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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.

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. 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. 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. 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. PROSPERO (CRD42017071440); registered 20 April, 2018.

Background Delirium and pain are common and serious postoperative complications. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia and to spare postoperative opioids. Some evidence also suggests that ketamine prevents delirium. The primary purpose of this trial was to evaluate the effectiveness of ketamine in preventing postoperative delirium in older adults after major surgery. Secondary outcomes, viewed as strongly related to delirium, were postoperative pain and opioid consumption. Methods This was a multicentre, international, randomised trial that enrolled adults older than 60 undergoing major cardiac and noncardiac surgery under general anaesthesia. Participants were enrolled prior to surgery and gave written informed consent. We used a computer-generated randomisation sequence. Patients at study sites were randomised to one of three study groups in blocks of 15 to receive intraoperative administration of (i) placebo (intravenous normal saline), (ii) low dose ketamine (0.5 mg/kg) or (iii) high dose ketamine (1 mg/kg). Study drug was administered following induction of anaesthesia, prior to surgical incision. Participants, clinicians, and investigators were all masked to group assignment. Delirium and pain were assessed twice daily in the first three postoperative days using the Confusion Assessment Method and Visual Analog Scale, respectively. Postoperative opioid use was recorded, and hallucinations and nightmares were assessed. Analyses were performed by intention-to-treat and adverse events were evaluated. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] trial is registered in clinicaltrials.gov; NCT01690988 Findings Between February 6, 2014 and June 26, 2016, 1360 patients assessed and 672 were randomised, with 222 in the placebo group, 227 in the low dose ketamine group, and 223 in the high dose ketamine group. There was no difference in postoperative delirium incidence between those in the combined ketamine groups and those who received placebo (19.45% vs. 19.82%, respectively; absolute difference, 0.36%; 95% CI, −6.07% to 7.38%; p=0.92). There were no significant differences among the three groups in maximum pain scores (p=0.88) or median opioid consumption (p=0.47) over time. There were more postoperative hallucinations (p=0.01) and nightmares (p=0.03) with escalating doses of ketamine. Adverse events (cardiovascular, renal, infectious, gastrointestinal, bleeding), whether viewed individually (P value for each >0.40) or collectively (82/222 [36.9%] in placebo group, 90/227 [39.6%] in low dose ketamine group, 91/223 in high dose ketamine group [40.8%]; P=0.69), did not differ significantly across the three groups. Interpretation The administration of a single subanaesthetic dose of ketamine to older adults during major surgery did not show evidence of reducing postoperative delirium, pain, or opioid consumption, and might cause harm by inducing negative experiences. Given current evidence and guidelines related to ketamine and postoperative analgesia, the unexpected secondary findings regarding pain and opioid consumption warrant replication or refutation in subsequent research. Funding The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The principal investigators (MSA and GAM) had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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.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.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; IIn 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.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 » à une stratégie « libérale », 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.Nous avons réalisé des recherches dans les bases de données MEDLINE (OvidSP), EMBASE (OvidSP) et Cochrane CENTRAL (Wiley) de leur création jusqu’au 1Sur 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; IDans 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.

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‐β 1/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‐β 1/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‐β 1 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.

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-β-Smad signaling in myofibroblasts, and might redirect the myofibroblast phenotype back to fibroblasts. Meox2 could alter TGF-β-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.

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. 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. 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). 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.