Brain neurotransmitter transporter/receptor genomics and efavirenz central nervous system adverse events

Objective We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. Participants and methods Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. Results Analyses included 167 cases with grade 2 or greater efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10−4). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10−27). Conclusion Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics. Correspondence to David W. Haas, MD, Vanderbilt Health, One Hundred Oaks, 719 Thompson Lane, Suite 47183, Nashville, TN 37204, USA Tel: +1 615 936 8594; fax: +1 615 936 2644; e-mail: david.haas@vanderbilt.edu Received December 11, 2017 Accepted May 10, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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A comparison of the incidence of supraventricular arrhythmias between thoracic paravertebral and intercostal nerve blocks in patients undergoing thoracoscopic surgery: A randomised trial

BACKGROUND Postoperative supraventricular arrhythmias are common in patients after thoracoscopic lobectomy. Inadequate pain control has long been recognised as a significant risk factor for arrhythmias. The performance of ultrasound-guided (USG) thoracic paravertebral block (PVB) is increasing as an ideal technique for postoperative analgesia. OBJECTIVE We conducted this study to evaluate whether a single-shot USG thoracic PVB would result in fewer postoperative supraventricular tachycardias (SVT) than intercostal nerve blocks (ICNBs) after thoracoscopic pulmonary resection. DESIGN A randomised controlled study. SETTING A single university hospital. PATIENTS Sixty-eight patients undergoing thoracoscopic lobectomy were randomised into two equal groups of 34. INTERVENTIONS For postoperative pain control, all patients received a total of 0.3 ml kg−1 of a mixture containing 0.5% ropivacaine and 1/200 000 epinephrine after placement of needles for either a single thoracic PVB or two individual ICNBs, both guided by ultrasound. Data were obtained during the first 48 postoperative hours. MAIN OUTCOME MEASURES The primary outcome was the incidence of SVT after thoracoscopic pulmonary resection. RESULTS During the first 48 postoperative hours, the incidences of SVT and atrial fibrillation were lower in the USG thoracic PVB group (14.7 vs. 46.9%, P = 0.004 and 3.0 vs. 18.8%, P = 0.037, respectively). The requirement for β-receptor blockade was more frequent in the ICNBs group than in the PVB group (5.9 vs. 25%, P = 0.033). CONCLUSION After placement of the needle using ultrasound guidance, a single-shot thoracic PVB is a well tolerated and effective technique to reduce the incidences of postoperative SVT and atrial fibrillation in patients undergoing thoracoscopic pulmonary resection. TRIAL REGISTRATION https://ift.tt/2LGPFWU, registration number: ChiCTR-IOR-17010952. Correspondence to Ying Cao, MD, PhD, School of Pharmacological Science, Southern Medical University, Guangzhou 510515, China Tel: +86 20 36591230; fax: +86 20 36591350; e-mail: yingcao1986@163.com © 2018 European Society of Anaesthesiology

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Safety of moderate-to-deep sedation performed by sedation practitioners: A national prospective observational study

BACKGROUND In the Netherlands, a significant proportion of moderate-to-deep sedation is performed by sedation practitioners under the indirect supervision of an anaesthesiologist but there are limited safety data available. OBJECTIVE To estimate the rate of sedation-related adverse events and patient relevant outcomes (PRO). DESIGN This was a prospective national observational study. Data were collected with a modified adverse event reporting tool from the International Sedation Task Force of the World Society of Intravenous Anaesthesia. SETTING A total of 24 hospitals in the Netherlands where moderate-to-deep sedation was performed by sedation practitioners from the 1 February 2015 to 1 March 2016. PATIENTS Consecutive adults undergoing moderate-to-deep sedation for gastrointestinal, pulmonary and cardiac procedures. INTERVENTION Observation: Analysis included descriptive statistics and a multivariate logistic regression model for an association between adverse events and PRO. MAIN OUTCOME MEASURES The primary outcome was the rate of unfavourable PRO (admission to ICU, permanent neurological deficit, pulmonary aspiration or death). Secondary outcome was the rate of moderate-to-good PRO (unplanned hospital admission or escalation of care). Composite outcome was the sum of all primary and secondary outcomes. RESULTS A total of 11 869 patients with a median age of 64 years [interquartile range 51 to 72] were included. ASA physical score distribution was: first, 19.1%; second, 57.6%; third, 21.6%; fourth, 1.2%. Minimal adverse events occurred in 1517 (12.8%), minor adverse events in 113 (1.0%) and major adverse events in 80 instances (0.7%). Primary outcome: Five (0.04%) unfavourable PRO were observed; four patients needing admission to the intensive care unit; and one died. Secondary outcome: 12 (0.1%) moderate-to-good PRO were observed. Moderate and major adverse events were associated with the composite outcome [3.7 (95% confidence interval 1.1 to 11.9) and 40.6 (95% confidence interval 11.0 to 150.4)], but not minimal or minor adverse events. CONCLUSION Moderate-to-deep sedation performed by trained sedation practitioners has a very low rate of unfavourable outcome. Correspondence to Benedikt Preckel, Department of Anaesthesia, Academic Medical Centre, Meibergdreef 9, 1105 AZ, 1100 DD Amsterdam, The Netherlands Tel: +00 31 205669111; fax: +00 31 206979441; e-mail: b.preckel@amc.nl © 2018 European Society of Anaesthesiology

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Challenges of bringing a new sedative to market!

Purpose of review The current review examines the success and failures of the development of new hypnotic compounds for the human market. One of the important aspects is that one of the key present agents, propofol, is considered by many anaesthesiologists as 'the ideal'. However, all drugs have adverse or side-effects. Recent findings The last 30 years since the introduction of propofol has seen many new compounds evaluated; but as at the present time, only three agents may achieve a pivotal position in the market – fospropofol (a sedative agent which may have a role in endoscopic surgery); remimazolam (a short-acting benzodiazepine) whose development is also being focused on the sedation rather than anaesthesia market; and the pregnane steroid, alfaxalone (an anaesthetic agent first introduced in 1972, but withdrawn in 1984 because of adverse allergic reactions to the solvent, Cremophor EL) now solvented in a cyclodextrin. Summary Studies of these three agents thus far have shown that none of them has any major adverse side-effects; all have properties which warrant further clinical evaluation. Correspondence to John W. Sear, 6 Whites Forge, Abingdon, Appleton OXON OX13 5LG, UK. E-mail: john.sear@gtc.ox.ac.uk Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Recent advances in respiratory monitory in nonoperating room anesthesia

Purpose of review Sedation for nonoperating room procedures is experiencing a considerable increase in demand. Respiratory compromise is one of the most common adverse events seen in sedation. Capnography is a modality that has been widely adopted in this area, but may not be well suited to the special demands of nonoperating room sedation. This review is an assessment of new technologies that may improve outcomes beyond those achievable with capnography. Recent findings New devices for detecting the onset of apnea and for assessing respiratory depression have emerged which have advantages over conventional capnography for detecting apnea without excessive false positive and false negative rates. In addition, monitors that assess respiratory drive have become available, and these may prove useful in regulating depth of sedation. Summary No single monitor is ideal for all settings. During brief endoscopic sedation, detection of apnea is paramount, while during longer procedures, avoiding excessive respiratory depression is more critical. The clinician must choose the appropriate monitor based on an understanding of the challenges of the particular environment. Correspondence to Jeff E. Mandel, Assistant Professor of Anesthesiology & Critical Care, Perelman School of Medicine at the University of Pennsylvania, 7003 Dulles Building, 3400 Spruce Street, Philadelphia, PA 190103, USA. E-mail: mandelj@uphs.upenn.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Epigenetics of pain mediators

Purpose of review The field of epigenetics continues its influential rise as a means to better understand an organism's unique developmental identity over a lifespan. Whereas a genome is constant and unchanging, an epigenome is dynamic and alterable. Epigenetic changes are in response to innumerable internal and external influences including environmental changes such as diet, exercise, disease, toxins, and stress. Epigenetics is of particular interest in the medical research community both for the potential to cause disease and as a target for therapeutic interventions. This article provides a succinct explanation of the potential for epigenetics to influence the understanding of pain as well as a review of relevant research on the topic. Recent findings Studies on epigenetics and pain remain largely preclinical and investigate the theoretical ability of epigenetics to alter the nociceptive pathways both in the periphery and centrally. Significant evidence now exists for the ability of epigenetics to modify broadly categorized pain types, including inflammatory, neuropathic, visceral, and cancer related. Summary Both patients and providers recognize that novel medications for the treatment of both acute and chronic pain conditions are sorely needed. The understanding of epigenetics and its influence on nociception remains in relative infancy but early evidence is strong for potential therapeutic benefits to treat these conditions. Correspondence to Daniel W. Odell, MD, Division of Pain Medicine, Department of Anesthesiology, University of Utah and Supportive Oncology and Survivorship, Huntsman Cancer Hospital, 30 N 1900 E Room 3C444, Salt Lake City, UT 84132-2501, USA. Tel: +1 801 581 6393; fax: +1 801 581 4367; e-mail: daniel.odell@hsc.utah.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Calculations of consciousness: electroencephalography analyses to determine anesthetic depth

Purpose of review Electroencephalography (EEG) was introduced into anesthesia practice in the 1990s as a tool to titrate anesthetic depth. However, limitations in current analysis techniques have called into question whether these techniques improve standard of care, or instead call for improved, more ubiquitously applicable measures to assess anesthetic transitions and depth. This review highlights emerging analytical approaches and techniques from neuroscience research that have the potential to better capture anesthetic transitions to provide better measurements of anesthetic depth. Recent findings Since the introduction of electroencephalography, neuroscientists, engineers, mathematicians, and clinicians have all been developing new ways of analyzing continuous electrical signals. Collaborations between these fields have proliferated several analytical techniques that demonstrate how anesthetics affect brain dynamics and conscious transitions. Here, we review techniques in the following categories: network science, integration and information, nonlinear dynamics, and artificial intelligence. Summary Up-and-coming techniques have the potential to better clinically define and characterize altered consciousness time points. Such new techniques used alongside traditional measures have the potential to improve depth of anesthesia measurements and enhance an understanding of how the brain is affected by anesthetic agents. However, new measures will be needed to be tested for robustness in real-world environments and on diverse experimental protocols. Correspondence to Sarah L. Eagleman, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Grant Building, 300 Pasteur Dr, S288, Palo Alto, CA 94305–5117, USA. Tel: +650 725 5851; fax: +650 725 8544; e-mail: seagle@stanford.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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