Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies.

BACKGROUND: Benzodiazepine use is associated with delirium, and guidelines recommend avoiding them in older and critically ill patients. Their perioperative use remains common because of perceived benefits. METHODS: We searched CENTRAL, MEDLINE, CINAHL, PsycInfo, and Web of Science from inception to June 2021. Pairs of reviewers identified randomised controlled trials and prospective observational studies comparing perioperative use of benzodiazepines with other agents or placebo in patients undergoing surgery. Two reviewers independently abstracted data, which we combined using a random-effects model. Our primary outcomes were delirium, intraoperative awareness, and mortality. RESULTS: We included 34 randomised controlled trials (n=4354) and nine observational studies (n=3309). Observational studies were considered separately. Perioperative benzodiazepines did not increase the risk of delirium (n=1352; risk ratio [RR] 1.43; 95% confidence interval [CI]: 0.9-2.27; I2=72%; P=0.13; very low-quality evidence). Use of benzodiazepines instead of dexmedetomidine did, however, increase the risk of delirium (five studies; n=429; RR 1.83; 95% CI: 1.24-2.72; I2=13%; P=0.002). Perioperative benzodiazepine use decreased the risk of intraoperative awareness (n=2245; RR 0.26; 95% CI: 0.12-0.58; I2=35%; P=0.001; very low-quality evidence). When considering non-events, perioperative benzodiazepine use increased the probability of not having intraoperative awareness (RR 1.07; 95% CI: 1.01-1.13; I2=98%; P=0.03; very low-quality evidence). Mortality was reported by one randomised controlled trial (n=800; RR 0.90; 95% CI: 0.20-3.1; P=0.80; very low quality). CONCLUSIONS: In this systematic review and meta-analysis, perioperative benzodiazepine use did not increase postoperative delirium and decreased intraoperative awareness. Previously observed relationships of benzodiazepine use with delirium could be explained by comparisons with dexmedetomidine. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42019128144.

Oxygen Management During Cardiopulmonary Bypass: A Single-Center, 8-Year Retrospective Cohort Study.

OBJECTIVE: To characterize the institutional oxygen management practices during cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery, including any potential changes during an 8-year study period. DESIGN: A retrospective cohort study. SETTING: A tertiary care cardiac surgical program. PARTICIPANTS: Patients who underwent cardiac surgery involving CPB, with or without hypothermic circulatory arrest (HCA), between January 1, 2010, and December 31, 2017. MEASUREMENTS AND MAIN RESULTS: In addition to baseline patient characteristics, the authors recorded the partial pressures of arterial oxygen (Pao2), fraction of inspired oxygen, and mixed venous oxygen saturation during CPB of 696 randomly selected patients during an 8-year study period. The overall mean Pao2 was 255 ± 48 mmHg, without any significant change during the 8-year study period (p = 0.30). The mean Pao2 of HCA patients was significantly higher than in patients without HCA (327 ± 93 mmHg v 252 ± 45 mmHg, respectively; p < 0.001). CONCLUSIONS: The current approach to oxygen management during CPB at the authors' institution is within the range of hyperoxemic levels, and these practices have not changed over time. The impact of these practices on patients' outcomes is not fully understood, and additional studies are needed to establish firm evidence to guide optimal oxygen management practice during CPB.

Postcardiac Surgery Acute Stroke Therapies: A Systematic Review.

OBJECTIVE: To identify interventions for the treatment of acute ischemic stroke after cardiac surgery and to report the efficacy of these treatments. DESIGN: Systematic review and narrative synthesis PARTICIPANTS: Patients with ischemic stroke after cardiac surgery. INTERVENTIONS: Treatment efficacy of intra-arterial thrombolysis (IAT) and/or endovascular mechanical thrombectomy (EMT). METHODS AND MAIN RESULTS: The MEDLINE (Ovid), Embase (Ovid), Scopus (Elsevier), and Cochrane Central Register of Controlled Trials (Wiley) databases were searched from January 1, 1990, until September 20, 2018. After reviewing 5,231 records, 8 case reports/series and 2 retrospective studies were included (n = 33). Three of these reports (n = 19) published between 2001 and 2003 described IAT, and 6 studies (n = 14) published between 2015 and 2019 reported the use of EMT. In the 19 patients who received IAT, 3 (16%) had good, 8 (42%) had moderate, and 8 (42%) had poor neurologic outcomes. In the 14 patients who received EMT, 7 (50%) had good, 5 (36%) had moderate, and 2 (14%) had poor neurologic outcomes. CONCLUSIONS: Endovascular thrombectomy, with or without IAT, is being used increasingly with success in patients presenting with postcardiac surgery stroke. However, the number of patients reported is too small to confidently understand its overall effect on neurologic outcomes in this setting.

The effect of restrictive versus liberal transfusion strategies on longer-term outcomes after cardiac surgery: a systematic review and meta-analysis with trial sequential analysis.

PURPOSE: Blood transfusions are frequently administered in cardiac surgery. Despite a large number of published studies comparing a "restrictive" strategy with a "liberal" strategy, no clear consensus has emerged to guide blood transfusion practice in cardiac surgery patients. The purpose of this study was to identify, critically appraise, and summarize the evidence on the overall effect of restrictive transfusion strategies compared with liberal transfusion strategies on mortality, other clinical outcomes, and transfusion-related outcomes in adult patients undergoing cardiac surgery. SOURCE: We searched MEDLINE (OvidSP), EMBASE (OvidSP) and Cochrane CENTRAL (Wiley) from inception to 1 December 2017 and queried clinical trial registries and conference proceedings for randomized-controlled trials of liberal vs restrictive transfusion strategies in cardiac surgery. PRINCIPAL FINDINGS: From 7,908 citations, we included ten trials (9,101 patients) and eight companion publications. Overall, we found no significant difference in mortality between restrictive and liberal transfusion strategies (risk ratio [RR], 1.08; 95% confidence interval [CI], 0.76 to 1.54; I2 = 33%; seven trials; 8,661 patients). The use of a restrictive transfusion strategy did not appear to adversely impact any of the secondary clinical outcomes. As expected, the proportion of patients who received red blood cells (RBCs) in the restrictive group was significantly lower than in the liberal group (RR, 0.68; 95% CI, 0.64 to 0.73; I2 = 56%; 5 trials; 8,534 patients). Among transfused patients, a restrictive transfusion strategy was associated with fewer transfused RBC units per patient than a liberal transfusion strategy. CONCLUSIONS: In adult patients undergoing cardiac surgery, a restrictive transfusion strategy reduces RBC transfusion without impacting mortality rate or the incidence of other perioperative complications. Nevertheless, further large trials in subgroups of patients, potentially of differing age, are needed to establish firm evidence to guide transfusion in cardiac surgery. TRIAL REGISTRATION: PROSPERO (CRD42017071440); registered 20 April, 2018.

RéSUMé: OBJECTIF: Les transfusions sanguines sont fréquentes après une chirurgie cardiaque. Malgré le nombre important d'études publiées comparant une stratégie « restrictive ¼ à une stratégie « libérale ¼, aucun consensus clair n'est apparu pour guider la pratique de la transfusion sanguine chez les patients de chirurgie cardiaque. L'objectif de cette étude était d'identifier, d'évaluer de façon critique et de résumer les données probantes sur l'effet global des stratégies de transfusion restrictives comparativement aux stratégies libérales sur la mortalité, les autres devenirs cliniques, et les devenirs liés à la transfusion chez des patients adultes subissant une chirurgie cardiaque. SOURCE: Nous avons réalisé des recherches dans les bases de données MEDLINE (OvidSP), EMBASE (OvidSP) et Cochrane CENTRAL (Wiley) de leur création jusqu'au 1er décembre 2017 et avons exploré les registres d'études cliniques et les actes de conférence pour en tirer les études randomisées contrôlées évaluant des stratégies transfusionnelles restrictives vs libérales en chirurgie cardiaque. CONSTATATIONS PRINCIPALES: Sur 7908 citations, nous avons inclus dix études (9101 patients) et huit publications connexes. Globalement, nous n'avons observé aucune différence significative en matière de mortalité entre les stratégies transfusionnelles restrictives et libérales (risque relatif [RR], 1,08; intervalle de confiance [IC] 95 %, 0,76 à 1,54; I2 = 33 %; sept études; 8661 patients). Le recours à une stratégie de transfusion restrictive n'a semblé avoir aucun impact négatif sur quelque résultat clinique secondaire que ce soit. Comme anticipé, la proportion de patients ayant reçu des érythrocytes dans le groupe restrictif était significativement plus basse que dans le groupe libéral (RR, 0,68; IC 95 %, 0,64 à 0,73; I2 = 56 %; 7 études; 8534 patients). Parmi les patients transfusés, une stratégie de transfusion restrictive a été associée à un nombre moindre d'unités d'érythrocytes transfusées par patient que dans une stratégie transfusionnelle libérale. CONCLUSION: Dans une population de patients adultes subissant une chirurgie cardiaque, une stratégie transfusionnelle restrictive réduit la transfusion d'érythrocytes sans avoir d'impact sur le taux de mortalité ou sur l'incidence d'autres complications périopératoires. D'autres grandes études sur différents sous-groupes de patients, peut-être d'âges différents, sont toutefois nécessaires afin d'établir des données probantes concluantes pour guider les transfusions en chirurgie cardiaque. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42017071440); enregistrée le 20 avril 2018.

Vitamins and Minerals for Migraine Prophylaxis: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the findings of randomized controlled trials (RCTs) on the efficacy and safety of vitamins and minerals for migraine prophylaxis. METHODS: We systematically searched bibliographic databases and relevant websites for parallel and crossover RCTs reporting efficacy and/or safety of vitamins and/or minerals for migraine prophylaxis. Our primary outcomes were migraine frequency (number of attacks) and duration (hours). Secondary outcomes were severity (intensity), days with migraine, and adverse events. Meta-analysis was conducted when analyzable data were available from at least two trials. RESULTS: Eighteen placebo-controlled trials met our eligibility criteria. Only coenzyme Q10 and magnesium contributed to meta-analyses. In adults, compared with placebo, coenzyme Q10 did not significantly decrease migraine frequency (mean difference (MD) -0.44 (-2.14 to 1.26); I2 53%; 2 trials; 97 participants; moderate strength of the evidence), duration (MD -1.97 (-4.82 to 0.87); I2 0%; 2 trials; 97 participants; moderate strength of the evidence), or severity (ratio of means (RoM) -0.05 (-0.20 to 0.11); I2 0%; 2 trials; 97 participants). In adults, compared with placebo, magnesium did not significantly decrease migraine severity (RoM -0.17 (-0.36 to 0.02); I2 48%; 3 trials; 226 participants; low strength of the evidence). Meta-analysis of other vitamins and minerals, and other outcomes were not feasible due to a lack of sufficiently reported data. CONCLUSIONS: Based on insufficient evidence, it is unknown if coenzyme Q10 and magnesium are effective for migraine prophylaxis in adults. High-quality, adequately powered RCTs are needed to fully evaluate the efficacy and safety of vitamins and minerals for migraine prophylaxis.

Autologous Bone Marrow Stem Cell Therapy in Patients With ST-Elevation Myocardial Infarction: A Systematic Review and Meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) on bone marrow stem cell (BMSC) therapy in ST-elevation myocardial infarction (STEMI) patients have reported conflicting results. Our main objective was to critically appraise and meta-analyze best-available evidence on efficacy and safety of intracoronary administration of autologous BMSC therapy in STEMI patients after primary percutaneous coronary intervention. METHODS: We conducted a search of MEDLINE, PubMed, EMBASE, CENTRAL, Global Health, CINAHL, and conference proceedings in February 2017. Our primary outcome was all-cause mortality. Secondary and safety outcomes included cardiac death, heart failure, arrhythmias, repeat myocardial infarction, or target vessel revascularizations; or improved health-related quality of life, left ventricular ejection fraction, or infarct size. Summary relative and absolute risks were obtained using random effects models. We also evaluated the strength of evidence. RESULTS: A comprehensive database search identified 42 RCTs (3365 STEMI patients). BMSC therapy did not significantly decrease mortality (risk ratio, 0.71; 95% confidence interval, 0.45-1.11; I2, 0%; absolute risk reduction, 0.1%; 95% confidence interval, -0.71 to 0.91; 40 trials; 3289 participants; I2, 0%; low strength of evidence). BMSC therapy had no effect on secondary or adverse outcomes. Trial sequential analysis for all-cause mortality showed no evidence of a clinically important difference, with a very low probability that future studies can change the current conclusion. CONCLUSIONS: On the basis of evidence from 42 RCTs published in the past 15 years, we provide conclusive evidence for a lack of beneficial effect for autologous BMSC therapy in patients with STEMI.

Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins.

HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1α) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX(-/-)/BAK(-/-) murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease.

Autophagy and apoptosis dysfunction in neurodegenerative disorders.

Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.

Novel non-canonical TGF-ß signaling networks: emerging roles in airway smooth muscle phenotype and function.

The airway smooth muscle (ASM) plays an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD). ASM cells express a wide range of receptors involved in contraction, growth, matrix protein production and the secretion of cytokines and chemokines. Transforming growth factor beta (TGF-ß) is one of the major players in determining the structural and functional abnormalities of the ASM in asthma and COPD. It is increasingly evident that TGF-ß functions as a master switch, controlling a network of intracellular and autocrine signaling loops that effect ASM phenotype and function. In this review, the various elements that participate in non-canonical TGF-ß signaling, including MAPK, PI3K, WNT/ß-catenin, and Ca(2+), are discussed, focusing on their effect on ASM phenotype and function. In addition, new aspects of ASM biology and their possible association with non-canonical TGF-ß signaling will be discussed.

Staphylococcus aureus in Acne Pathogenesis: A Case-Control Study.

BACKGROUND: There is considerable evidence which suggests a possible pathogenetic role for Staphylococcus aureus (S. aureus) in acne vulgaris. AIM: The study was to determine S. aureus colonization and antibiotic susceptibility patterns in patients with acne and of healthy people. MATERIALS AND METHODS: In the case-control study, a total of 324 people were screened for nasal carriage of S. aureus: 166 acne patients and 158 healthy persons. One control subject was individually matched to one case. Nasal swabs from anterior nares of individuals were cultured and identified as S. aureus. Antibiotic sensitivity was performed with recognized laboratory techniques. RESULTS: S. aureus was detected in 21.7% of the subjects in acne, and in 26.6% of control groups. There was no statistical difference in colonization rates between two groups (P=0.3). In patient group, most of S. aureus isolates were resistant to doxicycline and tetracycline (P=0.001), and were more sensitive to rifampicin compared to other drugs. In control samples, the isolated demonstrated higher resistance to cotrimoxazole compared to patient samples (P=0.0001). There was no difference between groups regarding resistance to rifampicin, vancomycin, methicillin, and oxacillin. CONCLUSION: It is still unclear whether S. aureus is actually a causal agent in the pathogenesis of acne. Based on microbiological data of both healthy and acne-affected persons, we propose that contribution of S. aureus in acne pathogenesis is controversial.

Mevalonate cascade regulation of airway mesenchymal cell autophagy and apoptosis: a dual role for p53.

Statins inhibit the proximal steps of cholesterol biosynthesis, and are linked to health benefits in various conditions, including cancer and lung disease. We have previously investigated apoptotic pathways triggered by statins in airway mesenchymal cells, and identified reduced prenylation of small GTPases as a primary effector mechanism leading to p53-mediated cell death. Here, we extend our studies of statin-induced cell death by assessing endpoints of both apoptosis and autophagy, and investigating their interplay and coincident regulation. Using primary cultured human airway smooth muscle (HASM) and human airway fibroblasts (HAF), autophagy, and autophagosome formation and flux were assessed by transmission electron microscopy, cytochemistry (lysosome number and co-localization with LC3) and immunoblotting (LC3 lipidation and Atg12-5 complex formation). Chemical inhibition of autophagy increased simvastatin-induced caspase activation and cell death. Similarly, Atg5 silencing with shRNA, thus preventing Atg5-12 complex formation, increased pro-apoptotic effects of simvastatin. Simvastatin concomitantly increased p53-dependent expression of p53 up-regulated modulator of apoptosis (PUMA), NOXA, and damage-regulated autophagy modulator (DRAM). Notably both mevalonate cascade inhibition-induced autophagy and apoptosis were p53 dependent: simvastatin increased nuclear p53 accumulation, and both cyclic pifithrin-α and p53 shRNAi partially inhibited NOXA, PUMA expression and caspase-3/7 cleavage (apoptosis) and DRAM expression, Atg5-12 complex formation, LC3 lipidation, and autophagosome formation (autophagy). Furthermore, the autophagy response is induced rapidly, significantly delaying apoptosis, suggesting the existence of a temporally coordinated p53 regulation network. These findings are relevant for the development of statin-based therapeutic approaches in obstructive airway disease.