Predictors for delayed awakening in adult glioma patients receiving awake craniotomy under monitored anesthesia care.

PURPOSE: Delayed awakening after anesthetic discontinuation during awake craniotomy is associated with somnolence during functional brain mapping. However, predictors of delayed awakening in patients receiving monitored anesthesia care for awake craniotomy are unknown. METHODS: This retrospective cohort study analyzed 117 adult patients with supratentorial glioma in or near eloquent areas who received monitored anesthesia care for awake craniotomy between July 2020 and January 2023 at Linkou Chang Gung Memorial Hospital. These patients were divided into two groups according to their time to awakening (ability to speak their names) after propofol cessation: longer or shorter than 20 min (median duration). Because propofol was solely used anesthetic from skin incision to dural opening, parameters in Schnider model for propofol target-controlled infusion, such as age, sex, and BMI, were adjusted or propensity-matched to compare their anesthetic, surgical, and histopathological profiles. RESULTS: After propensity-matched comparisons of age and BMI, significant predictors of delayed awakening included IDH1 wild-type tumors and repeated craniotomies. Subgroup analysis revealed that older age and larger T2 volume were predictors in patients undergoing the first craniotomy, while lower preoperative Karnofsky performance scale scores and depression were predictors in repeated craniotomy cases. Delayed awakening was also associated with somnolence and a lower gross total resection rate. CONCLUSION: Our retrospective analysis of patients receiving monitored anesthesia care for awake craniotomy revealed that delayed awakening after propofol discontinuation occurred more often in patients with IDH1 wild-type tumors and repeated craniotomies. Also, delayed awakening was associated with somnolence during functional mapping and a lower gross total resection rate.

Exploring the aging process of cognitively healthy adults by analyzing cerebrospinal fluid metabolomics using liquid chromatography-tandem mass spectrometry.

BACKGROUND: During biological aging, significant metabolic dysregulation in the central nervous system may lead to cognitive decline and neurodegeneration. However, the metabolomics of the aging process in cerebrospinal fluid (CSF) has not been thoroughly explored. METHODS: In this cohort study of CSF metabolomics using liquid chromatography-mass spectrometry (LC-MS), fasting CSF samples collected from 92 cognitively unimpaired adults aged 20-87 years without obesity or diabetes were analyzed. RESULTS: We identified 37 metabolites in these CSF samples with significant positive correlations with aging, including cysteine, pantothenic acid, 5-hydroxyindoleacetic acid (5-HIAA), aspartic acid, and glutamate; and two metabolites with negative correlations, asparagine and glycerophosphocholine. The combined alterations of asparagine, cysteine, glycerophosphocholine, pantothenic acid, sucrose, and 5-HIAA showed a superior correlation with aging (AUC = 0.982). These age-correlated changes in CSF metabolites might reflect blood-brain barrier breakdown, neuroinflammation, and mitochondrial dysfunction in the aging brain. We also found sex differences in CSF metabolites with higher levels of taurine and 5-HIAA in women using propensity-matched comparison. CONCLUSIONS: Our LC-MS metabolomics of the aging process in a Taiwanese population revealed several significantly altered CSF metabolites during aging and between the sexes. These metabolic alterations in CSF might provide clues for healthy brain aging and deserve further exploration.

Tracheostomy and venovenous extracorporeal membrane oxygenation for difficult airway patient with carinal melanoma: A case report and literature review.

BACKGROUND: Anesthesia for tracheal tumor resection is challenging, particularly in patients with a difficult upper airway. We report a case of a difficult upper airway with a metastatic tracheal tumor causing near-total left bronchial obstruction and requiring emergency tracheostomy and venovenous extracorporeal membrane oxygenation (VV-ECMO) support for rigid bronchoscopy-assisted tumor resection. CASE SUMMARY: A 41-year-old man with a history of right retromolar melanoma treated by tumor excision and myocutaneous flap reconstruction developed progressive dyspnea on exertion and syncope episodes. Chest computed tomography revealed a 3.0-cm tracheal mass at the carinal level, causing 90% tracheal lumen obstruction. Flexible bronchoscopy revealed a pigmented tracheal mass at the carinal level causing critical carinal obstruction. Because of aggravated symptoms, emergency rigid bronchoscopy for tumor resection and tracheal stenting were planned with standby VV-ECMO. Due to limited mouth opening, tracheostomy was necessary for rigid bronchoscopy access. While transferring the patient to the operating table, sudden desaturation occurred and awake fiberoptic nasotracheal intubation was performed for ventilation support. Femoral and internal jugular vein were catheterized to facilitate possible VV-ECMO deployment. During tracheostomy, progressive desaturation developed and VV-ECMO was instituted immediately. After tumor resection and tracheal stenting, VV-ECMO was weaned smoothly, and the patient was sent for intensive postoperative care. Two days later, he was transferred to the ward for palliative immunotherapy and subsequently discharged uneventfully. CONCLUSION: In a difficult airway patient with severe airway obstruction, emergency tracheostomy for rigid bronchoscopy access and standby VV-ECMO can be life-saving, and ECMO can be weaned smoothly after tumor excision. During anesthesia for patients with tracheal tumors causing critical airway obstruction, spontaneous ventilation should be maintained at least initially, and ECMO deployment should be prepared for high-risk patients, such as those with obstructive symptoms, obstructed tracheal lumen > 50%, or distal trachea location.

Metabolomic Signature of Diabetic Kidney Disease in Cerebrospinal Fluid and Plasma of Patients with Type 2 Diabetes Using Liquid Chromatography-Mass Spectrometry.

Diabetic kidney disease (DKD) is the major cause of end stage renal disease in patients with type 2 diabetes mellitus (T2DM). The subtle metabolic changes in plasma and cerebrospinal fluid (CSF) might precede the development of DKD by years. In this longitudinal study, CSF and plasma samples were collected from 28 patients with T2DM and 25 controls, during spinal anesthesia for elective surgery in 2017. These samples were analyzed using liquid chromatography-mass spectrometry (LC-MS) in 2017, and the results were correlated with current DKD in 2017, and the development of new-onset DKD, in 2021. Comparing patients with T2DM having new-onset DKD with those without DKD, revealed significantly increased CSF tryptophan and plasma uric acid levels, whereas phosphatidylcholine 36:4 was lower. The altered metabolites in the current DKD cases were uric acid and paraxanthine in the CSF and uric acid, L-acetylcarnitine, bilirubin, and phosphatidylethanolamine 38:4 in the plasma. These metabolic alterations suggest the defective mitochondrial fatty acid oxidation and purine and phospholipid metabolism in patients with DKD. A correlation analysis found CSF uric acid had an independent positive association with the urine albumin-to-creatinine ratio. In conclusion, these identified CSF and plasma biomarkers of DKD in diabetic patients, might be valuable for monitoring the DKD progression.

1H NMR metabolomic profiling of human cerebrospinal fluid in aging process.

The molecular process of biological aging might be accompanied by significant metabolic derangement, especially in the central nervous system (CNS), since the brain has an enormous energy demand. However, the metabolic signature of the aging process in cerebrospinal fluid (CSF) has not been thoroughly investigated, especially in the Asian population. In this prospective cohort study on CSF metabolomics using proton nuclear magnetic resonance (NMR) spectroscopy, fasting CSF samples from 75 cognitively unimpaired patients aged 20-92 years without diabetes or obesity, undergoing spinal anesthesia for elective surgery were analyzed. Several metabolites in CSF samples were identified as having a significant association with the aging process in cerebral circulation; among the metabolites, the levels of alanine, citrate, creatinine, lactate, leucine, tyrosine, and valine significantly increased in old patients compared to those in young patients. The combined CSF metabolite alterations in citrate, lactate, leucine, tyrosine, and valine had a superior correlation with the aging process in all age groups. In conclusion, our pilot study of aging CSF metabolomics in the Taiwanese population presents significantly altered CSF metabolites with potential relevance to the aging process. These metabolic alterations in CSF samples might imply increasing anaerobic glycolysis, mitochondrial dysfunction, and decreasing glucose utilization in cerebral circulation in aged patients.

Familial Aggregation and Heritability of Nonmedullary Thyroid Cancer in an Asian Population: A Nationwide Cohort Study.

PURPOSE: The purpose of this work is to assess the extent of familial aggregation of nonmedullary thyroid cancer (NMTC) and the relative risks (RRs) of chronic thyroid diseases and common malignancies in first-degree relatives of NMTC patients. METHODS: In the National Health Insurance Research database of Taiwan, all eligible individuals in 2016 were analyzed (n = 23 696 659) and the family structures of 38 686 patients diagnosed with NMTC between 1997 and 2016 were identified. The prevalence and RRs of NMTC, chronic thyroid diseases, and common malignancies in individuals with first-degree relatives with NMTC were examined. The accountability of heritability and environmental factors to NMTC susceptibility was estimated using the polygenic liability model. RESULTS: The prevalence of NMTC was 0.16% in the general population and 0.64% in individuals with first-degree relatives with NMTC. Regarding affected relatives, the RR (95% CI) for NMTC was 20.12 (4.86-83.29) for twins, 6.43 (4.80-8.62) for siblings, 5.24 (4.55-6.03) for offspring, 5.07 (4.41-5.81) for parents, and 2.07 (1.53-2.81) for spouses. The estimated genetic, common environmental, and nonshared environmental contributions to NMTC were 28.0%, 14.3%, and 57.7%, respectively. A family history of NMTC was associated with higher risks of thyroid nodules (RR, 2.26; 95% CI, 2.18-2.35), Hashimoto thyroiditis (2.11; 1.89-2.36), Graves disease (1.49; 1.42-1.57), lung cancer (1.56; 1.32-1.85), and leukemia and lymphoma (1.24; 1.03-1.50). CONCLUSION: Our findings demonstrate the importance of genetic and environmental contributions to NMTC susceptibility and highlight the coaggregation of chronic thyroid diseases and multiple malignancies with NMTC.

1H Nuclear Magnetic Resonance (NMR)-Based Cerebrospinal Fluid and Plasma Metabolomic Analysis in Type 2 Diabetic Patients and Risk Prediction for Diabetic Microangiopathy.

Insulin resistance and metabolic derangement are present in patients with type 2 diabetes mellitus (T2DM). However, the metabolomic signature of T2DM in cerebrospinal fluid (CSF) has not been investigated thus far. In this prospective metabolomic study, fasting CSF and plasma samples from 40 T2DM patients to 36 control subjects undergoing elective surgery with spinal anesthesia were analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy. NMR spectra of CSF and plasma metabolites were analyzed and correlated with the presence of T2DM and diabetic microangiopathy (retinopathy, nephropathy, and neuropathy) using an area under the curve (AUC) estimation. CSF metabolomic profiles in T2DM patients vs. controls revealed significantly increased levels of alanine, leucine, valine, tyrosine, lactate, pyruvate, and decreased levels of histidine. In addition, a combination of alanine, histidine, leucine, pyruvate, tyrosine, and valine in CSF showed a superior correlation with the presence of T2DM (AUC:0.951), diabetic retinopathy (AUC:0.858), nephropathy (AUC:0.811), and neuropathy (AUC:0.691). Similar correlations also appeared in plasma profiling. These metabolic alterations in CSF suggest decreasing aerobic metabolism and increasing anaerobic glycolysis in cerebral circulation of patients with T2DM. In conclusion, our results provide clues for the metabolic derangements in diabetic central neuropathy among T2DM patients; however, their clinical significance requires further exploration.

Epidemiology and Survival Outcomes of Lung Cancer: A Population-Based Study.

PURPOSE: Lung cancer has been the top-ranking cause of cancer deaths in Taiwan for decades. Limited data were available in global cancer surveillance regarding lung cancer epidemiology in Taiwan, and previous reports are outdated. PATIENTS AND METHODS: This population-based cohort study extracted data of patients with lung cancer from the Taiwan National Health Insurance database and determined the lung cancer incidence and prevalence during 2002-2014. Histological subtypes were retrieved from the Taiwan Cancer Registry database; survival rates were gathered from the National Death Registry. Average annual percentage changes (APCs) of prevalence, incidence, and overall survival were estimated by joinpoint regression analysis. RESULTS: Age-standardized incidence of lung cancer increased from 45.04 per 100,000 person-years in 2002 to 49.86 per 100,000 person-years in 2014, with an average APC of 0.7 (95% CI = 0.3-1.1; 0.2 in males, 2.0 in females). Lung cancer was more prevalent in male patients, but this increase gradually slowed down. Socioeconomic analysis showed that lung cancer has higher prevalence in patients with higher income level and urban residency. Adenocarcinoma was the most abundant histological subtype in Taiwan (adenocarcinoma-to-squamous cell carcinoma ratio = 4.16 in 2014), with a 2.4-fold increase of incident cases during 2002-2014 (from 43.47% to 64.89% of all lung cancer cases). The 5-year survival rate of lung cancer patients in 2010 was 17.34% (12.60% in male, 25.40% in female), with an average APC of 9.3 (6.3 in male, 11.8 in female) during 2002-2010. CONCLUSION: Average APCs of prevalence and incidence of lung cancer were 3.1 and 0.7, respectively, during 2002-2014 in Taiwan. The number of female patients and number of patients with adenocarcinoma have increased the most, with incident cases doubling in these years. Facing this fatal malignancy, it is imperative to improve risk stratification, encourage early surveillance, and develop effective therapeutics for lung cancer patients in Taiwan.

Familial aggregation of Parkinson's disease and coaggregation with neuropsychiatric diseases: a population-based cohort study.

BACKGROUND: Individuals with a family history of Parkinson's disease (PD) appear to have a higher risk of developing PD and other neuropsychiatric diseases. However, estimates of the relative risks (RRs) of PD and the roles of genetic and environmental factors in PD susceptibility are unclear. The aim of this study was to examine familial aggregation and genetic contributions to PD and the RRs of other neuropsychiatric diseases in relatives of PD patients. METHODS: In this population-based family cohort study, the records of all individuals actively registered in the Taiwan National Health Insurance Research Database in 2015 were queried (N=24,349,599). In total, 149,187 individuals with a PD-affected parent, 3,698 with an affected offspring, 3,495 with an affected sibling, and 15 with an affected twin were identified. Diagnoses of PD were ascertained between January 1, 1999, and December 31, 2015. The prevalence and RRs of PD and other neuropsychiatric diseases in individuals with first-degree relatives with PD, as well as the contributions of heritability and environmental factors to PD susceptibility were investigated. RESULTS: The prevalence of PD was 0.46% in the general population and 0.52% in individuals with first-degree relatives with PD. The RR (95% CI) for PD was 2.20 (1.41-3.45) for siblings, 1.59 (1.47-1.73) for parents, 1.86 (1.63-2.11) for offspring, 63.12 (16.45-242.16) for twins, and 1.46 (1.41-1.52) for spouses. The RR (95% CI) in individuals with first-degree relatives with PD was 1.66 (1.57-1.76) for essential tremor, 1.68 (1.61-1.75) for schizophrenia, and 1.20 (1.12-1.28) for Alzheimer's disease. The estimated contribution to the phenotypic variance of PD was 11.0% for heritability, 9.1% for shared environmental factors, and 79.9% for non-shared environmental factors. CONCLUSION: First-degree relatives of PD patients are more likely to develop PD and other neuropsychiatric diseases. Environmental factors account for a high proportion of the phenotypic variance of PD.

Impact of the pretransplant dialysis modality on kidney transplantation outcomes: a nationwide cohort study.

OBJECTIVE: Most patients with uraemia must undergo chronic dialysis while awaiting kidney transplantation; however, the role of the pretransplant dialysis modality on the outcomes of kidney transplantation remains obscure. The objective of this study was to clarify the associations between the pretransplant dialysis modality, namely haemodialysis (HD) or peritoneal dialysis (PD), and the development of post-transplant de novo diseases, allograft failure and all-cause mortality for kidney-transplant recipients. DESIGN: Retrospective nationwide cohort study. SETTING: Data retrieved from the Taiwan National Health Insurance Research Database. PARTICIPANTS: The National Health Insurance database was explored for patients who received kidney transplantation in Taiwan during 1998-2011 and underwent dialysis >90 days before transplantation. OUTCOME MEASURES: The pretransplant characteristics, complications during kidney transplantation and post-transplant outcomes were statistically analysed and compared between the HD and PD groups. Cox regression analysis was used to evaluate the HR of the dialysis modality on graft failure and all-cause mortality. The primary outcomes were long-term post-transplant death-censored allograft failure and all-cause mortality started after 90 days of kidney transplantation until the end of follow-up. The secondary outcomes were events during kidney transplantation and post-transplant de novo diseases adjusted by propensity score in log-binomial model. RESULTS: There were 1812 patients included in our cohort, among which 1209 (66.7%) and 603 (33.3%) recipients received pretransplant HD and PD, respectively. Recipients with chronic HD were generally older and male, had higher risks of developing post-transplant de novo ischaemic heart disease, tuberculosis and hepatitis C after adjustment. Pretransplant HD contributed to higher graft failure in the multivariate analysis (HR 1.38, p<0.05) after adjustment for the recipient age, sex, duration of dialysis and pretransplant diseases. There was no significant between-group difference in overall survival. CONCLUSIONS: Pretransplant HD contributed to higher risks of death-censored allograft failure after kidney transplantation when compared with PD.

Nationwide cohort study on the epidemiology and survival outcomes of thyroid cancer.

In the past three decades, the thyroid cancer incidence has surged globally. Herein, the Taiwan National Health Insurance database was used to identify thyroid cancer patients and to estimate the prevalence and incidence of thyroid cancer during 1997-2012. The Taiwan Cancer Registry and the National Death Registry databases were crosslinked to obtain information on the histological subtypes and survival rates. Joinpoint regression analysis was used for estimating the average annual percentage changes (APCs) in prevalence, incidence, and survival. The age-standardized incidence of thyroid cancer increased from 5.66 per 100,000 person-years in 1997 to 12.30 per 100,000 person-years in 2012, with an average APC of 5.1 (6.9 in males, 4.6 in females). Thyroid cancer was more prevalent in patients with high socioeconomic status and in urban areas. Papillary carcinoma was the most abundant subtype, with a 2.9-fold increase of incident cases noted during 1998-2012 (from 80.6% to 89.8% of all cases). Among the different treatments, partial thyroidectomy increased the most (average APC, 17.3). The overall survival rates by sex and subtype remained stable over time, with 5-year survival rates of 90.2% in 1997 and 92.4% in 2010. In conclusion, 2.2- and 4.2-fold increases in the incidence and prevalence of thyroid cancer, respectively, were observed during 1997-2012 in Taiwan. The surging incidence of thyroid cancer but stable survival rates, and mainly increased in the papillary subtype, altogether imply enhanced detection of subclinical lesions. A true increase due to environmental carcinogens might also be responsible, but warrant further investigations.

Impact of immunosuppressant therapy on new-onset diabetes in liver transplant recipients.

This nationwide, population-based study aimed to clarify the effects of immunosuppressive regimens on new-onset diabetes after liver transplantation (NODALT). The National Health Insurance database of Taiwan was explored for patients who received liver transplantation without pre-transplant diabetes from 1998 to 2012. Information regarding clinical conditions and immunosuppressant utilization among these patients was analyzed statistically. Of the 2,140 patients included in our study, 189 (8.8%) developed NODALT. The pre-transplant risk factors for NODALT were identified as old age, male sex, hepatitis C, alcoholic hepatitis, and immunosuppressant use of tacrolimus (TAC). All patients used corticosteroids as a baseline immunosuppressant. The immunosuppressant regimen of cyclosporine (CsA)+TAC+mycophenolate mofetil (MMF) contributed most to NODALT (adjusted hazard ratio 7.596) in comparison with the regimens of TAC+MMF and CsA+MMF; this regimen also contributed significantly to higher post-transplant bacteremia, urinary tract infection, pneumonia, renal failure, and mortality rate. In conclusion, our analysis confirmed TAC-based immunosuppression contributes to higher NODALT incidence than CsA-based regimen, and TAC-CsA conversion due to any causes might lead to worse clinical outcomes. Clinicians should make better risk stratifications before prescribing immunosuppressants for liver transplant recipients.

Epidemiology and survival outcome of breast cancer in a nationwide study.

Breast cancer is among the most prevalent cancers in Taiwan. The National Health Insurance database was used to identify patients with breast cancer and estimate the yearly prevalence and incidence of breast cancer between 1997 and 2013. Joinpoint regression analysis was used for the annual percentage change of incidence, prevalence, and survival outcome. Among 12,181,919 female beneficiaries in 2013, the prevalence was 834.37 per 100,000 persons (95% confidence interval, 829.28-839.45) and the incidence was 93.00 per 100,000 person-year (95% confidence interval, 91.27-94.73). The average annual percentage change of the age-standardized breast cancer incidence was 3.5 per 100,000 person-years (3.1-3.8; P < 0.05), suggesting an increase in breast cancer incidence over the study period. The 5-year mortality rate was 4.5% in 1997 and 4.4% in 2008. The 5-year mortality rate among patients with Charlson comorbidity index > 1 was 39.1% (19.2%-59.1%) in 1997 and 21.1% (15.7%-32.0%) in 2008, with an annual percentage change of -0.8 (-1.3 to 2.9), suggesting that the mortality rate was gradually decreasing in patients with comorbidities. In conclusion, 1 in 120 women in Taiwan has breast cancer and the incidence is rising, while the annual percentage change of breast cancer prevalence is decreasing. The mortality rate of breast cancer was essentially stable, but the 1-year, 2-year, and 5-year mortality rates in people with Charlson comorbidity index > 1 were declined.

Predictive risk index and prognosis of postoperative reintubation after planned extubation during general anesthesia: a single-center retrospective case-controlled study in Taiwan from 2005 to 2009.

OBJECTIVES: Postoperative reintubation after planned extubation (RAP) following general anesthesia is a major anesthetic morbidity. A previous study on RAP identified the various risk factors for RAP, including chronic obstructive pulmonary disease (COPD), pneumonia, systemic inflammatory response syndrome (SIRS), and airway surgery. However, the prognosis and predictive risk index of RAP were not investigated. METHODS: Data on surgical patients who were reintubated after planned extubation at the end of surgery between January 1, 2005 and December 31, 2009 were retrospectively sorted out from the quality assurance database of the Department of Anesthesiology, Chang Gung Memorial Hospital. Risk factors and prognosis of RAP cases were compared with the control group (successful planned extubation) using descriptive statistics and logistic regression. The RAP predictive risk index was developed from multivariate logistic regression and the predictive accuracy was evaluated by goodness-of-fit test. RESULTS: Of the 227,876 patients who were subjected to endotracheal intubation for general anesthesia, 130 (0.06%) sustained postoperative RAP. The control group consisted of 390 patients who were randomly selected from those who underwent endotracheal intubation without RAP. A total of 30 variables, including demographic, operative, anesthetic data, and prognosis were analyzed. We found that significant risk factors for RAP included COPD (odds ratio: 4.30), pneumonia (odds ratio: 6.60), ascites (odds ratio: 4.86), SIRS (odds ratio: 7.52), hypothermia (body temperature <35°C; odds ratio: 2.45), rocuronium as muscle relaxant (odds ratio: 1.90), inexperienced anesthetic service (odds ratio: 3.44), and airway surgery (odds ratio: 4.34). An RAP predictive risk index was developed and the predictive accuracy was confirmed by goodness-of-fit test as excellent discrimination (c statistic: 0.873). RAP significantly increased postoperative stay in hospital (odds ratio: 2.46) and intensive care unit, as well as tracheostomy and mortality (odds ratio: 58.52). CONCLUSION: The RAP predictive risk index included higher American Society of Anesthesiologists classification, conscious disturbance, COPD, pneumonia, SIRS, room air SpO2 <95%, hypothermia, airway surgery, and head and neck surgeries. The RAP predictive risk index provides us an opportunity to take preventive measures including renewal of risk-reduction protocols for high-risk patients.

Levobupivacaine differentially suppresses platelet aggregation by modulating calcium release in a dose-dependent manner.

OBJECTIVE: Levobupivacaine, an amide local anesthetic widely used in regional anesthesia, is reported in recent studies that it is a potent inhibitor of platelet functions. However, the concentrations of levobupivacaine were limitedly estimated in these reports. Additionally, the mechanisms by which it affects platelet function and blood coagulation is still not entirely known. The purpose of this study was to further investigate its effects on platelet function and the possible signaling mechanisms under various concentrations of levobupivacaine. METHODS: Blood samples collected from healthy volunteers were separated into whole blood, platelet-rich-plasma and washed platelets. The effect of levobupivacaine on platelet aggregation was studied using platelet function analyzer (PFA-100) and platelet aggregometer. Agonist-induced platelet adenosine triphosphate (ATP) release, cytosolic calcium mobilization, thromboxane B2 (TxB2) secretion and platelet P-selectin translocation under various concentrations of levobupivacaine were investigated. RESULTS: Our results indicated that levobupivacaine possessed negative effect on platelet aggregation. The closure times of (PFA-100) were lengthened and the agonist-induced platelet aggregation was significantly attenuated by levobupivacaine even at a low dose (50 µgml(-1)). Pretreatment with levobupivacaine produced significant changes in agonist-induced platelet P-selectin translocation, ATP release, thromboxane A2 (TxA2) production, and calcium mobilization in a dose-dependent manner. The p38 mitogen-activated protein kinases (MAPK), protein kinase C (PKC) δ subtype, cytosolic phospholipase A2 (cPLA2), and protein kinase B (PKB or Akt) were involved in collagen-induced platelet signaling, which would be responsible for antiplatelet effects of levobupivacaine. CONCLUSION: We explored possible targets of levobupivacaine on platelets aggregation signaling mechanisms. Our data revealed that p38 MAPK, PKC δ subtype, cPLA2, and Akt were pathways involved in collagen-induced platelet signaling, which might be responsible for antiplatelet effects of levobupivacaine. Our study did provide direct evidence bolstering the critical mechanisms of levobupivacaine within different contexts. Additionally, levobupivacaine imposed a negative effect on platelet aggregation through multiple signaling pathways.