Dynamic Nomogram for Predicting the Risk of Perioperative Neurocognitive Disorders in Adults.

BACKGROUND: Simple and rapid tools for screening high-risk patients for perioperative neurocognitive disorders (PNDs) are urgently needed to improve patient outcomes. We developed an online tool with machine-learning algorithms using routine variables based on multicenter data. METHODS: The entire dataset was composed of 49,768 surgical patients from 3 representative academic hospitals in China. Surgical patients older than 45 years, those undergoing general anesthesia, and those without a history of PND were enrolled. When the patient's discharge diagnosis was PND, the patient was in the PND group. Patients in the non-PND group were randomly extracted from the big data platform according to the surgical type, age, and source of data in the PND group with a ratio of 3:1. After data preprocessing and feature selection, general linear model (GLM), artificial neural network (ANN), and naive Bayes (NB) were used for model development and evaluation. Model performance was evaluated by the area under the receiver operating characteristic curve (ROCAUC), the area under the precision-recall curve (PRAUC), the Brier score, the index of prediction accuracy (IPA), sensitivity, specificity, etc. The model was also externally validated on the multiparameter intelligent monitoring in intensive care (MIMIC) Ⅳ database. Afterward, we developed an online visualization tool to preoperatively predict patients' risk of developing PND based on the models with the best performance. RESULTS: A total of 1051 patients (242 PND and 809 non-PND) and 2884 patients (6.2% patients with PND) were analyzed on multicenter data (model development, test [internal validation], external validation-1) and MIMIC Ⅳ dataset (external validation-2). The model performance based on GLM was much better than that based on ANN and NB. The best-performing GLM model on validation-1 dataset achieved ROCAUC (0.874; 95% confidence interval [CI], 0.833-0.915), PRAUC (0.685; 95% CI, 0.584-0.786), sensitivity (72.6%; 95% CI, 61.4%-81.5%), specificity (84.4%; 95% CI, 79.3%-88.4%), Brier score (0.131), and IPA (44.7%), and of which the ROCAUC (0.761, 95% CI, 0.712-0.809), the PRAUC (0.475, 95% CI, 0.370-0.581), Brier score (0.053), and IPA (76.8%) on validation-2 dataset. Afterward, we developed an online tool (https://pnd-predictive-model-dynnom.shinyapps.io/ DynNomapp/) with 10 routine variables for preoperatively screening high-risk patients. CONCLUSIONS: We developed a simple and rapid online tool to preoperatively screen patients' risk of PND using GLM based on multicenter data, which may help medical staff's decision-making regarding perioperative management strategies to improve patient outcomes.

The emerging roles of next-generation metabolomics in critical care nutrition.

Critical illness leads to millions of deaths worldwide each year, with a significant surge due to the COVID-19 pandemic. Patients with critical illness are frequently associated with systemic metabolic disorders and malnutrition. The idea of intervention for critically ill patients through enteral and parenteral nutrition has been paid more and more attention gradually. However, current nutritional therapies focus on evidence-based practice, and there have been lacking holistic approaches for nutritional support assessment. Metabolomics is a well-established omics technique in system biology that enables comprehensive profiling of metabolites in a biological system and thus provides the underlying information expressed and modulated by all other omics layers. In recent years, with the development of high-resolution and accurate mass spectrometry, metabolomics entered a new "generation", promoting its broader applications in critical care nutrition. In this review, we first described the technological development and milestones of next-generation metabolomics in the past 20 years. We then discussed the emerging roles of next-generation metabolomics in advancing our understanding of critical care nutrition, such as nutritional deficiency risk evaluation, metabolic mechanisms of nutritional therapies, and novel nutrition target identification.

Prediction of sepsis mortality using metabolite biomarkers in the blood: a meta-analysis of death-related pathways and prospective validation.

BACKGROUND: Sepsis is a leading cause of death in intensive care units (ICUs), but outcomes of individual patients are difficult to predict. The recently developed clinical metabolomics has been recognized as a promising tool in the clinical practice of critical illness. The objective of this study was to identify the unique metabolic biomarkers and their pathways in the blood of sepsis nonsurvivors and to assess the prognostic value of these pathways. METHODS: We searched PubMed, EMBASE, Cochrane, Web of Science, CNKI, Wangfang Data, and CQVIP from inception until July 2019. Eligible studies included the metabolomic analysis of blood samples from sepsis patients with the outcome. The metabolic pathway was assigned to each metabolite biomarker. The meta-analysis was performed using the pooled fold changes, area under the receiver operating characteristic curve (AUROC), and vote-counting of metabolic pathways. We also conducted a prospective cohort metabolomic study to validate the findings of our meta-analysis. RESULTS: The meta-analysis included 21 cohorts reported in 16 studies with 2509 metabolite comparisons in the blood of 1287 individuals. We found highly limited overlap of the reported metabolite biomarkers across studies. However, these metabolites were enriched in several death-related metabolic pathways (DRMPs) including amino acids, mitochondrial metabolism, eicosanoids, and lysophospholipids. Prediction of sepsis death using DRMPs yielded a pooled AUROC of 0.81 (95% CI 0.76-0.87), which was similar to the combined metabolite biomarkers with a merged AUROC of 0.82 (95% CI 0.78-0.86) (P > 0.05). A prospective metabolomic analysis of 188 sepsis patients (134 survivors and 54 nonsurvivors) using the metabolites from DRMPs produced an AUROC of 0.88 (95% CI 0.78-0.97). The sensitivity and specificity for the prediction of sepsis death were 80.4% (95% CI 66.9-89.4%) and 78.8% (95% CI 62.3-89.3%), respectively. CONCLUSIONS: DRMP analysis minimizes the discrepancies of results obtained from different metabolomic methods and is more practical than blood metabolite biomarkers for sepsis mortality prediction. TRIAL REGISTRATION: The meta-analysis was registered on OSF Registries, and the prospective cohort study was registered on the Chinese Clinical Trial Registry (ChiCTR1800015321).

[Effects of proliferator-activated receptor-γ agonist on vascular endothelial injuries in septic rats].

OBJECTIVE: To explore the effects of rosiglitazone, a synthetic ligand of proliferator-activated receptor-γ (PPAR-γ) on vascular endothelial injuries in septic rats. METHODS: A total of 40 male Sprague-Dawley rats were randomly divided into 4 groups of vehicle control, lipopolysaccharide (LPS), pretreatment of rosiglitazone (ROSI) and pretreatment of PPAR-γ antagonist 2-chloro-5-nitroaniline (GW9662) (n=10 each). At 4 hours post-intervention, blood samples were collected to detect the expression of PPAR-γ by immunocytochemistry and image analysis. And the following parameters of vascular endothelial injury were measured: Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), angiopoietin-2 (Ang-2), thrombomodulin (TM), anti-thrombin III (AT-III), tissue factor (TF), von Willebrand factor (vWF) and circulating endothelial cell (CEC). RESULTS: ① In ROSI group, the expression of PPAR-γ was significantly higher than that in LPS group (P<0.01). In GW9662 group, the expression of PPAR-γ had no significant difference compared to vehicle control group (P>0.05). ② The serum concentrations of VCAM-1, ICAM-1, Ang-2, TM, AT-III, TF and vWF were significantly higher in LPS group than those in vehicle control group (P<0.01). The concentrations of these parameters in ROSI group were significantly lower than those in LPS group (P<0.01). In GW9662 group, the concentrations of these parameters had no significant difference compared with LPS group (P>0.05). ③ The numbers of CEC were significantly higher in LPS group than those in vehicle control group (P<0.01). And the numbers of CEC were significantly lower in ROSI group than those in LPS group (P<0.01). In GW9662 group, the numbers of CEC had no significant difference compared with LPS group (P>0.05). CONCLUSION: Proliferator-activated receptor-γ agonist improves sepsis-induced vascular endothelial injury. And its mechanism may be through stabilizing vascular endothelial cell for improving serious inflammatory reaction and blood coagulation dysfunction.

Value function assessment to different RL algorithms for heparin treatment policy of patients with sepsis in ICU.

Heparin is a critical aspect of managing sepsis after abdominal surgery, which can improve microcirculation, protect organ function, and reduce mortality. However, there is no clinical evidence to support decision-making for heparin dosage. This paper proposes a model called SOFA-MDP, which utilizes SOFA scores as states of MDP, to investigate clinic policies. Different algorithms provide different value functions, making it challenging to determine which value function is more reliable. Due to ethical restrictions, we cannot test all policies on patients. To address this issue, we proposed two value function assessment methods: action similarity rate and relative gain. We experimented with heparin treatment policies for sepsis patients after abdominal surgery using MIMIC-IV. In the experiments, TD(0) shows the most reliable performance. Using the action similarity rate and relative gain to assess AI policy from TD(0), the agreement rates between AI policy and "good" physician's actual treatment are 64.6% and 73.2%, while the agreement rates between AI policy and "bad" physician's actual treatment are 44.1% and 35.8%, the gaps are 20.5% and 37.4%, respectively. External validation using action similarity rate and relative gain based on eICU resulted in agreement rates of 61.5% and 69.1% with the "good" physician's treatment, and 45.2% and 38.3% with the "bad" physician's treatment, with gaps of 16.3% and 30.8%, respectively. In conclusion, the model provides instructive support for clinical decisions, and the evaluation methods accurately distinguish reliable and unreasonable outcomes.

Extrahepatic Angiogenesis: A Potential Common Pathophysiological Basis of Multiple Organ Dysfunction in Rats with Cholestasis Cirrhosis.

BACKGROUND: In addition to intrahepatic angiogenesis, patients with cholestasis cirrhosis develop extrahepatic vasculature disorders and functional disturbances of multiple organ systems. Without effective intervention, these vascular disorders will eventually turn into multiple organs vascular syndromes, including the brain, lung and other organ systems. However, studies on the pathogenesis of vascular alterations among extrahepatic organ disturbances are still carried out separately, which hampered the successful translation of preclinical studies to the human setting and required further mechanistic insight into these complications. This study aims to investigate the relationship between extrahepatic angiogenesis and multiple organ impairment, and whether the vascular endothelial growth factor (VEGF) family members and their receptors are involved in this process. METHODS: Pathological changes of the multiple organs were determined by histopathological and immunohistochemical staining in the established common bile duct ligation (CBDL) rats, and angiogenesis was estimated by microvessel density (MVD). Levels of the VEGF family members and their receptors in the serum and organ tissues were also measured by using enzyme-linked immunosorbent assays. RESULTS: The MVD and VEGF family members and their receptors were significantly increased in CBDL rats with multiple organ injury, especially in the liver, lung and cerebral cortex. Meanwhile, we noticed moderate elevation of soluble receptor of the vascular endothelial growth factor-1 (sFlt-1) in the liver, lung, and cerebral cortex, whereas the levels of placental growth factor (PLGF) increased significantly. CONCLUSIONS: Extrahepatic angiogenesis may represent a common pathophysiological basis for multiple organ dysfunction and the sFlt-1/PLGF ratio could offer an avenue for further studies to target extrahepatic angiogenesis in cholestatic cirrhosis.

A new, feasible, and convenient method based on semantic segmentation and deep learning for hemoglobin monitoring.

Objective: Non-invasive methods for hemoglobin (Hb) monitoring can provide additional and relatively precise information between invasive measurements of Hb to help doctors' decision-making. We aimed to develop a new method for Hb monitoring based on mask R-CNN and MobileNetV3 with eye images as input. Methods: Surgical patients from our center were enrolled. After image acquisition and pre-processing, the eye images, the manually selected palpebral conjunctiva, and features extracted, respectively, from the two kinds of images were used as inputs. A combination of feature engineering and regression, solely MobileNetV3, and a combination of mask R-CNN and MobileNetV3 were applied for model development. The model's performance was evaluated using metrics such as R2, explained variance score (EVS), and mean absolute error (MAE). Results: A total of 1,065 original images were analyzed. The model's performance based on the combination of mask R-CNN and MobileNetV3 using the eye images achieved an R2, EVS, and MAE of 0.503 (95% CI, 0.499-0.507), 0.518 (95% CI, 0.515-0.522) and 1.6 g/dL (95% CI, 1.6-1.6 g/dL), which was similar to that based on MobileNetV3 using the manually selected palpebral conjunctiva images (R2: 0.509, EVS:0.516, MAE:1.6 g/dL). Conclusion: We developed a new and automatic method for Hb monitoring to help medical staffs' decision-making with high efficiency, especially in cases of disaster rescue, casualty transport, and so on.

Serum Soluble Vascular Endothelial Growth Factor Receptor 1 as a Potential Biomarker of Hepatopulmonary Syndrome.

Background and Aims: The results of basic research implicate the vascular endothelial growth factor (VEGF) family as a potential target of hepatopulmonary syndrome (HPS). However, the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS. Therefore, we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies. Methods: Clinically, patients with chronic liver disease from two medical centers were enrolled and examined for HPS. Patients were divided into HPS, intrapulmonary vascular dilation [positive contrast-enhanced echocardiography (CEE) and normal oxygenation] and CEE-negative groups. Baseline information and perioperative clinical data were compared between HPS and non-HPS patients. Serum levels of VEGF family members and their receptors were measured. In parallel, HPS rats were established by common bile duct ligation. Liver, lung and serum samples were collected for the evaluation of pathophysiologic changes, as well as the expression levels of the above factors. Results: In HPS rats, all VEGF family members and their receptors underwent significant changes; however, only soluble VEGFR1 (sFlt-1) and the sFlt-1/ placental growth factor (PLGF) ratio were changed in almost the same manner as those in HPS patients. Furthermore, through feature selection and internal and external validation, sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients. Conclusions: Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.

[Diagnostic value of citrulline and intestinal fatty acid binding protein on acute gastrointestinal injury in critical patients: a prospective study of 530 patients].

OBJECTIVE: To observe the incidence of acute gastrointestinal injury (AGI) in intensive care unit (ICU) patients, and to approach the value of serum citrulline and intestinal fatty acid binding protein (IFABP) on diagnosis of AGI in critical patients. METHODS: A prospective study was conducted. 576 critical patients admitted to ICU of Yantai Yuhuangding Hospital from February 2016 to February 2017 were enrolled. According to the AGI classification proposed by European Society of Intensive Care Medicine (ESICM) in 2012, the AGI and severity of the patients were observed. The general data, severity and prognosis of patients with different AGI grades were recorded. According to the random number table, 20 patients with normal kidney function from AGI I to IV were selected. The femoral artery blood was collected within 12 hours of ICU admission, and serum citrulline level was detected by high performance liquid chromatography (HPLC). Serum IFABP level was determined by enzyme-linked immunosorbent assay (ELISA). Twenty healthy subjects were selected as controls. The receiver operating characteristic curve (ROC) was drawn, and the predictive values of citrulline and IFABP for AGI diagnosis were evaluated. RESULTS: (1) 576 patients were enrolled in the analysis. Of which 530 patients (92.0%) had AGI, and 289 patients with grade I (54.5%), 154 with grade II (29.1%), 64 with grade III (12.1%), and 23 with grade IV (4.3%). With the increase in AGI classification, acute physiology and chronic health evaluation system II (APACHE II) score, sequential organ failure score (SOFA), the length of ICU stay and 28-day mortality were gradually increased. (2) Compared with health control group, the levels of serum citrulline in patients with different AGI grades were significantly decreased, and IFABP was significantly increased. With the increase in AGI classification, the citrulline level was gradually decreased, and IFABP level was gradually increased [citrulline levels (µmol/L) in AGI I,II,III,IV groups were 14.1±3.6, 12.7±3.1, 8.3±2.7, and 5.6±3.4, F = 3.287, P = 0.027, and IFABP levels (ng/L) were 526.7±204.9, 698.4±273.8, 894.7±455.9, and 1 062.8±532.2, F = 2.903, P = 0.043]. ROC curve analysis showed that citrulline had a higher predictive value for AGI diagnosis. The area under the ROC curve (AUC) was 0.927. When the cut-off value of citrulline was 9.7 µmol/L, the sensitivity and specificity were 87.5% and 87.5%, respectively. The AUC of IFABP was 0.043, which has no predictive value for the diagnosis of AGI. CONCLUSIONS: The AGI is extremely common in ICU. The higher the AGI grade is, the worse the prognosis is. Citrulline has high diagnostic value for AGI in critical patients, but IFABP has no predictive value on the diagnosis of AGI.

[The role of peroxisome proliferator-activated receptor-γ/nuclear factor-ΚB transduction pathway on coagulation disorders induced by sepsis].

OBJECTIVE: To determine the role of activated status of peroxisome proliferator-activated receptorγ/nuclear factor-ΚB (PPAR-γ/NF-ΚB ) in coagulation disorders induced by sepsis. METHODS: Forty male Sprague-Dawley (SD) rats were randomly divided into four groups, n=10 in each group: control group, lipopolysaccharide (LPS) challenged group, rosiglitazone (ROSI, selective agonist of PPAR-γ) pretreatment group, and GW9662 (PPAR-γ antagonist) pretreatment group. The sepsis model was reproduced by injection of 6 mg/kg LPS via sublingual vein, and the rats in control group were injected with 2 mL/kg normal saline. The rats in ROSI pretreatment group were given 0.3 mg/kg ROSI by sublingual venous injection followed by injection of LPS 30 minutes later; and in GW9662 pretreatment group rats were given 0.3 mg/kg GW9662 by sublingual venous injection followed by 0.3 mg/kg ROSI 15 minutes later, followed by injection of LPS 30 minutes later. Blood was collected at 4 hours after LPS administration, and the expressions of PPAR-γ and NF-ΚBp65 in peripheral blood mononuclear cell (PBMC) were determined with immunocytocheminal technique and graph analysis. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and D-dimer were determined simultaneously. RESULTS: (1) PPAR-γ/NF-ΚB pathway: the expressions of PPAR-γ and NF-ΚBp65 were lowered in control group, and they were expressed in cytoplasm. In LPS challenged group the expression of PPAR-γ (gray value) was slightly increased but with no significant difference as compared with control group (111.01±4.06 vs. 98.46±5.99, P>0.05). In ROSI pretreatment group the expression of PPAR-γ (gray value) was significantly higher than that in LPS challenged group (214.38±5.79 vs. 111.01±4.06, P<0.01), with dislocation into nuclei. In GW9662 pretreatment group the expression of PPAR-γ (gray value) was lowered but without significant difference compared with that of control group (44.21±2.64 vs. 98.46±5.99, P>0.05). In LPS challenged group the expression of NF-ΚBp65 (gray value) was significantly higher than that in control group (249.48±6.86 vs. 105.81±10.19, P<0.01), and it was translocated into the nuclei. In ROSI pretreatment group the expression of NF-ΚBp65 (gray value) was significantly lower than that in LPS challenged group (102.47±8.05 vs. 249.48±6.86, P<0.01), and it lied in cytoplasm. In GW9662 pretreatment group the expression of NF-ΚBp65 (gray value) showed no significant difference as compared with that of LPS challenged group (214.84±7.91 vs. 249.48±6.86, P>0.05). (2) Coagulation: compared with control group, PT and APTT were significantly prolonged, FIB was significantly decreased, and D-dimer was significantly increased in LPS challenged group [PT (s): 18.32±2.03 vs. 12.22±1.38, APTT (s): 40.05±2.72 vs. 26.64±2.73, FIB (g/L): 1.65±0.51 vs. 3.60±0.37, D-dimer (mg/L): 2.58±0.73 vs. 0.37±0.06, all P<0.01]. Compared with LPS challenged group, APTT and PT were significantly shortened, FIB was significantly increased, and D-dimer was significantly lowered in ROSI pretreatment group [PT (s): 13.93±1.67 vs. 18.32±2.03, APTT (s): 30.29±0.86 vs. 40.05±2.72, FIB (g/L): 3.18±0.69 vs 1.65±0.51, D-dimer (mg/L): 0.40±0.12 vs. 2.58±0.73, all P<0.01]. All parameters in GW9662 pretreatment group showed no significant difference as compared with those of LPS challenged group. CONCLUSIONS: PPAR-γ agonist ROSI may ameliorate coagulation disorders in septic rats. PPAR-γ/NF-ΚB transduction pathway plays an important role in septic coagulopathy.

Assessment of acute lung injury/acute respiratory distress syndrome using B-type brain natriuretic peptide.

OBJECTIVES: To investigate the clinical value of B-type natriuretic peptide (BNP) in the assessment of severity and prognosis in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). METHODS: Plasma BNP level, arterial blood gases, serum C-reactive protein level, alveolar-arterial oxygen tension difference and oxygenation index were measured in patients with and without ALI/ARDS within 24 h of admission to an intensive care unit. Patients with ALI/ARDS were divided into mild, moderate or severe groups according to the degree of hypoxaemia. Survival >28 days was recorded. RESULTS: A total of 59 patients with ALI/ARDS and 14 patients without ALI/ARDS were included in the study. Of the patients with ALI/ARDS, 18 had mild hypoxaemia, 20 had moderate hypoxaemia and 21 had severe hypoxaemia. The mean ± SD BNP level was significantly higher in all three ALI/ARDS groups (92.41 ± 28.19 pg/ml, 170.64 ± 57.34 pg/ml and 239.06 ± 59.62 pg/ml, respectively, in the mild, moderate and severe groups) than in the non-ALI/ARDS group (47.27 ± 19.63 pg/ml); the increase in BNP level with increasing severity was also statistically significant. When divided according to outcome, the BNP level in the death group (267.07 ± 45.06 pg/ml) was significantly higher than in the survival group (128.99 ± 45.42 pg/ml). CONCLUSIONS: The BNP level may be of value in evaluating severity and prognosis in patients with ALI/ARDS.