Preoperative Cognitive Abnormality, Intraoperative Electroencephalogram Suppression, and Postoperative Delirium: A Mediation Analysis.

BACKGROUND: Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. METHODS: This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. RESULTS: Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). CONCLUSIONS: A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.

The effect of intravenous ketamine on depressive symptoms after surgery: A systematic review.

STUDY OBJECTIVE: The development of depressive symptoms is an important complication experienced by patients postoperatively and is associated with poor clinical outcomes. Ketamine is a feasible treatment option for depressive symptoms after surgery due to its known antidepressant effect. This meta-analysis aimed to evaluate the current body of research regarding the effects of intravenous ketamine on depressive symptoms after surgery. DESIGN: A meta-analysis of randomized controlled trials. SETTING: Perioperative care area. PATIENTS: Adult surgical patients. MEASUREMENTS: Systematic literature search was performed in the CENTRAL, MEDLINE, and EMBASE databases, for randomized controlled trials comparing the effect of intravenous ketamine versus placebo on postoperative depressive symptoms as the primary outcome, with no language restrictions. Two independent reviewers screened records for inclusion, extracted data, and assessed risk of bias. Random effects models were used to pool overall estimates. Postoperative pain intensity was also examined. The GRADE approach was used to assess the quality of evidence. MAIN RESULTS: Out of 834 records screened, 9 studies met our inclusion criteria, comprising a total of 2468 patients. Compared with the control group, ketamine provided significant reduction of postoperative depression scale scores, by a standardized mean difference (SMD) of -0.89 (95% CI [-1.23, -0.73], P = 0.33, I2 = 13%; 4 studies) on postoperative day (POD) 1, SMD -0.51 (95% CI [-0.99, -0.04], P < 0.001, I2 = 93%; 4 studies) on POD 3, suggesting clinically relevant reduction in postoperative depressive symptoms. Postoperative depression scale scores on POD 7 were also reduced in patients receiving ketamine compared to the control group, with SMD -0.33 (95% CI [-0.52, -0.14], P = 0.36, I2 = 2%; 3 studies), but the minimal clinical difference of 0.5 SMD was not reached. No significant difference was observed in the postoperative depression scale over the long term at 30 days' follow-up (SMD -0.13, 95% CI [-0.25, 0.00], P = 0.07, I2 = 52%; 5 studies). A significant reduction of postoperative pain intensity on POD 1 was identified in patients following ketamine administration (SMD -1.29, 95% CI [-2.57, -0.01], P = 0.05, I2 = 98%; 5 studies). However, administration of ketamine resulted in a significantly increased risk of nausea and vomiting (RR 1.71, 95% CI [1.25, 2.33], P = 0.17, I2 = 35%; 6 studies), headache (RR 4.88, 95% CI [1.97, 12.06], P = 0.83, I2 = 0%; 4 studies), and hallucination (RR 34.94, 95% CI [8.59, 142.17], P = 0.44, I2 = 0%; 4 studies). CONCLUSIONS: The current evidence supports intravenous ketamine administration for the treatment of depressive symptoms after surgery. While ketamine administration has clinically significant side effects, future studies are needed in surgical populations at high risk of complications.

SIRT1 activation attenuates microglia-mediated synaptic engulfment in postoperative cognitive dysfunction.

Background: Postoperative cognitive dysfunction (POCD) is a debilitating neurological complication in surgical patients. Current research has focused mainly on microglial activation, but less is known about the resultant neuronal synaptic changes. Recent studies have suggested that Sirtuin-1 (SIRT1) plays a critical role in several different neurological disorders via its involvement in microglial activation. In this study, we evaluate the effects of SIRT1 activation in a POCD mouse model. Materials and methods: Exploratory laparotomy was performed in mice aged 12-14 months under sevoflurane anesthesia to establish our animal POCD model. Transcriptional changes in the hippocampus after anesthesia and surgery were evaluated by RNA sequencing. SIRT1 expression was verified by Western Blot. Mice were treated with SIRT1 agonist SRT1720 or vehicle after surgery. Changes in microglia morphology, microglial phagocytosis, presence of dystrophic neurites, and dendritic spine density were evaluated. Cognitive performance was evaluated using the Y maze and Morris water maze (MWM). Results: Sirtuin-1 expression levels were downregulated in POCD. Exposure to anesthesia and surgery lead to alteration in microglia morphology, increased synaptic engulfment, dendritic spine loss, and cognitive deficits. These effects were alleviated by SRT1720 administration. Conclusion: This study suggests an important neuroprotective role for SIRT1 in POCD pathogenesis. Increasing SIRT1 function represents a promising therapeutic strategy for prevention and treatment of POCD.

LncRNA NONMMUT055714 acts as the sponge of microRNA-7684-5p to protect against postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a neurological complication of surgery especially common in elderly patients. In this study, we investigated the role of NONMMUT055714 in POCD via regulation of miR-7684-5p. In a POCD mouse model, we induced overexpression of NONMUTT055714 via transfection of lentivrus into the hippocampus, and used the Morris water maze for assessment of cognitive function. Silencing of NONMUTT055714 and miR-7684-5p was induced in primary hippocampal neurons to observe the effects of these regulatory RNAs on cellular processes. Bioinformatics analysis and a double luciferase reporter experiment were performed to further explore the relationship between NONMMUT055714, miR-7684-5p, and SORLA. Cell and animal rescue experiments were performed to verify the ability of miR-7684-5p to reverse the protective effects of NONMMUT055714 overexpression in POCD. We observed that NONMMUT055714 has decreased expression in the POCD mouse model. Overexpression of NONMMUT055714 protected against cognitive impairment of the POCD mouse model in vivo. We identified miR-7684-5p as a NONMMUT055714-related miRNA and in turn as an upstream regulator of SORLA. We found that NONMMUT055714 downregulation is associated with decreased SORLA, increased Aß and p-tau expression, increased inflammatory biomarkers, increased markers of oxidative stress, and increased neuronal apoptosis in vitro. The effects of NONMMUT055714 downregulation were reversed by silencing miR-7684-5p in vitro and in vivo. Taken together, our findings suggest that NONMMUT055714 is protective against the development of POCD via its function as a ceRNA (or miRNA sponge) in the regulation of miR-7684-5p and SORLA. We therefore propose NONMMUT055714 as a novel target for the investigation and prevention of POCD.

Electroencephalography: Clinical Applications During the Perioperative Period.

Electroencephalography (EEG) monitoring has become technically feasible in daily clinical anesthesia practice. EEG is a sensitive method for detecting neurophysiological changes in the brain and represents an important frontier in the monitoring and treatment of patients in the perioperative period. In this review, we briefly introduce the essential principles of EEG. We review EEG application during anesthesia practice in the operating room, including the use of processed EEG in depth of anesthesia assessment, raw EEG monitoring in recognizing brain states under different anesthetic agents, the use of EEG in the prevention of perioperative neurocognitive disorders and detection of cerebral ischemia. We then discuss EEG utilization in the intensive care units, including the use of EEG in sedative level titration and prognostication of clinical outcomes. Existing literature provides insight into both the advances and challenges of the clinical applications of EEG. Future study is clearly needed to elucidate the precise EEG features that can reliably optimize perioperative care for individual patients.

Propofol Attenuates α-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke.

α-Synuclein is a soluble monomer abundant in the central nervous system. Aggregates of α-synuclein, consisting of higher-level oligomers and insoluble fibrils, have been observed in many chronic neurological diseases and are implicated in neurotoxicity and neurodegeneration. α-Synuclein has recently been shown to aggregate following acute ischemic stroke, exacerbating neuronal damage. Propofol is an intravenous anesthetic that is commonly used during intravascular embolectomy following acute ischemic stroke. While propofol has demonstrated neuroprotective properties following brain injury, the mechanism of protection in the setting of ischemic stroke is unclear. In this study, propofol administration significantly reduced the neurotoxic aggregation of α-synuclein, decreased the infarct area, and attenuated the neurological deficits after ischemic stroke in a mouse model. We then demonstrated that the propofol-induced reduction of α-synuclein aggregation was associated with increased mammalian target of rapamycin/ribosomal protein S6 kinase beta-1 signaling pathway activity and reduction of the excessive autophagy occurring after acute ischemic stroke.

Protocol for an observational study of delirium in the post-anaesthesia care unit (PACU) as a potential predictor of subsequent postoperative delirium.

INTRODUCTION: Postoperative delirium can be a serious consequence of major surgery, associated with longer hospital stays, readmission, cognitive and functional deterioration and mortality. Delirium is an acute, reversible disorder characterised by fluctuating course, inattention, disorganised thinking and altered level of consciousness. Delirium occurring in the hours immediately following anaesthesia and delirium occurring in the postoperative period of 1-5 days have been described as distinct clinical entities. This protocol describes an observational study with the aim of determining if delirium in the first hour following tracheal tube removal is a predictor of delirium in the 5 subsequent postoperative days. Improved understanding regarding the development of postoperative delirium would improve patient care and allow more effective implementation of delirium prevention measures. METHODS AND ANALYSIS: Patients enrolled to the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomised controlled trial will be eligible for this substudy. A validated delirium assessment method, the 3-min Diagnostic Confusion Assessment Method and the Richmond Agitation and Sedation Scale will be used to assess 100 patients for delirium at 30 min and 60 min following tracheal tube removal. Patients will also be assessed for delirium over postoperative days 1-5 using three validated methods, the Confusion Assessment Method (CAM), CAM for the Intensive Care Unit and structured chart review. Logistic regression analysis will then be performed to test whether immediately postoperative delirium independently predicts subsequent postoperative delirium. ETHICS AND DISSEMINATION: This observational substudy of ENGAGES has been approved by the ethics board of Washington University School of Medicine. Enrolment began in June 2016 and will continue until June 2017. Dissemination plans include presentations at scientific conferences and scientific publications. TRIAL REGISTRATION NUMBER: NCT02241655.

Human chondrocyte migration behaviour to guide the development of engineered cartilage.

Tissue-engineering techniques have been successful in developing cartilage-like tissues in vitro using cells from animal sources. The successful translation of these strategies to the clinic will likely require cell expansion to achieve sufficient cell numbers. Using a two-dimensional (2D) cell migration assay to first identify the passage at which chondrocytes exhibited their greatest chondrogenic potential, the objective of this study was to determine a more optimal culture medium for developing three-dimensional (3D) cartilage-like tissues using human cells. We evaluated combinations of commonly used growth factors that have been shown to promote chondrogenic growth and development. Human articular chondrocytes (AC) from osteoarthritic (OA) joints were cultured in 3D environments, either in pellets or encapsulated in agarose. The effect of growth factor supplementation was dependent on the environment, such that matrix deposition differed between the two culture systems. ACs in pellet culture were more responsive to bone morphogenetic protein (BMP2) alone or combinations containing BMP2 (i.e. BMP2 with PDGF or FGF). However, engineered cartilage development within agarose was better for constructs cultured with TGFß3. These results with agarose and pellet culture studies set the stage for the development of conditions appropriate for culturing 3D functional engineered cartilage for eventual use in human therapies. Copyright © 2015 John Wiley & Sons, Ltd.

Isolated oculomotor nerve palsy resulting from acute traumatic tentorial subdural hematoma.

Acute subdural hematoma (SDH) resulting from head trauma is a potentially life-threatening condition that requires expedient diagnosis and intervention to ensure optimal patient outcomes. Rapidly expanding or large hematomas, elevated intracranial pressure, and associated complications of brain herniation are associated with high mortality rates and poor recovery of neurological function. However, smaller bleeds (clot thickness <10 mm) or hematomas occurring in infrequent locations, such as the tentorium cerebelli, may be difficult to recognize and patients may present with unusual or subtle signs and symptoms, including isolated cranial nerve palsies. Knowledge of neuroanatomy supported by modern neuroimaging can greatly aid in recognition and diagnosis of such lesions. In this report, we present a case of isolated oculomotor nerve palsy resulting from compressive tentorial SDH following blunt head trauma, review the literature concerning similar cases, and make recommendations regarding the diagnosis of SDH in patients presenting with isolated cranial nerve palsies.

Treatment and prevention of infection following bites of the Antarctic fur seal (Arctocephalus gazella).

In recent decades, an increasing number of people have traveled to sub-Antarctic and Antarctic regions each year for research, tourism, and resource exploitation. Hunting of Antarctic fur seals (Arctocephalus gazella) almost pushed the species to extinction in the early 1900s, but populations have since shown rapid and substantial recovery. The species' range has re-expanded to include several islands south of the Antarctic Convergence, most notably South Georgia, and now overlaps with many popular Antarctic travel destinations. Both male and female fur seals can become extremely aggressive when provoked, and their bites, if not properly treated, pose a significant risk of infection by microorganisms not usually encountered in cases of animal bites. In this report, we present the case of a patient treated for a fur seal bite during an Antarctic expedition cruise, review the literature concerning seal bites, and suggest the use of antibiotic prophylaxis to prevent complications.

A case of cerebral aneurysm rupture and subarachnoid hemorrhage associated with air travel.

During air travel, passengers are exposed to unique conditions such as rapid ascent and descent that can trigger significant physiological changes. In addition, the cabins of commercial aircraft are only partially pressured to 552-632 mmHg or the equivalent terrestrial altitudes of 1,500-2,500 m (5,000-8,000 feet) above sea level. While studies in high-altitude medicine have shown that all individuals experience some degree of hypoxia, cerebral edema, and increased cerebral blood flow, the neurological effects that accompany these changes are otherwise poorly understood. In this study, we report a case of acute subarachnoid hemorrhage from a ruptured cerebral aneurysm associated with travel on commercial aircraft. We then review relevant cases of neurological incidents with possible air travel-related etiology and discuss the physiological factors that may have contributed to the patient's acute subarachnoid hemorrhage. In the future, this report may serve as reference for more detailed and conservative medical guidelines and recommendations regarding air travel.