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BackgroundAlthough the antiemetic effect of olanzapine on chemotherapy-induced nausea and vomiting has been characterized, the prophylactic role of olanzapine on postoperative nausea and vomiting (PONV) has not been fully elucidated. This clinical trial aims to examine the effectiveness of olanzapine for preventing PONV.MethodsPatients undergoing laparoscopic gynecological surgery at 5 university hospitals in Japan will be randomly assigned to receive either 5 mg of oral olanzapine or placebo 2 hours before the induction of anesthesia. All patients will receive intravenous dexamethasone at the induction of anesthesia. The primary outcome will be the incidence of postoperative nausea and vomiting within 24 hours after surgery. Secondary endpoints will include longitudinal changes in the incidence of postoperative nausea and vomiting and overall patient satisfaction.DiscussionThis trial will provide a high quality evidence whether olanzapine prevents PONV in gynecological laparoscopy patients at a high risk for PONV.Ethics and disseminationThe trial was approved by the institutional review board of the each participating study site. Study findings will be disseminated through peer-reviewed publications and in conference presentations.Trial registrationUMIN Clinical Trials Registry (UMIN-CTR) ID: 000022634, Registered on October 1, 2016 https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000026031

The aim of this study was to determine the anesthesia-promoting effects of hydroxyzine on electroencephalograms during sevoflurane anesthesia and during propofol anesthesia.We analyzed 40 patients scheduled for elective surgery under sevoflurane anesthesia (n = 20) or propofol anesthesia (n = 20). Anesthesia was adjusted at a bispectral index value of 50-60, and then 0.5 mg/kg of hydroxyzine was administered intravenously. We analyzed frontal electroencephalograms before and after hydroxyzine injection with power spectral and bicoherence analyses, which are suitable for assessing the anesthetic depth induced by γ-aminobutyric acid (GABA)ergic anesthetics.Hydroxyzine increased the α bicoherence peaks in both sevoflurane anesthesia (mean difference, 11.2%; 95% confidence interval (CI), 7.6 to 14.8; P 0.001) and propofol anesthesia (mean difference, 5.6%; 95% CI, 1.7 to 9.4; P = 0.008). Hydroxyzine increased the averaged δ bicoherence values in both sevoflurane anesthesia (mean difference, 5.5%; 95% CI, 2.1 to 8.8; P = 0.003) and propofol anesthesia (mean difference, 3.9%; 95% CI, 1.0 to 6.8; P = 0.011).Hydroxyzine enhances both sevoflurane anesthesia and propofol anesthesia probably by facilitation of GABAergic neural circuit mechanisms.The findings provide a new insight into the role of histaminergic neurons during general anesthesia in humans.

BackgroundThere is currently no subjective, definitive evaluation method for therapeutic indication other than symptoms in aortic regurgitation. Energy loss, a novel parameter of cardiac workload, can be visualized and quantified using echocardiography vector flow mapping. The purpose of the present study was to evaluate whether energy loss in patients with chronic aortic regurgitation can quantify their subjective symptoms more clearly than other conventional metrics.MethodsWe studied 15 patients undergoing elective aortic valve surgery for aortic regurgitation. We divided the patients into symptomatic and asymptomatic groups using their admission records. We analyzed the mean energy loss in one cardiac cycle using transesophageal echocardiography during the preoperative period. The relationships between symptoms, energy loss, and other conventional metrics were statistically analyzed.ResultsThere were seven and eight patients in the symptomatic and asymptomatic groups, respectively. The mean energy loss of one cardiac cycle was higher in the symptomatic group (121 mW/m [96–184]) than in the asymptomatic group (87 mW/m [80–103]) (p = 0.040), whereas the diastolic diameter was higher in the asymptomatic group (65 mm [59–78]) than in the symptomatic group (57 mm [51–57]) (p = 0.040). There was no significant difference between the symptomatic and asymptomatic groups in terms of other conventional metrics.ConclusionsAn energy loss can quantify patients' subjective symptoms more clearly than other conventional metrics. The small sample size is the primary limitation of our study, further studies assessing larger cohort of patients are warranted to validate our findings.

The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of methylnaltrexone (MNX) on remifentanil-induced behavioral hyperalgesia was assessed to distinguish contributions of the peripheral and/or central nervous system to remifentanil-induced hyperalgesia. Phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) in the dorsal root ganglion (DRG) neurons after remifentanil infusion, and the effect of a p38MAPK inhibitor on remifentanil-induced hyperalgesia were analyzed to investigate involvement of p38MAPK in the peripheral mechanisms of remifentanil-induced hyperalgesia. Spinal levels of prodynorphin mRNA after remifentanil infusion, and the effect of the BK2 bradykinin receptor antagonist on remifentanil-induced hyperalgesia were investigated to assess potential spinal mechanisms. The effects of MNX and BK2 antagonists on remifentanil-induced exacerbation of post-incisional hyperalgesia were also investigated using behavioral analysis. Remifentanil infusion induced hyperalgesia in the early (4 h to 2 days) and late (8–14 days) post-infusion periods. MNX inhibited hyperalgesia only during the early post-infusion period. p38MAPK phosphorylation was observed in the DRG neuron, and the p38MAPK inhibitor inhibited hyperalgesia during the early post-infusion period. Prodynorphin expression increased in the spinal cord, and a BK2 antagonist inhibited hyperalgesia during the late post-infusion period. Remifentanil-induced exacerbation of incisional hyperalgesia was inhibited by MNX and the BK2 antagonist. The present study demonstrated that remifentanil activates peripheral and spinal neurons to promote chronologically distinctive hyperalgesia. p38MAPK phosphorylation in the DRG neuron leads to peripherally-driven hyperalgesia during the early post-infusion period, while spinal dynorphin-bradykinin signaling promotes hyperalgesia during the late post-infusion period.

Objective Although the characteristics of electroencephalograms (EEGs) have been reported to change with age, anaesthesia-dependent oscillatory features and reactivity of the super-elderly EEG to anaesthesia have not been examined in detail. Methods Participants comprised 20 super-elderly patients (age; mean ± standard deviation, 87.1 ± 3.8 years) and 20 young adult patients (35.5 ± 8.5 years). At three levels of sevoflurane anaesthesia (minimum alveolar concentration [MAC] of 0.3, 0.7, and 1.4), oscillatory features of the frontal EEG were examined by analysing quadratic phase coupling (bicoherence) and power spectrum in α and δ-θ areas and compared in an anaesthesia-dependent manner, using the Friedman test. Results Among super-elderly individuals, bicoherences in the δ-θ area showed anaesthesia-dependent increases (median [interquartile range], 12.9% [5.2%], 19.2% [9.1%], 23.3% [8.7%]; 0.3, 0.7, 1.4 MAC sevoflurane, p = 0.000), whereas bicoherence in the α area did not change at these different anaesthesia levels (11.2% [3.9%], 12.5% [4.4%], 14.1% [5.7%], respectively; p = 0.142), counter to the results found in young adult patients, where both δ-θ and α bicoherences changed with anaesthesia. Conclusions In the super-elderly, δ-θ bicoherence of EEG shows anaesthesia- dependent changes, whereas α activity remains small irrespective of anaesthesia level. Significance Quantification of δ-θ bicoherence is a candidate for anaesthesia monitoring in the super-elderly.

Background Echocardiography vector flow mapping can assess dynamic flow to treat congenital heart diseases. We evaluated intracardiac flow, energy loss, left ventricular output kinetic energy, and energetic performance index using vector flow mapping during Glenn and Damus-Kaye-Stansel procedures in order to assess the efficacy of the surgery. Case presentation A 9-month-old boy underwent Glenn and Damus-Kaye-Stansel procedures. The energy loss depends on the left ventricular preload; therefore, energy loss decreased after the Glenn procedure. After the Damus-Kaye-Stansel procedure, the kinetic energy would increase owing to the integrated systemic outflow; however, in our case, kinetic energy decreased, which was potentially explained by the fact that kinetic energy also depends on the left ventricular preload. After the Glenn and Damus-Kaye-Stansel procedures, we detected an improvement in energetic performance index, indicating that the cardiac workload improved as well. Conclusion We revealed the efficiency of the Glenn and Damus-Kaye-Stansel procedures using vector flow mapping.

Additional file 5: Figure S5. Alignment of the class B metallo-β-lactamase family and their zinc enzymatic active center.

Along with the recent spread of multidrug-resistant bacteria, outbreaks of extended-spectrum β-lactamase (ESBL) and carbapenemase-producing bacteria present a serious challenge to clinicians. β-lactam antibiotics are the most frequently used antibacterial agents and ESBLs, and carbapenemases confer resistance not only to carbapenem antibiotics but also to penicillin and cephem antibiotics. The mechanism of β-lactam resistance involves an efflux pump, reduced permeability, altered transpeptidases, and inactivation by β-lactamases. Horizontal gene transfer is the most common mechanism associated with the spread of extended-spectrum β-lactam- and carbapenem resistance among pathogenic bacterial species. Along with the increase in antimicrobial resistance, many different types of ESBLs and carbapenemases have emerged with different enzymatic characteristics. For example, carbapenemases are represented across classes A to D of the Ambler classification system. Because bacteria harboring different types of ESBLs and carbapenemases require specific therapeutic strategies, it is essential for clinicians to understand the characteristics of infecting pathogens. In this review, we summarize the current knowledge on carbapenem resistance by ESBLs and carbapenemases, such as class A carbapenemases, class C extended-spectrum AmpC (ESAC), carbapenem-hydrolyzing class D β-lactamases (CHDLs), and class B metallo-β-lactamases, with the aim of aiding critical care clinicians in their therapeutic decision making.

Additional file 3: Figure S3. The alignment of class C β-lactamases.

Additional file 1: Figure S1. The similarities in the structures of class A β-lactamases and penicillin-binding protein (PBP).

Additional file 6: Figure S6. The alignment of primary sequences of the class B metallo-β-lactamase IMP family.

Additional file 2: Figure S2. The alignment of class A carbapenemases based on their primary sequences.

Additional file 4: Figure S4. Alignment of the class D β-lactamase OXA family (oxacillinase).

Additional file 7: Figure S7. The alignment of primary sequences of the class B metallo-β-lactamase VIM family.

Antimicrobial-resistant isolates of Pseudomonas aeruginosa collected from 2005 to 2014 in a university hospital in Kyoto, Japan, were retrospectively analyzed by multilocus sequence typing (MLST), exoenzyme genotype determination, integron characterization, and clinical associations. During the study, 1573 P. aeruginosa isolates were detected, and 41 of these were resistant to more than two classes of antimicrobial agents. Twenty-five (61.0%) isolates were collected from urine. All isolates were resistant to ciprofloxacin, 8 (19.5%) isolates showed resistance to imipenem/cilastatin, and 8 (19.5%) isolates showed resistance to meropenem. None of the isolates fulfilled the clinical criteria for multidrug-resistant P. aeruginosa. All isolates were negative in the metallo-β lactamase test. Thirty-six (87.8%) isolates were of the exoS˗exoU+ genotype and 5 (12.2%) isolates were of the exoS+exoU˗ genotype. Among 36 exoS˗exoU+ isolates, 33 (80.5%) were ST357, and 3 (7.3%) were ST235. Five isolates of exoS+exoU˗ were ST186, ST244, ST314, ST508, and ST512. Thirty-three isolates were positive for class 1 integrons and four different class 1 integrons were detected: aminoglycoside (2′) adenyltransferase and chloramphenicol transporter (AadB+CmlA6), OXA-4 β-lactamase and aminoglycoside 3′-adenyltransferase (OXA4+AadA2), AadB alone, and aminoglycoside acetyltransferase alone (AacA31). Among the 41 patients from which the isolates originated, the most common underlying disease was cancer in 16 patients (39%), and 9 patients (22.0%) died during the hospitalization period. There was no statistical correlation between MLST, exoenzyme genotype, and patient mortality. The results indicated outbreaks of fluoroquinolone-resistant P. aeruginosa in immunocompromised patients mainly due to the propagation of potentially virulent ST357 isolates possessing the exoU+ genotype.

Inhaled pathogens including Pseudomonas aeruginosa initially encounter airway epithelial cells (AECs), which are poised to evoke cell-intrinsic innate defense, affecting second tier of hematopoietic cell-mediated immune reaction. However, it is largely unknown how pulmonary immune responses mediated by a variety of immune cells are coordinated. Here we show that Regnase-1, an endoribonuclease expressed in AECs and immune cells, plays an essential role in coordinating innate responses and adaptive immunity against P. aeruginosa infection. Intratracheal treatment of mice with heat-killed P. aeruginosa resulted in prolonged disappearance of Regnase-1 consistent with sustained expression of Regnase-1 target inflammatory genes, whereas the transcription factor NF-κB was only transiently activated. AEC-specific deletion of Regnase-1 not only augmented innate defenses against P. aeruginosa but also enhanced secretion of Pseudomonas-specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance against P. aeruginosa re-infection in vivo. Although Regnase-1 directly controls distinct sets of genes in each of AECs and T cells, degradation of Regnase-1 in both cell types is beneficial for maximizing acquired immune responses. Collectively, these results demonstrate that Regnase-1 orchestrates AEC-mediated and immune cell-mediated host defense against pulmonary bacterial infection.

Vaccination against the type III secretion system of P. aeruginosa is a potential prophylactic strategy for reducing the incidence and improving the poor prognosis of P. aeruginosa pneumonia. In this study, the efficacies of three different adjuvants, Freund's adjuvant (FA), aluminum hydroxide (alum) and CpG oligodeoxynucleotide (ODN), were examined from the viewpoint of inducing PcrV-specific immunity against virulent P. aeruginosa. Mice that had been immunized intraperitoneally with recombinant PcrV formulated with one of the above adjuvants were challenged intratracheally with a lethal dose of P. aeruginosa. The PcrV-FA immunized group attained a survival rate of 91%, whereas the survival rates of the PcrV-alum and PcrV-CpG groups were 73% and 64%, respectively. In terms of hypothermia recovery after bacterial instillation, PcrV-alum was the most protective, followed by PcrV-FA and PcrV-CpG. The lung edema index was lower in the PcrV-CpG vaccination group than in the other groups. PcrV-alum immunization was associated with the greatest decrease in myeloperoxidase in infected lungs, and also decreased the number of lung bacteria to a similar number as in the PcrV-FA group. There was less neutrophil recruitment in the lungs of mice vaccinated with PcrV-alum or PcrV-CpG than in those of mice vaccinated with PcrV-FA or PcrV alone. Overall, in terms of mouse survival the PcrV-CpG vaccine, which could be a relatively safe next-generation vaccine, showed a comparable effect to the PcrV-alum vaccine.

Background The molecular mechanisms responsible for sustained pain after tissue injury are largely unknown. The aim of this study was to clarify the role of exchange protein directly activated by cyclic adenosine monophosphate (EPAC) in sustained postincisional nociception, using tissue injury-induced nociceptor priming, and involvement of p38 mitogen-activated protein kinase (p38MAPK) in EPAC-mediated nociceptor priming. Methods Plantar incisions were made in the hind paws of Sprague–Dawley rats (n = 144). Nociceptor priming was confirmed by behavior testing followed by prostaglandin E2 injection 14 to 21 days after the incision. ESI-09, a selective EPAC inhibitor, was administered to assess its effects on nociceptor priming. Expression of two isoforms of EPAC (EPAC1/EPAC2) in dorsal root ganglions from naive rats and those 14 days after the incision was detected by immunohistochemistry and Western blotting. Separately, FR167653, a selective p38MAPK inhibitor, was administered to assess its effect on EPAC1/EPAC2 expression and the development of nociceptor priming. Results Prostaglandin E2 injection 14 to 21 days after the plantar incision induced persistent mechanical hyperalgesia for 7 days. EPAC1/EPAC2 expression in dorsal root ganglion neurons was trivial in naive rats (7.7 ± 4.8% for EPAC1; 6.3 ± 4.1% for EPAC2) but markedly increased 14 days after the incision (21.0 ± 9.4% and 20.1 ± 3.8%, respectively). ESI-09 treatment inhibited prostaglandin E2-induced persistent mechanical hypersensitivity but had no effect on incision-induced acute nociceptive hypersensitivity. Treatment with FR167653 before the incision inhibited the development of nociceptor priming and incision-induced EPAC1/EPAC2 expression (8.5 ± 5.4% and 7.6 ± 3.3%, respectively). Conclusions Transient inflammatory stimulation causes long-lasting nociceptive hypersensitivity via nociceptor priming during the subacute period after incision. Acquired EPAC activity by p38MAPK in the dorsal root ganglion neurons is a key for this event.

The mechanisms underlying the effects of γ-globulin therapy for bacterial infections are thought to involve bacterial cell lysis via complement activation, phagocytosis via bacterial opsonization, toxin neutralization, and antibody-dependent cell-mediated cytotoxicity. Nevertheless, recent advances in the study of pathogenicity in gram-negative bacteria have raised the possibility of an association between γ-globulin and bacterial toxin secretion. Over time, new toxin secretion systems like the type III secretion system have been discovered in many pathogenic gram-negative bacteria. With this system, the bacterial toxins are directly injected into the cytoplasm of the target cell through a special secretory apparatus without any exposure to the extracellular environment and, therefore, with no opportunity for antibodies to neutralize the toxin. However, because antibodies against the V-antigen, which is located on the needle-shaped tip of the bacterial secretion apparatus, can inhibit toxin translocation, this raises the hope that the toxin might be susceptible to antibody targeting. Because multi-drug resistant bacteria are now prevalent, inhibiting this secretion mechanism is attractive as an alternative or adjunctive therapy against lethal bacterial infections. Thus, it would not be unreasonable to define the blocking effect of anti-V-antigen antibodies as the fifth mechanism for immunoglobulin action against bacterial infections.

BACKGROUND Incomplete reversal with a recommended 5-g dose of idarucizumab has been reported in patients with excessively high dabigatran concentrations. A timely detection of reversal failure after idarucizumab using whole blood (WB) coagulation testing is clinically useful. The aims of this study were to determine residual dabigatran activity after idarucizumab on thrombin generation (TG) using in vitro supratherapeutic dabigatran models and to compare 4 WB point-of-care tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and 2 thromboelastometry tests) with the TG results. METHODS Blood samples from 12 healthy volunteers were spiked in vitro with 0-5000 ng/mL of dabigatran. Dabigatran reversal was evaluated by adding 1000 μg/mL of idarucizumab (Praxbind) to dabigatran-spiked samples, which reflect the administration of 5-g idarucizumab to a 70-kg patient. Residual dabigatran activity was assessed using the calibrated automated TG (Thrombinoscope) in platelet-poor plasma samples. The TG results were compared with WB aPTT (DRIHEMATO APTT-S) and PT (DRIHEMATO PT-S) using CG02N analyzer, thromboelastometry (ROTEM) triggered by ellagic acid (INTEM) and tissue factor (EXTEM). RESULTS At a therapeutic concentration of dabigatran (200 ng/mL), the lag time was prolonged, and peak TG was decreased. The effects of dabigatran on TG were increased up to 1000 ng/mL, and TG was obliterated at higher supratherapeutic dabigatran levels (P < .001 versus control, respectively). TG was fully restored with idarucizumab when dabigatran was ≤2000 ng/mL, but residual anticoagulant activity was observed at higher dabigatran levels. Dabigatran prolonged WB aPTT and PT concentration dependently, and residual prolongations were observed when idarucizumab was added to 3000 or 5000 ng/mL of dabigatran (P < .001 versus control, respectively). In contrast, both INTEM and EXTEM clotting times were reversed toward reference ranges at all dabigatran concentrations when idarucizumab was added. CONCLUSIONS Our data indicate that the recommended dose of idarucizumab may not restore TG completely with excessively elevated concentrations of dabigatran. All WB measurements with aPTT, PT, and thromboelastometry predicted supratherapeutic dabigatran concentrations, whereas those tests varied in sensitivity to residual anticoagulant activity after reversal. WB aPTT corresponded well with plasma TG changes among those measurements, but the use of thromboelastometry may overestimate the effect of idarucizumab. Caution should be exercised before extrapolating in vitro point-of-care data to the clinical monitoring of dabigatran reversal.

Background Urea cycle disorders are rare; arginase-1 deficiency is one of those extremely rare autosomal recessive metabolic disorders. Arginase-1 is one among the enzymes involved in the production of urea from ammonia in the liver, and its deficiency produces the characteristic feature, hyperargininemia. Case presentation We report a case of a girl, aged 5 years and 10 months presenting with arginase-1 deficiency. The patient was scheduled to undergo strabismus surgery for intermittent exotropia under general anesthesia. Preoperative blood tests showed high serum arginine levels, but ammonia levels were within the normal range. Anesthesia was induced with sevoflurane and nitrous oxide via face mask and maintained with sevoflurane, fentanyl, and rocuronium. Vital signs were stable throughout the surgery. There was an intraoperative decrease in blood glucose levels (from 82 mg/dL to 42 mg/dL) that was treated with intravenous glucose. Arginine levels remained high after surgery; however, hyperammonemia did not develop. There were no complications and the patient was discharged on the following day. Conclusions We successfully performed general anesthesia in a child with hyperargininemia. Only a few cases of arginase-1 deficiency had been reported and much remains unknown about its pathology. Therefore, information sharing among medical professionals is essential to customize the plan for the management of this disorder in patients.

The V-antigen, a virulence-associated protein, was first identified inYersinia pestismore than half a century ago. Since then, other V-antigen homologs and orthologs have been discovered and are now considered vital molecules for the toxic effects mediated by the type III secretion system in infections caused by various pathogenic Gram-negative bacteria. After purifying recombinant V-antigen proteins including PcrV fromPseudomonas aeruginosa, LcrV fromYersinia, LssV fromPhotorhabdus luminescens, AcrV fromAeromonas salmonicida, and VcrV fromVibrio parahaemolyticus, we developed an enzyme-linked immunoabsorbent assay to measure titers against each V-antigen in the sera collected from 186 adult volunteers. Different titer-specific correlation levels were determined for the five V-antigens. The anti-LcrV and anti-AcrV titers shared the highest correlation with each other, with a correlation coefficient of 0.84. The next highest correlation coefficient was between anti-AcrV and anti-VcrV titers at 0.79, while the lowest correlation was found between anti-LcrV and anti-VcrV titers, which were still higher than 0.7 Sera from mice immunized with one of the five recombinant V-antigens displayed cross-antigenicity with some of the other four V-antigens, supporting the results from the human sera. Thus, the serum anti-V-antigen titer measurement system could potentially be used for epidemiological investigations on various pathogenic Gram-negative bacteria.

The secondary in-hospital epidemiological investigation for drug-resistant Pseudomonas aeruginosa infections was conducted to evaluate the in-hospital situation and identify any associations between exoenzyme genotypes and other genotypes and antimicrobial resistance characteristics, at the University Hospital in Kyoto, Japan, following a reported outbreak of antimicrobial-resistant P. aeruginosa ST357 between 2005 and 2014. Twelve of the 546 P. aeruginosa isolates collected during the follow-up period were resistant to more than two classes of antimicrobials. All isolates were resistant to fluoroquinolones and 8 (66.7%) showed carbapenem resistance. None of the isolates fulfilled the clinical criteria for multidrug-resistant P. aeruginosa. All isolates were metallo-β-lactamase test-negative. Among five exoS (−)exoU (+) isolates, three possessing a class 1 integron with gene cassette aadB + cmlA6 were classified as ST357, and one isolate containing a class 1 integron with aacA31 was ST235. Collectively, the second survey results confirm that the initial outbreak is currently undergoing convergence. By combining data from the first and second surveys, we showed that prevalent STs such as ST357 and ST235 are associated with fluoroquinolone resistance, class 1 integron-associated resistance to β-lactams and aminoglycosides, and cytotoxic exoU (+) genotypes. With the current worldwide spread of ST357 and ST235 isolates, it is important to evaluate epidemiological trends for high-risk P. aeruginosa isolates by continuous hospital monitoring.

Although the degree of dispersion in Poincare plots of electroencephalograms (EEG), termed the Poincare-index, detects the depth of anaesthesia, the Poincare-index becomes estranged from the bispectral index (BIS) at lighter anaesthesia levels. The present study introduces Poincare-index20–30 Hz, targeting the 20- to 30-Hz frequency, as the frequency range reported to contain large electromyogram (EMG) portions in frontal EEG. We combined Poincare-index20–30 Hz with the conventional Poincare-index0.5–47 Hz using a deep learning technique to adjust to BIS values, and examined whether this layered Poincare analysis can provide an index of anaesthesia level like BIS. A total of 83,867 datasets of these two Poincare-indices and BIS-monitor-derived parameters were continuously obtained every 3 s from 30 patients throughout general anaesthesia, and were randomly divided into 75% for a training dataset and 25% for a test dataset. Two Poincare-indices and two supplemental EEG parameters (EMG70–110 Hz, suppression ratio) in the training dataset were trained in a multi-layer perceptron neural network (MLPNN), with reference to BIS as supervisor. We then evaluated the trained MLPNN model using the test dataset, by comparing the measured BIS (mBIS) with BIS predicted from the model (PredBIS). The relationship between mBIS and PredBIS using the two Poincare-indices showed a tight linear regression equation: mBIS = 1.00 × PredBIS + 0.15, R = 0.87, p

p53 and parkin are involved in mitochondrial quality control. The present study aimed to characterize the functional significance of parkin/p53 in the development of mitochondrial dysfunction and the pathophysiology of neuropathic pain in type I diabetes. Type I diabetes was induced in mice (N = 170) using streptozotocin (STZ). Pifithrin-α, a selective p53 inhibitor, was administered to assess its effects on diabetic pain hypersensitivity, parkin expression and mitochondrial function. Expressions of parkin and p53, mitochondrial number and level of reactive oxygen species (ROS) in the dorsal root ganglion (DRG) were analyzed by immunohistochemistry, western blotting and real time PCR. Separately, mice were treated using intravenous methylglyoxal, then pain hypersensitivity and p53/parkin expression in the DRG were assessed. Mitochondrial membrane potential was also analyzed in cultured DRG neurons treated with methylglyoxal. Mice developed pain hypersensitivity for 3 weeks after STZ treatment. p53 expression was significantly increased (control, 0.68 ± 0.122; STZ, 1.88 ± 0.21) whereas parkin expression was significantly reduced (control, 1.02 ± 0.17; STZ, 0.59 ± 0.14), in the DRG after STZ treatment. Inhibition of p53 by pifithrin-α prevented STZ-induced pain hypersensitivity and parkin downregulation. Pifithrin-α also inhibited STZ-induced reductions in mitochondrial number and accumulation of mitochondrial ROS. Methylglyoxal elicited pain hypersensitivity and alteration of p53/parkin expression, similar to STZ. Methylglyoxal also decreased mitochondrial membrane potential in cultured DRG neurons. Alteration of p53/parkin expression produces mitochondrial dysfunction and ROS accumulation, leading to pain hypersensitivity in diabetic or methylglyoxal treated mice. Methylglyoxal produces neurological derangements similar to diabetes, via direct mechanisms on DRG neurons.

Background Advances in medical technology have resulted in an increased life expectancy in pediatric patients with congenital heart diseases. Assessment of health-related quality of life is crucial to improving their healthcare status. We aimed to assess post-surgical pain prevalence and its impact on health-related quality of life in pediatric patients who underwent cardiac surgery during childhood. Methods This cross-sectional study recruited patients aged 4 years or older who underwent cardiac surgery for congenital heart disease at least 1 year prior, during the age of 0-10 years, and were admitted for post-surgical follow-up at our institute. The prevalence, intensity, and location of pain and health-related quality of life were assessed in an interview. Perioperative information was collected from the patients' medical records. Health-related quality of life was assessed using the Pediatric quality of life inventory 4.0 (PedsQL). Results Pain was reported by 24 (17%) of the 141 participants. One-third of them reported moderate to severe pain that required medical intervention. After adjustment for several confounding factors, multivariable linear regression analysis demonstrated that the presence of pain and the number of surgeries were associated with lower total PedsQL scores. Conclusions Pain was present in 17% of the patients who underwent cardiac surgery during childhood. Presence of pain had a negative impact on long-term health-related quality of life after pediatric cardiac surgery.

Background The main cause of unsuccessful peripheral radial artery catheterization using traditional palpation is imprecisely locating the arterial center. The authors evaluated factors causing disparities between the arterial centers determined by palpation versus ultrasound. The authors applied them to create and test a novel catheterization training program. Methods The arterial central axis was determined by ultrasound and palpation in 350 adults. Potential independent predictors of disparity included sex, body mass index, pulse pressure, transverse arterial diameter, subcutaneous arterial depth, chronic hypertension, and experience as an anesthesiologist (less than 3 vs. greater than or equal to 3 yr). Using the results, the authors developed a radial artery catheterization training program. It was tested by enrolling 20 first-year interns, randomized to a training or control group. The time to successful insertion was the primary outcome measure. The success rate and time required for catheterization by palpation were evaluated in 100 adult patients per group. Results Independent predictors of central axis disparity were pulse pressure, subcutaneous radial artery depth, years of experience, and chronic hypertension. Training improved the catheterization time (training group 56 ± 2 s vs. control group 109 ± 2 s; difference –53 ± 3 s; 95% CI, –70 to –36 s; P < 0.0001) and total success rate (training group 83 of 100 attempts, 83%; 95% CI, 75 to 90 vs. control group 57 of 100, 57%; 95% CI, 47 to 66; odds ratio, 3.7; 95% CI, 2.7 to 5.1). Conclusions Misjudging the central axis position of the radial artery is common with a weak pulse and/or deep artery. The authors’ program, which focused on both these issues, shortened the time for palpation-guided catheterization and improved success.

Arterial pulse waveform analysis (APWA) with a semi-invasive cardiac output monitoring device is popular in perioperative hemodynamic and fluid management. However, in APWA, evaluation of hemodynamic data is not well discussed. In this study, we analyzed how we visually interpret hemodynamic data, including stroke volume variation (SVV) and stroke volume (SV) derived from APWA. We performed arithmetic estimation of the SVV-SV relationship and applied measured values to this estimation. We then collected measured values in six anesthesia cases, including three liver transplantations and three other types of surgeries, to apply them to this SVV-SVI (stroke volume variation index) plot. Arithmetic analysis showed that the relationship between SVV and SV can be drawn as hyperbolic curves. Plotting SVV-SV values in the semi-logarithmic scale showed linear correlations, and the slopes of the linear regression lines theoretically represented average mean cardiac contractility. In clinical measurements in APWA, plotting SVV and SVI values in the linear scale and the semi-logarithmic scale showed the correlations represented by hyperbolic curves and linear regression lines. The plots approximately shifted on the rectangular hyperbolic curves, depending on blood loss and blood transfusion. Arithmetic estimation is close to real measurement of the SVV-SV interaction in hyperbolic curves. In APWA, using SVV as an index of preload and the cardiac index or SVI derived from arterial pressure-based cardiac output as an index of cardiac function, is likely to be appropriate for categorizing hemodynamic stages as a substitute for Forrester subsets.

Purpose This study compared the analgesic effects of local infiltration analgesia (LIA) and femoral nerve block (FNB) after total knee arthroplasty (TKA) and assessed factors associated with analgesia obtained by these two methods. Materials and methods Study subjects included 66 patients (72 knees) who underwent TKA for osteoarthritis of the knee. Pain visual analogue scale (VAS), the amount of analgesics used, number of days to achieve 90° of flexion of the knee joint, date of initiating parallel-bar walking, range of motion of the knee joint at discharge, and adverse events were investigated. Results The VAS scores did not differ significantly between two groups, whereas the amount of analgesics used was significantly lower in the LIA group. Preoperative flexion contracture was significantly more severe in the LIA group with high VAS compared with low VAS. No serious adverse event occurred in the LIA or FNB group. Conclusions The lower analgesic usage in the LIA group than the FNB group indicates that the analgesic effect of LIA was greater than that of singleshot FNB after TKA. There were no serious complications in either group. The postoperative analgesic effect of LIA was smaller in patients with severe than less severe preoperative flexion contracture.

To survive, organisms require mechanisms that enable them to sense changes in the outside environment, introduce necessary responses, and resist unfavorable distortion. Consequently, through evolutionary adaptation, cells have become equipped with the apparatus required to monitor their fundamental intracellular processes and the mechanisms needed to try to offset malfunction without receiving any direct signals from the outside environment. It has been shown recently that eukaryotic cells are equipped with a special mechanism that monitors their fundamental cellular functions and that some pathogenic proteobacteria can override this monitoring mechanism to cause harm. The monitored cellular activities involved in the stressed intracellular response have been researched extensively in Caenorhabditis elegans, where discovery of an association between key mitochondrial activities and innate immune responses was named "cellular associated detoxification and defenses (cSADD)." This cellular surveillance pathway (cSADD) oversees core cellular activities such as mitochondrial respiration and protein transport into mitochondria, detects xenobiotics and invading pathogens, and activates the endocrine pathways controlling behavior, detoxification, and immunity. The cSADD pathway is probably associated with cellular responses to stress in human inflammatory diseases. In the critical care field, the pathogenesis of lethal inflammatory syndromes (e.g., respiratory distress syndromes and sepsis) involves the disturbance of mitochondrial respiration leading to cell death. Up-to-date knowledge about monitored cellular activities and cSADD, especially focusing on mitochondrial involvement, can probably help fill a knowledge gap regarding the pathogenesis of lethal inflammatory syndromes in the critical care field.

Multi-drug resistant Pseudomonas aeruginosa causes the type of acute lung injury that is strongly associated with bacteremia, sepsis, and mortality, especially under immunocompromised conditions. Although administration of immunoglobulin solution is an applicable immunotherapy in immunocompromised patients, efficacy of immunoglobulin administration against multi-drug resistant P. aeruginosa pneumonia has not been well evaluated. In this study, we investigated the effectiveness of prophylactic administration of immunoglobulin solution (IVIG) in comparison with that of other types of antimicrobial agents, such as anti-PcrV IgG, piperacillin/tazobactam, or colistin in an immunocompromised mouse model of P. aeruginosa pneumonia. Colistin was the most effective agent for preventing acute lung injury, bacteremia, cytokinemia, and sepsis. Among the four tested antimicrobial agents, after colistin, anti-PcrV IgG and IVIG were the most effective at protecting mice from mortality. Piperacillin/tazobactam did not prevent acute lung injury or bacteremia; rather, it worsened lung histology. The data suggest that using an agent for which a positive result in an in vitro susceptibility test has been obtained may not always prevent acute lung injury in a leukopenic host infected with P. aeruginosa. Clinicians should consider the possibility of discrepancies between in vitro and in vivo tests because the absence of in vitro bactericidal activity in an antimicrobial agent is not always a reliable predictor of its lack of ability to eradicate bacteria in vivo, even in immunocompromised hosts. Based on our findings, the potential protective effects of IVIG against the acute lung injury induced by P. aeruginosa should be reevaluated.

Of the various virulence mechanisms of the opportunistic pathogen Pseudomonas aeruginosa, the type III secretion system (TTSS) has been characterized as a major factor associated with acute lung injury, bacteremia and mortality. In addition, PcrV, a component protein of the TTSS, has been characterized as a protective antigen against infection with P. aeruginosa. This study comprised an epidemiological analysis of serum anti-PcrV titers in a cohort of Japanese adults. From April 2012 to March 2013, serum anti-PcrV titers of 198 volunteer participants undergoing anesthesia for scheduled surgeries were measured. The median, minimum and maximum serum anti-PcrV titers among the 198 participants were 4.09 nM, 1.01 nM and 113.81 nM, respectively. The maximum peaks in the histogram were within the anti-PcrV 2.00-4.99 nM titer range; values for 115 participants (58.1%) were within this range. Anti-PcrV titers were more than approximately three-fold greater (>12 nM) than the median value in 21 participants (10.6%). Ten-year interval age increases, history of treatment for traffic trauma, and a history of past surgery each showed statistically significant associations with higher anti-PcrV titers (i.e., >10 nM) than did the other factors assessed by binomial analysis. This study revealed a considerable variation in anti-PcrV titers in adult subjects without any obvious histories of infection with P. aeruginosa.

A 4-month-old female infant who weighed 3.57 kg with severe subglottic stenosis underwent tracheostomy under extracorporeal cardiopulmonary support. First, we set up extracorporeal cardiopulmonary support to the infant and then successfully intubated an endotracheal tube with a 2.5 mm inner diameter before tracheostomy by otolaryngologists. Extracorporeal cardiopulmonary support is an alternative for maintenance of oxygenation in difficult airway management in infants.

Virulent and multidrug-resistant Pseudomonas aeruginosa causes a lethal pneumonia, especially in patients who are artificially ventilated. It has been reported that the virulence mechanism used by P. aeruginosa, which is linked to acute lung injury, is strongly associated with the type III secretion system, and specific antibodies targeting this system have shown a protective effect in both experimental and clinical settings. We investigated the effect of administering IV immunoglobulins on P. aeruginosa pneumonia, including its associated bacteremia and mortality, although focusing especially on type III secretion system-associated P. aeruginosa virulence.Prospective randomized and controlled animal study.University laboratory.Male ICR mice.Mice were infected intratracheally with a lethal dose of the virulent P. aeruginosa PA103 strain. IV immunoglobulin administration was examined in three different settings: 1) premixed; 2) pre-IV, prophylactic administration before bacterial infection; and 3) post-IV, therapeutic administration after bacterial infection. The effect of specific antigen titer depletion of IV immunoglobulins was also examined.Survival and body temperature were monitored for 24 hours. Bacteremia, cytokine concentration, myeloperoxidase activity, WBC counts in the blood, and lung bacterial load were evaluated. Survival improved significantly in mice that received IV immunoglobulins (p0.05). Lung edema, lung bacteriologic load, and bacteremia decreased significantly in the IV immunoglobulin-treated mice (p0.05). The mechanism of protection was associated with the presence of antibodies against both PcrV and some bacterial surface antigens in the IV immunoglobulins.IV immunoglobulin administration had a significantly protective effect against lethal infection from virulent P. aeruginosa. Prophylactic IV immunoglobulin administration at the highest dose was comparable with that achieved by administrating a specific anti-PcrV polyclonal IgG into the mice. The mechanism of protection is likely to involve the synergic action of anti-PcrV titers and antibodies against some surface antigen(s) that block the type III secretion system-associated virulence of P. aeruginosa.

We report a case of severe anaphylactic shock in a 5-month-old infant who was scheduled to undergo an external inguinal hernia repair under general anesthesia. Rocuronium used for anesthesia induction was the most likely cause of anaphylaxis. High levels of serum tryptase and histamine detected in the blood sample collected during the anaphylactic reaction confirmed the diagnosis of anaphylactic shock. The patient’s clinical status improved within 90 min of intervention by the intravenous injection of vasopressors and a steroid. Surgery was canceled, and the patient stayed in the pediatric intensive care unit (PICU) under artificial ventilation for 5 h before safe extubation. The patient achieved full recovery the next day, without any sequelae. The rescheduled surgery was successfully completed 5 months later under general anesthesia without the use of neuromuscular blocking agents.

Mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase that controls protein synthesis in the nervous system. Here, we characterized the role of protein synthesis regulation due to mTOR signaling in rat dorsal root ganglion (DRG) following plantar incision. The number of phosphorylated mTOR (p-mTOR)-positive neurons was increased 2-4days after the incision. Rapamycin inhibited p-mTOR expression in the DRG and thermal hypersensitivity 3days but not 1day after the incision. Vesicular glutamate transporter 2 (VGLUT2) expression was increased after the plantar incision, which was inhibited by rapamycin. These results demonstrated that tissue injury induces phosphorylation of mTOR and increased protein level of VGLUT2 in the DRG neurons. mTOR phosphorylation involves in maintenance of injury-induced thermal hypersensitivity.

BACKGROUND Recombinant activated factor VII (rFVIIa) concentrate reduces allogeneic blood transfusions, but it may increase thromboembolic complications in complex cardiac surgery. The mixture of activated factor VII (FVIIa) and factor X (FX) (FVIIa/FX) (FVIIa:FX = 1:10) is a novel bypassing agent for hemophilia patients. We hypothesized that the combination of FX and FVIIa could improve thrombin generation (TG) in acquired multifactorial coagulation defects such as seen in cardiac surgery and conducted in vitro evaluation of FVIIa/FX in parallel with other coagulation factor concentrates using in vitro and in vivo diluted plasma samples. METHODS Plasma samples were collected from 9 healthy volunteers and 12 cardiac surgical patients. We measured TG (Thrombinoscope) using in vitro 50% dilution plasma and in vivo dilution plasma after cardiopulmonary bypass, in parallel with thromboelastometry (ROTEM) and standard coagulation assays. In vitro additions of FVIIa/FX (0.35, 0.7, and 1.4 μg/mL, based on the FVIIa level), rFVIIa (1.4, 2.8, and 6.4 μg/mL), prothrombin complex concentrate (0.3 international unit), and 20% plasma replacement were evaluated. RESULTS In diluted plasma, the addition of either FVIIa/FX or rFVIIa shortened the lag time and increased the peak TG, but the effect in lag time of FVIIa/FX at 0.35 μg/mL was more extensive than rFVIIa at 6.4 μg/mL. Prothrombin complex concentrate increased peak TG by increasing the prothrombin level but failed to shorten the lag time. No improvement in any of the TG variables was observed after 20% volume replacement with plasma. The addition of factor concentrates normalized prothrombin time/international normalized ratio but not with plasma replacement. In cardiac patients, similar patterns were observed on TG in post-cardiopulmonary bypass samples. FVIIa/FX shortened clotting time (CT) in a concentration-dependent manner on CT on thromboelastometry. Plasma replacement did not improve CT, but a combination of plasma and FVIIa/FX (0.35 μg/mL) more effectively shortened CT than FVIIa/FX alone. CONCLUSIONS The combination of FVIIa and FX improved TG more efficiently than rFVIIa alone or plasma in dilutional coagulopathy models. The required FVIIa dose in FVIIa/FX was considerably lower than those reported during bypassing therapy in hemophilia patients (1.4-2.8 μg/mL). The combination of plasma could restore coagulation more efficiently compared to FVIIa/FX alone. Lesser FVIIa requirement to exert procoagulant activity may be favorable in terms of reducing systemic thromboembolic complications.

Akiko Okamoto,1,2 Masaki Yamasaki,3 Isao Yokota,4 Maiko Mori,3 Megumi Matsuda,3 Yosuke Yamaguchi,3 Shunsuke Yamakita,3 Hiroshi Ueno,2 Teiji Sawa,3 Tetsuya Taguchi,1 Toyoshi Hosokawa,2 Fumimasa Amaya3 1Department of Endocrinological and Breast Surgery, 2Department of Pain Management and Palliative Care Medicine, 3Department of Anesthesiology, 4Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan Purpose: Predictive value and accuracy of the acute pain trajectory were compared with those of pain intensity at 1 day after the surgery for pain prevalence at 6 months after the surgery.Materials and methods: Female patients scheduled for breast cancer surgery were eligible for this study. Patients were questioned about pain intensity daily during the 7 days after surgery. Presence of pain, its location, and intensity as well as the Japanese version of the quality of the recovery-40 (QOR-40) were determined in an interview prior to and at 6 months after the surgery. Acute pain trajectory was determined by a group-based trajectory modeling analysis that was based on the pain intensity at 1–7 days after surgery. Predictive value of the acute pain trajectory for the presence of pain at 6 months after the surgery was assessed by a logistic regression model. The predictive value was compared with pain intensity at 1 day after the surgery.Results: A total of 123 participants completed the 6-month follow-up. The three-cluster model (mild, moderate, and severe pain) was considered to be the most statistically appropriate model for the acute pain trajectory. After 6 months, 51.2% and 8.9% of participants reported pain and severe pain, respectively. Presence of pain at 6 months after the surgery was associated with poor recovery. The severe pain cluster was significantly associated with the presence of pain at 6 months after the surgery (adjusted odds ratio, 9.40; P

The electromyogram (EMG) activity has been reported to falsely increase BIS. Conversely, EMG seems necessary to constitute the high BIS indicative of an awake condition, and may play a fundamental role in calculating BIS, rather than distorting the appropriate BIS. However, exactly how EMG is associated with a high BIS remains unclear. We intended to clarify the respective contributions of EMG and various electroencephalogram (EEG) parameters to high BIS. In 79 courses of anaesthesia, BIS monitor-derived EMG parameters (EMGLOW), and other processed EEG parameters [SEF95 (spectral edge frequency 95%), SynchFastSlow (bispectral parameter), BetaRatio (frequency parameter), total power subtypes in five frequency range], were obtained simultaneously with BIS, every 3 s. These EEG parameters were used for receiver operating characteristic (ROC) analysis of detecting three BIS levels (BIS 80, BIS 70, and BIS 60) to assess their diagnosabilities. A total of 218,418 data points derived from 79 cases were used for analysis. Area under the ROC curve (AUC) was calculated and optimal cut-off (threshold) was determined by Youden index. As the results, for detecting BIS 80, the AUC of EMGLOW was 0.975 [0.974-0.977] (mean [95% confidence interval]), significantly higher than any other processed EEG parameters such as BetaRatio (0.832 [0.828-0.835]), SEF95 (0.821 [0.817-0.826]) and SynchFastSlow (0.769 [0.764-0.774]) (p 0.05 each). The threshold of EMGLOW for detecting BIS 80 was 35.7 dB, with high sensitivity (92.5%) and high specificity (96.5%). Our results suggest EMG contributes considerably to the diagnosis of high BIS, and is particularly essential for determining BIS 80.

An effective vaccine against Pseudomonas aeruginosa would be hugely beneficial to people who are susceptible to the serious infections it can cause. Vaccination against PcrV of the P. aeruginosa type III secretion system is a potential prophylactic strategy for improving the incidence and prognosis of P. aeruginosa pneumonia. Here, the effect of nasal PcrV adjuvanted with CpG oligodeoxynucleotide (CpG) was compared with a nasal PcrV/aluminum hydroxide gel (alum) vaccine. Seven groups of mice were vaccinated intranasally with one of the following: 1, PcrV-CpG; 2, PcrV-alum; 3, PcrV alone; 4, CpG alone; 5, alum alone; 6 and 7, saline control. Fifty days after the first immunization, anti-PcrV IgG, IgA and IgG isotype titers were measured; significant increases in these titers were detected only in the PcrV-CpG vaccinated mice. The vaccinated mice were then intratracheally infected with a lethal dose of P. aeruginosa and their body temperatures and survival monitored for 24 hr, edema, bacteria, myeloperoxidase activity and lung histology also being evaluated at 24 hr post-infection. It was found that 73% of the PcrV-CpG-vaccinated mice survived, whereas fewer than 30% of the mice vaccinated with PcrV-alum or adjuvant alone survived. Lung edema and other inflammation-related variables were less severe in the PcrV-CpG group. The significant increase in PcrV-specific IgA titers detected following PcrV-CpG vaccination is probably a component of the disease protection mechanism. Overall, our data show that intranasal PcrV-CpG vaccination has potential efficacy for clinical application against P. aeruginosa pneumonia.

Objectives Platelet defect mechanisms after cardiopulmonary bypass remain unclear. Our hypothesis microRNA expressions in circulating platelets significantly change between pre and post cardiopulmonary bypass, and consequent messenger RNA and protein expression level alterations cause postcardiopulmonary bypass platelet defect. Design Single-center prospective observational study. Setting Operating room of Kyoto Prefectural University of Medicine. Patients Twenty-five adult patients scheduled for elective cardiac surgeries under cardiopulmonary bypass. Interventions None. Measurements and main results In the initial phase, changes in microRNA expression between pre and post cardiopulmonary bypass underwent next generation sequencing analysis (10 patients). Based on the results, we focused on changes in mir-10b and mir-96, which regulate glycoprotein 1b and vesicle-associated membrane protein 8, respectively, and followed them until messenger RNA and protein syntheses (15 patients) using quantitative polymerase chain reaction and Western blotting. Seven microRNAs including mir-10b and mir-96 exhibited significant differences in the initial phase. In the subsequent phase, mir-10b-5p and mir-96-5p overexpressions were confirmed, and glycoprotein 1b and vesicle-associated membrane protein 8 messenger RNA levels were significantly decreased after cardiopulmonary bypass: fold differences (95% CI): mir-10b-5p: 1.35 (1.05-2.85), p value equals to 0.01; mir-96-5p: 1.59 (1.06-2.13), p value equals to 0.03; glycoprotein 1b messenger RNA: 0.46 (0.32-0.60), p value of less than 0.001; and vesicle-associated membrane protein messenger RNA: 0.70 (0.56-0.84), p value of less than 0.001. Glycoprotein 1b and vesicle-associated membrane protein 8 were also significantly decreased after cardiopulmonary bypass: glycoprotein 1b: 82.6% (71.3-93.8%), p value equals to 0.005; vesicle-associated membrane protein 8: 79.0% (70.7-82.3%), p value of less than 0.001. Conclusions Expressions of several microRNAs in circulating platelets significantly changed between pre and post cardiopulmonary bypass. Overexpressions of mir-10b and mir-96 decreased glycoprotein 1b and vesicle-associated membrane protein 8 messenger RNA as well as protein, possibly causing platelet defect after cardiopulmonary bypass.

Additional table. Sensitivity analysis for BMI missing data (DOCX 19 kb)

Background Although midbrain dopaminergic pathways are known to contribute to arousal and emergence from anesthesia, few reports exist regarding the anesthetic effects of dopamine D2 receptor antagonism in humans. This study examined the effect of the D2 receptor antagonist droperidol on sevoflurane anesthesia by examining α and slow wave electroencephalogram oscillations. Methods Forty-five patients, age 20 to 60 yr, were enrolled. Frontal electroencephalograms were continuously collected for offline analysis via Bispectral Index monitoring. After induction of anesthesia, end-tidal sevoflurane concentration was deliberately maintained at 1%, and intravenous droperidol (0.05 mg/kg bolus) was administered. Electroencephalogram changes were examined in power spectrum and bicoherence, before and 10 min after droperidol injection, then compared using the Wilcoxon signed-ranks test and/or paired t test. Results Droperidol significantly augmented the α-bicoherence peak induced by sevoflurane from 30.3% (24.2%, 42.4%) to 50.8% (41.7%, 55.2%) (median [25th, 75th percentiles]; P < 0.0001), Hodges-Lehman median difference, 15.8% (11.3 to 21.4%) (95% CI). The frequency of the α-bicoherence peak was simultaneously shifted to the lower frequency; from 11.5 (11.0, 13.0) to 10.5 (10.0, 11.0) Hz (median [25th, 75th percentiles], P < 0.0001). Averaged bicoherence in the δ-θ area increased conspicuously from 17.2% (15.6 to 18.7%) to 25.1% (23.0 to 27.3%) (mean [95% CI]; P < 0.0001), difference, 8.0% (6.0 to 9.9%). Conclusions Droperidol augments both α and δ-θ bicoherences while shifting the α-bicoherence peaks to lower frequencies, and enhances the effect of sevoflurane anesthesia on the electroencephalogram via γ-aminobutyric acid–mediated oscillatory network regulation.