Peripheral interleukin-6-associated microglial QUIN elevation in basolateral amygdala contributed to cognitive dysfunction in a mouse model of postoperative delirium.

Background: Developing effective approaches for postoperative delirium has been hampered due to the lack of a pathophysiologically similar animal model to offer insights into the pathogenesis. The study, therefore, aimed to develop a delirium-like mouse model and explore the underlying mechanism. Methods: The three cycles of 10-min clamp following 5-min reopening of the superior mesenteric artery (SMA) were performed in adult male C57BL/6 mice to induce a delirium-like phenotype. Composite Z score calculated based on the results of Open Field, Y Maze and Buried Food Tests was employed to assess the delirium phenotype in mice. Microglia activities were monitored by immunofluorescence staining and comprehensive morphological analysis. Systemic administration of minocycline (MINO), IL-6 antibody or IL-6 neutralizing antibody, was applied to manipulate microglia. The expressions of Indoleamine 2,3-dioxygenase-1 (IDO-1) and quinolinic acid (QUIN) were examined by RT-PCR and High-Performance Liquid Chromatography/Mass Spectrometry, respectively. Cytokines were measured using fluorescence activated cell sorting method. Results: The repeated ischemia/reperfusion (I/R) surgery caused significant anxiety (P < 0.05) and cognition decline in working memory and orientation (P < 0.05) in mice at postoperative 24 h. The composite Z score, indicating an overall disturbance of brain function, fluctuated over 24 h after I/R surgery (P < 0.001). Immunofluorescent staining showed that the percentage of microglia in the basolateral amygdala (BLA) (P < 0.05) was reactivated after I/R surgery and was negatively correlated with dwell time at Y maze (R = -0.759, P = 0.035). Inhibiting microglia activities by MINO reduced QUIN productions (P < 0.01) that improved cognitive deficits (P < 0.05). The peripheral IL-6 might cause IL-6 elevation in the BLA. Systemic administration of IL-6 antibodies suppressed I/R-induced IL-6 elevations (P < 0.05), microglial reactivations (P < 0.05), IDO-1 expressions (P < 0.01), and neuroactive metabolite QUIN productions (P < 0.05) in the BLA, resulting in a recovery of cognitive deficits (P < 0.05). Injection of IL-6 exerted opposite effects. Conclusion: The repeated intestinal I/R surgery-induced mouse model is a simple and reproducible one of postoperative delirium. Peripheral IL-6-associated microglial QUIN elevations in the BLA contributed to cognitive dysfunction in the model of postoperative delirium.

Effect of motor subtypes of delirium in the intensive care unit on fast-track failure after cardiac surgery.

OBJECTIVE: The purpose of the study was to evaluate the association between motor subtypes of postoperative delirium in the intensive care unit and fast-track failure (a composite outcome of prolonged stay in the intensive care unit >48 hours, intensive care unit readmission, and 30-day mortality) after cardiac surgery. METHODS: This was a secondary analysis of a prospective cohort study of 600 consecutive adults undergoing cardiac surgery at a university hospital in Hong Kong (July 2013 to July 2015). The motor subtypes of delirium were classified using the Richmond Agitation Sedation Score and Confusion Assessment Method intensive care unit assessments performed by trained bedside nurses. A generalized estimating equation was used to estimate a common relative risk of fast-track failure associated with motor subtypes. RESULTS: The incidences of hypoactive, hyperactive, and mixed motor subtypes were 4.3% (n = 26), 4.0% (n = 24), and 5.5% (n = 33), respectively. Fast-track failure occurred in 88 patients (14.7%). There was an association between delirium (all subtypes) and fast-track failure (P = .048); hyperactive delirium (relative risk, 1.95; 95% confidence interval, 0.96-3.94); hypoactive delirium (relative risk, 2.79; 95% confidence interval, 1.34-5.84); and mixed delirium (relative risk, 2.55; 95% confidence interval, 1.11-5.88). Hypoactive and mixed subtypes were associated with prolonged intensive care unit stay (both P = .001). CONCLUSIONS: Patients with pure hypoactive delirium had a similar risk of developing fast-track failure as other motor subtypes. Differentiation of motor subtypes is unlikely to be clinically important for prognostication of fast-track failure. However, because delirium is associated with poor outcomes, potential treatment strategies should address all subtypes equally.

Pharmacologic agents for the prevention and treatment of delirium in patients undergoing cardiac surgery: systematic review and metaanalysis.

OBJECTIVES: Postcardiac surgery delirium is associated with increased risks of morbidity, cognitive decline, poor health-related quality of life and mortality, and higher healthcare costs. We performed a systematic review of randomized controlled trials to examine the effect of pharmacologic agents for the prevention and the treatment of delirium after cardiac surgery. DATA SOURCES: Electronic search on PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, ISI Web of Science, and CINAHL up to December 2013. STUDY SELECTION: Randomized controlled trials of pharmacologic agents used for the prevention and the treatment of delirium after emergency or elective cardiac surgery in adults. DATA EXTRACTION: We extracted data on patient population, pharmacologic agents, delirium characteristics, rescue treatment, length of stays in the ICU and hospital, and mortality. For each trial, we assessed the risk of bias domains and rated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS: Of the 13 studies (10 prevention and three treatment) involving 5,848 patients, one multicentered randomized controlled trial on prophylactic dexamethasone made up 77% of the total sample size. The use of pharmacologic agents (dexamethasone, rivastigmine, risperidone, ketamine, dexmedetomidine, propofol, and clonidine) reduced the risk of delirium (relative risk, 0.57; 95% CI, 0.40-0.80) with quality of evidence rated as moderate. There was high quality of evidence for no increased risk of mortality (relative risk, 0.89; 95% CI, 0.57-1.38) associated with the use of prophylactic pharmacologic agents. Metaanalysis of treatment trials was not undertaken because of high heterogeneity. In two small trials (total number of patients = 133), haloperidol did not appear to be effective in treating delirium. CONCLUSIONS: Moderate to high-quality evidence supports the use of pharmacologic agents for the prevention of delirium, but results are based largely on one randomized controlled trial. The evidence for treating postcardiac surgery delirium with pharmacologic agents is inconclusive.

Anesthetic isoflurane posttreatment attenuates experimental lung injury by inhibiting inflammation and apoptosis.

We investigated the effect of 1.4% isoflurane (ISO) on the development of inflammation and apoptosis caused by zymosan (ZY) in mice. We found that ZY-challenged mice exhibited significant body weight loss, markedly high mortality, and significant lung injury characterized by the deterioration of histopathology, histologic scores, and wet-to-dry ratio after ISO treatment. ISO dramatically attenuated ZY-induced lung neutrophil recruitment and inflammation, as evidenced by the reduced levels of total cells, neutrophils, and proinflammatory cytokines (i.e., tumor necrosis factor- α , interleukin- (IL-) 1 ß , IL-6, and macrophage inflammatory protein-2) in bronchoalveolar lavage fluid and of their mRNA expression in lung tissues. ISO also inhibited ZY-induced expression and activation of nuclear factor-kappaB p65 and inducible nitric oxide synthase in pulmonary tissue. ZY administration also resulted in the upregulation of heme oxygenase-1 expression and activity in the lung, which was further enhanced by ISO treatment. Moreover, ISO markedly prevented ZY-induced pulmonary cell apoptosis in mice, as reflected by the decrease in expression of procaspase-8, procaspase-3, cleaved caspase-8, and cleaved caspase-3, as well as in caspase-3 activity and Bcl-2-associated X/B-cell lymphoma 2 ratio. These results indicate that ISO is a potential therapeutic drug for treating ZY-induced lung injury, and further investigations are warranted.