Anesthesiology

Innovation in sedation and analgesia training Purpose of review We reviewed evidence of recent innovations in sedation education and discuss experiences with sedation training in Taiwan. Recent findings Current Status of Sedation Training: Didactic training and supervised clinical mentoring are common methods of sedation training. Although training course designed by professional societies to meet individual hospital credentialing requirements, the course content and training expectations vary and are likely inadequate to non-anesthesiologist sedation practitioners. Less Common Forms of Sedation Training: These include screen-based simulation, high-fidelity manikin-based simulation. Screen-based simulation sedation training is popular, convenient, and relatively inexpensive. Although there are numerous courses available, course content has not been standardized. High-fidelity simulation has been accepted to improve knowledge, self-confidence, awareness of emergency, crisis resource management, and teamwork, but it is costly, time intensive, and requires expertise in using simulation equipment. Although screen-based training is attractive and convenient, there is no evidence to suggest that it can replace high-fidelity simulation. Another recently developed education modality is virtual reality simulation. It has gained recent popularity as an immersive approach to medical training, but minimal content has been developed for sedation training. Beyond training, several other potential innovations may improve sedation effectiveness and patient safety. These include adherence to practice guidelines established by professional organizations, utilization of a pre-procedure sedation checklist, interpreting capnography, and implementation of real-time bedside drug displays that provide predictions of concentrations and their associated effects. Summary Effective sedation education and training, especially for nonanesthesiologists, is essential to improve patient safety for procedural sedation. Several innovative approaches have been proposed and are relatively early in their development and implementation. Further studies designed to assess the impact of these new training modalities on patient safety and outcomes are warranted. Correspondence to Hung-Wei Cheng, MD, Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Taipei, Taiwan ROC. Tel: +886 2 28757549; fax: +886 2 28751597; e-mail: hwc1127@gmail.com Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Moderate and deep sedation training and pharmacology for nonanesthesiologists: recommendations for effective practice Purpose of review The purpose of this review is to discuss current drugs used for intravenous moderate and deep sedation by nonanesthesiologists in the United States. We also explore training expectations for moderate and deep sedation as they play key roles in anesthetic selection and preprocedural planning. Recent findings Although opioids and benzodiazepines are considered the standard for moderate sedation, increased interest in propofol, dexmedetomidine, and other sedative-hyptonic drugs require additional attention in terms of training providers and complying with current practice guidelines. Summary Moderate sedation providers should be familiar with titrating benzodiazepines and opioids to achieve targeted sedation. The use of propofol and ketamine is generally reserved for deep sedation by qualified professionals. However, the role of dexmedetomidine in procedural sedation continues to evolve as its use is explored in moderate sedation. Providers of all sedation types should be aware of hypotension, apnea, hypoventilation, and hypoxia that can develop and they should be able to manage the patient under these circumstances. Preprocedural planning is an integral training expectation to minimize patient risks. Correspondence to Richard D. Urman, MD, MBA, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, 75 Francis Street – CWN L1, Boston, MA 02115, USA. Tel: +1 617 732 8222; e-mail: rurman@bwh.harvard.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Airway rescue during sedation: a proposed airway rescue pathway for nonanesthesiologists Out-of-operating room procedures that require sedation are expanding in number and scope. With this expansion, the number of nonanesthesiologist sedation practitioners is growing as well. Professional societies and governing bodies have issued extensive sedation guidelines and practice recommendations. Despite these guidelines and the significant harm that can result from adverse events in patients undergoing sedation, training for nonanesthesiologist sedation practitioners is inconsistent and largely inadequate to prepare them for rare but severe adverse events they may encounter. Purpose of review This review summarizes key features of adverse airway and respiratory events for which sedation providers must be prepared to diagnose and treat in a timely manner. Key features include elements of the presedation patient evaluation that are predictive of adverse airway and respiratory events; patient profiles, target sedation levels, and procedure types that should prompt a consult with an anesthesiologist; necessary clinical skills, essential equipment, and reversal drugs necessary to manage adverse airway and respiratory events; and a proposed airway rescue pathway that describes a sequence of interventions and prompts to call for help when encountering an adverse airway or respiratory event. Recent findings Several studies have reported adverse events from sedation. Although the overall rate can approach 4.5%, the incidence of events associated with severe harm is low (e.g., <0.5%). Some of those that are most harmful are prolonged ventilatory compromise leading to hypoxic brain injury or death. Inadequate clinical skills that contribute to these poor outcomes include undetected or delayed detection of hypopnea or apnea, undetected or delayed detection of partial or complete airway obstruction, inadequate rescue skills to manage drug-induced ventilatory depression or airway obstruction, and/or a delay or no attempt to call for expert help followed by a timely response and intervention from that expert help. Summary To improve outcomes in detecting and managing adverse airway and respiratory events, nonanesthesiologists sedation practitioners must be trained in patient selection, monitoring, pharmacology, physiology, and airway management. One gap in sedation training curriculum is a roadmap to use when managing an adverse airway or respiratory events. This review puts forth a suggested airway rescue pathway for nonanesthesiologist sedation practitioners to use as a decision aid during an adverse airway or respiratory event associated with procedural sedation. Correspondence to Elizabeth M. Thackeray, MD, MPH, Department of Anesthesiology, University of Utah, 30 North 1900 East, Room 3C444, Salt Lake City, UT 84132, USA. Tel: +1 801 581 6393; e-mail: Elizabeth.thackeray@hsc.utah.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

The rise, fall, and future direction of computer-assisted personalized sedation Purpose of review The first computer-assisted personalized sedation (CAPS) device was developed to address the growing demand for routine endoscopy procedures in the United States in the early 2000s. This review will describe the environment that gave rise to CAPS and summarize the design of that first device. It will then discuss the market forces that led to the fall of CAPS, with sales of the device ending 2 years after commercialization. Recent findings CAPS was initially conceived as a means to enable proceduralists to administer conscious sedation with propofol safely. In the nearly 20 years since its conception, the expectations of patients and proceduralists for endoscopy sedation, have evolved from conscious sedation to deep. Due to the increased risk inherent in deep sedation, future CAPS devices should be tools for anesthesiologists, not proceduralists. Summary Over $2 billion are spent annually for anesthesia services in routine endoscopic procedures for low-risk patients; a spending rate that is not sustainable. CAPS, in an 'anesthesia oversight' model similar to medical supervision, has a future as a cost-efficient means for anesthesia services to provide sedation in endoscopy and other nonoperating room venues. Anesthesiologists should work with medical device companies and payers to develop a CAPS 'anesthesia oversight' model. Correspondence to Paul J. Niklewski, PhD, CARE/Crawley Building, Suite E-870 3230, Eden Avenue, Cincinnati, OH 45267, USA. Tel: +1 513 558 7333; e-mail: niklewpj@ucmail.uc.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Hyperventilation in neurological patients: from physiology to outcome evidence Purpose of review Hyperventilation is commonly used in neurological patients to decrease elevated intracranial pressure (ICP) or relax a tense brain. However, the potentially deleterious effects of hyperventilation may limit its clinical application. The aim of this review is to summarize the physiological and outcome evidence related to hyperventilation in neurological patients. Recent findings Physiologically, hyperventilation may adversely decrease cerebral blood flow (CBF) and the match between the cerebral metabolic rate and CBF. In patients with severe traumatic brain injury (TBI), prolonged prophylactic hyperventilation with arterial carbon dioxide tension (PaCO2) less than 25 mmHg or during the first 24 h after injury is not recommended. Most patients (>90%) with an aneurysmal subarachnoid hemorrhage undergo hyperventilation (PaCO2 <35 mmHg); however, whether hyperventilation is associated with poor outcomes in this patient population is controversial. Hyperventilation is effective for brain relaxation during craniotomy; however, this practice is not based on robust outcome evidence. Summary Although hyperventilation is commonly applied in patients with TBI or intracranial hemorrhage or in those undergoing craniotomy, its effects on patient outcomes have not been proven by quality research. Hyperventilation should be used as a temporary measure when treating elevated ICP or to relax a tense brain. Outcome research is needed to better guide the clinical use of hyperventilation in neurological patients. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Correspondence to E. Wang, Department of Anesthesiology, Xiangya Hospital Central South University, Xiangya Road 87#, Changsha 410008, PR China. Tel: +86-0731-84327413; fax: +86-0731-84327413; e-mail: ewang324@csu.edu.cn Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

The impact of frailty and sarcopenia on patient outcomes after complex spine surgery Purpose of review Frailty and sarcopenia represent a state of increased fragility and decreased reserve, and both have been associated with worse outcomes after surgery. The present review focuses on the definitions and measurement tools used to assess frailty and sarcopenia in patients with spinal disorder, and the relationships between frailty, sarcopenia, and postoperative outcomes in patients undergoing complex spine surgery. Recent findings Complex spine surgery is associated with a high rate of adverse events when using a validated, prospective data collection system. Recent studies have demonstrated that patients with spine surgery with frailty and sarcopenia have a higher risk of adverse events, although this relationship varies depending on the measurement tool and specific population studied. Both general and specific frailty assessment tools have been used in the spine surgery population, however the optimal tool is not known. Spinal disorders such as lumbar stenosis contribute to the frailty phenotype, and may be reversible with surgery. Summary Frailty and sarcopenia are increasingly recognized as important predictors of adverse outcomes after complex spine surgery. The optimal tool to measure frailty and sarcopenia in patients with spinal disorders remains unclear, and the role of surgery as an intervention to reverse frailty requires further investigation. Correspondence to Dr Alana M. Flexman, Department of Anesthesiology and Perioperative Care, Vancouver General Hospital, Room 2449 JPP 899 West 12th Avenue, Vancouver, BC, Canada, V5Z 1M9. Tel: +1 604 875 4304; fax: +1 604 875 5209; e-mail: alana.flexman@vch.ca Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Monitoring standards in sedation and analgesia: the odyssey of capnography in sedation for gastroenterology procedures Purpose of review Capnography is an excellent tool for early detection of hypoxemia and apnea in patients undergoing sedation for gastrointestinal endoscopy. The current American Society of Anesthesiology (ASA) guidelines recommend the use of capnography in any patient undergoing moderate sedation. The purpose of this review was to compile the most recent data available on capnography use in gastrointestinal endoscopy with the focus primarily on the use of capnography in moderate sedation cases. Recent findings Recent high-quality studies have evaluated the utility of capnography in low risk patients undergoing moderate sedation and have found no benefit with addition of capnography. Summary Capnography is beneficial when used for patients who are at a higher risk for sedation-related complications. There is no benefit when capnography is used in low risk patients undergoing routine upper endoscopy and colonoscopy under moderate sedation but there is benefit when used in advanced endoscopic procedures that require deeper sedation and have longer procedure times. Correspondence to John J. Vargo, MD, MPH, Director, Endoscopy Operations Enterprise, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel: +1 216 445 5012; e-mail: vargoj@ccf.org Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Safety in the nonoperating room anesthesia suite is not an accident: lessons from the National Transportation Safety Board Purpose of review To review the findings of National Transportation Safety Board-related airline near misses and catastrophes and apply these principles to the nonoperating room anesthesia (NORA) suite. Recent findings NORA is a specialty that has seen tremendous growth. In 2019, NORA contributes to a larger proportion of anesthesia practice than ever before. With this growth, the NORA anesthesiologist and team are challenged to provide safe, high-quality care for more patients, often with complex comorbidities, and are forced to utilize deeper levels of sedation and anesthesia than ever before. These added pressures create new avenues for human error and adverse outcomes. Summary Safety in modern anesthesia practice often draws comparison to the aviation industry. From distinct preoperational checklists, defined courses of action, safety monitoring and the process of guiding individuals through a journey, there are many similarities between the practice of anesthesia and flying an airplane. Consistent human performance is paramount to creating safe outcomes. Although human errors are inevitable in any complex process, the goal for both the pilot and physician is to ensure the safety of their passengers and patients, respectively. As the airline industry has had proven success at managing human error with a dramatic improvement in safety, a deeper look at several key examples will allow for comparisons of how to implement these strategies to improve NORA safety. Correspondence to Jason D. Walls, MD, Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USA. Tel: +1 215 662 3773; e-mail: jason.walls@uphs.upenn.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Transfusion in adults and children undergoing neurosurgery: the outcome evidence Purpose of review Transfusion is a common practice during neurosurgery. However, there is no evidence-based consensus on transfusion practice in neurosurgery. This review summarizes the evidence pertinent to the commonly used transfusion triggers in neurosurgical patients. Recent findings In the field of neurosurgery, there is only one randomized controlled trial, performed in patients with traumatic brain injury, to investigate the transfusion trigger of red blood cells. There is a lack-of-quality evidence pertinent to the transfusion triggers of other blood products. Most of the transfusion triggers used for neurosurgical patients are extrapolated from the evidence based on studies performed in nonneurosurgical patients. Clinical experience and expert opinions have played a major role in transfusion practice in neurosurgery. Summary There is a scarcity of high-quality outcome-based evidence for transfusion practice in neurosurgery. In the absence of quality evidence, the transfusion practice in neurosurgical patients should be based on the understanding of the complex pathophysiology related to anemia and coagulopathy and the balance between the risks and benefits associated with blood product transfusion. The practice guided by tissue oximeter and viscoelastic tests appears promising, but needs to be validated by future studies. Correspondence to Tianlong Wang, MD, PhD, Department of Anesthesiology, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China. Tel: +86 139 1052 5304; e-mail: w_tl5595@hotmail.com Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

Do you remember 'supply and demand'? No abstract available

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Transplantation

An interdisciplinary approach to the older transplant patient: strategies for improving clinical outcomes Purpose of review Describe the latest investigations into the role of frailty and assessment of other aging-related issues in the solid organ transplant candidate and recipient. This information is relevant for all involved in the care of transplant patients, but is especially relevant in infectious diseases, given the increased burden of infection seen in older and frailer patients. Recent findings The Fried Frailty Phenotype (FFP) and Short Performance Physical Battery (SPPB) are well validated tools for measuring frailty in older adults. Recently, these frailty tools have also been used to predict a range of clinical outcomes in adults with endstage organ disease undergoing advanced therapies including mechanical circulatory device (MCSD) or transplantation including death on the waiting list, length of hospital stay, need for readmission, infection, and death. Frailty may also be estimated by chart review and comorbidity assessment. Other aging-related evaluations of interest are cognitive function, sarcopenia, and nutritional status. The strength of association for each tool varies by the type of end organ disease, although there are many findings in common across organ types. Summary As trends in the aging of the population continue to impact transplant and MCSD candidates and recipients, it is increasingly important for providers to be cognizant of the methods for assessment of aging-associated dysfunction including frailty and sarcopenia. Correspondence to Joanna Schaenman, Division of Infectious Diseases, Department of Medicine, David Geffen School of medicine at UCLA, CHS 37-121, Los Angeles, CA 90095, USA. Tel: +1 310 825 7225; e-mail: jschaenman@mednet.ucla.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Kidney transplantation across minor ABO incompatibility: the use of A: 2: to B transplants Purpose of review On 4 December 2014, the new kidney allocation system (KAS) went into effect. As part of this system, UNOS approved for the first time a national system with a specific mechanism affording priority to allocate kidneys across so-called 'minor ABO incompatibility' from blood group A2 donors into blood group B recipients. This significantly increased the number of such transplants done and the opportunities to learn about the specifics of such transplants. Recent findings A2 to B transplants have been demonstrated to be well tolerated, effective, and cost-effective ways of addressing disparities in the allocation system. Further data about the use of anti-A titers and the limits to successful transplant have better defined the bounds of who can benefit from such transplants. Summary The success thus far with A2 to B transplants should increase comfort and acceptance of the allocation policy changes and we should see further increases in centers willing to use such transplants to better address inequalities in the system. Correspondence to Alexander J. Gilbert, MD, 3800 Reservoir Road, NW, PHC Building, 2nd Floor, Washington DC 20007, USA. Tel: +1 202 444 0621; e-mail: Alexander.J.Gilbert@gunet.georgetown.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Machine perfusion in kidney transplantation Purpose of review The shortage of kidneys for transplantation has led to an urgent need to efficiently utilize the available cadaveric kidneys. Efficient use of machine perfusion may potentially lead to increased use of marginal kidneys by lowering the incidence of delayed graft function (DGF) and improving graft outcomes. Recent findings Machine perfusion has had a resurgence in the last 10–15 years over static cold storage (SCS). Hypothermic machine perfusion (HMP), the most commonly utilized type of machine perfusion reduces the rates of DGF when compared with SCS with a trend towards improving the overall graft survival. Summary Despite reduction in the rates of DGF by HMP, its effect on long-term renal and patient outcomes is not clearly known. There is limited clinical literature in the use of normothermic machine perfusion (NMP) but a few pilot studies have shown its potential to resuscitate commonly discarded kidneys. In addition to preservation, machine perfusion also allows for various diagnostic and therapeutic interventions during the preservation period to assess and optimize the viability of the procured kidney. Correspondence to Ashish Kataria, MD, Division of Nephrology, Department of Medicine, University at Buffalo, Buffalo, NY 14225, USA. Tel: +1 716 898 3337; e-mail: ashishka@buffalo.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Community-acquired respiratory viruses Purpose of review Community-acquired respiratory viruses (CARV) have been historically linked to upper respiratory tract infections; however, new data has emerged in recent years that has provided new insight into their role as causative pathogens for lower respiratory tract infections. We aim to discuss the importance of recognition of viruses both epidemiologically and clinically as causes of lower respiratory tract infection. Recent findings With advances of molecular testing it is now possible to identify viruses from clinical specimens which have many implications that range from therapeutics to antibiotic stewardship. Recent studies suggest that most of the cases of community-acquired pneumonia are caused by viruses, which corresponds to a paradigm shift for most clinicians. Summary As community-acquired lower respiratory infections are the most common cause of ICU admission in the USA, it is important for medical providers to be aware of the association with viruses, especially in patients with immunosuppression because of solid organ transplant and hematologic malignancies when sometimes diagnosis can be challenging and patients can be exposed to unnecessary antibiotics. Correspondence to Emily Blodget, MD, MPH, Division of Infectious Diseases, University of Southern California, Keck School of Medicine, 2020 Zonal Avenue, IRD Room 436, Los Angeles, CA 90033, USA. Tel.: +1 323 409 4444;. fax: +1 323 226 7726; e-mail: eblodget@med.usc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Innovations in kidney paired donation transplantation Purpose of review To analyze the innovations that have increased the reliability, convenience, and outcomes of kidney paired donation (KPD) that has led to thousands of living donor kidney transplants across the United States. Recent findings Over the past 10 years, KPD has grown over 200% on an annual basis. Though concerns had existed over cold ischemia time, research has shown that there is no correlation between travel time of a shipped kidney and the transplant outcome. The voucher program has started to continue to expand how to overcome obstacles to donation by solving the issue of a pair chronological incompatibility. Summary KPD is a relatively new field and the innovations it has spawned should continue to improve availability of high-quality living donor organs. The introduction of the family voucher should continue this trend. Correspondence to Thomas D'Alessandro, National Kidney Registry, 42 Fire Island Avenue, Babylon, NY 11702, USA. Tel: +1 631 560 7887; fax: +1 800 401 8919; e-mail: TDAlessandro@kidneyregistry.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Coccidioidomycosis in solid organ transplant recipients Purpose of review The purpose of the review is an update of diagnosis and treatment of coccidioidomycosis infection in solid organ transplant (SOT) patients. Endemic fungal infections continue to be a cause of serious morbidity and mortality in transplant recipients. Recent findings In transplant patients there are recommendations regarding screening in areas that are endemic for coccidioidomycosis. This screening involves serologic testing and chest imaging. In endemic areas pretransplant seropositivity varies from 1.4 to 5.6%. In immunocompromised patients with elevated complement fixation titers, evaluation of cerebrospinal fluid is recommended even in the absence of symptoms. Although coccidioidomycosis can be a self-limited disease in immunocompotent patients, all SOT patients should be treated regardless of severity. This may include intravenous amphotericin B in severe cases and fluconazole therapy in milder episodes. In those SOT recipients with evidence of prior coccidioidomycosis, lifelong secondary prophylaxis with fluconazole given risk of recurrent disease. Summary Coccidioidomycosis continues to be a cause of serious morbidity and mortality in transplant recipients but with proper screening and treatment can be successfully managed. Correspondence to Emily Blodget, MD, Division of Infectious Disease, Keck School of Medicine of University of Southern California, 2020 Zonal Avenue, Room 436, Los Angeles, CA 90033, USA. Tel: +1 323 409 4444; e-mail: eblodget@med.usc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Carbapenemase-producing organisms in solid organ transplantation Purpose of review Carbapenem-resistant enterobacteriaceae (CRE) are a critical healthcare threat. Infections caused by CRE disproportionately affect transplant patients. Retrospective case studies suggest that up to 10% of transplant recipients develop a CRE infection. The current literature is reviewed with a particular focus on transplant-specific implications. Recent findings There are specific risks inherent to transplant recipients that result in an elevated risk for CRE carriage and subsequent infection. Additionally, the manifestations of these infections are dependent on the specific transplant type. The optimal treatment of CRE infections in transplant recipients has not been defined. Summary A reduction in the regional community CRE burden can lead to a secondary reduction in their occurrence within vulnerable transplant populations. Therefore, core principles of antibiotic stewardship and infection control within all levels of the healthcare system remains the most effective strategy for addressing the current health crisis. Simultaneously, an integrated approach to risk stratification and an approach to treatment is postulated for management of CRE infection within the solid-organ transplant population. Correspondence to Darren Wong, MD, Division of Infectious Diseases, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA. Tel: +1 323 409 4397; e-mail: darrenww@med.usc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Current state of organ transplant tolerance Purpose of review Immunological tolerance has long been considered the 'holy grail' of organ transplantation. Although tolerance has been an active area of research for 70 years, its clinical application has only been possible in the last two decades and widespread use remains an, as yet, unattained goal. Recent advances in the understanding of immune regulation have identified many new approaches to tolerance induction and several clinical trials are currently aimed at bringing this treatment to more patients. Recent findings Mixed chimerism remains the most successful approach to tolerance induction. However, many treatments, including adoptive transfer of regulatory T cells, regulatory B cells, and immune suppressive dendritic cells and myeloid derived suppressor cells have shown great promise in preclinical models. Recent clinical studies have found that both kidney and liver operational tolerance are achievable in the appropriate settings. Furthermore, combining multiple tolerance approaches has shown potential to produce durable and safer tolerance. Summary Tolerance to protect kidney and liver allografts has become a valuable therapy in the correct circumstances. Through further clinical trials and an improved understanding of immune regulatory components, tolerance is poised to have a significant impact on transplantation in the years to come. Correspondence to James F. Markmann, MD, PhD, Massachusetts General Hospital, 55 Fruit Street – White 507, Boston, MA 02114, USA. Tel: +1 617 643 4533; fax: +1 617 643 4579; e-mail: jmarkmann@partners.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Updates on antiviral drugs for cytomegalovirus prevention and treatment Purpose of review Cytomegalovirus (CMV) is the most common infection after organ transplant. In addition to causing a viral syndrome and infection, it also increases the risk for complications in the organ transplant, along with higher overall morbidity and mortality. Prevention and ideal treatment of CMV is paramount for optimal outcomes, both for individuals as well as for transplant programs. New guidelines and novel therapies are changing the way we manage disease. Recent findings Several new antiviral agents have emerged in recent times, including letermovir, maribavir, and brincidofovir, enhancing our ability to prevent and treat CMV. Recent data on novel agents will be reviewed, with an emphasis on recent guidelines and best practices. Summary Optimal treatment, influenced by recent advances in the field, including management of resistant virus, results in better outcomes with this significant and virulent virus. Correspondence to Camille N. Kotton, Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Cox 5th floor, Boston, MA 02114, USA. Tel: +1 617 724 0082 (Karen Manning, Administrative Assistant); fax: +1 617 726 7653; e-mail: ckotton@partners.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The past, present, and future of costimulation blockade in organ transplantation Purpose of review Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability to target various costimulation pathways continues to evolve. Recent findings Since the approval of belatacept in kidney transplantation, many additional biologics have been developed targeting clinically relevant costimulation signaling axes including CD40-CD40L, inducible costimulator-inducible costimulator ligand (ICOS-ICOSL), and OX40-OX40L. Currently, the effects of costimulation blockade on posttransplant humoral responses, tolerance induction, and xenotransplantation are under active investigation. Here, we will discuss these pathways as well as preclinical and clinical outcomes of biologics targeting these pathways in organ transplantation. Summary Targeting costimultion is a promising approach for not only controlling T cell but also B cell responses. Consequently, costimulation blockade shows considerable potential for improving outcomes in antibody-mediated rejection and xenotransplantation. Correspondence to Stuart J. Knechtle, MD, 330 Trent Drive, DUMC Box 3512, Durham, NC 27710, USA. Tel: +1 919 613 9687; fax: +1 919 684 8716; e-mail: stuart.knechtle@dm.duke.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Neurosurgical Anesthesiology

Patient-specific ICP Epidemiologic Thresholds in Adult Traumatic Brain Injury: A CENTER-TBI Validation Study Background: Patient-specific epidemiologic intracranial pressure (ICP) thresholds in adult traumatic brain injury (TBI) have emerged, using the relationship between pressure reactivity index (PRx) and ICP, displaying stronger association with outcome over existing guideline thresholds. The goal of this study was to explore this relationship in a multi-center cohort in order to confirm the previous finding. Methods: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit cohort, we derived individualized epidemiologic ICP thresholds for each patient using the relationship between PRx and ICP. Mean hourly dose of ICP was calculated for every patient for the following thresholds: 20, 22 mm Hg and the patient's individual ICP threshold. Univariate logistic regression models were created comparing mean hourly dose of ICP above thresholds to dichotomized outcome at 6 to 12 months, based on Glasgow Outcome Score—Extended (GOSE) (alive/dead—GOSE≥2/GOSE=1; favorable/unfavorable—GOSE 5 to 8/GOSE 1 to 4, respectively). Results: Individual thresholds were identified in 65.3% of patients (n=128), in keeping with previous results (23.0±11.8 mm Hg [interquartile range: 14.9 to 29.8 mm Hg]). Mean hourly dose of ICP above individual threshold provides superior discrimination (area under the receiver operating curve [AUC]=0.678, P=0.029) over mean hourly dose above 20 mm Hg (AUC=0.509, P=0.03) or above 22 mm Hg (AUC=0.492, P=0.035) on univariate analysis for alive/dead outcome at 6 to 12 months. The AUC for mean hourly dose above individual threshold trends to higher values for favorable/unfavorable outcome, but fails to reach statistical significance (AUC=0.610, P=0.060). This was maintained when controlling for baseline admission characteristics. Conclusions: Mean hourly dose of ICP above individual epidemiologic ICP threshold has stronger associations with mortality compared with the dose above Brain Trauma Foundation defined thresholds of 20 or 22 mm Hg, confirming prior findings. Further studies on patient-specific epidemiologic ICP thresholds are required. P.S. and M.C. are joint senior authors. The CENTER-TBI High Resolution Sub-Study Participants and Investigators: Anke Audny (Department of Physical Medicine and Rehabilitation, University Hospital Northern Norway), Beer Ronny (Department of Neurology, Neurological Intensive Care Unit, Medical University of Innsbruck, Innsbruck, Austria), Bellander Bo-Michael (Department of Neurosurgery & Anesthesia & Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden), Buki Andras (Department of Neurosurgery, University of Pecs and MTA-PTE Clinical Neuroscience MR Research Group and Janos Szentagothai Research Centre, University of Pecs, Hungarian Brain Research Program, Pecs, Hungary), Chevallard Giorgio (NeuroIntensive Care, Niguarda Hospital, Milan, Italy), Chieregato Arturo (NeuroIntensive Care, Niguarda Hospital, Milan, Italy), Citerio Giuseppe (NeuroIntensive Care Unit, Department of Anesthesia & Intensive Care, ASST di Monza, Monza, Italy, School of Medicine and Surgery, Università Milano Bicocca, Milano, Italy), Czeiter Endre (Department of Neurosurgery, University of Pecs and MTA-PTE Clinical Neuroscience MR Research Group and Janos Szentagothai Research Centre, University of Pecs, Hungarian Brain Research Program [Grant No. KTIA 13 NAP-A-II/8], Pecs, Hungary), Depreitere Bart (Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium), Eapen George✠ (Death), Frisvold Shirin (Department of Anesthesiology and Intensive care, University Hospital Northern Norway, Tromso, Norway), Helbok Raimund (Department of Neurology, Neurological Intensive Care Unit, Medical University of Innsbruck, Innsbruck, Austria), Jankowski Stefan (Neurointensive Care, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK), Kondziella Daniel (Departments of Neurology, Clinical Neurophysiology and Neuroanesthesiology, Region Hovedstaden Rigshospitalet, Copenhagen, Denmark), Koskinen Lars-Owe (Department of Clinical Neuroscience, Neurosurgery, Umea University Hospital, Umea, Sweden), Meyfroidt Geert (Intensive Care Medicine, University Hospitals Leuven, Leuven, Belgium), Moeller Kirsten (Department Neuroanesthesiology, Region Hovedstaden Rigshospitalet, Copenhagen, Denmark), Nelson David (Department of Neurosurgery & Anesthesia & Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden), Piippo-Karjalainen Anna (Helsinki University Central Hospital, Helsinki, Finland), Radoi Andreea (Department of Neurosurgery, Vall d'Hebron University Hospital, Barcelona, Spain), Ragauskas Arminas (Department of Neurosurgery, Kaunas University of technology and Vilnius University, Vilnius, Lithuania), Raj Rahul (Helsinki University Central Hospital, Helsinki, Finland), Rhodes Jonathan (Department of Anaesthesia, Critical Care & Pain Medicine NHS Lothian & University of Edinburg, Edinburgh, UK), Rocka Saulius (Department of Neurosurgery, Kaunas University of technology and Vilnius University, Vilnius, Lithuania), Rossaint Rolf (Department of Anaesthesiology, University Hospital of Aachen, Aachen, Germany), Sahuquillo Juan (Department of Neurosurgery, Vall d'Hebron University Hospital, Barcelona, Spain), Sakowitz Oliver (Klinik für Neurochirurgie, Klinikum Ludwigsburg, Ludwigsburg, Germany, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany), Stevanovic Ana (Department of Anaesthesiology, University Hospital of Aachen, Aachen, Germany), Sundström Nina (Department of Radiation Sciences, Biomedical Engineering, Umea University Hospital, Umea, Sweden), Takala Riikka (Perioperative Services, Intensive Care Medicine, and Pain Management, Turku University Central Hospital and University of Turku, Turku, Finland), Tamosuitis Tomas (Neuro-intensive Care Unit, Kaunas University of Health Sciences, Kaunas, Lithuania), Tenovuo Olli (Rehabilitation and Brain Trauma, Turku University Central Hospital and University of Turku, Turku, Finland), Vajkoczy Peter (Neurologie, Neurochirurgie und Psychiatrie, Charité—Universitätsmedizin Berlin, Berlin, Germany), Vargiolu Alessia (NeuroIntensive Care Unit, Department of Anesthesia & Intensive Care, ASST di Monza, Monza, Italy), Vilcinis Rimantas (Department of Neurosurgery, Kaunas University of Health Sciences, Kaunas, Lithuania), Wolf Stefan (Interdisciplinary Neuro Intensive Care Unit, Charité—Universitätsmedizin Berlin, Berlin, Germany), Younsi Alexander (Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany). Data used in preparation of this manuscript were obtained in the context of CENTER-TBI, a large collaborative project with the support of the European Union 7th Framework program (EC grant 602150). Additional funding was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind and from Integra LifeSciences Corporation. D.K.M. was also supported by funding from the National Institute for Health Research (NIHR, UK) through a Senior Investigator award and the Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. The study also received additional support from the NIHR Clinical Research network. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care, UK. F.A.Z. is supported by the University of Manitoba Thorlakson Chair for Surgical Research Establishment Grant, University of Manitoba VPRI Research Investment Fund (RIF), Winnipeg Health Sciences Centre (HSC) Foundation, and the University of Manitoba Rudy Falk Clinician-Scientist Professorship. P.S. and M.C. receive part of licensing fees for the software ICM+ (Cambridge Enterprise Ltd, UK) used for data collection and analysis in this study. The remaining authors have no conflicts of interest to disclose. Address correspondence to: Frederick A. Zeiler, BSc, MD, PhD, FRCSC (Neurosurgery), E-mail: umzeiler@myumanitoba.ca. Received January 14, 2019 Accepted April 25, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Journal Club No abstract available

Real-Time Monitoring of Cerebral Blood Flow and Cerebral Oxygenation During Rapid Ventricular Pacing in Neurovascular Surgery: A Pilot Study Background: Rapid ventricular pacing (RVP) can be used to produce short periods of flow arrest during dissection or rupture of a cerebral aneurysm but carries the risk of inducing cerebral ischemia. This study evaluates the intraoperative effect of RVP on local cerebral blood flow (CBF) and cerebral oxygenation during neurovascular surgery. Materials and Methods: Five patients undergoing elective cerebrovascular surgery were included in a single-center prospective study. RVP was applied in pacing periods of 40 seconds with 30% and 100% FiO2. Regional cerebral oxygenation was monitored using a Foresight near-infrared spectroscopy sensor. A Clark-type electrode and a thermal diffusion microprobe located in the white matter were used to monitor brain tissue pO2 and CBF, respectively. Results: CBF response to RVP closely followed the blood pressure pattern and resulted in a low-flow state. Unlike CBF, brain tissue pO2 and regional cerebral oxygenation showed a delayed response to RVP, decreasing beyond the pacing period and slowly recovering after RVP cessation. We found a correlation between brain tissue pO2 and regional cerebral oxygenation. Increasing the inspired oxygen concentration had a positive impact on absolute regional cerebral oxygenation and brain tissue pO2 values, but the pattern resulting from applying RVP remained unaltered. Conclusions: RVP reduces CBF and cerebral oxygenation. Brain tissue pO2 and regional cerebral oxygenation are correlated but unlike CBF respond to RVP in a delayed manner. Further research is required to evaluate the impact of longer RVP bursts on brain oxygenation. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Vera Saldien, MD. E-mail: vera.saldien@uza.be. Received January 29, 2019 Accepted May 1, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Effective Cerebral Perfusion Pressure: Does the Estimation Method Make a Difference? Introduction: The effective cerebral perfusion pressure (CPPe), zero-flow pressure (ZFP), and resistance area product (RAP) are important determinants of cerebral blood flow. ZFP and RAP are usually estimated by linear regression analysis of pressure-velocity relationships of the middle cerebral artery. The aim of this study was to validate 4 other estimation methods against the standard linear regression method. Methods: In a previous study, electroencephalography, arterial blood pressure, and middle cerebral artery flow velocity were measured in patients during internal cardioverter defibrillator implantation procedures to determine the electroencephalography frequency ranges that represent ischemic changes during periods of circulatory arrest. In this secondary analysis, arterial blood pressure and middle cerebral artery flow velocity were used to estimate CPPe, ZFP, and RAP by 4 different methods—the 3-point intercept calculation (LR3, systolic/mean/diastolic) and methods described by Czosnyka (systolic/diastolic), Belford (mean/diastolic), and Schmidt (systolic/diastolic)—and compare them with the reference linear regression method. CPPe was calculated as the difference between mean arterial pressure and ZFP. The primary endpoint was the difference, correlation, and agreement of these differently estimated CPPe measurements. Results: In total, 174 measurements in 35 patients were collected under steady-state conditions before the first circulatory arrest phase during internal cardioverter defibrillator testing. CPPe, ZFP, and RAP measurements based on the 3-point intercept and Czosnyka calculation methods showed small mean differences, good agreement, low percentage errors, and excellent correlation when compared with the reference method. Agreement and correlation were moderate for the Belford method and unsatisfactory for the Schmidt method. Conclusions: CPPe, ZFP, and RAP measurements based on 2 alternative calculation methods are comparable to the linear regression reference method. The primary analysis was supported by The Netherlands Heart Foundation (grant no. 93.149) (Visser et al, 2001). In the secondary analysis, support was provided solely from institutional and/or departmental sources. Work is attributed to: Erasmus MC, Rotterdam, NL. The authors acknowledge that the enclosed manuscript is part of a larger series of prospective studies about cerebral circulation and cerebral metabolism in the perioperative setting. In 56 patients during internal cardioverter defibrillator (ICD) device testing under general anesthesia, we determined 4 main EEG frequency ranges that represent ischemic changes during short periods of circulatory arrest. These former results have been published (Visser et al, 2001). Medical Ethical Research Committee Utrecht. Trial: Cerebral effects of repeated periods of circulatory arrest by induced ventricular fibrillation during ICD implantation (Cerebrale effecten van herhaalde perioden van circulatiestilstand door geïnduceerd kamerfibrilleren tijdens ICD implantatie), Nr.:92/59. The trial was planned and done before CONSORT 2010. Dutch laws did not require international registration of this type of clinical trial at that time. The Netherlands Trial register does not accept closed studies (www.trialregister.nl). A registration at "clinical trials" was not possible, too (www.clinicaltrials.gov). Here, the completion date of our study was before December 26, 2007, which is an exclusion criterion following the FDAAA 801 note (https://clinicaltrials.gov/ct2/manage-recs/fdaaa). The authors have no conflicts of interest to disclose. Address correspondence to: Frank Grüne, MD, E-mail: f.grune@erasmusmc.nl. Received March 31, 2018 Accepted April 18, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Optimizing Design for the Way Clinicians Use Critical Event Cognitive Aids No abstract available

The Effect of Depth of Anesthesia on Hemodynamic Changes Induced by Therapeutic Compression of the Trigeminal Ganglion Background: Percutaneous compression of the trigeminal ganglion (PCTG) has been used to treat trigeminal neuralgia since 1983. A PCTG-related trigeminocardiac reflex (TCR) can induce dramatic hemodynamic disturbances. This study investigates the effects of depth of propofol anesthesia on hemodynamic changes during PCTG. Materials and Methods: A total of 120 patients who underwent PTCG for trigeminal neuralgia were randomly assigned to control group-intravenous saline pretreatment before PCTG puncture and anesthesia targeted to bispectral index (BIS) 40 to 60 throughout, and study group-intravenous propofol 1 to 2 mg/kg pretreatment to deepen anesthesia to BIS<40 before PCTG. Mean arterial pressure, heart rate (HR), cardiac output, system vascular resistance, and BIS were measured at 9 time points during the procedure, and the incidence of the TCR was observed at T5 and T6. Results: BIS was lower in the study group compared with the control after pretreatment with propofol or saline, respectively. Compared with the control group, mean arterial pressure was lower in the study group at several points during the procedure, but there was no difference in HR between the 2 groups at any point. Cardiac output was higher and system vascular resistance lower in the study compared with the control group. In the control group, 42 (70.0%) and 52 (86.7%) of patients developed a TCR at the 2 points, and 37 (67.1%) and 45 (75.0%) in the study group. There was no difference in the incidence of TCR between the 2 groups. Conclusion: Increasing the depth of propofol anesthesia partially attenuated PTCG-related elevation of blood pressure but did not modify the abrupt reduction in HR. This work was funded by the Liaoning Natural Science Foundation of China (no. 20170540524) and the National Nature Science Foundation of China (no. 81671311 and no. 81870838), the Key Research and Development Program of Liaoning Province (no. 2018225004), and the Outstanding Scientific Fund of Shengjing Hospital (no. 201708). Supported by the Department of Anaesthesiology, Second Department of Neurosurgery, People's Hospital of China Medical University (Liaoning Provincial People's Hospital), and the Department of Anaesthesiology, Shengjing Hospital of China Medical University, P.R. China. C.-M.W.: wrote the manuscript. Z.-Y.G. and Q.-C.W.: were responsible for data statistics. All operations were performed by Y.M. J.Z., and P.Z. intensively supervised the work and substantially helped in the writing process. All authors read and approved the final manuscript. The authors have no conflicts of interest to disclose. Address correspondence to: Ping Zhao, MD, E-mail: zhaopingdoctor@yeah.net. Received January 9, 2019 Accepted April 10, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Defining a Taxonomy of Intracranial Hypertension: Is ICP More Than Just a Number? Intracranial pressure (ICP) monitoring and control is a cornerstone of neuroanesthesia and neurocritical care. However, because elevated ICP can be due to multiple pathophysiological processes, its interpretation is not straightforward. We propose a formal taxonomy of intracranial hypertension, which defines ICP elevations into 3 major pathophysiological subsets: increased cerebral blood volume, masses and edema, and hydrocephalus. (1) Increased cerebral blood volume increases ICP and arises secondary to arterial or venous hypervolemia. Arterial hypervolemia is produced by autoregulated or dysregulated vasodilation, both of which are importantly and disparately affected by systemic blood pressure. Dysregulated vasodilation tends to be worsened by arterial hypertension. In contrast, autoregulated vasodilation contributes to intracranial hypertension during decreases in cerebral perfusion pressure that occur within the normal range of cerebral autoregulation. Venous hypervolemia is produced by Starling resistor outflow obstruction, venous occlusion, and very high extracranial venous pressure. Starling resistor outflow obstruction tends to arise when cerebrospinal fluid pressure causes venous compression to thus increase tissue pressure and worsen tissue edema (and ICP elevation), producing a positive feedback ICP cycle. (2) Masses and edema are conditions that increase brain tissue volume and ICP, causing both vascular compression and decrease in cerebral perfusion pressure leading to oligemia. Brain edema is either vasogenic or cytotoxic, each with disparate causes and often linked to cerebral blood flow or blood volume abnormalities. Masses may arise from hematoma or neoplasia. (3) Hydrocephalus can also increase ICP, and is either communicating or noncommunicating. Further research is warranted to ascertain whether ICP therapy should be tailored to these physiological subsets of intracranial hypertension. Supported by Department of Health and Human Services, National Institutes of Health, and National Institute of Neurological Disorders and Stroke, 1R01NS082309-01A1. W.A.K.: funded by 1R01NS082309-01A1. Legal consultant; multiple legal and health care entities. Royalty payments Oxford University Press and Elsevier. Honoraria NIH study sections. Editorial Board Neurocritical Care. Editorial Board J Neurosurg Anesth. Coauthor on provisional patent number 17-8261/103241.000816 Trustees of the University of Pennsylvania. R.B.: funded by 1R01NS082309-01A1. Coauthor on provisional patent number 17-8261/103241.000816 Trustees of the University of Pennsylvania. The remaining authors have no conflicts of interest to disclose. Address correspondence to: W. Andrew Kofke, MD, MBA. E-mail: kofkea@uphs.upenn.edu. Received November 26, 2018 Accepted April 14, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Subanesthetic Dose of Ketamine Improved CFA-induced Inflammatory Pain and Depression-like Behaviors Via Caveolin-1 in Mice Background: Ketamine, a commonly used nonbarbiturate anesthetic drug, possesses antidepressant properties at subanesthetic doses; however, the underlying mechanisms remain unclear. Materials and Methods: The analgesic and antidepressant effects of ketamine were explored using a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model in vivo. Mice were first divided into sham or CFA injection group randomly, and were observed for mechanical hyperalgesia, depression-like behavior, and mRNA expression of caveolin-1. Then ketamine was administered in CFA-treated mice at day 7. Results: The behavioral testing results revealed mechanical hyperalgesia and depression in mice from days 7 to 21 after CFA injection. Ketamine reversed depression-like behaviors induced by CFA injection. It also restored the brain-regional expression levels of caveolin-1 in CFA-treated mice. In addition, caveolin-1 mRNA and protein expression were increased in the prefrontal cortex and nucleus accumbens of CFA-treated mice. However, ketamine reversed the increase in caveolin-1 expression in the ipsilateral and contralateral prefrontal cortex and nucleus accumbens, supporting the distinct roles of specific brain regions in the regulation of pain and depression-like behaviors. Conclusions: In CFA-treated mice that exhibited pain behavior and depression-like behavior, ketamine reversed depression-like behavior. The prefrontal cortex and nucleus accumbens are the important brain regions in this regulation network. Despite these findings, other molecules and their mechanisms in the signal pathway, as well as other regions of the brain in the pain matrix, require further exploration. J.L. and R.H. contributed equally to this work. J.W. and Q.Z. are co-first authors. This work was funded by the Beijing Municipal Administration of Hospitals' Ascent Plan (code number DFL20180502) and Clinical Medicine Development of Special Funding Support (code number ZYLX201708). R.H. is a member of the Editorial Board of the Journal of Neurosurgical Anethesiology. The authors have no conflicts of interest to disclose. Address correspondence to: Ruquan Han, MD, PhD. E-mail: ruquan.han@ccmu.edu.cn. Received November 21, 2018 Accepted April 8, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Remifentanil Patient-controlled Analgesia in Awake Craniotomy: An Introduction of an Innovative Technique No abstract available

Effect of Daytime Versus Night-Time on Outcome in Patients Undergoing Emergent Neurosurgical Procedures Background: Timing of neurosurgical procedures is controversial. Challenges identified with night-time surgeries include physician fatigue and sleep deprivation, and fewer staff and resources compared with daytime surgery. These might contribute to medical errors and complications, and, hence, worse patient outcomes. Methods: This single center retrospective study of 304 patients who underwent emergent neurosurgical procedures between January 1, 2010 and December 31, 2016 included 2 groups based on the timing of surgery: daytime (7:00 AM to 6:59 PM) and night-time (7:00 PM to 6:59 AM) surgery groups. Patient demographics, diagnosis, surgical characteristics, complications, and neurological outcome were obtained from the medical records. Results: There was no difference in patient demographics, intraoperative complications, and length of surgery between the 2 groups. Although there was no statistically significant difference in neurological outcome between the 2 groups at hospital discharge and 1 month postdischarge, there was a higher proportion of patients in the night-time surgical group with unfavorable neurological outcome (Glasgow Outcome Score 1 to 3) at both these times. There were differences in hospital length of stay, location of postoperative management (postanesthesia care unit or intensive care unit), midline shift, baseline Glasgow Coma Scale score, and acuity of surgery between the 2 groups. Logistic regression analysis showed that age, baseline Glasgow Coma Scale score, surgery acuity status, procedure type, and intraoperative complications influenced neurological outcome. Conclusions: This study found no difference in the rate of unfavorable neurological outcome in patients undergoing emergent neurosurgical procedures during the daytime and night-time. However, our findings cannot exclude the possibility of an association between timing of surgery and outcome given its limitations, including small sample size and omission of potentially confounding variables. Further well-designed prospective trials are warranted to confirm our findings. This study is a part of Bachelor of Science (Medicine) project thesis of A.H.Q., and he received a stipend from the University of Manitoba to conduct this research project. This project is funded by Anesthesia Oversight Committee, Department of Anesthesiology, Perioperative and Pain Medicine, University of Manitoba, Winnipeg, Canada. T.C. (primary supervisor) received the above-mentioned grant. Support was provided solely from institutional and/or departmental sources. Presented at: Neuroanesthesia Rounds, August 15, 2018, University of Manitoba; Bachelor of Science (Medicine) Research Symposium, August 23, 2018, University of Manitoba. The authors have no conflicts of interest to disclose. Address correspondence to: Tumul Chowdhury, MD, DM, FRCPC. E-mail: tumul.chowdhury@umanitoba.ca. Received September 9, 2018 Accepted March 12, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Clinical Nuclear Medicine

Diverse Behavior in 18F-Fluorocholine PET/CT of Brain Tumors in Patients With Neurofibromatosis Type 1 Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that causes CNS tumors in around 20% of patients, being pilocytic astrocytomas (PA), and particularly optic pathway gliomas (OPG), the most common. We present three cases of NF1 patients referred for 18F-fluorocholine PET/CT because of suspected glioma in the setting of ongoing FUMEGA (Functional and Metabolic Glioma Analysis) trial. One case turned out to be a WHO grade I ganglioglioma; the second was a high grade glioma; and the last one (negative in PET) a probable low-grade glioma. Received for publication November 8, 2018; revision accepted April 14, 2019. No disclaimer. All the authors have participated in the writing and revision of this article and take public responsibility for its content. The present publication is approved by all authors and by the responsible authorities where the work was carried out. All the authors confirm the fact that the article is not under consideration for publication elsewhere. Compliance with Ethical Standards. Conflicts of interest and sources of funding: none declared. Research involving Human Participants and/or Animals: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study. Correspondence to: Francisco José Pena Pardo, MD, Nuclear Medicine Department, University General Hospital, C/ Obispo Rafael Torija s/n. 13005, Ciudad Real, Spain. E-mail: fjpena@msn.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Asymptomatic Bone Marrow Edema Detected by 67Ga Scintigraphy A 46-year-old woman presented with a complaint of fever. CRP was 2.1 mL/L in blood, white blood cell count was 20–29/hpf, and bacterial count was 3418/μL in a urinalysis. 67Ga scan revealed accumulation of 67Ga in the left distal femur, although she had no symptoms around the site. MRI demonstrated diffuse high signal intensity on T2-weighted STIR images. Osteomyelitis was suspected, and biopsy was performed. Bacterial culture of the bone marrow was negative, and histological examination showed no infiltration of inflammatory cells. Two months after the biopsy, disappearance of altered signal intensity of MRI was observed. Received for publication February 15, 2019; revision accepted April 27, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Shinji Miwa, MD, PhD, Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan. E-mail: smiwa001@yahoo.co.jp. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Multifocal Small Bowel Carcinoid: Evaluation by 68Ga-DOTATATE PET: Erratum No abstract available

Thyroid Cancer Bone Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort Purpose Bone metastasis (BM) in differentiated thyroid cancer (DTC) is the second most common site of metastasis after lung. Bone metastases are associated with worse prognosis in DTC. In this study, we examined risk factors for overall survival in patients with BM and for the first time explore the pattern of genomic alterations in DTC BM. Patients and Methods A Health Insurance Portability and Accountability Act (HIPAA) compliant, institutional review board–approved retrospective evaluation of the medical record was performed for all patients treated at a single institution for thyroid cancer over a 16-year period. Seventy-four patients met inclusion criteria. Multiple prognostic factors including age, sex, genes, radioactive iodine, and radiation or kinase inhibitor therapies were analyzed. Univariate and multivariate analyses were performed. Results Treatment with external beam radiation was found to significantly increase survival (P = 0.03). The 5-year survival rate was 59% and median survival was 92 months. Patients who developed bone metastasis earlier tend to live longer (P = 0.06). The presence of TERT and BRAF mutations did not significantly worsen the prognosis (P = 0.10). Conclusion Patients with DTC can benefit from early treatment with external beam radiation therapy, especially those who develop bone metastasis within 3 years of primary TC diagnosis. Kinase inhibitor treatment tended to prolong survival but not in a statistically significant manner. Sex, age, and TERT or BRAF genetic mutations did not significantly affect the prognosis. Received for publication October 26, 2018; revision accepted March 30, 2019. Conflicts of interest and sources of funding: This study was supported by R01 CA201250-01A1 "124I-NaI PET: Building block for precision medicine in metastatic thyroid cancer" Grant (JRO, RKG, SML) as well as by the Center for Targeted Radioimmunotherapy and Diagnosis and the Ludwig Center for Cancer Immunotherapy. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. None declared to all authors. Correspondence to: Joseph R. Osborne, MD, PhD, Chief of Nuclear Medicine Department of Radiology New York—Presbyterian Weill Cornell Medical Center 520 E 70th Street, Starr-2, New York, NY 10021. E-mail: jro7001@med.cornell.edu. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Comparison of 11C-Choline and 11C-Methionine PET/CT in Multiple Myeloma Purpose PET/CT with both 11C-choline and 11C-methionine has recently been reported to offer advantages over 18F-FDG for imaging in multiple myeloma (MM). The aim of this study was to directly compare the diagnostic performance of both non-FDG radiotracers in MM patients. Methods Nineteen patients with a history of MM (n = 18) or solitary bone plasmacytoma (n = 1) underwent both 11C-choline and 11C-methionine PET/CT for diagnostic imaging. In this retrospective analysis, scans were compared on a patient and on a lesion basis. In 12 patients, respective tracer uptake in the iliac crest was correlated with the extent of malignant bone marrow plasma cell infiltration. Results 11C-methionine detected more intramedullary MM lesions in 8 (42.1%) of 19 patients. In the remainder (11/19 [57.9%]), both 11C-choline and 11C-methionine provided equal results. 11C-methionine demonstrated higher lesion-to-muscle ratios (P = 0.0001). In the 12 patients in whom a recent bone marrow biopsy was available, SUVmean as well as SUVmax correlated significantly with the degree of malignant plasma cell infiltration for both 11C-methionine (SUVmean: r = 0.85, P < 0.001; SUVmax: r = 0.82, P = 0.001) and 11C-choline (SUVmean: r = 0.72, P < 0.008; SUVmax: r = 0.73; P = 0.006). Conclusions Our data suggest that 11C-methionine PET/CT might be more sensitive than 11C-choline PET/CT for the detection of active MM lesions. Received for publication January 23, 2019; revision accepted April 11, 2019. C.L. and M.K. contributed equally to this work. Author Contributions: Conception and design: C.L., M.K., L.R., H.H. Development of methodology: C.L., M.D.V., M.S., K.M.K., H.H., S.S. Acquisition of data: C.L., M.K., M.D.V., M.S., L.R., K.M.K. Analysis and interpretation of data: C.L., M.K., M.D.V., M.S., L.R., K.M.K., H.H. Writing, review and/or revision of the manuscript: all authors. Administrative, technical, or material support: HE, A.K.B., H.H., S.S. Supervision: H.E., A.K.B., HH, S.S. All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. This work was supported by Wilhelm-Sander-Stiftung (grant 2017.061.1). Conflicts of interest and sources of funding: none declared. Correspondence to: Constantin Lapa, MD, Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Strasse 6, D-97080 Würzburg, Germany. E-mail: lapa_c@ukw.de. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.nuclearmed.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

18F-Fluciclovine PET/CT in Suspected Residual or Recurrent High-Grade Glioma Purpose To retrospectively investigate the uptake of 18F-fluciclovine on PET/CT in patients with suspected recurrent high-grade glioma (HGG). Methods Twenty-one patients were included. The standard of truth was histopathologic interpretation if available. When histopathology was not available or rebiopsy did not show signs of malignancy, clinical follow-up including MRI and clinical outcome was considered the standard of truth. Results All 21 patients met the reference standard of either histopathologic proof of HGG recurrence (n = 10) or disease progression clinically and with tumor growth corresponding to the primary tumor sites on follow-up MRI (n = 11). Median time from PET/CT to death was 5 months (range, 1–20 months). Median time from primary diagnosis to death was 14.5 months (range, 6 to >400). Average SUVmax of the lesions was 8.3 ± 5.3 (SD) and 0.34 ± 0.13 for normal brain tissue. Median lesion-to-background ratio was 21.6 (range, 3.1–84.4). In 4 patients, 18F-fluciclovine PET/CT detected small satellite tumors that had not been reported on MR. Conclusions The uptake of 18F-fluciclovine in clinically and/or histopathologically confirmed recurrent HGG is high compared with the uptake reported for other amino acid PET tracers. Because of the high tumor uptake and thus high tracer contrast, small satellite tumors with a diameter below usual reported PET spatial resolution and not reported on MRI were detected in 4 patients. As no patients with confirmed treatment-related changes were included, we cannot as of yet ascertain the ability of 18F-fluciclovine PET to discriminate between recurrent HGG and treatment-related changes, for example, pseudoprogression and radionecrosis. Received for publication September 7, 2018; revision accepted April 11, 2019. Conflicts of interest and sources of funding: Blue Earth Diagnostics Ltd, marketer of 18F-fluciclovine (Axumin), has supported research funding to Oslo University Hospital, Oslo, Norway, for clinical studies using 18F-fluciclovine PET/CT in prostate cancer performed by the authors T.V.B. and T.B.-G. T.B.-G. has received honorarium from Blue Earth Diagnostics Ltd for giving user training lectures on 18F-fluciclovine in prostate cancer in June and November 2018. No financial support has been received for this retrospective registry study. Concerning this study, there is nothing to disclose for any of the authors. Correspondence to: Trond V. Bogsrud, MD, PhD, University Hospital of North Norway, Sykehusvegen 38, 9019 Tromsø, Norway. E-mail: Trond.Bogsrud@unn.no. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Interlesional Heterogeneity of Metastatic Neuroendocrine Tumors Based on 18F-DOPA PET/CT Purpose Neuroendocrine tumors (NETs) can produce neuroendocrine amines resulting in symptoms. Selecting the most active amine-producing tumor lesions for local treatment might be beneficial for patients with metastatic small intestinal NET. Tumor burden correlates with catecholamine pathway activity. We analyzed interlesional heterogeneity with 18F-DOPA PET scans in patients with small intestinal NET and investigated if lesions with substantially higher 18F-DOPA uptake could be identified. Methods In this retrospective, observational study, the 18F-DOPA uptake was calculated by dividing SUVpeak of the lesion by the SUVmean of the background organ. The magnitude of heterogeneity between lesions within a patient was calculated by dividing the lesion with the highest by the one with the lowest 18F-DOPA uptake. Lesions with a higher 18F-DOPA uptake than the upper inner or outer fence (>1.5 or 3 times the interquartile range above the third quartile) were defined as lesions with mild or extreme high 18F-DOPA uptake, respectively, and presence of these was determined in patients with 10 lesions or more. Results 18F-DOPA was detected over 680 lesions in 38 patients, of which 35 were serotonin producing. 18F-DOPA uptake varied with a median of 8-fold up to 44-fold between lesions within a patient. In 12 of 20 evaluable patients, lesions with mild high 18F-DOPA uptake were found, and in 5, lesions with extreme high 18F-DOPA uptake. Conclusions 18F-DOPA-PET showed considerable heterogeneity in 18F-DOPA uptake between tumor lesions and identified lesions within patients with mild or extreme high 18F-DOPA uptake. Received for publication October 26, 2018; revision accepted April 11, 2019. Aline M. van der Loo–van der Schaaf is now with the Medical Center Zuiderzee, Lelystad, the Netherlands. Conflicts of interest and sources of funding: none declared. Correspondence to: Annemiek M. E. Walenkamp, MD, PhD, Department of Medical Oncology, University of Groningen, University Medical Center Groningen, DA11 PO Box 30.001, 9700 RB Groningen, the Netherlands. E-mail: a.walenkamp@umcg.nl. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.nuclearmed.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Rapid Decomposition of 99mTc-MAA Complex During Lung Perfusion Imaging A 30-year-old woman with a recent episode of dyspnea was presented. The lung perfusion scan using 99mTc-MAA (macro-aggregated albumin) initially revealed an acceptable lung-to-background activity ratio implying a proper radiopharmaceutical preparation and radiolabeling efficiency. Unexpectedly, later during the scan, rapidly increasing concentration of activity was observed in salivary glands, thyroid and stomach. Rapid breakdown of 99mTc-MAA complexes was considered as a likely explanation for the increase in the circulatory level of the free pertechnetate. Received for publication February 7, 2019; revision accepted April 22, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Mohsen Qutbi, Department of Nuclear Medicine, Taleghani Hospital, Yaman St., Velenjak, Tehran 1985711151, Iran. E-mail: mohsen.qutbi@gmail.com, mohsen.qutbi@sbmu.ac.ir. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Midgut NET With Orbital, Myocardial, Testicular, Lymph Nodal and Pulmonary Metastases Presenting With Bilateral Proptosis—Role of 68Ga-DOTANOC PET/CT Neuroendocrine tumors (NET) are rare neoplasms and commonly metastasize to liver, lymph nodes and less frequently to bones and lungs. Metastases to other organs are extremely rare and we report a case of NET clinically presenting with bilateral proptosis secondary to metastases in orbits. 68Ga-DOTANOC PET/CT demonstrated somatostatin receptor overexpressing lesions in bilateral orbits, small intestine, lymph nodes, lungs, heart and testes in the absence of liver metastases. Received for publication March 7, 2019; revision accepted April 13, 2019. Conflicts of interest and sources of funding: none declared. Correspondence to: Dr Raja Senthil, Department of Nuclear Medicine and PET/CT, VPS Lakeshore Hospital, Maradu, Nettoor (PO), Kochi, Kerala 682040, India. E-mail: senthilrajapgi@yahoo.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Efficacy of 177Lu Peptide Receptor Radionuclide Therapy for the Treatment of Neuroendocrine Tumors: A Meta-analysis Objective The purpose of this study was to assess the efficacy of 177Lu-labeled peptide receptor radionuclide therapy (PRRT) induction treatments for patients with unresectable metastatic neuroendocrine tumors. Methods MEDLINE, EMBASE, and Ovid were systematically searched with keywords "lutetium," "Lu-177," "PRRT," "neuroendocrine," and "prognosis." Studies evaluating treatment with 177Lu-labeled PRRT were assessed for disease response and/or disease control rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 or 1.1, modified RECIST, Southwest Oncology Group (SWOG), or modified SWOG criteria. Pooled proportions of disease response and control rates were calculated for both fixed- and random-effects models. Results Eighteen studies with 1920 patients were included (11 with 1268 patients using RECIST and 6 with 804 patients using SWOG). By RECIST criteria, the pooled disease response rate by random-effects model was 29.1% (95% confidence interval [CI], 20.2%–38.9%), and disease control rate was 74.1% (95% CI, 67.8%–80.0%). By SWOG criteria, the pooled disease response rate by random-effects model was 30.6% (95% CI, 20.7%–41.5%), and disease control rate was 81.1% (95% CI, 76.4%–85.4%). Conclusions Induction therapy, typically 4 treatments, with 177Lu PRRT is an effective method of treating unresectable metastatic neuroendocrine tumors with significant disease response and control rates. Received for publication March 19, 2019; revision accepted April 11, 2019. Conflicts of interest and sources of funding: T.P.W.M. is a paid consultant with Galapagos LLC and has received speaker fees from Novartis. The authors otherwise have none declared. Correspondence to: Todd P. W. McMullen, MD, PhD, Department of Surgery, University of Alberta Hospital, 8440-112 St NW, 2D4.41 Walter C. Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada T6G 2B7. E-mail: todd.mcmullen@ahs.ca. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
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