Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest Trial (GOT ICE): A Randomized Clinical Trial Comparing Outcomes After Aortic Arch Surgery.

BACKGROUND: Deep hypothermia has been the standard for hypothermic circulatory arrest (HCA) during aortic arch surgery. However, centers worldwide have shifted toward lesser hypothermia with antegrade cerebral perfusion. This has been supported by retrospective data, but there has yet to be a multicenter, prospective randomized study comparing deep versus moderate hypothermia during HCA. METHODS: This was a randomized single-blind trial (GOT ICE [Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest]) of patients undergoing arch surgery with HCA plus antegrade cerebral perfusion at 4 US referral aortic centers (August 2016-December 2021). Patients were randomized to 1 of 3 hypothermia groups: DP, deep (≤20.0 °C); LM, low-moderate (20.1-24.0 °C); and HM, high-moderate (24.1-28.0 °C). The primary outcome was composite global cognitive change score between baseline and 4 weeks postoperatively. Analysis followed the intention-to-treat principle to evaluate if: (1) LM noninferior to DP on global cognitive change score; (2) DP superior to HM. The secondary outcomes were domain-specific cognitive change scores, neuroimaging findings, quality of life, and adverse events. RESULTS: A total of 308 patients consented; 282 met inclusion and were randomized. A total of 273 completed surgery, and 251 completed the 4-week follow-up (DP, 85 [34%]; LM, 80 [34%]; HM, 86 [34%]). Mean global cognitive change score from baseline to 4 weeks in the LM group was noninferior to the DP group; likewise, no significant difference was observed between DP and HM. Noninferiority of LM versus DP, and lack of difference between DP and HM, remained for domain-specific cognitive change scores, except structured verbal memory, with noninferiority of LM versus DP not established and structured verbal memory better preserved in DP versus HM (P = 0.036). There were no significant differences in structural or functional magnetic resonance imaging brain imaging between groups postoperatively. Regardless of temperature, patients who underwent HCA demonstrated significant reductions in cerebral gray matter volume, cortical thickness, and regional brain functional connectivity. Thirty-day in-hospital mortality, major morbidity, and quality of life were not different between groups. CONCLUSIONS: This randomized multicenter study evaluating arch surgery HCA temperature strategies found low-moderate hypothermia noninferior to traditional deep hypothermia on global cognitive change 4 weeks after surgery, although in secondary analysis, structured verbal memory was better preserved in the deep group. The verbal memory differences in the low- and high-moderate groups and structural and functional connectivity reductions from baseline merit further investigation and suggest opportunities to further optimize brain perfusion during HCA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02834065.

Hevin/Sparcl1 drives pathological pain through spinal cord astrocyte and NMDA receptor signaling.

High endothelial venule protein/SPARC-like 1 (hevin/Sparcl1) is an astrocyte-secreted protein that regulates synapse formation in the brain. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared with WT mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than WT mice from neuropathic pain after nerve injury. Intrathecal injection of WT hevin was sufficient to induce persistent mechanical allodynia in naive mice. In hevin-null mice with nerve injury, adeno-associated-virus-mediated (AAV-mediated) re-expression of hevin in glial fibrillary acidic protein-expressing (GFAP-expressing) spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin-potentiated N-Methyl-D-aspartic acid (NMDA) currents are mediated by GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing Ab against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin that was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid and substantial increases in SPARCL1/HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal Ab may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.

In vivo single microglial cell isolation after intracerebral hemorrhage in mice.

Failure to translate promising potential therapeutics for intracerebral hemorrhage (ICH) partially results from limited understanding of cellular mechanisms underlying brain injury and repair. Understanding neural repair mechanisms after brain injury requires intricate comprehension of microglial behavior; however, studying individual microglial cell behavior is challenging. Further single cell isolation techniques may be an excellent means to expand known differences in male and female microglial cell response to ICH. In this study, 24 h after intrastriatal collagenase injection, one male and one female CX3CR1-GFP mouse underwent ex vivo microglial cell isolation via micropipette from perihematomal regions and equivalent location of contralateral striata. After cell collection, individual and grouped cell samples underwent reverse transcription and analyses for gene expression using Fluidigm RT-PCR technology. Data were analyzed by t-tests and visualized as a heatmap of the log2 Ct values. Gene expression assays were chosen for target-specific amplification, including markers of M1 pro-inflammatory microglial phenotype (i.e., Tnf, Il6, Fcgr3/CD16), M2 anti-inflammatory markers (i.e., Mrc1/CD206, Arg1, Tgfb1), and genes involved in the toll-like receptor pathway (i.e., Tlr2, Tlr4 and Myd88). Greater number of individual microglia cells expressed Mcr1, Tlr2, and Arg1 in perihematomal tissue than in contralateral hemispheres. Additionally, more male microglia expressed Myd88, Tlr2, Il6, and Arg1 than did female microglia. Single cell microglial isolation is feasible after in vivo rodent ICH. Differential gene expression can be detected between individual cells from different brain regions and experimental conditions. Cell-specific analyses will contribute to improved understanding of microglial roles in both post-ICH pathogenesis and recovery.

The impact of perioperative stroke and delirium on outcomes after surgical aortic valve replacement.

OBJECTIVE: The effects of stroke and delirium on postdischarge cognition and patient-centered health outcomes after surgical aortic valve replacement (SAVR) are not well characterized. Here, we assess the impact of postoperative stroke and delirium on these health outcomes in SAVR patients at 90 days. METHODS: Patients (N = 383) undergoing SAVR (41% received concomitant coronary artery bypass graft) enrolled in a randomized trial of embolic protection devices underwent serial neurologic and delirium evaluations at postoperative days 1, 3, and 7 and magnetic resonance imaging at day 7. Outcomes included 90-day functional status, neurocognitive decline from presurgical baseline, and quality of life. RESULTS: By postoperative day 7, 25 (6.6%) patients experienced clinical stroke and 103 (28.5%) manifested delirium. During index hospitalization, time to discharge was longer in patients experiencing stroke (hazard ratio, 0.62; 95% confidence interval [CI], 0.42-0.94; P = .02) and patients experiencing delirium (hazard ratio, 0.68; 95% CI, 0.54-0.86; P = .001). At day 90, patients experiencing stroke were more likely to have a modified Rankin score >2 (odds ratio [OR], 5.9; 95% CI, 1.7-20.1; P = .01), depression (OR, 5.3; 95% CI, 1.6-17.3; P = .006), a lower 12-Item Short Form Survey physical health score (adjusted mean difference -3.3 ± 1.9; P = .08), and neurocognitive decline (OR, 7.8; 95% CI, 2.3-26.4; P = .001). Delirium was associated with depression (OR, 2.2; 95% CI, 0.9-5.3; P = .08), lower 12-Item Short Form Survey physical health (adjusted mean difference -2.3 ± 1.1; P = .03), and neurocognitive decline (OR, 2.2; 95% CI, 1.2-4.0; P = .01). CONCLUSIONS: Stroke and delirium occur more frequently after SAVR than is commonly recognized, and these events are associated with disability, depression, cognitive decline, and poorer quality of life at 90 days postoperatively. These findings support the need for new interventions to reduce these events and improve patient-centered outcomes.

The Magnitude of Blood Pressure Reduction Predicts Poor In-Hospital Outcome in Acute Intracerebral Hemorrhage.

BACKGROUND: Early systolic blood pressure (SBP) reduction is believed to improve outcome after spontaneous intracerebral hemorrhage (ICH), but there has been a limited assessment of SBP trajectories in individual patients. We aimed to determine the prognostic significance of SBP trajectories in ICH. METHODS: We collected routine data on spontaneous ICH patients from two healthcare systems over 10 years. Unsupervised functional principal components analysis (FPCA) was used to characterize SBP trajectories over first 24 h and their relationship to the primary outcome of unfavorable shift on modified Rankin scale (mRS) at hospital discharge, categorized as an ordinal trichotomous variable (mRS 0-2, 3-4, and 5-6 defined as good, poor, and severe, respectively). Ordinal logistic regression models adjusted for baseline SBP and ICH volume were used to determine the prognostic significance of SBP trajectories. RESULTS: The 757 patients included in the study were 65 ± 23 years old, 56% were men, with a median (IQR) Glasgow come scale of 14 (8). FPCA revealed that mean SBP over 24 h and SBP reduction within the first 6 h accounted for 76.8% of the variation in SBP trajectories. An increase in SBP reduction (per 10 mmHg) was significantly associated with unfavorable outcomes defined as mRS > 2 (adjusted-OR = 1.134; 95% CI 1.044-1.233, P = 0.003). Compared with SBP reduction < 20 mmHg, worse outcomes were observed for SBP reduction = 40-60 mmHg (adjusted-OR = 1.940, 95% CI 1.129-3.353, P = 0.017) and > 60 mmHg, (adjusted-OR = 1.965, 95% CI 1.011, 3.846, P = 0.047). Furthermore, the association of SBP reduction and outcome varied according to initial hematoma volume. Smaller SBP reduction was associated with good outcome (mRS 0-2) in small (< 7.42 mL) and medium-size (≥ 7.42 and < 30.47 mL) hematomas. Furthermore, while the likelihood of good outcome was low in those with large hematomas (≥ 30.47 mL), smaller SBP reduction was associated with decreasing probability of severe outcome (mRS 5-6). CONCLUSION: Our analyses suggest that in the first 6 h SBP reduction is significantly associated with the in-hospital outcome that varies with initial hematoma volume, and early SBP reduction > 40 mmHg may be harmful in ICH patients. For early SBP reduction to have an effective therapeutic effect, both target levels and optimum SBP reduction goals vis-à-vis hematoma volume should be considered.

Longitudinal Changes in Regional Cerebral Perfusion and Cognition After Cardiac Operation.

BACKGROUND: Cardiac operation has been associated with increased risk of postoperative cognitive decline, as well as dementia risk in the general population. Few studies, however, have examined the impact of coronary revascularization or valve replacement or repair operation on longitudinal cerebral perfusion changes or their association with cognitive function. METHODS: We examined longitudinal changes in cerebral perfusion among 54 individuals with cardiac disease; 27 undergoing cardiac operation and 27 matched control patients. Arterial spin labeling magnetic resonance perfusion imaging was used to quantify cerebral blood flow within the anterior communicating artery, middle cerebral artery (MCA), and posterior communicating artery vascular territories before operation and postoperatively at 6 weeks and 1 year. Cognitive performance was examined during the same intervals by using a battery of tests that tapped memory, executive, information processing and upper extremity motor functions. Repeated measures, mixed models were used to examine for perfusion changes and the association between perfusion changes and cognition. RESULTS: Significant postoperative increases in perfusion were observed at 6 weeks within the MCA vascular territory after cardiac operation (p = 0.035 for interaction). Perfusion changes were most notable in distal territories of the MCA and posterior communicating artery at 6 weeks, with no additional changes at 1 year. Postoperative increases in MCA perfusion at 6 weeks were associated with improved psychomotor speed (ß = 0.35, p = 0.016), whereas no important differences were found between the groups in vascular territory perfusion and cognition at 1 year. CONCLUSIONS: Cardiac operation is associated with important short-term increases in MCA perfusion with associated improvements in psychomotor speed.

Minority Patients are Less Likely to Undergo Withdrawal of Care After Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Prior studies of patients in the intensive care unit have suggested racial/ethnic variation in end-of-life decision making. We sought to evaluate whether race/ethnicity modifies the implementation of comfort measures only status (CMOs) in patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH). METHODS: We analyzed data from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a prospective cohort study specifically designed to enroll equal numbers of white, black, and Hispanic subjects. ICH patients aged ≥ 18 years were enrolled in ERICH at 42 hospitals in the USA from 2010 to 2015. Univariate and multivariate logistic regression analyses were implemented to evaluate the association between race/ethnicity and CMOs after adjustment for potential confounders. RESULTS: A total of 2705 ICH cases (912 black, 893 Hispanic, 900 white) were included in this study (mean age 62 [SD 14], female sex 1119 [41%]). CMOs patients comprised 276 (10%) of the entire cohort; of these, 64 (7%) were black, 79 (9%) Hispanic, and 133 (15%) white (univariate p < 0.001). In multivariate analysis, compared to whites, blacks were half as likely to be made CMOs (OR 0.50, 95% CI 0.34-0.75; p = 0.001), and no statistically significant difference was observed for Hispanics. All three racial/ethnic groups had similar mortality rates at discharge (whites 12%, blacks 9%, and Hispanics 10%; p = 0.108). Other factors independently associated with CMOs included age (p < 0.001), premorbid modified Rankin Scale (p < 0.001), dementia (p = 0.008), admission Glasgow Coma Scale (p = 0.009), hematoma volume (p < 0.001), intraventricular hematoma volume (p < 0.001), lobar (p = 0.032) and brainstem (p < 0.001) location and endotracheal intubation (p < 0.001). CONCLUSIONS: In ICH, black patients are less likely than white patients to have CMOs. However, in-hospital mortality is similar across all racial/ethnic groups. Further investigation is warranted to better understand the causes and implications of racial disparities in CMO decisions.

The Effect of Propofol vs. Isoflurane Anesthesia on Postoperative Changes in Cerebrospinal Fluid Cytokine Levels: Results from a Randomized Trial.

INTRODUCTION: Aside from direct effects on neurotransmission, inhaled and intravenous anesthetics have immunomodulatory properties. In vitro and mouse model studies suggest that propofol inhibits, while isoflurane increases, neuroinflammation. If these findings translate to humans, they could be clinically important since neuroinflammation has detrimental effects on neurocognitive function in numerous disease states. MATERIALS AND METHODS: To examine whether propofol and isoflurane differentially modulate neuroinflammation in humans, cytokines were measured in a secondary analysis of cerebrospinal fluid (CSF) samples from patients prospectively randomized to receive anesthetic maintenance with propofol vs. isoflurane (registered with http://www.clinicaltrials.gov, identifier NCT01640275). We measured CSF levels of EGF, eotaxin, G-CSF, GM-CSF, IFN-α2, IL-1RA, IL-6, IL-7, IL-8, IL-10, IP-10, MCP-1, MIP-1α, MIP-1ß, and TNF-α before and 24 h after intracranial surgery in these study patients. RESULTS: After Bonferroni correction for multiple comparisons, we found significant increases from before to 24 h after surgery in G-CSF, IL-10, IL-1RA, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1ß, and TNF-α. However, we found no difference in cytokine levels at baseline or 24 h after surgery between propofol- (n = 19) and isoflurane-treated (n = 21) patients (p > 0.05 for all comparisons). Increases in CSF IL-6, IL-8, IP-10, and MCP-1 levels directly correlated with each other and with postoperative CSF elevations in tau, a neural injury biomarker. We observed CSF cytokine increases up to 10-fold higher after intracranial surgery than previously reported after other types of surgery. DISCUSSION: These data clarify the magnitude of neuroinflammation after intracranial surgery, and raise the possibility that a coordinated neuroinflammatory response may play a role in neural injury after surgery.

Aggressiveness of care following intracerebral hemorrhage in women and men.

OBJECTIVE: To compare comorbidities and use of surgery and palliative care between men and women with intracerebral hemorrhage (ICH). METHODS: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter, case-control study of ICH risk factors and outcomes. We compared comorbidities, treatments, and use of do-not-resuscitate (DNR) orders in men vs women. Multivariate analysis was used to assess the likelihood of ICH surgery and palliative care after adjustment for variables that were p < 0.1 in univariate analyses and backward elimination to retain those that were significant (p < 0.05). RESULTS: Women were older on average (65.0 vs 59.9, p < 0.0001), and higher proportions of women had previous stroke (24.1% vs 19.3%, p = 0.002), had dementia (6.1% vs 3.4%, p = 0.0007), lived alone (23.1% vs 18.0%, p = 0.0005), and took anticoagulants (12.8% vs 10.1% p = 0.02), compared with men. Men had higher rates of alcohol and cocaine use. After adjusting for age, hematoma volume, and ICH location, there was no difference in rates of surgical treatment by sex (odds ratio [OR] 0.93 for men vs women, 95% confidence interval [CI] 0.68-1.28, p = 0.67), and there was no difference in DNR/comfort care decisions after adjustment for ICH score, prior stroke, and dementia (OR 0.96, CI 0.77-1.22, p = 0.76). CONCLUSIONS: After ICH, women do not receive less aggressive care than men after controlling for the substantial comorbidity differences. Future studies on sex bias should include the presence of comorbidities, prestroke disability, and other factors that may influence management.

Neuromuscular Disease in the Neurointensive Care Unit.

Neuromuscular diseases are syndromic disorders that affect nerve, muscle, and/or neuromuscular junction. Knowledge about the management of these diseases is required for anesthesiologists, because these may frequently be encountered in the intensive care unit, operating room, and other settings. The challenges and advances in management for some of the neuromuscular diseases most commonly encountered in the operating room and neurointensive care unit are reviewed.

The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial.

BACKGROUND: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-ß (Aß). OBJECTIVE: We asked whether isoflurane and propofol have differential effects on the tau/Aß ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. METHODS: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS: The CSF tau/Aß ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aß ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aß levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). CONCLUSION: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aß ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aß ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage.

In models of acute brain injury, progesterone improves recovery through several mechanisms including modulation of neuroinflammation. Secondary injury from neuroinflammation is a potential therapeutic target after intracerebral hemorrhage (ICH). For potential translation of progesterone as a clinical acute ICH therapeutic, the present study sought to define efficacy of exogenous progesterone administration in ICH-relevant experimental paradigms. Young and aged C57BL/6 male, female, and ovariectomized (OVX) mice underwent left intrastriatal collagenase (0.05-0.075 U) or autologous whole blood (35 µl) injection. Progesterone at varying doses (4-16 mg/kg) was administered at 2, 5, 24, 48, and 72 h after injury. Rotarod and Morris water maze latencies were measured on days 1-7 and days 28-31 after injury, respectively. Hematoma volume, brain water content (cerebral edema), complementary immunohistochemistry, multiplex cytokine arrays, and inflammatory proteins were assessed at prespecified time points after injury. Progesterone (4 mg/kg) administration improved rotarod and water maze latencies (p < 0.01), and decreased cerebral edema (p < 0.05), microglial proliferation, and neuronal loss (p < 0.01) in young and aged male, young OVX, and aged female mice. Brain concentration of proinflammatory cytokines and Toll-like receptor-associated proteins were also decreased after progesterone (4 mg/kg) treatment (p < 0.01). Progesterone-treated young female mice showed no detectable effects. Exogenous progesterone improved short- and long-term neurobehavioral recovery and modulated neuroinflammation in male and OVX mice after ICH. Future studies should validate these findings, and address timing and length of administration before translation to clinical trial.

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage.

BACKGROUND: Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats. METHODS: ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridial collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h after injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, proinflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury. RESULTS: Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and proinflammatory transcription factor phosphorylated nuclear factor-x03BA;B p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected. CONCLUSIONS: Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.

Intravenous immunoglobulin G improves neurobehavioral and histological outcomes after traumatic brain injury in mice.

Intravenous immunoglobulin (IVIG) may improve neuroinflammation after traumatic brain injury (TBI). IVIG administration after TBI improved rotarod latencies over the first 7 days (p=0.039) and water maze latencies over 29-32 days (p=0.027), decreased F4/80-positive cells at 2 (p=0.001) and 7 days (p<0.001), decreased Fluoro-Jade B-positive cells (p=0.020), increased NeuN-positive cells (p=0.014), decreased IL-6 production at 4 (p=0.032) and 24h (p=0.023), and decreased blood-brain barrier breakdown by IgG extravasation (p=0.001) and brain edema (p=0.006); however, TNF-α concentration was unchanged. IVIG administration was associated with long-term neurobehavioral and histological improvement through modulation of neuroinflammation and blood-brain barrier permeability in a murine TBI model.

Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia.

Female sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide (NO) and prostaglandin E2 (PGE2), mediated by inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. We hypothesized that female gonadal steroids reduce microglia mediated neuroinflammation. In this study, the progesterone's effects on tumor necrosis factor alpha (TNF-α), iNOS, and COX-2 expression were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Further, investigation included nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. LPS (30 ng/ml) upregulated TNF-α, iNOS, and COX-2 protein expression in BV-2 cells. Progesterone pretreatment attenuated LPS-stimulated TNF-α, iNOS, and COX-2 expression in a dose-dependent fashion. Progesterone suppressed LPS-induced NF-κB activation by decreasing inhibitory κBα and NF-κB p65 phosphorylation and p65 nuclear translocation. Progesterone decreased LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase and extracellular regulated kinase MAPKs. These progesterone effects were inhibited by its antagonist mifepristone. In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation. This suggests progesterone may be used as a potential neurotherapeutic to treat inflammatory components of acute brain injury.

Predictors of electrocerebral inactivity with deep hypothermia.

OBJECTIVE: Cooling to electrocerebral inactivity (ECI) by electroencephalography (EEG) remains the gold standard to maximize cerebral and systemic organ protection during deep hypothermic circulatory arrest (DHCA). We sought to determine predictors of ECI to help guide cooling protocols when EEG monitoring is unavailable. METHODS: Between July 2005 and July 2011, 396 patients underwent thoracic aortic operation with DHCA; EEG monitoring was used in 325 (82%) of these patients to guide the cooling strategy, and constituted the study cohort. Electroencephalographic monitoring was used for all elective cases and, when available, for nonelective cases. Multivariable linear regression was used to assess predictors of the nasopharyngeal temperature and cooling time required to achieve ECI. RESULTS: Cooling to a nasopharyngeal temperature of 12.7°C or for a duration of 97 minutes was required to achieve ECI in >95% of patients. Only 7% and 11% of patients achieved ECI by 18°C or 50 minutes of cooling, respectively. No independent predictors of nasopharyngeal temperature at ECI were identified. Independent predictors of cooling time included body surface area (18 minutes/m(2)), white race (7 minutes), and starting nasopharyngeal temperature (3 minutes/°C). Low complication rates were observed (ischemic stroke, 1.5%; permanent paraparesis/paraplegia, 1.5%; new-onset dialysis, 2.2%; and 30-day/in-hospital mortality, 4.3%). CONCLUSIONS: Cooling to a nasopharyngeal temperature of 12.7°C or for a duration of 97 minutes achieved ECI in >95% of patients in our study population. However, patient-specific factors were poorly predictive of the temperature or cooling time required to achieve ECI, necessitating EEG monitoring for precise ECI detection.

Tumor necrosis factor α antagonism improves neurological recovery in murine intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype characterized by a prominent neuroinflammatory response. Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH. To test this hypothesis, the tumor necrosis factor alpha (TNF-α) antibody CNTO5048 was administered to mice after ICH induction, and histological and functional endpoints were assessed. METHODS: Using 10 to 12-week-old C57BL/6J male mice, ICH was induced by collagenase injection into the left basal ganglia. Brain TNF-α concentration, microglia activation/macrophage recruitment, hematoma volume, cerebral edema, and rotorod latency were assessed in mice treated with the TNF-α antibody, CNTO5048, or vehicle. RESULTS: After ICH induction, mice treated with CNTO5048 demonstrated reduction in microglial activation/macrophage recruitment compared to vehicle-treated animals, as assessed by unbiased stereology (P = 0.049). This reduction in F4/80-positive cells was associated with a reduction in cleaved caspase-3 (P = 0.046) and cerebral edema (P = 0.026) despite similar hematoma volumes, when compared to mice treated with vehicle control. Treatment with CNTO5048 after ICH induction was associated with a reduction in functional deficit when compared to mice treated with vehicle control, as assessed by rotorod latencies (P = 0.024). CONCLUSIONS: Post-injury treatment with the TNF-α antibody CNTO5048 results in less neuroinflammation and improved functional outcomes in a murine model of ICH.

Does midline shift predict postoperative nausea in brain tumor patients undergoing awake craniotomy? A retrospective analysis.

BACKGROUND: The presence of midline shift on neuroradiologic studies in brain tumor patients represents mass effect from the tumor and surrounding edema. We hypothesized that baseline cerebral edema as measured by midline shift would increase postoperative nausea (PON). We studied the incidence of PON in brain tumor patients, with and without midline shift on preoperative magnetic resonance (MRI) or computed tomographic (CT) imaging, undergoing awake craniotomy. METHODS: After IRB approval, we retrospectively extracted data from perioperative records between January 2005 and December 2010. Post-craniotomy nausea and pain scores were collected. Intraoperative anti-emetic, anesthetic, and analgesic regimens were assessed. Both the rescue anti-emetic and cumulative postoperative analgesic requirements were collected up to 12 hours postoperatively. The amount of midline shift on preoperative neuroimaging was gathered from radiology reports. Univariate comparisons between groups (no midline shift vs. midline shift) were made with t-tests for continuous variables, and chi-square tests for categorical variables. A multivariable analysis was performed to identify predictors of postoperative nausea. Limitations of this study include the retrospective design and the inability to gather accurate data regarding vomiting from the medical record. RESULTS: Data from 386 patients were available for analysis. Patients were divided into two groups: no midline shift (n = 283) and midline shift (n = 103). The mean midline shift distance was 5.96 mm (95% CI [5.32, 6.59]). There was no difference in the incidence of nausea or pain scores between the two groups. More malignant brain tumor patients were in the midline shift group, as determined by the postoperative histopathological diagnosis (P < 0.05). Patients in the midline shift group also had longer anesthesia and surgical times (P < 0.05). CONCLUSION: In patients undergoing a standardized anesthetic for awake craniotomy for tumor resection, the presence of preoperative midline shift did not correlate with postoperative nausea.