The effect of perioperative benzodiazepine administration on postoperative nausea and vomiting: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Despite recent systematic reviews suggesting their benefit for postoperative nausea, vomiting, or both (PONV) prevention, benzodiazepines have not been incorporated into guidelines for PONV prophylaxis because of concerns about possible adverse effects. We conducted an updated meta-analysis to inform future practice guidelines. METHODS: We included randomised controlled trials (RCTs) of all languages comparing benzodiazepines with non-benzodiazepine comparators in adults undergoing inpatient surgery. Our outcomes were postoperative nausea, vomiting, or both. We assessed risk of bias for RCTs using the Cochrane Risk of Bias tool. We pooled data using a random-effects model and assessed the quality of evidence for each outcome using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: We screened 31 413 abstracts and 950 full texts. We included 119 RCTs; 104 were included in quantitative synthesis. Based on moderate certainty evidence, we found that perioperative benzodiazepine administration reduced the incidence of PONV (52 studies, n=5086, relative risk [RR]: 0.77, 95% confidence interval [CI] 0.66-0.89; number needed to treat [NNT] 16; moderate certainty), postoperative nausea (55 studies, n=5916, RR: 0.72, 95% CI 0.62-0.83; NNT 21; moderate certainty), and postoperative vomiting (52 studies, n=5909, RR: 0.74, 95% CI 0.60-0.91; NNT 55; moderate certainty). CONCLUSIONS: Moderate quality evidence shows that perioperative benzodiazepine administration decreases the incidence of PONV. The results of this systematic review and meta-analysis will inform future clinical practice guidelines. SYSTEMATIC REVIEW PROTOCOL: The protocol for this systematic review was pre-registered with PROSPERO International Prospective Register of Systematic Reviews (CRD42022361088) and published in BMJ Open (PMID 31831540).

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.

Morbidity and mortality in patients managed with high compared with low blood pressure targets during on-pump cardiac surgery: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Many believe that blood pressure management during cardiac surgery is associated with postoperative outcomes. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the impact of high compared with low intraoperative blood pressure targets on postoperative morbidity and mortality in adults undergoing cardiac surgery on cardiopulmonary bypass (CPB). Our primary objective was to inform the design of a future large RCT. SOURCE: We searched MEDLINE, EMBASE, Web of Science, CINAHL, and CENTRAL for RCTs comparing high with low intraoperative blood pressure targets in adult patients undergoing any cardiac surgical procedure on CPB. We screened reference lists, grey literature, and conference proceedings. PRINCIPAL FINDINGS: We included eight RCTs (N =1,116 participants); all examined the effect of blood pressure management only during the CPB. Trial definitions of high compared with low blood pressure varied and, in some, there was a discrepancy between the target and achieved mean arterial pressure. We observed no difference in delirium, cognitive decline, stroke, acute kidney injury, or mortality between high and low blood pressure targets (very-low to low quality evidence). Higher blood pressure targets may have increased the risk of requiring a blood transfusion (three trials; n = 456 participants; relative risk, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.01; moderate quality evidence) but this finding was based on a small number of trials. CONCLUSION: Individual trial definitions of high and low blood pressure targets varied, limiting inferences. The effect of high (compared with low) blood pressure targets on other morbidity and mortality after cardiac surgery remains unclear because of limitations with the body of existing evidence. Research to determine the optimal management of blood pressure during cardiac surgery is required. STUDY REGISTRATION: PROSPERO (CRD42020177376); registered: 5 July 2020.

RéSUMé: OBJECTIF: Pour beaucoup, la prise en charge de la pression artérielle pendant la chirurgie cardiaque serait associée aux issues postopératoires. Nous avons réalisé une revue systématique et une méta-analyse d'études randomisées contrôlées (ERC) afin de déterminer l'impact de cibles peropératoires de pression artérielle élevées par rapport à des cibles basses sur la morbidité et la mortalité postopératoires d'adultes bénéficiant d'une chirurgie cardiaque sous circulation extracorporelle (CEC). Notre objectif principal était d'orienter la conception d'une future ERC d'envergure. SOURCES: Nous avons analysé les bases de données MEDLINE, EMBASE, Web of Science, CINAHL et CENTRAL afin d'en tirer les ERC comparant des cibles de pression artérielle peropératoire élevées à des cibles basses chez des patients adultes bénéficiant d'une intervention chirurgicale cardiaque sous CEC. Nous avons passé au crible les listes de références, la littérature grise et les travaux de congrès. CONSTATATIONS PRINCIPALES: Nous avons inclus huit ERC (N = 1116 participants); toutes les études ont examiné l'effet de la prise en charge de la pression artérielle uniquement pendant la CEC. Les définitions d'une pression artérielle élevée ou basse variaient d'une étude à l'autre et, dans certains cas, un écart a été noté entre la pression artérielle cible et la pression artérielle moyenne atteinte. Nous n'avons observé aucune différence dans les taux de delirium, de déclin cognitif, d'accident vasculaire cérébral, d'insuffisance rénale aiguë ou de mortalité entre les cibles de pression artérielle élevée et basse (données probantes de qualité très faible à faible). Des cibles de pression artérielle plus élevées pourraient avoir augmenté le risque de transfusion sanguine (trois études; n = 456 participants; risque relatif, 1,4; intervalle de confiance à 95 %, 1,1 à 1,9; P = 0,01; données probantes de qualité modérée), mais ce résultat se fondait sur un petit nombre d'études. CONCLUSION: Les définitions individuelles des cibles d'hypertension et d'hypotension artérielle variaient, ce qui a limité les inférences. L'effet de cibles de pression artérielle élevée (par rapport à une pression artérielle basse) sur d'autres mesures de la morbidité et de la mortalité après une chirurgie cardiaque demeure incertain en raison des limites de l'ensemble des données probantes existantes. Des recherches visant à déterminer la prise en charge optimale de la pression artérielle pendant la chirurgie cardiaque sont nécessaires. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42020177376); enregistrée le 5 juillet 2020.

Restricted versus liberal intraoperative benzodiazepine use in cardiac anaesthesia for reducing delirium (B-Free Pilot): a pilot, multicentre, randomised, cluster crossover trial.

BACKGROUND: Delirium is common after cardiac surgery and is associated with adverse outcomes. Perioperative benzodiazepine use is associated with delirium and is common during cardiac surgery, which may increase the risk of postoperative delirium. We undertook a pilot study to inform the feasibility of a large randomised cluster crossover trial examining whether an institutional policy of restricted benzodiazepine administration during cardiac surgery (compared with liberal administration) would reduce delirium. METHODS: We conducted a two-centre, pilot, randomised cluster crossover trial with four 4 week crossover periods. Each centre was randomised to a policy of restricted or liberal use, and then alternated between the two policies during the remaining three periods. Our feasibility outcomes were adherence to each policy (goal ≥80%) and outcome assessment (one delirium assessment per day in the ICU in ≥90% of participants). We also evaluated the incidence of intraoperative awareness in one site using serial Brice questionnaires. RESULTS: Of 800 patients undergoing cardiac surgery during the trial period, 127/800 (15.9%) had delirium. Of these, 355/389 (91.3%) received benzodiazepines during the liberal benzodiazepine periods and 363/411 (88.3%) did not receive benzodiazepines during the restricted benzodiazepine periods. Amongst the 800 patients, 740 (92.5%) had ≥1 postoperative delirium assessment per day in the ICU. Of 521 patients screened for intraoperative awareness, one patient (0.2%), managed during the restricted benzodiazepine period (but who received benzodiazepine), experienced intraoperative awareness. CONCLUSIONS: This pilot study demonstrates the feasibility of a large, multicentre, randomised, cluster crossover trial examining whether an institutional policy of restricted vs liberal benzodiazepine use during cardiac surgery will reduce postoperative delirium. CLINICAL TRIAL REGISTRATION: NCT03053869.

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.

Protocol for the electroencephalography guidance of anesthesia to alleviate geriatric syndromes (ENGAGES-Canada) study: A pragmatic, randomized clinical trial.

Background:  There is some evidence that electroencephalography guidance of general anesthesia can decrease postoperative delirium after non-cardiac surgery.  There is limited evidence in this regard for cardiac surgery.  A suppressed electroencephalogram pattern, occurring with deep anesthesia, is associated with increased incidence of postoperative delirium (POD) and death.  However, it is not yet clear whether this electroencephalographic pattern reflects an underlying vulnerability associated with increased incidence of delirium and mortality, or whether it is a modifiable risk factor for these adverse outcomes. Methods:  The Electroe ncephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes ( ENGAGES-Canada) is an ongoing pragmatic 1200 patient trial at four Canadian sites.  The study compares the effect of two anesthetic management approaches on the incidence of POD after cardiac surgery.  One approach is based on current standard anesthetic practice and the other on electroencephalography guidance to reduce POD. In the guided arm, clinicians are encouraged to decrease anesthetic administration, primarily if there is electroencephalogram suppression and secondarily if the EEG index is lower than the manufacturers recommended value (bispectral index (BIS) or WAVcns below 40 or Patient State Index below 25).  The aim in the guided group is to administer the minimum concentration of anesthetic considered safe for individual patients.  The primary outcome of the study is the incidence of POD, detected using the confusion assessment method or the confusion assessment method for the intensive care unit; coupled with structured delirium chart review.  Secondary outcomes include unexpected intraoperative movement, awareness, length of intensive care unit and hospital stay, delirium severity and duration, quality of life, falls, and predictors and outcomes of perioperative distress and dissociation. Discussion:  The ENGAGES-Canada trial will help to clarify whether or not using the electroencephalogram to guide anesthetic administration during cardiac surgery decreases the incidence, severity, and duration of POD. Registration: ClinicalTrials.gov ( NCT02692300) 26/02/2016.

Ski drives an acute increase in MMP-9 gene expression and release in primary cardiac myofibroblasts.

Many etiologies of heart disease are characterized by expansion and remodeling of the cardiac extracellular matrix (ECM or matrix) which results in cardiac fibrosis. Cardiac fibrosis is mediated in cardiac fibroblasts by TGF-ß1 /R-Smad2/3 signaling. Matrix component proteins are synthesized by activated resident cardiac fibroblasts known as myofibroblasts (MFB). These events are causal to heart failure with diastolic dysfunction and reduced cardiac filling. We have shown that exogenous Ski, a TGF-ß1 /Smad repressor, localizes in the cellular nucleus and deactivates cardiac myofibroblasts. This deactivation is associated with reduction of myofibroblast marker protein expression in vitro, including alpha smooth muscle actin (α-SMA) and extracellular domain-A (ED-A) fibronectin. We hypothesize that Ski also acutely regulates MMP expression in cardiac MFB. While acute Ski overexpression in cardiac MFB in vitro was not associated with any change in intracellular MMP-9 protein expression versus LacZ-treated controls,exogenous Ski caused elevated MMP-9 mRNA expression and increased MMP-9 protein secretion versus controls. Zymographic analysis revealed increased MMP-9-specific gelatinase activity in myofibroblasts overexpressing Ski versus controls. Moreover, Ski expression was attended by reduced paxillin and focal adhesion kinase phosphorylation (FAK - Tyr 397) versus controls. As myofibroblasts are hypersecretory and less motile relative to fibroblasts, Ski's reduction of paxillin and FAK expression may reflect the relative deactivation of myofibroblasts. Thus, in addition to its known antifibrotic effects, Ski overexpression elevates expression and extracellular secretion/release of MMP-9 and thus may facilitate internal cytoskeletal remodeling as well as extracellular ECM components. Further, as acute TGF-ß1 treatment of primary cardiac MFB is known to cause rapid translocation of Ski to the nucleus, our data support an autoregulatory role for Ski in mediating cardiac ECM accumulation.

The Ski-Zeb2-Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype.

Cardiac fibrosis is linked to fibroblast-to-myofibroblast phenoconversion and proliferation but the mechanisms underlying this are poorly understood. Ski is a negative regulator of TGF-ß-Smad signaling in myofibroblasts, and might redirect the myofibroblast phenotype back to fibroblasts. Meox2 could alter TGF-ß-mediated cellular processes and is repressed by Zeb2. Here, we investigated whether Ski diminishes the myofibroblast phenotype by de-repressing Meox2 expression and function through repression of Zeb2 expression. We show that expression of Meox1 and Meox2 mRNA and Meox2 protein is reduced during phenoconversion of fibroblasts to myofibroblasts. Overexpression of Meox2 shifts the myofibroblasts into fibroblasts, whereas the Meox2 DNA-binding mutant has no effect on myofibroblast phenotype. Overexpression of Ski partially restores Meox2 mRNA expression levels to those in cardiac fibroblasts. Expression of Zeb2 increased during phenoconversion and Ski overexpression reduces Zeb2 expression in first-passage myofibroblasts. Furthermore, expression of Meox2 is decreased in scar following myocardial infarction, whereas Zeb2 protein expression increases in the infarct scar. Thus Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by upregulating the expression of Meox2. This cascade might regulate cardiac myofibroblast phenotype and presents therapeutic options for treatment of cardiac fibrosis.

Autophagy regulates trans fatty acid-mediated apoptosis in primary cardiac myofibroblasts.

Trans fats are not a homogeneous group of molecules and less is known about the cellular effects of individual members of the group. Vaccenic acid (VA) and elaidic acid (EA) are the predominant trans monoenes in ruminant fats and vegetable oil, respectively. Here, we investigated the mechanism of cell death induced by VA and EA on primary rat ventricular myofibroblasts (rVF). The MTT assay demonstrated that both VA and EA (200µM, 0-72 h) reduced cell viability in rVF (P<0.001). The FACS assay confirmed that both VA and EA induced apoptosis in rVF, and this was concomitant with elevation in cleaved caspase-9, -3 and -7, but not caspase-8. VA and EA decreased the expression ratio of Bcl2:Bax, induced Bax translocation to mitochondria and decrease in mitochondrial membrane potential (Δψ). BAX and BAX/BAK silencing in mouse embryonic fibroblasts (MEF) inhibited VA and EA-induced cell death compared to the corresponding wild type cells. Transmission electron microscopy revealed that VA and EA also induced macroautophagosome formation in rVF, and immunoblot analysis confirmed the induction of several autophagy markers: LC3-ß lipidation, Atg5-12 accumulation, and increased beclin-1. Finally, deletion of autophagy genes, ATG3 and ATG5 significantly inhibited VA and EA-induced cell death (P<0.001). Our findings show for the first time that trans fat acid (TFA) induces simultaneous apoptosis and autophagy in rVF. Furthermore, TFA-induced autophagy is required for this pro-apoptotic effect. Further studies to address the effect of TFA on the heart may reveal significant translational value for prevention of TFA-linked heart disease.

Age of puberty in a representative sample of Iranian girls.

BACKGROUND: To obtain normal references for growth and pubertal development in a given population, assessment of pubertal stages is of great importance. This study aimed to determine the age of appearance of secondary sexual characteristics in a representative sample of Iranian girls. METHODS: This cross-sectional study was conducted during 2005-2006 in 3192 girl students, aged 6-17 years, in Isfahan, Iran. Participants were selected by multistage random cluster sampling from school students. Secondary sexual characteristics were evaluated by inspection and palpation, and were recorded according to Tanner staging. The self-reported date of menarche (if any) was recorded as well. Data were analyzed with Probit analysis based on the status quo method. RESULTS: The median ages (10th-90th percentile) of Tanner stage 2 breast development (B2) and Tanner stage 2 pubic hair growth (PH2) were 10.14 years (8.33-11.95 years) and 10.78 years (9.09-12.48 years), respectively. The ages of the 3rd percentile for B2 and PH2 were 7.48 and 8.29 years, respectively. The median age of menarche among the 3192 girls who had experienced menarche was 12.65 years (11.18-14.11 years). CONCLUSIONS: The median age of puberty onset is 10.14 years, and the onset of puberty before 7.5 years is considered as precocious puberty in a representative sample of Iranian girls. The values obtained from the present study can provide baseline data for analysis of time trends, as well as for international comparisons.