ATF3 is a neuron-specific biomarker for spinal cord injury and ischaemic stroke.

BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.

The role of cultural competency training to address health disparities in surgical settings.

BACKGROUND: Disparities in health care delivered to marginalized groups are unjust and result in poor health outcomes that increase the cost of care for everyone. These disparities are largely avoidable and health care providers, have been targeted with education and specialised training to address these disparities. SOURCES OF DATA: In this manuscript we have sought out both peer-reviewed material on Pubmed, as well as policy statements on the potential role of cultural competency training (CCT) for providers in the surgical care setting. The goal of undertaking this work was to determine whether there is evidence that these endeavours are effective at reducing disparities. AREAS OF AGREEMENT: The unjustness of health care disparities is universally accepted. AREAS OF CONTROVERSY: Whether the outcome of CCT justifies the cost has not been effectively answered. GROWING POINTS: These include the structure/content of the CCT and whether the training should be delivered to teams in the surgical setting. AREAS TIMELY FOR DEVELOPING RESEARCH: Because health outcomes are affected by many different inputs, should the effectiveness of CCT be improvement in health outcomes or should we use a proxy or a surrogate of health outcomes.

Clinical Use of Adrenergic Receptor Ligands in Acute Care Settings.

In this chapter, we review how ligands, both agonists and antagonists, for the major classes of adrenoreceptors, are utilized in acute care clinical settings. Adrenergic ligands exert their effects by interacting with the three major classes of adrenoceptors. Adrenoceptor agonists and antagonists have important applications, ranging from treatment of hypotension to asthma, and have proven to be extremely useful in a variety of clinical settings of acute care from the operating room to the critical care environment. Continued research interpreting the mechanisms of adrenoreceptors may help the discovery of new drugs with more desirable clinical profiles.

Resolution of elevated interleukin-6 after surgery is associated with return of normal cognitive function.

BACKGROUND: Unresolved surgical inflammation might induce chronic cognitive decline in older adults. Although inflammatory biomarkers have been correlated with perioperative cognitive impairment and delirium, the effects of prolonged inflammation on cognition are not well studied. This prospective cohort study investigated 1-yr dynamics in plasma interleukin-6 levels and executive function. METHODS: Patients undergoing major surgery (n=170) aged ≥65 yr completed Trail Making Test B and other neuropsychological assessments with plasma interleukin-6 levels collected on postoperative days 1-9 and 90, and at 1-yr. Mixed-effects analyses were conducted for Trail Making Test B (and other assessments), including interleukin-6 levels, time, and additional confounders (fixed effects), and a random effect for participant. RESULTS: Changes in interleukin-6 levels were associated with changes in Trail Making Test B over 1 yr in a generalised additive model (ß=0.074, P<0.001) supporting that unresolved inflammation impaired executive function. This result was robust to confounders, outlier rejection, and fitting to non-linear models. Changes in interleukin-6 levels also correlated with changes in Trail Making Test A and Controlled Oral Word Association Test. Sensitivity analyses conducted on binary definitions of cognitive decline (>1, >1.5, or >2 standard deviations from baseline) were also associated with interleukin-6 changes. CONCLUSIONS: Delayed resolution of inflammation is associated with cognitive impairment after surgery. Monitoring interleukin-6 might provide an opportunity to intervene with anti-inflammatory therapies in vulnerable patients. CLINICAL TRIAL REGISTRATION: NCT01980511, NCT03124303.

High Mobility Group Box 1 (HMGB1): Potential Target in Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) remains a challenge for intensivists that is exacerbated by lack of an effective diagnostic tool and an unambiguous definition to properly identify SAE patients. Risk factors for SAE development include age, genetic factors as well as pre-existing neuropsychiatric conditions. Sepsis due to certain infection sites/origins might be more prone to encephalopathy development than other cases. Currently, ICU management of SAE is mainly based on non-pharmacological support. Pre-clinical studies have described the role of the alarmin high mobility group box 1 (HMGB1) in the complex pathogenesis of SAE. Although there are limited data available about the role of HMGB1 in neuroinflammation following sepsis, it has been implicated in other neurologic disorders, where its translocation from the nucleus to the extracellular space has been found to trigger neuroinflammatory reactions and disrupt the blood-brain barrier. Negating the inflammatory cascade, by targeting HMGB1, may be a strategy to complement non-pharmacologic interventions directed against encephalopathy. This review describes inflammatory cascades implicating HMGB1 and strategies for its use to mitigate sepsis-induced encephalopathy.

Paradoxical increases in anterior cingulate cortex activity during nitrous oxide-induced analgesia reveal a signature of pain affect.

The general consensus is that increases in neuronal activity in the anterior cingulate cortex (ACC) contribute to pain's negative affect. Here, using in vivo imaging of neuronal calcium dynamics in mice, we report that nitrous oxide, a general anesthetic that reduces pain affect, paradoxically, increases ACC spontaneous activity. As expected, a noxious stimulus also increased ACC activity. However, as nitrous oxide increases baseline activity, the relative change in activity from pre-stimulus baseline was significantly less than the change in the absence of the general anesthetic. We suggest that this relative change in activity represents a neural signature of the affective pain experience. Furthermore, this signature of pain persists under general anesthesia induced by isoflurane, at concentrations in which the mouse is unresponsive. We suggest that this signature underlies the phenomenon of connected consciousness, in which use of the isolated forelimb technique revealed that pain percepts can persist in anesthetized patients.

Involvement of KCa3.1 channel activity in immediate perioperative cognitive and neuroinflammatory outcomes.

BACKGROUND: Potassium channels (KCa3.1; Kv1.3; Kir2.1) are necessary for microglial activation, a pivotal requirement for the development of Perioperative Neurocognitive Disorders (PNDs). We previously reported on the role of microglial Kv1.3 for PNDs; the present study sought to determine whether inhibiting KCa3.1 channel activity affects neuroinflammation and prevents development of PND. METHODS: Mice (wild-type [WT] and KCa3.1-/-) underwent aseptic tibial fracture trauma under isoflurane anesthesia or received anesthesia alone. WT mice received either TRAM34 (a specific KCa3.1 channel inhibitor) dissolved in its vehicle (miglyol) or miglyol alone. Spatial memory was assessed in the Y-maze paradigm 6 h post-surgery/anesthesia. Circulating interleukin-6 (IL-6) and high mobility group box-1 protein (HMGB1) were assessed by ELISA, and microglial activitation Iba-1 staining. RESULTS: In WT mice surgery induced significant cognitive decline in the Y-maze test, p = 0.019), microgliosis (p = 0.001), and increases in plasma IL-6 (p = 0.002) and HMGB1 (p = 0.001) when compared to anesthesia alone. TRAM34 administration attenuated the surgery-induced changes in cognition, microglial activation, and HMGB1 but not circulating IL-6 levels. In KCa3.1-/- mice surgery neither affected cognition nor microgliosis, although circulating IL-6 levels did increase (p < 0.001). CONCLUSION: Similar to our earlier report with Kv1.3, perioperative microglial KCa3.1 blockade decreases immediate perioperative cognitive changes, microgliosis as well as the peripheral trauma marker HMGB1 although surgery-induced IL-6 elevation was unchanged. Future research should address whether a synergistic interaction exists between blockade of Kv1.3 and KCa3.1 for preventing PNDs.

Contribution of intraoperative electroencephalogram suppression to frailty-associated postoperative delirium: mediation analysis of a prospective surgical cohort.

BACKGROUND: Frailty is a risk factor for postoperative delirium (POD), and has led to preoperative interventions that have reduced, but not eliminated, the risk. We hypothesised that EEG suppression, another risk factor for POD, mediates some of the frailty risk for POD. METHODS: A prospective cohort study enrolled patients aged 65 yr or older, scheduled for noncardiac surgery under total intravenous anaesthesia. Frailty was assessed using the FRAIL scale. Cumulative duration of EEG suppression, defined as an amplitude between -5 and 5 µV for >0.5 s during anaesthesia, was measured. POD was diagnosed by either confusion assessment method (CAM), CAM-ICU, or medical records. The severity of POD was assessed using the Delirium Rating Scale - Revised-98 (DRS). Mediation analysis was used to estimate the relationships between frailty, EEG suppression, and severity of POD. RESULTS: Among 252 enrolled patients, 51 were robust, 129 were prefrail, and 72 were frail. Patients classified as frail had higher duration of EEG suppression than either the robust (19 vs 0.57 s, P<0.001) or prefrail groups (19 vs 3.22 s, P<0.001). Peak delirium score was higher in the frail group than either the robust (17 vs 15, P<0.001) or prefrail groups (17 vs 16, P=0.007). EEG suppression time mediated 24.2% of the frailty-DRS scores association. CONCLUSION: EEG suppression time mediated a statistically significant portion of the frailty-POD association in older noncardiac surgery patients. Trials directed at reducing EEG suppression time could result in intraoperative interventions to reduce POD in frail patients. CLINICAL TRIAL REGISTRATION: ChiCTR2000041092 (Chinese Clinical Trial Registry).

Longitudinal Profiling of Plasma Cytokines and Its Association With Postoperative Delirium in Elderly Patients Undergoing Major Lower Limb Surgery: A Prospective Observational Study.

BACKGROUND: Surgery is accompanied by a systemic inflammatory response that may presage delirium in susceptible individuals. Little is known about the trajectory of plasma proinflammatory cytokines and their potential associations with postoperative delirium (POD). The current study longitudinally assessed both pro and anti-inflammatory plasma cytokine response and development of POD in older surgical patients to investigate associations with individual and/or clusters of cytokines that may indicate pathogenic mechanisms. METHODS: A prospective longitudinal study sought to enroll patients >60 years old who were scheduled for major lower limb surgery under general anesthesia. Blood was obtained preoperatively and postoperatively from day 1 through postoperative day 4 for measurement of plasma interleukin-1ß (IL-1ß), IL-2, IL-4, IL-6, soluble IL-6 receptor (sIL-6R), IL-10, and tumor necrosis factor-α (TNF-α). Participants were assessed for POD twice daily for 4 days using the confusion assessment method. Trajectory of postoperative changes in plasma cytokines was determined by a group-based trajectory modeling analysis that was informed by distinct cytokines identified by time-dependent Cox regression model. RESULTS: One hundred eighty-eight patients were assessed for eligibility of whom 129 underwent major surgery and 126 had complete datasets for final analysis. POD was diagnosed in 31 of 126 patients (24.6%). Time-dependent Cox regression model identified that higher IL-6 and sIL-6R levels were associated with higher risk of developing POD. A two-cluster model (stable lower and fluctuating higher levels) was considered to be the most statistically appropriate model for IL-6 and sIL-6R trajectory. More participants with fluctuating higher IL-6 were delirious (73.3% vs 18.0%, P = .001) as were those with fluctuating higher sIL-6R (81.3% vs 16.4%, P = .001). CONCLUSIONS: As higher IL-6 and sIL-6R levels were significantly associated with higher risk of POD and the combination is required for IL-6 trans-signaling, it is possible that activation of this pathway may be associated with POD. Furthermore, it will be important to determine whether high levels of the combination of IL-6 and sIL-6R can be an early biomarker for the subsequent development of POD.

Comparison of the prognostic value of early-phase proton magnetic resonance spectroscopy and diffusion tensor imaging with serum neuron-specific enolase at 72 h in comatose survivors of out-of-hospital cardiac arrest-a substudy of the XeHypotheca trial.

PURPOSE: We compared the predictive accuracy of early-phase brain diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS), and serum neuron-specific enolase (NSE) against the motor score and epileptic seizures (ES) for poor neurological outcome after out-of-hospital cardiac arrest (OHCA). METHODS: The predictive accuracy of DTI, 1H-MRS, and NSE along with motor score at 72 h and ES for the poor neurological outcome (modified Rankin Scale, mRS, 3 - 6) in 92 comatose OHCA patients at 6 months was assessed by area under the receiver operating characteristic curve (AUROC). Combined models of the variables were included as exploratory. RESULTS: The predictive accuracy of fractional anisotropy (FA) of DTI (AUROC 0.73, 95% CI 0.62-0.84), total N-acetyl aspartate/total creatine (tNAA/tCr) of 1H-MRS (0.78 (0.68 - 0.88)), or NSE at 72 h (0.85 (0.76 - 0.93)) was not significantly better than motor score at 72 h (0.88 (95% CI 0.80-0.96)). The addition of FA and tNAA/tCr to a combination of NSE, motor score, and ES provided a small but statistically significant improvement in predictive accuracy (AUROC 0.92 (0.85-0.98) vs 0.98 (0.96-1.00), p = 0.037). CONCLUSION: None of the variables (FA, tNAA/tCr, ES, NSE at 72 h, and motor score at 72 h) differed significantly in predicting poor outcomes in this patient group. Early-phase quantitative neuroimaging provided a statistically significant improvement for the predictive value when combined with ES and motor score with or without NSE. However, in clinical practice, the additional value is small, and considering the costs and challenges of imaging in this patient group, early-phase DTI/MRS cannot be recommended for routine use. TRIAL REGISTRATION: ClinicalTrials.gov NCT00879892, April 13, 2009.

Age-Related Perioperative Neurocognitive Disorders: Experimental Models and Druggable Targets.

With the worldwide increase in life span, surgical patients are becoming older and have a greater propensity for postoperative cognitive impairment, either new onset or through deterioration of an existing condition; in both conditions, knowledge of the patient's preoperative cognitive function and postoperative cognitive trajectory is imperative. We describe the clinical utility of a tablet-based technique for rapid assessment of the memory and attentiveness domains required for executive function. The pathogenic mechanisms for perioperative neurocognitive disorders have been investigated in animal models in which excessive and/or prolonged postoperative neuroinflammation has emerged as a likely contender. The cellular and molecular species involved in postoperative neuroinflammation are the putative targets for future therapeutic interventions that are efficacious and do not interfere with the surgical patient's healing process.

Interleukin-6 trans-signalling in hippocampal CA1 neurones mediates perioperative neurocognitive disorders in mice.

BACKGROUND: Interleukin-6 (IL-6), a pleiotropic cytokine with both degenerative and regenerative properties, is necessary and sufficient to provoke perioperative neurocognitive disorders after aseptic trauma in mice. IL-6 initiates its actions after binding to either membrane-bound IL-6 receptor α (mIL-6Rα) through classical signalling, or soluble IL-6 receptor (IL-6R) through trans-signalling; both signalling pathways require the transducer gp130. We investigated the site and type of IL-6 signalling that pertains in a tibial fracture aseptic trauma model of perioperative neurocognitive disorder. METHODS: Wild-type or genetically altered adult mice that lacked molecules unique to either classical or trans-IL-6 signalling underwent tibial fracture under isoflurane anaesthesia. In separate cohorts, we assessed postoperative memory using a trace fear conditioning paradigm (72 h postoperatively), and post-receptor IL-6 signalling (24 h postoperatively) using phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in CA1 hippocampal neurones. Fracture healing was assessed at postoperative day 15 after inhibiting either both forms of IL-6 signalling with BE0047 or only trans-signalling with sgp130Fc. RESULTS: The surgical phenotype of memory decline (decrease in freezing in trace fear conditioning) and upregulated IL-6 signalling (pSTAT3) did not occur after pretreatment before surgery with either BE0047 or sgp130Fc, or after depleting gp130 from CA1 neurones. The surgical phenotype still occurred when IL-6Rα was depleted in either CA1 hippocampal neurones (freezing time, 38.9% [11.5%] vs 58.4% [12.3%]; pSTAT+ CA1 neurones, 31.7 [4.9] vs 7.0 [3.1]) or microglia (freezing time, 40.1% [13.9%] vs 65.2% [12.6%]; pSTAT+ CA1 neurones, 30.1 [5.5] vs 7.9 [3.2]). In global IL-6Rα-/- mice, hyper-IL-6, the trans-signalling agonist, produced the surgical phenotype when administered i.c.v. (freezing time, 42.4% [8.8%] vs 59.7% [10.4%]; pSTAT+ cells, 29.3 [4.3] vs 10.0 [4.4]). Bone-fracture healing (% of fracture callus comprised of new collagen) was significantly greater with sgp130Fc than with BE0047 (52.2% [8.3%] vs 39.7% [7.9%]). CONCLUSIONS: After orthopaedic trauma, IL-6 produces perioperative neurocognitive disorders through IL-6 trans-signalling in mouse CA1 neurones. Druggable targets of the trans-signalling pathway should be sought to reduce perioperative neurocognitive disorders while allowing the healing properties of classical IL-6 signalling.

Considerations for the implementation of machine learning into acute care settings.

INTRODUCTION: Management of patients in the acute care setting requires accurate diagnosis and rapid initiation of validated treatments; therefore, this setting is likely to be an environment in which cognitive augmentation of the clinician's provision of care with technology rooted in artificial intelligence, such as machine learning (ML), is likely to eventuate. SOURCES OF DATA: PubMed and Google Scholar with search terms that included ML, intensive/critical care unit, electronic health records (EHR), anesthesia information management systems and clinical decision support were the primary sources for this report. AREAS OF AGREEMENT: Different categories of learning of large clinical datasets, often contained in EHRs, are used for training in ML. Supervised learning uses algorithm-based models, including support vector machines, to pair patients' attributes with an expected outcome. Unsupervised learning uses clustering algorithms to define to which disease grouping a patient's attributes most closely approximates. Reinforcement learning algorithms use ongoing environmental feedback to deterministically pursue likely patient outcome. AREAS OF CONTROVERSY: Application of ML can result in undesirable outcomes over concerns related to fairness, transparency, privacy and accountability. Whether these ML technologies irrevocably change the healthcare workforce remains unresolved. GROWING POINTS: Well-resourced Learning Health Systems are likely to exploit ML technology to gain the fullest benefits for their patients. How these clinical advantages can be extended to patients in health systems that are neither well-endowed, nor have the necessary data gathering technologies, needs to be urgently addressed to avoid further disparities in healthcare.

Defining the role of Interleukin-6 for the development of perioperative neurocognitive disorders: Evidence from clinical and preclinical studies.

For most, staying "mentally sharp" as they age is a very high priority that may be thwarted by the consequences of a postoperative complication unrelated to the disorder which necessitated the surgical intervention. Perioperative neurocognitive disorder (PND) is an overarching term for cognitive impairment in surgical patients, that includes conditions from delirium to dementia, affecting more than 7 million patients annually in the US, and which threatens both functional independence and life. Clinical trials and meta-analyses have identified the association between PNDs and increased perioperative levels of Interleukin-6 (IL-6), a pleiotropic cytokine that is both necessary and sufficient for postoperative memory decline in a preclinical model of PND. Recently, we reported that, in adult male wild-type mice subjected to tibial fracture under general anesthesia, IL-6 trans-signaling in hippocampal CA1 neurons mediates surgery-induced memory impairment. As there are no therapeutic options for preventing or reversing PNDs, patients and their caregivers, as well as the healthcare industry, endure staggering costs. Olamkicept, a highly selective IL-6 trans-signaling blocker has shown to be efficacious and safe in clinical trials involving patients with inflammatory bowel disease, another condition for which IL-6 trans-signaling is the mediating mechanism. Subject to a demonstration that olamkicept is effective in preventing cognitive impairment in vulnerable (aged and Alzheimer's Disease) preclinical PND models, clinical trials involving aged and/or cognitively impaired surgical patients should be undertaken to study olamkicept's utility for PNDs.

Effect of Intraoperative Dexmedetomidine on Recovery of Gastrointestinal Function After Abdominal Surgery in Older Adults: A Randomized Clinical Trial.

Importance: Postoperative ileus is common after abdominal surgery, and small clinical studies have reported that intraoperative administration of dexmedetomidine may be associated with improvements in postoperative gastrointestinal function. However, findings have been inconsistent and study samples have been small. Further examination of the effects of intraoperative dexmedetomidine on postoperative gastrointestinal function is needed. Objective: To evaluate the effects of intraoperative intravenous dexmedetomidine vs placebo on postoperative gastrointestinal function among older patients undergoing abdominal surgery. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at the First Affiliated Hospital of Anhui Medical University in Hefei, China (lead site), and 12 other tertiary hospitals in Anhui Province, China. A total of 808 participants aged 60 years or older who were scheduled to receive abdominal surgery with an expected surgical duration of 1 to 6 hours were enrolled. The study was conducted from August 21, 2018, to December 9, 2019. Interventions: Dexmedetomidine infusion (a loading dose of 0.5 µg/kg over 15 minutes followed by a maintenance dose of 0.2 µg/kg per hour) or placebo infusion (normal saline) during surgery. Main Outcomes and Measures: The primary outcome was time to first flatus. Secondary outcomes were postoperative gastrointestinal function measured by the I-FEED (intake, feeling nauseated, emesis, physical examination, and duration of symptoms) scoring system, time to first feces, time to first oral feeding, incidence of delirium, pain scores, sleep quality, postoperative nausea and vomiting, hospital costs, and hospital length of stay. Results: Among 808 patients enrolled, 404 were randomized to receive intraoperative dexmedetomidine, and 404 were randomized to receive placebo. In total, 133 patients (60 in the dexmedetomidine group and 73 in the placebo group) were excluded because of protocol deviations, and 675 patients (344 in the dexmedetomidine group and 331 in the placebo group; mean [SD] age, 70.2 [6.1] years; 445 men [65.9%]) were included in the per-protocol analysis. The dexmedetomidine group had a significantly shorter time to first flatus (median, 65 hours [IQR, 48-78 hours] vs 78 hours [62-93 hours], respectively; P < .001), time to first feces (median, 85 hours [IQR, 68-115 hours] vs 98 hours [IQR, 74-121 hours]; P = .001), and hospital length of stay (median, 13 days [IQR, 10-17 days] vs 15 days [IQR, 11-18 days]; P = .005) than the control group. Postoperative gastrointestinal function (as measured by the I-FEED score) and delirium incidence were similar in the dexmedetomidine and control groups (eg, 248 patients [72.1%] vs 254 patients [76.7%], respectively, had I-FEED scores indicating normal postoperative gastrointestinal function; 18 patients [5.2%] vs 12 patients [3.6%] had delirium on postoperative day 3). Conclusions and Relevance: In this randomized clinical trial, the administration of intraoperative dexmedetomidine reduced the time to first flatus, time to first feces, and length of stay after abdominal surgery. These results suggest that this therapy may be a viable strategy to enhance postoperative recovery of gastrointestinal function among older adults. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800017232.

High-Mobility Group Box-1 and Its Potential Role in Perioperative Neurocognitive Disorders.

Aseptic surgical trauma provokes the release of HMGB1, which engages the innate immune response after binding to pattern-recognition receptors on circulating bone marrow-derived monocytes (BM-DM). The initial systemic inflammation, together with HMGB1, disrupts the blood-brain barrier allowing penetration of CCR2-expressing BM-DMs into the hippocampus, attracted by the chemokine MCP-1 that is upregulated by HMGB1. Within the brain parenchyma quiescent microglia are activated and, together with the translocated BM-DMs, release proinflammatory cytokines that disrupt synaptic plasticity and hence memory formation and retention, resulting in postoperative cognitive decline (PCD). Neutralizing antibodies to HMGB1 prevents the inflammatory response to trauma and PCD.

Effect of Inhaled Xenon on Cardiac Function in Comatose Survivors of Out-of-Hospital Cardiac Arrest-A Substudy of the Xenon in Combination With Hypothermia After Cardiac Arrest Trial.

This explorative substudy aimed at determining the effect of inhaled xenon on left ventricular function by echocardiography in comatose survivors of out-of-hospital cardiac arrest. DESIGN: A randomized two-group single-blinded phase 2 clinical drug trial. SETTING: A multipurpose ICU in two university hospitals. PATIENTS: Of the 110 randomized comatose survivors after out-of-hospital cardiac arrest with a shockable rhythm in the xenon in combination with hypothermia after cardiac arrest trial, 38 patients (24-76 yr old) with complete echocardiography were included in this study. INTERVENTIONS: Patients were randomized to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours or hypothermia treatment alone. Echocardiography was performed at hospital admission and 24 ± 4 hours after hypothermia. MEASUREMENTS AND MAIN RESULTS: Left ventricular ejection fraction, myocardial longitudinal systolic strain, and diastolic function were analyzed blinded to treatment. There were 17 xenon and 21 control patients in whom echocardiography was completed. Clinical characteristics did not differ significantly between the groups. At admission, ejection fraction was similar in xenon and control patients (39% ± 10% vs 38% ± 11%; p = 0.711) but higher in xenon than control patients after hypothermia (50% ± 10% vs 42% ± 10%; p = 0.014). Global longitudinal systolic strain was similar in xenon and control patients at admission (-9.0% ± 3.8% vs -8.1% ± 3.6%; p = 0.555) but better in xenon than control patients after hypothermia (-14.4.0% ± 4.0% vs -10.5% ± 4.0%; p = 0.006). In patients with coronary artery disease, longitudinal strain improved in the nonischemic myocardial segments in xenon patients. There were no changes in diastolic function between the groups. CONCLUSIONS: Among comatose survivors of a cardiac cause out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia was associated with greater recovery of left ventricular systolic function in comparison with hypothermia alone.