Effect of General Anesthetics on Caspase-3 Levels in Patients With Aneurysmal Subarachnoid Hemorrhage: A Preliminary Study Background: General anesthesia has been associated with neuronal apoptosis and activation of caspases. Apoptosis is a crucial factor in early brain injury following aneurysmal subarachnoid hemorrhage (aSAH). We conducted a double-blind, prospective, randomized pilot study to evaluate the effect of 4 anesthetic agents on cerebrospinal fluid (CSF) and serum caspase-3 levels in aSAH patients. Materials and Methods: A total of 44 good-grade aSAH patients with preoperative lumbar drain scheduled for surgical clipping or endovascular coiling were randomized to receive maintenance of anesthesia with propofol, isoflurane, sevoflurane, or desflurane. Caspase-3 levels were measured in CSF and serum samples collected at baseline, 1 hour after induction, and 1 hour after cessation of anesthesia. Results: Compared with baseline, there was a decrease in CSF caspase-3 levels and an increase in serum caspase-3 levels 1 hour after exposure to all 4 anesthetic agents; levels returned to baseline values after cessation of anesthesia. Median CSF caspase-3 levels at baseline, 1 hour after anesthesia exposure, and 1 hour after cessation of anesthesia were 0.0679, 0.0004, and 0.0689 ng/mL, respectively (P<0.05). Median serum caspase-3 levels at baseline, 1 hour after anesthesia exposure, and 1-hour after cessation of anesthesia were 0.0028, 0.0682, and 0.0044 ng/mL, respectively (P<0.05). Conclusions: Propofol, isoflurane, sevoflurane, or desflurane have similar effects on CSF and serum caspase-3. The reduction of intraoperative CSF caspase-3 levels suggests a possible role for general anesthesia in neuroresuscitation by slowing the neuronal apoptotic pathway. M.B., A. Kuberan, and H.B.: study concept. M.B., H.B., A.R., S.D., N.P, and A. Kumar: study design. M.B., A.K.S., S.D., A. Kumar, T.S., and M.K.: enrolment of patients, collection of baseline data. N.P., A.K.S., T.S., and M.K.: anesthesia and collection of intraoperative data. M.B., A.R., H.B., A. Kuberan, H.B., A.K.S., T.S., M.K.: analysis and interpretation of data. M.B., A. Kuberan, H.B., and P.S.G.: contribution in statistical analysis. M.B., H.B., A. Kuberan, P.S.G., A.R., A.K., S.D., and N.P.: drafting of the manuscript. H.B, A. Kuberan, M.B., and P.S.G.: critical revision of the manuscript. M.B. and H.B.: principal investigator and overall responsibility for the trial. Supported by PGIMER, Chandigarh. The authors have no conflicts of interest to disclose. Address correspondence to: Hemant Bhagat, DM. E-mail: hembhagat@rediffmail.com. Received March 16, 2019 Accepted August 16, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Ischemia-modified Albumin as a Biomarker for Prediction of Poor Outcome in Patients With Traumatic Brain Injury: An Observational Cohort Study Background: Biomarkers can assist in outcome prediction and therapeutic decision making after traumatic brain injury (TBI). The aim of this study was to evaluate the role of ischemia-modified albumin (IMA) in the prediction of mortality in patients with TBI. Methods: In this observational study IMA was measured on admission to intensive care unit (D0) and 24 hours later (D1) in a cohort of patients with mixed TBI severity. The primary outcome was the correlation between IMA and 28-day mortality. Secondary outcomes included the incidence of elevated IMA, and the correlation between the severity of TBI and IMA, and between IMA and change in Glasgow coma score (GCS). The area under receiver operating characteristic curve analysis was performed to detect optimal IMA cut-off value for the detection of mortality. Results: Fifty-four patients were included in the study; IMA was elevated in 49 (90.7%) on admission to the intensive care unit. Of the 49 patients with elevated IMA, 22 had a decrease in IMA while 27 had an increase by 24 hours. IMA levels were higher at D0 and D1 (P<0.001 for both) in patients who died compared with those who survived. Twenty-one patients died (mortality rate 38.9%); all had elevated IMA on D0 and D1 and higher IMA levels at D1 compared with D0. Optimal cut-off values for IMA predicted mortality with 76.2% sensitivity and 81.8% specificity at D0 and with 100% sensitivity and specificity at D1. IMA values at D0 and D1 were correlated with D0 and D1 GCS, respectively (both P<0.001). Conclusion: IMA levels were elevated in patients following TBI, and can predict mortality with high sensitivity and specificity. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Rania S. Fahmy, MD. E-mail: ransam98@gmail.com. Received April 17, 2019 Accepted August 2, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

General Anesthesia Versus Conscious Sedation in Endovascular Thrombectomy for Stroke: A Meta-Analysis of 4 Randomized Controlled Trials Background: In ischemic stroke patients, studies have suggested that clinical outcomes following endovascular thrombectomy are worse after general anesthesia (GA) compared with conscious sedation (CS). Most data are from observational trials, which are prone to measure and unmeasure confounding. We performed a systematic review and meta-analysis of thrombectomy trials where patients were randomized to GA or CS, and compared efficacy and safety outcomes. Methods: The Medline, Embase, and Cochrane databases were searched for randomized controlled trials comparing GA to CS in endovascular thrombectomy. Efficacy outcomes included successful recanalization (Thrombolysis in Cerebral Infarction score of 2b to 3), and good functional outcome, defined as a modified Rankin Scale score of 0 to 2 at 3 months. Safety outcomes included intracerebral hemorrhage and 3-month mortality. Results: Four studies were identified and included in the random effects meta-analysis. Patients treated with GA achieved a higher proportion of successful recanalization (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.26-3.62; P=0.005) and good functional outcome (OR: 1.71, 95% CI: 1.13-2.59; P=0.01). For every 7.9 patients receiving GA, one more achieved good functional outcome compared with those receiving CS. There were no significant differences in intracerebral hemorrhage (OR: 0.61, 95% CI: 0.20-1.85; P=0.38) or 3-month mortality (OR: 0.62, 95% CI: 0.33-1.17; P=0.14) between GA and CS patients. Conclusions: In centers with high quality, specialized neuroanesthesia care, GA treated thrombectomy patients had superior recanalization rates and better functional outcome at 3 months than patients receiving CS. Presented at The 5th European Stroke Organisation Conference, Milan, 2019. Supported by Neurological Foundation of New Zealand and Julius Brendel Trust. 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 June 19, 2019 Accepted August 29, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Pressure Autoregulation Evaluated Measuring Brain Tissue Oxygen Tension in Patients With Moyamoya Syndrome No abstract available

Hypertonic Saline Versus Mannitol for Traumatic Brain Injury: A Systematic Review and Meta-Analysis With Trial Sequential Analysis Background: Mannitol and hypertonic saline are widely used to treat raised intracranial pressure (ICP) after traumatic brain injury (TBI), but the clinical superiority of one over the other has not been demonstrated. Methods: According to the PRISMA statement, this meta-analysis reports on randomized controlled trials investigating hypertonic saline compared with mannitol in the treatment of elevated ICP following TBI. The protocol for the literature searches (Medline, Embase, Central databases), quality assessment, endpoints (mortality, favorable outcome, brain perfusion parameters), and statistical analysis plan (including a trial sequential analysis) were prospectively specified and registered on the PROSPERO database (CRD42017057112). Results: A total of 12 randomized controlled trials with 464 patients were eligible for inclusion in this analysis. Although there was a nonsignificant trend in favor of hypertonic saline, there were no significant differences in mortality between the 2 treatments (relative risk [RR]: 0.69, 95% confidence interval [CI]: 0.45, 1.04; P=0.08). There were also no significant differences in favorable neurological outcome between hypertonic saline (HS) and mannitol (RR: 1.28, 95% CI: 0.86, 1.90; P=0.23). There was no difference in ICP at 30 to 60 minutes after treatment (mean difference [MD]: −0.19 mm Hg, 95% CI: −0.54, 0.17; P=0.30), whereas ICP was significantly lower after HS compared with mannitol at 90 to 120 minutes (MD: −2.33 mm Hg, 95% CI: −3.17, −1.50; P<0.00001). Cerebral perfusion pressure was higher between 30 to 60 and 90 to 120 minutes after treatment with HS compared with after treatment with mannitol (MD: 5.48 mm Hg, 95% CI: 4.84, 6.12; P<0.00001 and 9.08 mm Hg, 95% CI: 7.54, 10.62; P<0.00001, respectively). Trial sequential analysis showed that the number of cases was insufficient to produce reliable statements on long-term outcomes. Conclusion: There are indications that HS might be superior to mannitol in the treatment of TBI-related raised ICP. However, there are insufficient data to reach a definitive conclusion, and further studies are warranted. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Franz Schwimmbeck. E-mail: franz.schwimmbeck@med.uni-muenchen.de. Received November 12, 2018 Accepted August 12, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Site of Occlusion May Influence Decision to Perform Thrombectomy Under General Anesthesia or Conscious Sedation Background: Although mechanical thrombectomy has become the standard of care for large-vessel occlusion, the role of conscious sedation versus general anesthesia (GA) with intubation during thrombectomy remains controversial. Aphasia may increase patient agitation or apparent uncooperativeness/confusion and thereby lead to higher use of GA. The purpose of this study was to identify risk factors for GA and determine if the side of vessel occlusion potentially impacts GA rates. Materials and Methods: Patients who underwent mechanical thrombectomy of the middle cerebral artery (MCA) for acute ischemic stroke at our institution between April 2014 and July 2017 were retrospectively reviewed. Patient characteristics, procedural factors, and outcomes were assessed using multivariate regression analyses. Mediation analysis was utilized to investigate whether aphasia lies on the causal pathway between left-sided MCA stroke and GA. Results: Overall, 112 patients were included: 62 with left-sided and 50 with right-sided MCA occlusion. Patients with left-sided MCA occlusion presented with aphasia significantly more often those with right-sided occlusion (90.3% vs. 32.0%; P<0.001). GA rates were significantly higher for patients with left-sided compared with right-sided MCA occlusion (45.2% vs. 20.0%; P=0.028). Aphasia mediated 91.3% of the effect of MCA stroke laterality on GA (P=0.02). GA was associated with increased door-to-groin-puncture time (106.4% increase; 95% confidence interval, 24.1%-243.4%; P=0.006) and adverse discharge outcome (odds ratio, 1.04; 95% confidence interval, 1.01-1.07; P=0.019). Conclusions: Patients who had a stroke with left-sided MCA occlusion are more likely to undergo GA for mechanical thrombectomy than those with right-sided MCA occlusion. Aphasia may mediate this effect and understanding this relationship may decrease GA rates through modification of management protocols, potentially leading to improved clinical outcomes. Our study suggests that GA should preferentially be considered for the subset of patients with acute ischemic stroke undergoing mechanical thrombectomy for left-sided MCA occlusion. Supported the National Institutes of Health grant number TL1TR001443 awarded to M.G.B. J.A.S., M.G.B., K.M.K., A.R.W., and A.A.K.: designed the study and participated in initial data collection. J.A.S., R.C.R., D.R.S-D., S.E.O., J.S.P., and A.A.K.: monitored data collection. J.A.S., M.G.B., K.M.K., and A.W.: curated the existing data and completed additional data collection. J.A.S., M.G.B., A.R.W., R.C.R., D.R.S-D., S.E.O., J.S.P., and A.A.K.: wrote the statistical analysis plan. J.A.S., M.G.B., K.M.K., and A.R.W.: cleaned and analyzed the data. J.A.S., M.G.B., and K.M.K.: drafted and revised the paper. A.R.W., R.C.R., D.R.S-D., S.E.O., J.S.P., and A.A.K.: revised the paper. The authors have no conflicts of interest to disclose. Address correspondence to: Alexander A. Khalessi, MD, MS. E-mail: akhalessi@ucsd.edu. Received April 5, 2019 Accepted July 31, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved

Does Thoracolumbar Interfascial Plane Block Provide More Focused Analgesia Than Erector Spinae Plane Block in Lumbar Spine Surgery? No abstract available

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