IMPORTANCE Intraoperative electroencephalogram (EEG) waveform suppression, often suggesting excessive general anesthesia, has been associated with postoperative delirium. OBJECTIVE To assess whether EEG-guided anesthetic administration decreases the incidence of postoperative delirium. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 1232 adults aged 60 years and older undergoing major surgery and receiving general anesthesia at Barnes-Jewish Hospital in St INTERVENTIONS Patients were randomized 1:1 (stratified by cardiac vs noncardiac surgery and positive vs negative recent fall history) to receive EEG-guided anesthetic administration (n = 614) or usual anesthetic care (n = 618). MAIN OUTCOMES AND MEASURES The primary outcome was incident delirium during postoperative days 1 through 5. Intraoperative measures included anesthetic concentration, EEG suppression, and hypotension. Adverse events included undesirable intraoperative movement, intraoperative awareness with recall, postoperative nausea and vomiting, medical complications, and death. RESULTSOf the 1232 randomized patients (median age, 69 years [range, 60 to 95]; 563 women [45.7%]), 1213 (98.5%) were assessed for the primary outcome. Delirium during postoperative days 1 to 5 occurred in 157 of 604 patients (26.0%) in the guided group and 140 of 609 patients (23.0%) in the usual care group (difference, 3.0% [95% CI, −2.0% to 8.0%]; P = .22). Median end-tidal volatile anesthetic concentration was significantly lower in the guided group than the usual care group (0.69 vs 0.80 minimum alveolar concentration; difference, −0.11 [95% CI, −0.13 to −0.10), and median cumulative time with EEG suppression was significantly less (7 vs 13 minutes; difference, −6.0 [95% CI, −9.9 to −2.1]). There was no significant difference between groups in the median cumulative time with mean arterial pressure below 60 mm Hg (7 vs 7 minutes; difference, 0.0 [95% CI, −1.7 to 1.7]). Undesirable movement occurred in 137 patients (22.3%) in the guided and 95 (15.4%) in the usual care group. No patients reported intraoperative awareness. Postoperative nausea and vomiting was reported in 48 patients (7.8%) in the guided and 55 patients (8.9%) in the usual care group. Serious adverse events were reported in 124 patients (20.2%) in the guided and 130 (21.0%) in the usual care group. Within 30 days of surgery, 4 patients (0.65%) in the guided group and 19 (3.07%) in the usual care group died.CONCLUSIONS AND RELEVANCE Among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium. This finding does not support the use of EEG-guided anesthetic administration for this indication. 40. Muhlhofer WG, Zak R, Kamal T, et al. Burst-suppression ratio underestimates absolute duration of electroencephalogram suppression compared with visual analysis of intraoperative electroencephalogram.

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...

IntroductionPostoperative delirium, arbitrarily defined as occurring within 5 days of surgery, affects up to 50% of patients older than 60 after a major operation. This geriatric syndrome is associated with longer intensive care unit and hospital stay, readmission, persistent cognitive deterioration and mortality. No effective preventive methods have been identified, but preliminary evidence suggests that EEG monitoring during general anaesthesia, by facilitating reduced anaesthetic exposure and EEG suppression, might decrease incident postoperative delirium. This study hypothesises that EEG-guidance of anaesthetic administration prevents postoperative delirium and downstream sequelae, including falls and decreased quality of life.Methods and analysisThis is a 1232 patient, block-randomised, double-blinded, comparative effectiveness trial. Patients older than 60, undergoing volatile agent-based general anaesthesia for major surgery, are eligible. Patients are randomised to 1 of 2 anaesthetic approaches. One group receives general anaesthesia with clinicians blinded to EEG monitoring. The other group receives EEG-guidance of anaesthetic agent administration. The outcomes of postoperative delirium (≤5 days), falls at 1 and 12 months and health-related quality of life at 1 and 12 months will be compared between groups. Postoperative delirium is assessed with the confusion assessment method, falls with ProFaNE consensus questions and quality of life with the Veteran's RAND 12-item Health Survey. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 95% CIs and will be considered statistically significant at a two-sided p<0.05.Ethics and disseminationElectroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) is approved by the ethics board at Washington University. Recruitment began in January 2015. Dissemination plans include presentations at scientific conferences, scientific publications, internet-based educational materials and mass media.Trial registration numberNCT02241655; Pre-results.

Heart failure is increasing in prevalence, with approximately 26 million patients affected worldwide. This represents a significant cause of morbidity and mortality. Statistics regarding heart failure patient age, hospitalization likelihood, and mortality differ significantly by country. Heart failure patients are typically classified by ejection fraction, with distinct phenotypes associated with reduced ejection fraction (rEF) or preserved ejection fraction (pEF). Heart failure has a significant financial impact related to hospitalization, medication, and procedural expenses. The costs of heart failure also extend to the reduced quality of life conferred by heart failure symptoms. Management of heart failure includes a variety of interventions, including mechanical circulatory support (MCS). MCS, including left ventricular assist devices (LVADs), right ventricular assist devices (RVADs) and extracorporeal membrane oxygenation (ECMO),has been a means of managing end stage heart failure. Given the relative scarcity of transplant organs, the utilization of MCS, particularly as a bridge to transplantation (BTT) has grown significantly. In this review, we discuss statistics related to heart failure and MCS. We evaluate how patients are classified and examine global trends and regional differences. We then address MCS therapies, the costs associated with heart failure, the impact of heart failure on patient quality of life, and data regarding morbidity and mortality.

(20,21,23,33,64), neurite outgrowth (1, 8, 57), endothelial cell contraction (23,69,70), and resistance to mechanical perturbations (8,11,31). These myosin II-based cellular events have been considered to be regulated solely by an increase in cytosolic Ca 2ϩ according to the classic smooth muscle model of Ca 2ϩ -coupled contraction. However, within the last 10 years myosin II motor activity has been shown to be activated by Ca 2ϩ -independent pathways (39,41,63,68) in addition to Ca 2ϩ -dependent pathways (7,23,32,70). Ca 2ϩ -dependent cell contraction results from an influx of Ca 2ϩ from the extracellular space or the release of Ca 2ϩ from sequestered internal stores. Ca 2ϩ binds to calmodulin (CaM); the Ca 2ϩ /CaM complex in turn binds to and activates the serine/threonine protein kinase, myosin light chain kinase (MLCK). The active MLCK complex catalyzes myosin II regulatory light chain (RLC) phosphorylation at two sites, Ser-19 and Thr-18. Phosphorylation at these sites is required for myosin II filament formation (6), myosin II interaction with F-actin (23), and an increase in myosin II ATPase activity (7). These phosphorylation driven events are essential for initiation and maintenance of myosin II-based contraction. MLCK, the enzyme responsible for initiating Ca 2ϩ -dependent contraction, exists in several isoforms, resulting from splice variants with distinct intracellular localizations and tissue distributions (3,5,32,52). To date, all MLCK isoforms have been shown biochemically to be strictly dependent on Ca 2ϩ /CaM for activation and are known to catalyze phosphorylation of a single substrate, myosin II RLC.The discovery of the Rho family of proteins initiated study of possible Ca 2ϩ -independent regulation of myosin II motor activity and contraction. A range of protein kinases have now been shown to activate myosin II motor activity by catalyzing phosphorylation of myosin II RLC in vitro or in vivo, including Rho-kinase (2), p21-associated protein kinase (PAK) (9, 73), and integrin-linked kinase (ILK) (10). The most intensively studied of the Ca 2ϩ -independent activators of myosin II motor activity and contraction are those regulated by the Rho family of proteins. Rho is a member of the Ras superfamily of small GTPases, which functions as a molecular switch cycling between the active GTP-bound and inactive GDP-bound state. In the active GTP state, RhoA interacts with its effector molecules to initiate downstream responses. Of several possible Rho effector proteins (4, 17) that bind to GTP-bound Rho, the serine/threonine kinase, Rho-kinase, is the one that has been implicated in the regulation of myosin II and contraction.Rho-kinase exists in two isoforms, ROK␣/ROCK-II (43, 46) and ROK␤/ROCK-I/p160 ROCK (29, 42); both are ubiquitously expressed in various tissues and cells. Rho-kinase isoforms range in mass from 150 to 160 kDa and contain a kinase domain in their NH 2 -terminal domains, a central coil-coiled domain, and a pleckstrin homology domain in the COOH-terminal domains. The coil-coiled domai...