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
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