Anesthesia-induced Recognition Deficit is Improved in Postnatally Gonadectomized Male Rats Background: Preclinical investigations of the effects of general anesthesia on the young brain show differences in vulnerability of males and females to anesthetic exposure at different times during development. However, the mechanism underlying this sex difference is poorly understood. Perinatal testosterone is the primary determinant of sexual differentiation and likely plays an important role in defining the period of susceptibility to anesthetic injury. We investigated whether the removal of testosterone through gonadectomy shortly after birth would improve cognitive outcomes in male rodents after early anesthesia exposure. Methods: Male Sprague Dawley rats underwent gonadectomy at postnatal day 2 (P2), followed by exposure to 6 hours of isoflurane at P7. A control cohort of gonad-intact male littermates was simultaneously exposed. All rats were subjected to a series of object recognition and association tasks beginning at P42. Cell death in the thalamus and hippocampus was assessed in a separate cohort. Results: All groups performed similarly on the Novel Object Recognition task; however, the gonad-intact isoflurane group exhibited decreased performance in the more difficult tasks. This deficit was ameliorated in the gonadectomized group. Cell death was similar between both isoflurane-exposed groups, regardless of gonadectomy. Conclusions: The absence of testosterone does not block cell death after anesthesia in specific brain regions of interest; however, does provide some neuroprotection as evidenced by the improved cognitive test performance during adulthood. These findings suggest that testosterone may be mechanistically involved in the sex-specific effects of anesthetic injury on the developing brain by extending the vulnerable period in male rats. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Jeffrey W. Sall, MD, PhD. E-mail: Jeffrey.Sall@ucsf.edu. Received May 12, 2019 Accepted July 23, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Anesthesia and Cognitive Outcome in Elderly Patients: A Narrative Viewpoint Better ways to manage preoperative, intraoperative and postoperative care of surgical patients is the bailiwick of anesthesiologists. Although we care for patients of all ages, protecting the cognitive capacity of elderly patients more frequently requires procedures and practices that go beyond routine care for nonelderly adults. This narrative review will consider current understanding of the reasons that elderly patients need enhanced care, and recommendations for that care based on established and recent empirical research. In that latter regard, unless and until we are able to classify anesthetic neurotoxicity as a rare complication, the first-do-no-harm approach should: (1) add anesthesia to surgical intervention on the physiological cost side of the cost/benefit ratio when making decisions about whether and when to proceed with surgery; (2) minimize anesthetic depth and periods of electroencephalographic suppression; (3) limit the duration of continuous anesthesia whenever possible; (4) consider the possibility that regional anesthesia with deep sedation may be as neurotoxic as general anesthesia; and (5) when feasible, use regional anesthesia with light or no sedation. Details of previous presentation of the work (or part thereof): Some sections of this manuscript are similar to sections of American Society of Anesthesiologists (ASA) Refresher Course Lecture (RCL) Outlines for RCL’s that Dr. Cottrell has presented at ASA Annual Meetings over the past 30+ years. Those RCL Outlines have been distributed to attendees of ASA Annual Meetings as part of the fee for attending the meetings (formerly in print, subsequently digital only). They have also been made available to ASA members that do not attend Annual Meetings at a substantial cost at the ASA “store,” and to nonmembers at a substantially higher cost at the ASA “store.” For examples, see: www.asahq.org/shop-asa#sort=%40fsearchdate77238%20descending Under the original meaning of “publish”—to make written material available to the public—given the limited distribution and cost of ASA Refresher Course Lecture Outlines, we do not consider those Outlines to have been “published” in the conventional sense. That view is supported by the ASA’s stipulation that authors of RCL Outlines retain copyright of their material. The authors have no funding or conflicts of interest to disclose. Address correspondence to: John Hartung, PhD. E-mail: john.hartung@downstate.edu. Received February 5, 2019 Accepted July 30, 2019 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/ Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

A Retrospective Observational Study of the Neuroendocrine Stress Response in Patients Undergoing Endoscopic Transsphenoidal Surgery for Removal of Pituitary Adenomas: Total Intravenous Versus Balanced Anesthesia Background: Anesthetic technique affects the neuroendocrine stress response to surgery. In this retrospective study, we compared the neuroendocrine stress response in patients undergoing endoscopic transsphenoidal pituitary adenoma surgery (ETSPAS) with total intravenous anesthesia (TIVA) with propofol-remifentanil or balanced anesthesia (BAL) with sevoflurane-remifentanil. Materials and Methods: Eighty-nine patients undergoing ETSPAS were anesthetized with either propofol-remifentanil (TIVA group, n=62) or sevoflurane-remifentanil (BAL group, n=27). Data were retrospectively collected regarding preoperative and immediate postoperative serum levels of adrenocorticotropic hormone (ACTH) and cortisol (primary outcome measures), as well as other pituitary hormones and their target organ hormones (secondary outcome measures). Results: There were no significant differences in preoperative pituitary hormone levels between the 2 groups. The immediate postoperative ACTH (89.5 [62.1 to 162.6] vs. 256.0 [92.0 to 570.7] pg/mL; P<0.001) level was lower in the TIVA group than in the BAL group, whereas immediate postoperative cortisol levels were similar between the 2 groups. The immediate postoperative thyroid-stimulating hormone (1.85 [1.21 to 2.98] vs. 1.21 [0.44 to 1.71] μIU/mL; P=0.003), triiodothyronine (91.0 [82.0 to 103.0] vs. 69.1 [64.6 to 76.2] ng/dL; P<0.001), luteinizing hormone (2.2 [1.2 to 4.0] vs. 1.0 [0.5 to 2.3] mIU/mL; P=0.005), and prolactin (22.6±15.8 vs. 12.8±10.2 ng/mL; P=0.005) levels were higher in the TIVA group compared with the BAL group. In both groups, none of the patients who had sufficient preoperative ACTH without hydrocortisone supplementation (n=15) showed hypocortisolism in the immediate postoperative measurement. Conclusions: Compared with BAL, TIVA resulted in reduced release of ACTH and increased release of thyroid-stimulating hormone, triiodothyronine, luteinizing hormone, and prolactin in patients undergoing ETSPAS. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Hee-Pyoung Park, MD, PhD. E-mail: hppark@snu.ac.kr. Received April 18, 2019 Accepted July 16, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Intravenous Propofol Versus Volatile Anesthetics For Stroke Endovascular Thrombectomy Background: The choice of anesthetic technique for ischemic stroke patients undergoing endovascular thrombectomy is controversial. Intravenous propofol and volatile inhalational general anesthetic agents have differing effects on cerebral hemodynamics, which may affect ischemic brain tissue and clinical outcome. We compared outcomes in patients undergoing endovascular thrombectomy with general anesthesia who were treated with propofol or volatile agents. Methods: Consecutive endovascular thrombectomy patients treated using general anesthesia were identified from our prospective database. Baseline patient characteristics, anesthetic agent, and clinical outcomes were recorded. Functional independence at 3 months was defined as a modified Rankin Scale of 0 to 2. Results: There were 313 patients (182 [58.1%] men; mean±SD age, 64.7±15.9 y; 257 [82%] anterior circulation), of whom 254 (81%) received volatile inhalational (desflurane or sevoflurane), and 59 (19%) received intravenous propofol general anesthesia. Patients with propofol anesthesia had more ischemic heart disease, higher baseline National Institutes of Health Stroke Scale scores, more basilar artery occlusion, and were less likely to be treated with intravenous thrombolysis. Multivariable logistic regression analysis showed that propofol anesthesia was associated with improved functional independence at 3 months (odds ratio=2.65; 95% confidence interval, 1.14-6.22; P=0.03) and a nonsignificant trend toward reduced 3-month mortality (odds ratio=0.37; 95% CI, 0.12-1.10; P=0.07). Conclusion: In stroke patients undergoing endovascular thrombectomy treated using general anesthesia, there may be a differential effect between intravenous propofol and volatile inhalational agents. These results should be considered hypothesis-generating and be tested in future randomized controlled trials. Supported by the Neurological Foundation of New Zealand. An earlier version of this work was presented at the 5th European Stroke Organisation Conference, Milan, Italy; 2019. The authors have no conflicts of interest to disclose. Address correspondence to: P. Alan Barber, MBChB, PhD, FRACP. E-mail: a.barber@auckland.ac.nz. Received April 16, 2019 Accepted July 23, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Intraoperative-evoked Potential Monitoring: From Homemade to Automated Systems No abstract available

Cortical Oscillations and Connectivity During Postoperative Recovery Background: The objective of this study was to test whether postoperative electroencephalographic (EEG) biomarkers, parietal alpha power and frontal-parietal connectivity, were associated with measures of clinical recovery in adult surgical patients. Methods: This is a secondary analysis of a prospective cohort study that analyzed intraoperative connectivity patterns in adult surgical patients (N=53). Wireless, whole-scalp EEG data were collected in the postanesthesia care unit and assessed for relevance to clinical and neurocognitive recovery. Parietal alpha power and frontal-parietal connectivity (estimated by weighted phase lag index) were tested for associations with postanesthesia care unit discharge readiness and University of Michigan Sedation Scale scores upon postoperative admission. Bivariable correlation and regression models were constructed to test for unadjusted associations, then multivariable regression models were constructed to adjust for confounding. Results: Postoperative EEG patterns were characterized by a predominance of alpha parietal power and frontal-parietal connectivity. Neither relative parietal alpha power (% alpha, −0.25; 95% confidence interval [CI], −1.41 to 0.90; P=0.657) nor alpha frontal-parietal connectivity (weighted phase lag index, −82; 95% CI, −237 to 73; P=0.287) were associated with time until postanesthesia discharge criteria were met. Furthermore, neither alpha power (−0.03; 95% CI, −0.07 to 0.01; P=0.206) nor alpha frontal-parietal connectivity (−4.2; 95% CI, −11 to 2.6; P=0.226) were associated with sedation scores upon initial assessment. Conclusions: In a pragmatic study investigating clinically relevant endpoints of postoperative recovery, we found no correlation with surrogate measures of brain neurodynamics. These data contribute to the overall impetus of developing anesthetic-invariant and generalizable markers of brain recovery. Supported by the National Institutes of Health, Bethesda, MD, Grants R01GM098578 and K23GM126317 (P.E.V.). Previous presentations of the work: the authors previously published a separate, distinct line of analysis from these participants that focused on dynamic cortical connectivity patterns intraoperatively (Vlisides et al. Anesthesiology 2019;130(6):885–897). In addition, data from this investigation were presented in poster format at the 2019 University of Michigan School of Nursing Honors Symposium (September 4, 2019, Ann Arbor, MI). The authors have no conflicts of interest to disclose. Address correspondence to: Phillip E. Vlisides, MD. E-mail: pvliside@med.umich.edu. Received April 24, 2019 Accepted July 19, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Impact of a Perioperative Protocol on Length of ICU and Hospital Stay in Complex Spine Surgery Background: In an attempt to improve patient care, a perioperative complex spine surgery management protocol was developed through collaboration between spine surgeons and neuroanesthesiologists. The aim of this study was to investigate whether implementation of the protocol in 2015 decreased total hospital and intensive care unit (ICU) length of stay (LOS) and complication rates after elective complex spine surgery. Materials and Methods: A retrospective cohort study was conducted by review of the medical charts of patients who underwent elective complex spine surgery at an academic medical center between 2012 and 2017. Patients were divided into 2 groups based on the date of their spine surgery in relation to implementation of the spine surgery protocol; before-protocol (January 2012 to March 2015) and protocol (April 2015 to March 2017) groups. Outcomes in the 2 groups were compared, focusing on hospital and ICU LOS, and complication rates. Results: A total of 201 patients were included in the study; 107 and 94 in the before-protocol and protocol groups, respectively. Mean (SD) hospital LOS was 14.8±10.8 days in the before-protocol group compared with 10±10.7 days in the protocol group (P<0.001). The spine surgery protocol was the primary factor decreasing hospital LOS; incidence rate ratio 0.78 (P<0.001). Similarly, mean ICU LOS was lower in the protocol compared with before-protocol group (4.2±6.3 vs. 6.3±7.3 d, respectively; P=0.011). There were no significant differences in the rate of postoperative complications between the 2 groups (P=0.231). Conclusion: Implementation of a spine protocol reduced ICU and total hospital LOS stay in high-risk spine surgery patients. Study was presented under the name: “Protocolized Perioperative Care for Complex Spine Surgeries and the Resulting Reduction in ICU/Hospital Length of Stay” at: (1) American Society of Anesthesiologists (ASA) Annual Meeting in San Francisco, October 13, 2018 (Session EA-19-1). (2) SNACC Annual Meeting in San Francisco on October 12, 2018. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Eugenia Ayrian, MD. E-mails: eayrian@med.usc.edu; eugenia.ayrian@gmail.com. Received August 28, 2018 Accepted July 11, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Erector Spinae Plane Block For Postoperative Analgesia in Lumbar Spine Surgery: Is There a Better Option? No abstract available

Correlation Between Electroencephalography and Automated Pupillometry in Critically Ill Patients: A Pilot Study Background: Electroencephalography (EEG) is widely used in the monitoring of critically ill comatose patients, but its interpretation is not straightforward. The aim of this study was to evaluate whether there is a correlation between EEG background pattern/reactivity to stimuli and automated pupillometry in critically ill patients. Methods: Prospective assessment of pupillary changes to light stimulation was obtained using an automated pupillometry (NeuroLight Algiscan, ID-MED, Marseille, France) in 60 adult patients monitored with continuous EEG. The degree of encephalopathy and EEG reactivity were scored by 3 independent neurophysiologists blinded to the patient’s history. The median values of baseline pupil size, pupillary constriction, constriction velocity, and latency were collected for both eyes. To assess sensitivity and specificity, we calculated areas under the receiver-operating characteristic curve. Results: The degree of encephalopathy assessed by EEG was categorized as mild (42%), moderate (37%), severe (10%) or suppression-burst/suppression (12%); a total of 47/60 EEG recordings were classified as “reactive.” There was a significant difference in pupillary size, constriction rate, and constriction velocity, but not latency, among the different EEG categories of encephalopathy. Similarly, reactive EEG tracings were associated with greater pupil size, pupillary constriction rate, and constriction velocity compared with nonreactive recordings; there were no significant differences in latency. Pupillary constriction rate values had an area under the curve of 0.83 to predict the presence of severe encephalopathy or suppression-burst/suppression, with a pupillary constriction rate of < 20% having a sensitivity of 85% and a specificity of 79%. Conclusions: Automated pupillometry can contribute to the assessment of cerebral dysfunction in critically ill patients. S.H., L.P., L.C., J.-L.V., and F.S.T.: conceived and designed the study. F.S.T., S.H., L.P., N.G., and L.C.: selected the population. S.H., L.P., L.C., and L.F.: screened and collected data from the population. L.F., B.L., and N.G.: analyzed the EEG recordings. F.S.T., J.C., and N.G.: conduced the statistical analysis. F.S.T., M.O., S.H., and L.P.: wrote the first draft of the manuscript. J.C., N.G., B.L., L.F. and J.-L.V.: revised the text for intellectual content. All the co-authors read and approved the final text. M.O. received lecture fees from Neuroptics. The remaining authors have no conflicts of interest to disclose. Address correspondence to: Fabio S. Taccone, MD, PhD. E-mail: ftaccone@ulb.ac.be. Received January 9, 2019 Accepted June 13, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Perioperative Management of Direct Oral Anticoagulants in Intracranial Surgery The use of direct oral anticoagulants is increasing rapidly, because of perceived benefits over older agents, such as predictable pharmacokinetics and a reduced risk of bleeding. Elderly patients, who are more likely to be prescribed these drugs, are also presenting for neurosurgical procedures more often. The combination of these factors will result in neurosurgeons and neuroanesthesiologists encountering patients prescribed direct oral anticoagulants on an increasingly frequent basis. This review provides a summary of the current evidence pertaining to the perioperative management of these drugs, in the context of elective and emergency intracranial surgery. It highlights emerging therapies, including specific antidotes, as well as areas where the evidence base is likely to improve in the future. The authors have no funding or conflicts of interest to disclose. Address correspondence to: John Porter, MD, FRCA, FFICM, E-mail: johnporter@nhs.net. Received March 30, 2019 Accepted June 12, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved