studies evaluating the prognostic value of NPs in HF patients have reported varying effects, arriving at best estimates requires a systematic review. We systematically summarized the best evidence regarding the prognostic value of brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality and hospitalizations in ambulatory heart failure (HF) patients. We searched bibliographic databases from 2005 to 2018 and included studies evaluating the association of BNP or NT-proBNP with mortality or hospitalization using multivariable Cox proportional hazard models. We pooled hazard ratios using random-effect models, explored heterogeneity using pre-specified subgroup analyses, and evaluated the certainty of evidence using the Grading of Recommendations and Development Evaluation framework. We identified 67 eligible studies reporting on 76,178 ambulatory HF patients with a median BNP of 407 pg/mL (261-574 pg/mL). Moderate to high-quality evidence showed that a 100-pg/mL increase in BNP was associated with a 14% increased hazard of mortality (HR 1.14, 95% CI 1.06-1.22); a 1-log-unit increase was associated with a 51% increased hazard of mortality (HR 1.51, 95% CI 1.41-1.61) and 48% increased hazard of mortality or hospitalization (HR 1.48, 95% CI 1.29-1.69). With moderate to high certainty, we observed a 14% independent relative increase in mortality, translating to a clinically meaningful increase in absolute risk even for low-risk patients. The observed associations may help in developing more accurate risk models that incorporate NPs and accurately prognosticate HF patients.

Comparative benefits and harms of individual opioids for chronic non-cancer pain: a systematic review and network meta-analysis of randomised trials.

BACKGROUND: Most systematic reviews of opioids for chronic pain have pooled treatment effects across individual opioids under the assumption they provide similar benefits and harms. We examined the comparative effects of individual opioids for chronic non-cancer pain through a network meta-analysis of randomised controlled trials. METHODS: We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials to March 2021 for studies that enrolled patients with chronic non-cancer pain, randomised them to receive different opioids, or opioids vs placebo, and followed them for at least 4 weeks. Certainty of evidence was evaluated using the GRADE approach. RESULTS: We identified 82 eligible trials (22 619 participants) that evaluated 14 opioids. Compared with placebo, several opioids showed superiority to others for analgesia and improvement in physical function; however, when restricted to pooled-effect estimates supported by moderate certainty evidence, no differences between opioids were evident. Among opioids with moderate certainty evidence, all increased the risk of gastrointestinal adverse events compared with placebo, although no opioids were more harmful than others. Low to very low certainty evidence suggests that extended-release vs immediate-release opioids may provide similar benefits for pain relief and physical functioning, and gastrointestinal harms. CONCLUSIONS: Our findings support the pooling of effect estimates across different types and formulations of opioids to inform effectiveness for chronic non-cancer pain.

Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

Asymptomatic bacteriuria (ASB) is a common finding in many populations, including healthy women and persons with underlying urologic abnormalities. The 2005 guideline from the Infectious Diseases Society of America recommended that ASB should be screened for and treated only in pregnant women or in an individual prior to undergoing invasive urologic procedures. Treatment was not recommended for healthy women; older women or men; or persons with diabetes, indwelling catheters, or spinal cord injury. The guideline did not address children and some adult populations, including patients with neutropenia, solid organ transplants, and nonurologic surgery. In the years since the publication of the guideline, further information relevant to ASB has become available. In addition, antimicrobial treatment of ASB has been recognized as an important contributor to inappropriate antimicrobial use, which promotes emergence of antimicrobial resistance. The current guideline updates the recommendations of the 2005 guideline, includes new recommendations for populations not previously addressed, and, where relevant, addresses the interpretation of nonlocalizing clinical symptoms in populations with a high prevalence of ASB.

Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

Asymptomatic bacteriuria (ASB) is a common finding in many populations, including healthy women and persons with underlying urologic abnormalities. The 2005 guideline from the Infectious Diseases Society of America recommended that ASB should be screened for and treated only in pregnant women or in an individual prior to undergoing invasive urologic procedures. Treatment was not recommended for healthy women; older women or men; or persons with diabetes, indwelling catheters, or spinal cord injury. The guideline did not address children and some adult populations, including patients with neutropenia, solid organ transplants, and nonurologic surgery. In the years since the publication of the guideline, further information relevant to ASB has become available. In addition, antimicrobial treatment of ASB has been recognized as an important contributor to inappropriate antimicrobial use, which promotes emergence of antimicrobial resistance. The current guideline updates the recommendations of the 2005 guideline, includes new recommendations for populations not previously addressed, and, where relevant, addresses the interpretation of nonlocalizing clinical symptoms in populations with a high prevalence of ASB.

Evidence-based guidelines for supportive care of patients with Ebola virus disease.

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

Anti-Ebola therapy for patients with Ebola virus disease: a systematic review.

BACKGROUND: Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014-2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. METHODS: We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. RESULTS: From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, - 36 to 7%). Studies of convalescent plasma, interferon-ß-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. CONCLUSIONS: Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal.

[The BMJ Rapid Recommendations: towards a new model for the production of clinical practice guidelines]. / « BMJ Rapid Recommendations ¼ : vers un nouveau modèle de recommandations pour la pratique clinique.

Guidelines play a central role in clinical practice, but their development often does not meet trustworthiness standards, which makes them vulnerable to conflict of interest. Additional problems -include their insufficient updating, and current formats that do not support shared decision-making. To address these issues, we have created the Rapid Recommendations, in collaboration with the British -Medical Journal. In this innovative approach, we a) identify new practice-changing evidence ; b) incorporate them in updated -systematics reviews in about 45 days ; c) gather an international and unconflicted panel including patients and d) publish trust-worthy recommendation in about 90 days, along with new multilayered evidence summaries and tools that facilitate shared decision-making.

Les guidelines ont une place centrale dans notre pratique clinique, mais leur développement manque souvent de rigueur et de transparence, rendant leurs recommandations vulnérables aux conflits d'intérêts. S'y ajoutent les problèmes de mise à jour insuffisante, et des formats qui ne facilitent pas leur adaptation locale ou la décision médicale partagée. En -réponse à ces problèmes, nous avons conçu les RapidRecs en collaboration avec le British Medical Journal. Cette approche innovante consiste à : a) identifier des -nouvelles études pouvant changer la pratique ; b) les incorporer dans des revues systématiques en -environ 45 jours ; c) rassembler un panel international indépendant, sans conflit d'intérêts et incluant des patients et d) émettre des recommandations -selon GRADE en environ 90 jours, avec des outils didactiques -facilitant la décision -médicale partagée.

Corticosteroids in Patients Hospitalized With Community-Acquired Pneumonia: Systematic Review and Individual Patient Data Metaanalysis.

Background: Our aim was to evaluate the benefits and harms of adjunctive corticosteroids in adults hospitalized with community-acquired pneumonia (CAP) using individual patient data from randomized, placebo-controlled trials and to explore subgroup differences. Methods: We systematically searched Medline, Embase, Cochrane Central, and trial registers (all through July 2017). Data from 1506 individual patients in 6 trials were analyzed using uniform outcome definitions. We investigated prespecified effect modifiers using multivariable hierarchical regression, adjusting for pneumonia severity, age, and clustering effects. Results: Within 30 days of randomization, 37 of 748 patients (5.0%) assigned to corticosteroids and 45 of 758 patients (5.9%) assigned to placebo died (adjusted odds ratio [aOR], 0.75; 95% confidence interval [CI], .46 to 1.21; P = .24). Time to clinical stability and length of hospital stay were reduced by approximately 1 day with corticosteroids (-1.03 days; 95% CI, -1.62 to -.43; P = .001 and -1.15 days; 95% CI, -1.75 to -.55; P < .001, respectively). More patients with corticosteroids had hyperglycemia (160 [22.1%] vs 88 [12.0%]; aOR, 2.15; 95% CI, 1.60 to 2.90; P < .001) and CAP-related rehospitalization (33 [5.0%] vs 18 [2.7%]; aOR, 1.85; 95% CI, 1.03 to 3.32; P = .04). We did not find significant effect modification by CAP severity or degree of inflammation. Conclusions: Adjunct corticosteroids for patients hospitalized with CAP reduce time to clinical stability and length of hospital stay by approximately 1 day without a significant effect on overall mortality but with an increased risk for CAP-related rehospitalization and hyperglycemia.

An Exploratory Reanalysis of the Randomized Trial on Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome.

OBJECTIVES: In the Acute Respiratory Distress Syndrome Network randomized controlled trial, methylprednisolone treatment was associated with increased return to mechanical ventilation with partial loss of early improvements. We hypothesize a causal relationship between protocol-driven rapid discontinuation of methylprednisolone post extubation and return to mechanical ventilation. To explore this possibility, we investigated the timing that events occurred in each treatment arm during active treatment intervention (efficacy) and after stopping therapy. DESIGN AND SETTINGS: Retrospective intention-to-treat analysis of multicenter randomized controlled trial. PATIENTS AND INTERVENTIONS: Patients were randomized to methylprednisolone (2 mg/kg/d) or placebo (89 vs 91). The target sample size was reduced post hoc and provided 80% power for an optimistic 50% mortality reduction. MEASUREMENTS AND MAIN RESULTS: Findings are reported as methylprednisolone versus placebo. By day 28, fewer patients died before achieving extubation (15.7% vs 25.3% and risk ratio, 0.62; 95% CI, 0.34-1.13), more achieved successful extubation (71.9% vs 49.5% and risk ratio, 1.45; CI, 1.14-1.85), time to successful extubation was shorter (hazard ratio, 2.05; CI, 1.42-2.96), and more were discharged alive from the ICU (65.2% vs 48.3%; risk ratio, 1.35; CI, 1.04-1.75). After treatment discontinuation, more methylprednisolone-treated patients returned to mechanical ventilation (26.6% vs 6.7%; risk ratio, 3.98; CI, 1.24-12.79)-consistent with reconstituted systemic inflammation in the presence of adrenal suppression. Participants returning to mechanical ventilation without reinstitution of methylprednisolone had increased risk of ventilator dependence and mortality. Despite loss of early benefits, methylprednisolone was associated with sizable and significant improvements in all secondary outcomes and reduction in serious complications (shock and severe infections). CONCLUSIONS: During active intervention, methylprednisolone was safe and effective in achieving disease resolution. Our findings support rapid glucocorticoid discontinuation post extubation as likely cause of disease relapse. Gradual tapering might be necessary to preserve the significant improvements achieved during methylprednisolone administration.

Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review and meta-analysis addresses the efficacy and safety of corticosteroids in critically ill patients with sepsis. DATA SOURCES: We updated a comprehensive search of MEDLINE, EMBASE, CENTRAL, and LILACS, and unpublished sources for randomized controlled trials that compared any corticosteroid to placebo or no corticosteroid in critically ill children and adults with sepsis. STUDY SELECTION: Reviewers conducted duplicate screening of citations, data abstraction, and, using a modified Cochrane risk of bias tool, individual study risk of bias assessment. DATA EXTRACTION: A parallel guideline committee provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. We assessed overall certainty in evidence using Grading of Recommendations Assessment, Development and Evaluation methodology and performed all analyses using random-effect models. For subgroup analyses, we performed metaregression and considered p value less than 0.05 as significant. DATA SYNTHESIS: Forty-two randomized controlled trials including 10,194 patients proved eligible. Based on low certainty, corticosteroids may achieve a small reduction or no reduction in the relative risk of dying in the short-term (28-31 d) (relative risk, 0.93; 95% CI, 0.84-1.03; 1.8% absolute risk reduction; 95% CI, 4.1% reduction to 0.8% increase), and possibly achieve a small effect on long-term mortality (60 d to 1 yr) based on moderate certainty (relative risk, 0.94; 95% CI, 0.89-1.00; 2.2% absolute risk reduction; 95% CI, 4.1% reduction to no effect). Corticosteroids probably result in small reductions in length of stay in ICU (mean difference, -0.73 d; 95% CI, -1.78 to 0.31) and hospital (mean difference, -0.73 d; 95% CI, -2.06 to 0.60) (moderate certainty). Corticosteroids result in higher rates of shock reversal at day 7 (relative risk, 1.26; 95% CI, 1.12-1.42) and lower Sequential Organ Failure Assessment scores at day 7 (mean difference, -1.39; 95% CI, -1.88 to -0.89) (high certainty). Corticosteroids likely increase the risk of hypernatremia (relative risk, 1.64; 95% CI, 1.32-2.03) and hyperglycemia (relative risk, 1.16; 95% CI, 1.08-1.24) (moderate certainty), may increase the risk of neuromuscular weakness (relative risk, 1.21; 95% CI, 1.01-1.52) (low certainty), and appear to have no other adverse effects (low or very low certainty). Subgroup analysis did not demonstrate a credible subgroup effect on any of the outcomes of interest (p > 0.05 for all). CONCLUSIONS: In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness.

Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis.

The impact of transfusing fresher vs older red blood cells (RBCs) on patient-important outcomes remains controversial. Two recently published large trials have provided new evidence. We summarized results of randomized trials evaluating the impact of the age of transfused RBCs. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Database for Systematic Reviews, and Cochrane CENTRAL for randomized controlled trials enrolling patients who were transfused fresher vs older RBCs and reported outcomes of death, adverse events, and infection. Independently and in duplicate, reviewers determined eligibility, risk of bias, and abstracted data. We conducted random effects meta-analyses and rated certainty (quality or confidence) of evidence using the GRADE approach. Of 12 trials that enrolled 5229 participants, 6 compared fresher RBCs with older RBCs and 6 compared fresher RBCs with current standard practice. There was little or no impact of fresher vs older RBCs on mortality (relative risk [RR], 1.04; 95% confidence interval [CI], 0.94-1.14; P = .45; I(2) = 0%, moderate certainty evidence) or on adverse events (RR, 1.02; 95% CI, 0.91-1.14; P = .74; I(2) = 0%, low certainty evidence). Fresher RBCs appeared to increase the risk of nosocomial infection (RR, 1.09; 95% CI, 1.00-1.18; P = .04; I(2) = 0%, risk difference 4.3%, low certainty evidence). Current evidence provides moderate certainty that use of fresher RBCs does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates. The existing evidence provides no support for changing practices toward fresher RBC transfusion.

α-Blockers for uncomplicated ureteric stones: a clinical practice guideline.

OBJECTIVE: To develop an evidence-based recommendation concerning the use of α-blockers for uncomplicated ureteric stones based on an up-to-date Cochrane review, as the role of medical expulsive therapy for uncomplicated ureteric stones remains controversial in the light of new contradictory trial evidence. METHODS: We applied the Rapid Recommendations approach to guideline development, which represents an innovative approach by an international collaborative network of clinicians, researchers, methodologists and patient representatives seeking to rapidly respond to new, potentially practice-changing evidence with recommendations developed according to standards for trustworthy guidelines. RESULTS: The panel suggests the use of α-blockers in addition to standard care over standard care alone in patients with uncomplicated ureteric stones (weak recommendation based on low-quality evidence). The panel judged that the net benefit of α-blockers was small and that there was considerable uncertainty about patients' values and preferences. This means that the panel expects that most patients would choose treatment with α-blockers but that a substantial proportion would not. This recommendation applies to both patients in whom the presence of ureteric stones is confirmed by imaging, as well as patients in whom the diagnosis is made based on clinical grounds only. CONCLUSION: The Rapid Recommendations panel suggests the use of α-blockers for patients with ureteric stones. Shared decision-making is emphasised in making the final choice between the treatment options.

Antiretroviral resistance testing in HIV-positive people.

BACKGROUND: Resistance to antiretroviral therapy (ART) among people living with human immunodeficiency virus (HIV) compromises treatment effectiveness, often leading to virological failure and mortality. Antiretroviral drug resistance tests may be used at the time of initiation of therapy, or when treatment failure occurs, to inform the choice of ART regimen. Resistance tests (genotypic or phenotypic) are widely used in high-income countries, but not in resource-limited settings. This systematic review summarizes the relative merits of resistance testing in treatment-naive and treatment-exposed people living with HIV. OBJECTIVES: To evaluate the effectiveness of antiretroviral resistance testing (genotypic or phenotypic) in reducing mortality and morbidity in HIV-positive people. SEARCH METHODS: We attempted to identify all relevant studies, regardless of language or publication status, through searches of electronic databases and conference proceedings up to 26 January 2018. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov to 26 January 2018. We searched Latin American and Caribbean Health Sciences Literature (LILACS) and the Web of Science for publications from 1996 to 26 January 2018. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and observational studies that compared resistance testing to no resistance testing in people with HIV irrespective of their exposure to ART.Primary outcomes of interest were mortality and virological failure. Secondary outcomes were change in mean CD4-T-lymphocyte count, clinical progression to AIDS, development of a second or new opportunistic infection, change in viral load, and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed each reference for prespecified inclusion criteria. Two review authors then independently extracted data from each included study using a standardized data extraction form. We analysed data on an intention-to-treat basis using a random-effects model. We performed subgroup analyses for the type of resistance test used (phenotypic or genotypic), use of expert advice to interpret resistance tests, and age (children and adolescents versus adults). We followed standard Cochrane methodological procedures. MAIN RESULTS: Eleven RCTs (published between 1999 and 2006), which included 2531 participants, met our inclusion criteria. All of these trials exclusively enrolled patients who had previous exposure to ART. We found no observational studies. Length of follow-up time, study settings, and types of resistance testing varied greatly. Follow-up ranged from 12 to 150 weeks. All studies were conducted in Europe, USA, or South America. Seven studies used genotypic testing, two used phenotypic testing, and two used both phenotypic and genotypic testing. Only one study was funded by a manufacturer of resistance tests.Resistance testing made little or no difference in mortality (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.36 to 2.22; 5 trials, 1140 participants; moderate-certainty evidence), and may have slightly reduced the number of people with virological failure (OR 0.70, 95% CI 0.56 to 0.87; 10 trials, 1728 participants; low-certainty evidence); and probably made little or no difference in change in CD4 cell count (mean difference (MD) -1.00 cells/mm³, 95% CI -12.49 to 10.50; 7 trials, 1349 participants; moderate-certainty evidence) or progression to AIDS (OR 0.64, 95% CI 0.31 to 1.29; 3 trials, 809 participants; moderate-certainty evidence). Resistance testing made little or no difference in adverse events (OR 0.89, 95% CI 0.51 to 1.55; 4 trials, 808 participants; low-certainty evidence) and probably reduced viral load (MD -0.23, 95% CI -0.35 to -0.11; 10 trials, 1837 participants; moderate-certainty evidence). No studies reported on development of new opportunistic infections or quality of life. We found no statistically significant heterogeneity for any outcomes, and the I² statistic value ranged from 0 to 25%. We found no subgroup effects for types of resistance testing (genotypic versus phenotypic), the addition of expert advice to interpretation of resistance tests, or age. Results for mortality were consistent when we compared studies at high or unclear risk of bias versus studies at low risk of bias. AUTHORS' CONCLUSIONS: Resistance testing probably improved virological outcomes in people who have had virological failure in trials conducted 12 or more years ago. We found no evidence in treatment-naive people. Resistance testing did not demonstrate important patient benefits in terms of risk of death or progression to AIDS. The trials included very few participants from low- and middle-income countries.

Cerebral Embolic Protection Devices During Transcatheter Aortic Valve Implantation: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Silent ischemic embolic lesions are common after transcatheter aortic valve implantation (TAVI). The use of embolic protection devices (EPD) may reduce the occurrence of these embolic lesions. Thus, a quantitative overview and credibility assessment of the literature was necessary to draw a robust message about EPD. Therefore, the aim of this meta-analysis was to study whether the use of EPD reduces silent ischemic and clinically evident cerebrovascular events associated with TAVI. METHODS: We conducted a comprehensive search to identify studies that evaluated patients undergoing TAVI with or without EPD. Random-effects meta-analyses were performed to estimate the effect of EPD compared with no-EPD during TAVI using aggregate data. RESULTS: Sixteen studies involving 1170 patients (865/305 with/without EPD) fulfilled the inclusion criteria. The EPD delivery success rate was reported in all studies and was achieved in 94.5% of patients. Meta-analyses evaluating EPD versus without EPD strategies could not confirm or exclude any differences in terms of clinically evident stroke (relative risk, 0.70; 95% confidence interval [CI], 0.38-1.29; P=0.26) or 30-day mortality (relative risk, 0.58; 95% CI, 0.20-1.64; P=0.30). There were no significant differences in new-single, multiple, or total number of lesions. The use of EPD was associated with a significantly smaller ischemic volume per lesion (standardized mean difference, -0.52; 95% CI, -0.85 to -0.20; P=0.002) and smaller total volume of lesions (standardized mean difference, -0.23; 95% CI, -0.42 to -0.03; P=0.02). Subgroup analysis by type of valve showed an overall trend toward significant reduction in new lesions per patient using EPD (standardized mean difference, -0.41; 95% CI, -0.82 to 0.00; P=0.05), driven by self-expanding devices. CONCLUSIONS: The use of EPD during TAVI may be associated with smaller volume of silent ischemic lesions and smaller total volume of silent ischemic lesions. However, EPD may not reduce the number of new-single, multiple, or total number of lesions. There was only very low quality of evidence showing no significant differences between patients undergoing TAVI with or without EPD with respect to clinically evident stroke and mortality.

A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension.

PURPOSE: Clinicians must balance the risks from hypotension with the potential adverse effects of vasopressors. Experts have recommended a mean arterial pressure (MAP) target of at least 65 mmHg, and higher in older patients and in patients with chronic hypertension or atherosclerosis. We conducted a systematic review of randomized-controlled trials comparing higher vs lower blood pressure targets for vasopressor therapy administered to hypotensive critically ill patients. METHODS: We searched MEDLINE®, EMBASE™, and the Cochrane Central Register of Controlled Trials for studies of higher vs lower blood pressure targets for vasopressor therapy in critically ill hypotensive adult patients. Two reviewers independently assessed trial eligibility based on titles and abstracts, and they then selected full-text reports. Outcomes, subgroups, and analyses were prespecified. We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the overall confidence in the estimates of intervention effects. RESULTS: Of 8001 citations, we retrieved 57 full-text articles and ultimately included two randomized-controlled trials (894 patients). Higher blood pressure targets were not associated with lower mortality (relative risk [RR], 1.05; 95% confidence interval [CI], 0.90 to 1.23; P = 0.54), and neither age (P = 0.17) nor chronic hypertension (P = 0.32) modified the overall effect. Nevertheless, higher blood pressure targets were associated with a greater risk of new-onset supraventricular cardiac arrhythmia (RR, 2.08; 95% CI, 1.28 to 3.38; P < 0.01). CONCLUSION: Current evidence does not support a MAP target > 70 mmHg in hypotensive critically ill adult patients requiring vasopressor therapy.

Corticosteroid Therapy for Patients Hospitalized With Community-Acquired Pneumonia: A Systematic Review and Meta-analysis.

BACKGROUND: Community-acquired pneumonia (CAP) is common and often severe. PURPOSE: To examine the effect of adjunctive corticosteroid therapy on mortality, morbidity, and duration of hospitalization in patients with CAP. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through 24 May 2015. STUDY SELECTION: Randomized trials of systemic corticosteroids in hospitalized adults with CAP. DATA EXTRACTION: Two reviewers independently extracted study data and assessed risk of bias. Quality of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation system by consensus among the authors. DATA SYNTHESIS: The median age was typically in the 60s, and approximately 60% of patients were male. Adjunctive corticosteroids were associated with possible reductions in all-cause mortality (12 trials; 1974 patients; risk ratio [RR], 0.67 [95% CI, 0.45 to 1.01]; risk difference [RD], 2.8%; moderate certainty), need for mechanical ventilation (5 trials; 1060 patients; RR, 0.45 [CI, 0.26 to 0.79]; RD, 5.0%; moderate certainty), and the acute respiratory distress syndrome (4 trials; 945 patients; RR, 0.24 [CI, 0.10 to 0.56]; RD, 6.2%; moderate certainty). They also decreased time to clinical stability (5 trials; 1180 patients; mean difference, -1.22 days [CI, -2.08 to -0.35 days]; high certainty) and duration of hospitalization (6 trials; 1499 patients; mean difference, -1.00 day [CI, -1.79 to -0.21 days]; high certainty). Adjunctive corticosteroids increased frequency of hyperglycemia requiring treatment (6 trials; 1534 patients; RR, 1.49 [CI, 1.01 to 2.19]; RD, 3.5%; high certainty) but did not increase frequency of gastrointestinal hemorrhage. LIMITATIONS: There were few events and trials for many outcomes. Trials often excluded patients at high risk for adverse events. CONCLUSION: For hospitalized adults with CAP, systemic corticosteroid therapy may reduce mortality by approximately 3%, need for mechanical ventilation by approximately 5%, and hospital stay by approximately 1 day. PRIMARY FUNDING SOURCE: None.