Does Respiratory Variation in Inferior Vena Cava Diameter Predict Fluid Responsiveness in Mechanically Ventilated Patients? A Systematic Review and Meta-analysis.

BACKGROUND: We performed a systematic review and meta-analysis of studies investigating the diagnostic accuracy of respiratory variation in inferior vena cava diameter (ΔIVC) for predicting fluid responsiveness in patients receiving mechanical ventilation. METHODS: MEDLINE, EMBASE, the Cochrane Library, and Web of Science were screened from inception to February 2017. The meta-analysis assessed the pooled sensitivity, specificity, diagnostic odds ratio, and area under the receiver operating characteristic curve. In addition, heterogeneity and subgroup analyses were performed. RESULTS: A total of 12 studies involving 753 patients were included. Significant heterogeneity existed among the studies, and meta-regression indicated that ventilator settings were the main sources of heterogeneity. Subgroup analysis indicated that ΔIVC exhibited better diagnostic performance in the group of patients ventilated with tidal volume (TV) ≥8 mL/kg and positive end-expiratory pressure (PEEP) ≤5 cm H2O than in the group ventilated with TV <8 mL/kg or PEEP >5 cm H2O, as demonstrated by higher sensitivity (0.80 vs 0.66; P = .02), specificity (0.94 vs 0.68; P < .001), diagnostic odds ratio (68 vs 4; P < .001), and area under the receiver operating characteristic curve (0.88 vs 0.70; P < .001). The best ΔIVC threshold for predicting fluid responsiveness was 16% ± 2% in the group of TV ≥8 mL/kg and PEEP ≤5 cm H2O, whereas in the group of TV <8 mL/kg or PEEP >5 cm H2O, this threshold was 14% ± 5%. CONCLUSIONS: ΔIVC shows limited ability for predicting fluid responsiveness in distinct ventilator settings. In patients with TV ≥8 mL/kg and PEEP ≤5 cm H2O, ΔIVC was an accurate predictor of fluid responsiveness, while in patients with TV <8 mL/kg or PEEP >5 cm H2O, ΔIVC was a poor predictor. Thus, intensivists must be cautious when using ΔIVC.

[Clinical value of lung ultrasound in the late goal-directed fluid removal in critically ill patients underwent fluid resuscitation].

OBJECTIVE: To investigate the clinical value of lung ultrasound in the late goal -directed fluid removal in critically ill patients underwent fluid resuscitation. METHODS: A prospective study was conducted. Forty patients underwent fluid resuscitation were enrolled in the Department of Surgical Intensive Care Unit of The First Affiliated Hospital of Sun Yat-sen University from Jan 2015 to June 2015. Lung and heart ultrasound were conducted for lung B-lines and left ventricular ejection fraction (EF). Serum amino-terminal pro-brain natriuretic peptide (NT-proBNP), central venous pressure (CVP) and serum creatinine were also measured and fluid balance was recorded in all patients enrolled. RESULTS: Among the 40 patients enrolled, 35 patients survived and 5 died. In patients survived, B-lines reached its peak at 12(30)h after admitted to ICU. It started to decrease instantly after the peak and reached zero at (39±34) h. A higher peak was followed with more fluids to be removed later and longer ICU stay (P<0.01). Moreover, when compared with the survivors, B-lines in death reached a higher peak[7(8) vs 3(4), P<0.01]and without the tendency to drop down. EF was lower in death than in survivor (44.5%±3.5% vs 69.2%±11.0%, P<0.05). A lower EF was found to be followed with a higher peak of B-lines. The peak time of NT-proBNP and clinical dehydration treatment were later than the peak time of B-lines in survivors. CONCLUSIONS: Fluid overloading occurs in late stage after resuscitation in critically ill patients. Lung ultrasound B-lines, which is more sensitive than the NT-proBNP and CVP, could help to monitor the patient's fluid status and guide the late goal-directed fluid removal.

Early sedation using ciprofol for intensive care unit patients requiring mechanical ventilation: a pooled post-hoc analysis of data from phase 2 and phase 3 trials.

BACKGROUND: Ciprofol was approved for use in intensive care unit (ICU) patients requiring sedation during mechanical ventilation in July 2022. A pooled post-hoc analysis of phase 2 and phase 3 trials was conducted primarily to explore hypotension-free outcome in ICU patients who required mechanical ventilation and achieved the target light sedation goal at an early stage after being sedated with ciprofol or propofol. METHODS: All eligible ICU patients who were expected to require sedation for 6-24 h were randomly assigned in a 2:1 ratio to either a ciprofol or propofol group. Ciprofol or propofol was initially infused at loading doses of 0.5 or 1.0 mg/kg followed by maintenance doses of 0.3 or 1.5 mg/kg/h. Ciprofol or propofol dosages were adjusted up or down at rates of 0.05-0.10 mg/kg/h or 0.25-0.50 mg/kg/h, respectively, to achieve the target light sedation (a Richmond Agitation-Sedation Scale of -2 to + 1). The primary post-hoc outcome was the hypotension-free rate in patients who had achieved the target sedation goal after 30-min administration of ciprofol or propofol. RESULTS: In total, 174 patients were enrolled for pooled post-hoc analysis, of whom 116 and 58 were assigned to the ciprofol and propofol groups, respectively. The hypotension-free rate was significantly higher in patients who achieved the target sedation goal after 30-min administration of ciprofol (93.0% vs. 81.0%, P = 0.018), and especially in the subgroups of males and patients aged < 65 years. Multivariable analysis revealed that ciprofol treatment, a younger age and lower baseline body mass index were independent favorable predictors for a higher hypotension-free rate in patients who achieved the target sedation goal after 30-min of drug administration. Moreover, hypotension-free patients who reached the target sedation level after 30 min had a more favorable short-term prognosis including a lower incidence of drug-related treatment-emergent adverse events, shorter time to extubation and fewer dose adjustments of ciprofol or propofol (all P < 0.05). CONCLUSION: ICU patients undergoing mechanical ventilation and sedated with ciprofol had significantly lower rate of hypotension during the early phase of achieving light sedation during a 6-24 h period, leading to a more favorable short-term prognosis (within 24 h). TRIAL REGISTRATION: Phase 2 trial (clinicaltrials.gov, NCT04147416. Registered November 1, 2019, https://classic. CLINICALTRIALS: gov/ct2/show/NCT04147416 ) and phase 3 trial (clinicaltrials.gov, NCT04620031. Registered November 6, 2020, https://classic. CLINICALTRIALS: gov/ct2/show/NCT04620031 ).

The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial.

INTRODUCTION: Severe sepsis is associated with a high mortality rate despite implementation of guideline recommendations. Adjunctive treatment may be efficient and require further investigation. In light of the crucial role of immunologic derangement in severe sepsis, thymosin alpha 1 (Tα1) is considered as a promising beneficial immunomodulatory drug. The trial is to evaluate whether Tα1 improves 28-day all-cause mortality rates and immunofunction in patients with severe sepsis. METHODS: We performed a multicenter randomized controlled trial in six tertiary, teaching hospitals in China between May 12, 2008 and Dec 22, 2010. Eligible patients admitted in ICU with severe sepsis were randomly allocated by a central randomization center to the control group or Tα1 group (1:1 ratio). The primary outcome was death from any cause and was assessed 28 days after enrollment. Secondary outcomes included dynamic changes of Sequential Organ Failure Assessment (SOFA) and monocyte human leukocyte antigen-DR (mHLA-DR) on day 0, 3, 7 in both groups. All analyses were done on an intention-to-treat basis. RESULTS: A total of 361 patients were allocated to either the control group (n = 180) or Tα1 (n = 181) group. The mortalities from any cause within 28 days in the Tα1 group and control group were 26.0% and 35.0% respectively with a marginal P value (nonstratified analysis, P = 0.062; log rank, P = 0.049); the relative risk of death in the Tα1 group as compared to the control group was 0.74 (95% CI 0.54 to 1.02). Greater improvement of mHLA-DR was observed in the Tα1 group on day 3 (mean difference in mHLA-DR changes between the two groups was 3.9%, 95% CI 0.2 to 7.6%, P = 0.037) and day 7 (mean difference in mHLA-DR changes between the two groups was 5.8%, 95% CI 1.0 to 10.5%, P = 0.017) than in the control group. No serious drug-related adverse event was recorded. CONCLUSIONS: The use of Tα1 therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00711620.

Study Protocol of a Multicenter, Randomized, Single-Blind Trial: Efficacy and Safety of Remimazolam Tosylate for Sedation in ICU Patients.

INTRODUCTION: Pharmacodynamic and pharmacokinetic studies in animal experiments and a phase 1 study suggested remimazolam tosylate as an effective and safe sedation/anesthetic agent. However, the effects and safety dose of remimazolam for light sedation in intensive care unit (ICU) patients are not clear and should be confirmed in a phase 2 study. METHODS: Sixty ICU patients requiring sedation treatment and undergoing mechanical ventilation will be enrolled and randomly assigned to a high dose group (HD group, 30 cases) and a low dose group (LD group, 30 cases) in a 1:1 ratio. Patients in both groups will be sedated using remimazolam tosylate in a primary dose of 0.08 mg/kg and a range of 0-2.0 mg/kg/h after randomization. Dose adjustment will be made at the range of every 0.1 mg/kg/h in the LD group and 0.2 mg/kg/h in the HD group to maintain the target Richmond Agitation and Sedation Score (RASS) at - 2 to + 1. The primary outcome will be the proportion of subjects that meet the following conditions: the time within the range of RASS (- 2 to + 1) accounts for 70% of the study drug administration time; without other rescue treatments. Secondary outcomes including the percentage time to reach the sedation goal; the proportion of subjects receiving rescue sedation and/or analgesic, and the mean dose of rescue drug throughout the study period; duration of mechanical ventilation; recovery time to full consciousness and nursing scores. Evaluations of safety including adverse events (AEs), serious AEs, physical examination, laboratory examination, etc. OUTCOME: The results of this study will provide crucial information for the use of remimazolam tosylate for ICU sedation. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05152303.

Dynamic increase in myoglobin level is associated with poor prognosis in critically ill patients: a retrospective cohort study.

Background: Myoglobin is an important biomarker for monitoring critically ill patients. However, the relationship between its dynamic changes and prognosis remains unclear. Methods: We retrospectively enrolled 11,218 critically ill patients from a general and surgical intensive care unit (ICU) of a tertiary hospital between June 2016 and May 2020. Patients with acute cardiovascular events, cardiac and major vascular surgeries, and rhabdomyolysis were excluded. To investigate the early myoglobin distribution, the critically ill patients were stratified according to the highest myoglobin level within 48 h after ICU admission. Based on this, the critically ill patients with more than three measurements within 1 week after ICU admission were included, and latent class trajectory modeling was used to classify the patients. The characteristics and outcomes were compared among groups. Sensitivity analysis was performed to exclude patients who had died within 72 h after ICU admission. Restricted mean survival time regression model based on pseudo values was used to determine the 28-day relative changes in survival time among latent classes. The primary outcome was evaluated with comparison of in-hospital mortality among each Trajectory group, and the secondary outcome was 28-day mortality. Results: Of 6,872 critically ill patients, 3,886 (56.5%) had an elevated myoglobin level (≥150 ng/mL) at admission to ICU, and the in-hospital mortality significantly increased when myoglobin level exceeded 1,000 µg/mL. In LCTM, 2,448 patients were unsupervisedly divided into four groups, including the steady group (n = 1,606, 65.6%), the gradually decreasing group (n = 523, 21.4%), the slowly rising group (n = 272, 11.1%), and the rapidly rising group (n = 47, 1.9%). The rapidly rising group had the largest proportion of sepsis (59.6%), the highest median Sequential Organ Failure Assessment (SOFA) score (10), and the highest in-hospital mortality (74.5%). Sensitivity analysis confirmed that 98.2% of the patients were classified into the same group as in the original model. Compared with the steady group, the rapidly rising group and the slowly rising group were significantly related to the reduction in 28-day survival time (ß = -12.08; 95% CI -15.30 to -8.86; ß = -4.25, 95% CI -5.54 to -2.97, respectively). Conclusion: Elevated myoglobin level is common in critically ill patients admitted to the ICU. Dynamic monitoring of myoglobin levels offers benefit for the prognosis assessment of critically ill patients.

[The study of the risk factors of fungal infection after liver transplantation].

OBJECTIVE: To explore the risk factors of fungal infection so as to provide rationales for the prevention of fungal infection after liver transplantation. METHODS: The clinical data of 94 cases of fungal infections after liver transplantation from January 1, 2003 to November 30, 2010 at our hospital were collected as the infective group. A total of 603 liver transplant patients without fungal infections during the same period were selected as the control group. χ(2) test and t test were utilized for the analysis of possible risk factors for fungal infection. RESULTS: Fungal infection rate was 13.5% (94/697) after liver transplantation and mortality rate of fungal infection 86.2% (81/94). Candida albicans was the majority infective fungi. And the main site of infection was the lungs. The postoperative acute physiology and chronic health evaluation III (APACHE III) score of the infective group was significantly higher than that of the control group (26.0 ± 5.4 vs 21.5 ± 4.7, P < 0.01). The number of patients with primary liver cancer was lower than that of the control group (26.6% vs 45.8%, P < 0.01). The number of decompensated HBV cirrhosis and diabetics in the infective group was higher than that of the control group at pre-operation (23.4% vs 11.6%, 9.6% vs 2.8%, both P < 0.01). The number of patients with postoperative mechanical ventilation over 10 days, postoperative antibiotics over 14 days, postoperative cardiopulmonary dysfunction and liver function recovery time over 7 days, parenteral nutrition over 12 days and hyperglycemia over 7 days in the infective group were significantly higher than that in the control group (all P < 0.01). CONCLUSION: Preoperative primary disease, postoperative disease severity, postoperative organ dysfunction, long-term mechanical ventilation, antibiotics and hyperglycemia, etc. may be the important risk factors of fungal infection after liver transplantation.

Lymphocyte trajectories are associated with prognosis in critically ill patients: A convenient way to monitor immune status.

Background: Immunosuppression is a risk factor for poor prognosis of critically ill patients, but current monitoring of the immune status in clinical practice is still inadequate. Absolute lymphocyte count (ALC) is not only a convenient biomarker for immune status monitoring but is also suitable for clinical application. In this study, we aimed to explore different trajectories of ALC, and evaluate their relationship with prognosis in critically ill patients. Methods: We retrospectively enrolled 10,619 critically ill patients admitted to a general intensive care unit (ICU) with 56 beds from February 2016 to May 2020. Dynamic ALC was defined as continuous ALC from before ICU admission to 5 days after ICU admission. Initial ALC was defined as the minimum ALC within 48 h after ICU admission. Group-based trajectory modeling (GBTM) was used to group critically ill patients according to dynamic ALC. Multivariate cox regression model was used to determine the independent association of trajectory endotypes with death and persistent inflammation, immunosuppression, catabolism syndrome (PICS). Results: A total of 2022 critically ill patients were unsupervisedly divided into four endotypes based on dynamic ALC, including persistent lymphopenia endotype (n = 1,211; 58.5%), slowly rising endotype (n = 443; 22.6%), rapidly decreasing endotype (n = 281; 14.5%) and normal fluctuation endotype (n = 87; 4.4%). Among the four trajectory endotypes, the persistent lymphopenia endotype had the highest incidence of PICS (24.9%), hospital mortality (14.5%) and 28-day mortality (10.8%). In multivariate cox regression model, persistent lymphopenia was associated with increased risk of 28-day mortality (HR: 1.54; 95% CI: 1.06-2.23), hospital mortality (HR: 1.66; 95% CI: 1.20-2.29) and PICS (HR: 1.79; 95% CI: 1.09-2.94), respectively. Sensitivity analysis further confirmed that the ALC trajectory model of non-infected patients and non-elderly patients can accurately distinguished 91 and 90% of critically ill patients into the same endotypes as the original model, respectively. Conclusion: The ALC trajectory model is helpful for grouping critically ill patients, and early persistent lymphopenia is associated with poor prognosis. Notably, persistent lymphopenia may be a robust signal of immunosuppression in critically ill patients.

Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis.

INTRODUCTION: Many studies have shown that monocyte human leukocyte antigen-DR (mHLA-DR) expression may be a good predictor for mortality in severe septic patients. On the contrary, other studies found mHLA-DR was not a useful prognostic marker in severe sepsis. Few studies have taken changes of mHLA-DR during treatment into consideration. The objective of this study was to estimate the prognostic value of changes of mHLA-DR to predict mortality in severe sepsis. METHODS: In this prospective observational study, mHLA-DR was measured by flow cytometry in peripheral blood from 79 adult patients with severe sepsis. mHLA-DR levels were determined on day 0, 3, 7 after admission to the surgical intensive care unit (SICU) with a diagnosis of severe sepsis. ΔmHLA-DR3 and ΔmHLA-DR7 were defined as the changes in mHLA-DR value on day 3 and day 7 compared to that on day 0. Data were compared between 28-day survivors and non-survivors. Receiver operating characteristic (ROC) curves were plotted to measure the performance and discriminating threshold of ΔmHLA-DR3, ΔmHLA-DR7, ΔmHLA-DR7-3, mHLA-DR0, mHLA-DR3 and mHLA-DR7 in predicting mortality of severe sepsis. RESULTS: ROC curve analysis showed that ΔmHLA-DR3 and ΔmHLA-DR7 were reliable indicators of mortality in severe sepsis. A ΔmHLA-DR3 value of 4.8% allowed discrimination between survivors and non-survivors with a sensitivity of 89.0% and a specificity of 93.7%; similarly, ΔmHLA-DR7 value of 9% allowed discrimination between survivors and non-survivors with a sensitivity of 85.7% and a specificity of 90.0%. Patients with ΔmHLA-DR3 ≤ 4.8% had higher mortality than those with ΔmHLA-DR3 > 4.8% (71.4% vs. 2.0%, OR 125.00, 95% CI 13.93 to 1121.67); patients with ΔmHLA-DR7 ≤ 9% had higher mortality than those with ΔmHLA-DR7 > 9% (52.9% vs. 2.0%, OR 54.00, 95% CI 5.99 to 486.08). The mean change of mHLA-DR significantly increased in the survivor group with the passage of time; from day 0 to day 3 and day 7, changes were 6.45 and 16.90 (P < 0.05), respectively. CONCLUSIONS: The change of mHLA-DR over time may be a reliable predictor for mortality in patients with severe sepsis.

Early lactate clearance as a reliable predictor of initial poor graft function after orthotopic liver transplantation.

BACKGROUND: Initial poor graft function (IPGF) following orthotopic liver transplantation is a major determinant of postoperative survival and morbidity. Lactate clearance is a good marker of liver function. In this study, we investigated the clinical utility of early lactate clearance as an early and accurate predictor for IPGF following liver transplantation. METHODS: This was a prospective observational study of 222 patients referred to the surgical intensive care unit (SICU) after orthotopic liver transplantation. The IPGF group consisted of patients with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1500 IU/L within 72 hours after orthotopic liver transplantation. Early lactate clearance was defined as lactate at SICU presentation (hour 0) minus lactate at hour 6, divided by lactate at SICU presentation. The model for end-stage liver disease (MELD) score, Child-Pugh score and laboratory data including AST, ALT, total bilirubin (TB) and prothrombin time (PT) were recorded at SICU presentation and compared between the non-IPGF and IPGF groups. Receiver operating characteristic (ROC) curves were plotted to measure the performance of early lactate clearance, MELD score, Child-Pugh score, TB and PT. RESULTS: IPGF occurred in 45 of the 222 patients (20.3%). The early lactate clearance in the non-IPGF group was markedly higher than that in the IPGF group (43.2+/-13.8% vs 13.4+/-13.7% P<0.001). The optimum cut-off value for early lactate clearance predicting IPGF was 24.8% (sensitivity 95.5%, specificity 88.9%). The area under the curve of the ROC was 0.961, which was significantly superior to MELD score, Child-Pugh score, TB and PT. Patients with early lactate clearance ≤24.8% had a higher IPGF rate (OR=169) and a higher risk of in-hospital mortality (OR=3.625). CONCLUSIONS: Early lactate clearance can serve as a prompt and accurate bedside predictor of IPGF. Patients with early lactate clearance less than 24.8% are associated with a higher incidence of IPGF.

Factors influencing postembolization syndrome in patients with hepatocellular carcinoma undergoing first transcatheter arterial chemoembolization.

CONTEXT: Postembolization syndrome (PES) is the most common complication in patients with hepatocellular carcinoma (HCC) who had undergone transcatheter arterial chemoembolization (TACE). PES was defined as fever, nausea and/or vomiting, and abdominal pain and these symptoms develop within 1-3 days after TACE. However, few studies have explored the factors influencing PES in patients with TACE for the first time. AIMS: We explored the factors influencing PES in patients with HCC undergoing TACE for the first time. SETTINGS AND DESIGN: The present study was a hospital-based study conducted in the tertiary care hospital of Guangzhou with a retrospective study design. SUBJECTS AND METHODS: In this single-center retrospective study, a total of 242 patients with HCC were included in the first TACE program between November 1, 2018 and November 31, 2019. STATISTICAL ANALYSIS USED: T-test and Chi-square test revealed the factors affecting the occurrence of PES. Correlation analysis (Spearman) explored the relationship between these factors and PES. Binary logistics analyzed the predictive factors of PES. RESULTS: The probability of PES in patients with HCC undergoing TACE for the first time was 55.45%. Types of embolic agents (r = 0.296), types of microspheres (r = 0.510), number of microspheres (r = 0.130), maximum diameter of microspheres used (r = 0.429), type of drug (r = 0.406), and drug loading (r = 0.433) were positively correlated with PES (P < 0.05). Serum albumin was negatively correlated with PES (P = 0.008, r = -0.170). Binary logistic regression analysis revealed that drug loading microspheres (odds ratio [OR] = 0.075, 95% confidence interval [CI] = 0.031-0.180) and serum albumin (OR = 0.182, 95% CI = 0.068-0.487) were the protective factors influencing PES, while drug loading was the risk factor of PES (OR = 1.407, 95% CI = 1.144-1.173). CONCLUSIONS: Drug loading microspheres, serum albumin, and drug loading were the predictors of PES after the first TACE.

Mortality prediction using clinical and laboratory features in elderly patients with severe community-acquired pneumonia.

BACKGROUND: Severe community-acquired pneumonia (SCAP) is a serious health threat in elderly individuals, and a prospective, observational study was conducted to explore the prognostic factors. METHODS: Patients (≥65 years old) with SCAP that had an intensive care unit (ICU) stay >24 h were recruited at our center. Clinical and laboratory data were collected and various assessment scores were calculated. The follow-up period was censored at the date of death or at hospital discharge, whichever came first. RESULTS: A total of 120 elderly patients with SCAP were included. Among them, 61 were cured (survival group) and 59 died due to SCAP (mortality group). Multivariate logistic regression analysis showed that chronic obstructive pulmonary disorder (COPD, ß=2.061, P=0.008) and CD3+CD4+ T cell count (ß=-0.019, P=0.017) were independent prognostic factors for death in elderly patients with SCAP. The area under the receiver operating characteristic (ROC) curve (AUROC) for the age- and gender-adjusted model was estimated to be 0.915 [95% confidence interval (CI): 0.858-0.972] for mortality, and the sensitivity and specificity of the model were 91.53% and 86.89%, respectively. CONCLUSIONS: Our findings suggest that COPD and the CD3+CD4+ T cell count are independent prognostic factors for mortality, and the constructed model was moderately accurate in the prediction of mortality for elderly patients with SCAP.

Does End-Expiratory Occlusion Test Predict Fluid Responsiveness in Mechanically Ventilated Patients? A Systematic Review and Meta-Analysis.

BACKGROUND: We performed a systematic review and meta-analysis of studies investigating the end-expiratory occlusion (EEO) test induced changes in cardiac index (CI) and in arterial pressure as predictors of fluid responsiveness in adults receiving mechanical ventilation. METHODS: MEDLINE, EMBASE, Cochrane Database, and Chinese database were screened for relevant original and review articles. The meta-analysis determined the pooled sensitivity, specificity, diagnostic odds ratio, area under the receiver operating characteristic curve (AUROC), and threshold for the EEO test assessed with CI and arterial pressure. In addition, heterogeneity and subgroup analyses were performed. RESULTS: We included 13 studies involving 479 adult patients and 523 volume expansion. Statistically significant heterogeneity was identified, and meta-regression indicated that prone position was the major sources of heterogeneity. After removal of the study performed in prone position, heterogeneity became nonsignificant. EEO-induced changes in CI (or surrogate) are accurate for predicting fluid responsiveness in semirecumbent or supine patients, with excellent pooled sensitivity of 92% (95% CI, 0.88-0.95, I = 0.00%), specificity of 89% (95% CI, 0.83-0.93, I = 34.34%), and a summary AUROC of 0.95 (95% CI, 0.93-0.97). The mean threshold was an EEO-induced increase in CI (or surrogate) of more than 4.9 ± 1.5%. EEO test exhibited better diagnostic performance in semirecumbent or supine patients than prone patients, with higher AUROC (0.95 vs. 0.65; P < 0.001). In addition, EEO test exhibited higher specificity (0.93 vs. 0.83, P < 0.001) in patients ventilated with low tidal volume compared with normal or nearly normal tidal volume. However, EEO test was less accurate when its hemodynamic effects were detected on arterial pressure. EEO-induced changes in arterial pressure exhibited a lower sensitivity (0.88 vs. 0.92; P = 0.402), specificity (0.77 vs. 0.90; P = 0.019), and AUROC (0.87 vs. 0.96; P < 0.001) compared with EEO-induced changes in CI (or surrogate). CONCLUSIONS: EEO test is accurate to predict fluid responsiveness in semirecumbent or supine patients but not in prone patients. EEO test exhibited higher specificity in patients ventilated with low tidal volume, and its accuracy is better when its hemodynamic effects are assessed by direct measurement of CI than by the arterial pressure.

Transesophageal echocardiography instead or in addition to transthoracic echocardiography in evaluating haemodynamic problems in intubated critically ill patients.

BACKGROUND: Transesophageal echocardiography (TEE) performed by intensivists is increasingly used in critically ill patients. However, TEE is usually not the preferred monitoring tool, especially when transthoracic echocardiography (TTE) appears to have addressed the clinical problems. As a result, it remains largely unknown whether TEE is a clinically valuable replacement or supplement for TTE as a primary tool in evaluating haemodynamic problems in critically ill surgical patients. The purpose of this study was to assess the diagnostic and therapeutic value of TEE instead or in addition to TTE in critically ill surgical patients with hemodynamic instability. METHODS: A prospective observational study was conducted. A total of 68 consecutive patients were enrolled from December 2016 to February 2018. TEE was routinely performed in addition to TTE, and the imaging data from TTE and TEE were successively disclosed to two different primary physicians, who reported any resulting changes in management. The two physicians were required to reach a consensus if there was any disagreement. The results of the additional TEE examination were compared with the clinical findings and TTE information. The image quality of TTE views was classified as a good (score 2), suboptimal (score 1) or poor view (score 0). According to the scores of TTE images, the patients were divided into two groups: patients with adequate TTE views (score ≥6) and inadequate TTE views (score <6). RESULTS: The results of additional TEE examination were classified into four categories. TEE failed to provide additional information about the initial diagnosis and therapy (class 1) in 26 patients (38.2%). Of the remaining 42 patients (61.8%), TEE instead or in addition to TTE revealed new findings or led to significant changes in therapy, as TTE supplied inadequate information. TEE used in addition to TTE led to a new diagnosis without therapeutic implications (class 2) in 11 patients (16.2%) and made a major clinical contribution leading to a therapeutic change (class 3) in 23 patients (33.8%). TEE used instead of TTE determined the diagnosis and therapy in 8 patients (11.8%) whose haemodynamic problems could not be addressed by TTE (class 4). In total, TEE had critical therapeutic benefits (class 3 and 4) that was not provided by TTE in 31 patients (45.6%). Of particular concern was that TEE had a higher proportion of therapeutic benefits to patients with inadequate TTE views than those with adequate TTE views (54.3% vs. 27.3%, P=0.036). CONCLUSIONS: TEE as a feasible clinical tool is useful for critically ill surgical patients with hemodynamic instability, especially for the patients with inadequate TTE views. TEE instead or in addition to TTE could provide valuable information for diagnosis, which may bring significant therapeutic benefits.

Mesenteric Lymph Duct Drainage Attenuates Lung Inflammatory Injury and Inhibits Endothelial Cell Apoptosis in Septic Rats.

The present study was to investigate the effect of mesenteric lymph duct drainage on lung inflammatory response, histological alteration, and endothelial cell apoptosis in septic rats. Animals were randomly assigned into four groups: control, sham surgery, sepsis, and sepsis plus mesenteric lymph drainage. We used the colon ascendens stent peritonitis (CASP) procedure to induce the septic model in rats, and mesenteric lymph drainage was performed with a polyethylene (PE) catheter inserted into mesenteric lymphatic. The animals were sacrificed at the end of CASP in 6 h. The mRNA expression levels of inflammatory mediators were measured by qPCR, and the histologic damage were evaluated by the pathological score method. It was found that mesenteric lymph drainage significantly reduced the expression of TNF-α, IL-1ß, and IL-6 mRNA in the lung. Pulmonary interstitial edema and infiltration of inflammatory cells were alleviated by mesenteric lymph drainage. Moreover, increased mRNA levels of TNF-α, IL-1ß, IL-6 mRNA, and apoptotic rate were observed in PMVECs treated with septic lymph. These results indicate that mesenteric lymph duct drainage significantly attenuated lung inflammatory injury by decreasing the expression of pivotal inflammatory mediators and inhibiting endothelial apoptosis to preserve the pulmonary barrier function in septic rats.

Early Immunoparalysis Was Associated with Poor Prognosis in Elderly Patients with Sepsis: Secondary Analysis of the ETASS Study.

PURPOSE: Although immune dysfunction has been investigated in adult septic patients, early immune status remains unclear. In this study, our primary aim was to assess early immune status in adult patients with sepsis stratified by age and its relevance to hospital mortality. PATIENTS AND METHODS: A post hoc analysis of a multicenter, randomized controlled trial was conducted; 273 patients whose immune status was evaluated within 48 hours after onset of sepsis were enrolled. Early immune status was evaluated by the percentage of monocyte human leukocyte antigen-DR (mHLA-DR) in total monocytes within 48 hours after onset of sepsis and it was classified as immunoparalysis (mHLA-DR ≤30%) or non-immunoparalysis (>30%). Three logistic regression models were conducted to explore the associations between early immunoparalysis and hospital mortality. We also developed two sensitivity analyses to find out whether the definition of early immune status (24 hours vs 48 hours after onset of sepsis) and immunotherapy affect the primary outcome. RESULTS: Of the 181 elderly (≥60yrs) and 92 non-elderly (<60yrs) septic patients, 71 (39.2%) and 25 (27.2%) died in hospital, respectively. The percentage of early immunoparalysis in the elderly was twice of that in the non-elderly patients (32% vs 16%, p=0.006). For the elderly, hospital mortality was higher in the immunoparalysis ones than the non-immunoparalysis ones (53.4% vs 32.5%, p=0.009). But there was no significant difference in hospital mortality between immunoparalysis non-elderly patients and non-immunoparalysis non-elderly ones (33.5% vs 26.0%, p=0.541). By means of logistic regression models, we found that early immunoparalysis was independently associated with increased hospital mortality in elderly, but not in non-elderly patients. Sensitivity analysis further confirmed the definition of early immune status and immunotherapy did not affect the outcomes. CONCLUSION: The elderly were more susceptible to early immunoparalysis after onset of sepsis. Early immunoparalysis was independently associated with poor prognosis in elderly, but not in non-elderly patients.

Immunotherapy improves immune homeostasis and increases survival rate of septic patients.

OBJECTIVE: To investigate the efficacy of immunotherapy on septic patients with Ulinastatin plus Thymosin-alpha(1). METHODS: Seventy postoperative septic patients were divided into two groups at random: the immunotherapy group (n equal to 36) and the conventional therapy group (n=34). Patients in the immunotherapy group received intravenous Ulinastatin of 200 000 U, 3 times per day for 3 days, Ulinastatin of 100 000 U, 3 times per day for 4 days, and subcutaneous injection of Thymosin-alpha(1) of 1.6 mg, twice per day for 3 days, then once per day for 4 days. While conventional therapies such as antibiotics and fluid resuscitation were undertaken in both groups. The expression levels of serum tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), IgG, C3, T lymphocyte subsets, CD14+ monocyte human leukocyte antigen (locus) DR (HLA-DR) and patients'28-day survival rate of the two groups were observed and evaluated. RESULTS: The survival rate was significantly higher in the immunotherapy group (63.9%; 23/36) compared with the conventional therapy group (41.2%; 14/34). The serum TNF-alpha levels [(1.38+/-0.50) ng/ml in the immunotherapy group vs (1.88+/-0.53) ng/ml in the conventional group, P less than 0.05] and the serum IL-10 levels [(217.52+/-15.71) ng/ml vs (101.53+/-16.57) ng/ml, P less than 0.05] were significantly different between the two groups. The serum IgG levels in the immunotherapy group [(17.65+/-6.81) g/L] were significantly higher than in the conventional group [(11.94+/-5.32) g/L]. There were also significant differences in the expression levels of CD4+ T lymphocyte (35%+/-13% in the immunotherapy group vs 21%+/-7% in the conventional group, P less than 0.05) and CD14+ monocyte HLA-DR (50%+/-5% in the former vs 35%+/-4% in the latter, P less than 0.05). CONCLUSIONS: Immunotherapy with Ulinastatin plus Thymosin-alpha(1) can enhance the inflammatory response, improve the immune homeostasis, and increase the survival rate of septic patients.

[Effect of ethyl pyruvate on mitochondrial dynamics of lipopolysaccharide-induced human kidney-2 cells].

OBJECTIVE: To examine the effects of ethyl pyruvate (EP) on mitochondrial dynamics and cell apoptosis in lipopolysaccharide (LPS)-induced human kidney-2 (HK-2) cells. METHODS: HK-2 cells were divided into three groups: HK-2 cells were challenged with LPS (800 µg/L) for 24 hours as LPS group, or LPS mixed with EP (0.25 mmol/L) for 24 hours as EP group. Cells were incubated with normal saline for 24 hours as control group. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and intracellular adenosine triphosphate (ATP) were detected by enzyme linked immunosorbent assay (ELISA). JC-1 staining and Annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) assays were used to evaluate mitochondrial membrane potential and cell apoptosis, respectively. Western Blot was used to evaluate the protein expressions of mitochondrial dynamics, including death-associated protein kinase 2 (DAPK-2), mitofusin (Mfn-1 and Mfn-2), and apoptotic associated biomarkers, including caspase-3, caspase-9, Bcl-2, Bcl-xL, cytochrome C (Cyt C), and DNA repair enzyme poly ADP-ribose polymerase (PARP). RESULTS: Compared with the NC group, MDA, IL-6, TNF-α of LPS group were significantly increased, the expression of SOD, mitochondrial membrane potential and ATP level were significantly decreased, the expression of mitochondrial fission protein DAPK-2 was significantly increased, and mitochondrial fusion proteins Mfn-1 and Mfn-2 were significantly decreased, cell apoptosis and apoptotic protein caspase-3, caspase-9 and Cyt C were increased, and anti-apoptotic protein Bcl-2, Bcl-xL, PARP were significantly decreased. Compared with the LPS group, the oxidative activities and inflammatory factors above were inhibited in EP group [MDA (µmol/L): 12.35±2.21 vs. 45.95±1.76, SOD (kU/L): 54.68±1.42 vs. 40.73±1.60, IL-6 (ng/L): 67.87±2.61 vs. 338.92±20.91, TNF-α (ng/L): 19.23±1.80 vs. 180.69±6.51], mitochondrial membrane potential and ATP level were significantly increased [mitochondrial membrane potential: (99.43±0.25)% vs. (69.40±0.75)%, ATP (×106 RLU): 0.19±0.01 vs. 0.12±0.05], the expression of mitochondrial fission protein was significantly decreased (DAPK-2/ß-actin: 0.03±0.01 vs. 0.61±0.02), mitochondrial fusion proteins were significantly increased (Mfn-1/ß-actin: 0.43±0.04 vs. 0.17±0.01, Mfn-2/ß-actin: 0.201±0.004 vs. 0.001±0.001), percentage of cell apoptosis was significantly decreased [(5.25±0.17)% vs. (34.42±0.64)%], the expressions of apoptotic proteins were significantly decreased (caspase-3/ß-actin: 0.25±0.15 vs. 1.76±0.01, caspase-9/ß-actin: 0.09±0.02 vs. 1.52±0.12, Cyt C/ß-actin: 0.001±0.001 vs. 0.350±0.030), and the expressions of anti-apoptotic proteins and PARP were significantly increased (Bcl-2/ß-actin: 0.500±0.010 vs. 0.009±0.004, Bcl-xL/ß-actin: 0.550±0.010 vs. 0.009±0.001, PARP/ß-actin: 0.94±0.01 vs. 0.16±0.13), with statistically significant differences (all P < 0.05). CONCLUSIONS: There are enhanced mitochondrial fission and diminished mitochondrial fusion in LPS-induced HK-2 cells. EP can protect mitochondria functions by regulate mitochondrial dynamics, and reducethe apoptosis of LPS-induced HK-2 cells.

[The study of the mechanism of the effect of heparin on tissue perfusion of sepsis patients].

OBJECTIVE: To assess the role of heparin administration in the early stage of sepsis and its mechanism of action. METHODS: This was a prospective study. One hundred and nineteen patients were enrolled in the study and were randomly divided into control group (64 cases) and therapy group (55 cases). Except the basic therapy of sepsis given to patients in both groups, the patients in the control group received normal saline, while the patients in the therapy group received heparin 2 mg.kg(-1).d(-1) with the aid of intravenous pump continuously after the onset of sepsis. The platelet count (PLT), D-dimer, and lactic acid in the blood were analyzed before therapy and on the 1st, 3rd, 5th and 10th day. The bleeding tendency was also observed. In every patient an acute physiology and chronic heath evaluation II (APACHE II) score was made. RESULTS: Patients in both groups had a similar APACHE II score. The pathogenetic and therapeutic condition were similar in both groups. The rate of the active bleeding in the therapy group was lower significantly than that of the control group (12.5% vs. 5.4%, P < 0.05). The PLT of the therapy group decreased on the 1st day, but began to rise on the 3rd day gradually, and up to the same level of the admission day on the 10th day. The PLT of the control group decreased progressively every day (P < 0.05 or P < 0.01). D-dimer in the therapy group raised significantly on the 1st day, but lowered to normal level after 3 days. D-dimer in the control group went up progressively every day (all P < 0.01). Lactic acid in the therapy group went up significantly on the 1st day (P < 0.01), but it no longer rose after 3 days (all P > 0.05). The lactic acid level in the control group rose progressively every day (all P < 0.01). There were no significant differences for the PLT, D-dimer, and lactic acid between the two groups before therapy and on the 1st day (all P > 0.05). However, on the 3rd, 5th and 10th day, the PLT in the therapy group was significant higher than that of the control group, the D-dimer and the lactic acid level in the therapy group were significantly lower than that of the control group (P < 0.05 or P < 0.01). CONCLUSION: The use of heparin at the earlier period of sepsis can inhibit the lowering of PLT and increase of D-dimer and lactic acid significantly, prevent microvascular thrombosis, improve the tissue perfusion, and decrease active bleeding.

PKR inhibition mediates endotoxin tolerance in macrophages through inactivation of PI3K/AKT signaling.

Following long­term exposure to endotoxins, macrophages enter an immunosuppressive state that renders them unable respond to subsequent exposures to endotoxin, a phenomenon that is termed 'endotoxin tolerance'. Endotoxin tolerance increases the risks of secondary infection and mortality in patients with sepsis. In endotoxin­tolerant macrophages, the mixed variation of gene transcription is referred to as macrophage reprogramming. The mechanisms underlying macrophage reprogramming remain unclear at present. Interferon­induced double­stranded RNA­dependent protein kinase (PKR) is a widely expressed serine/threonine protein kinase. In addition to antiviral effects, PKR regulates the transcription of inflammatory cytokines by affecting transcription factors. However, the role of PKR in macrophage reprogramming remains to be elucidated. In the present study, the expression of inflammatory cytokines differed in lipopolysaccharide (LPS)­tolerant RAW264.7 macrophages compared with LPS­activated macrophages. Specifically, reverse transcription­quantitative polymerase chain reaction results demonstrated that the mRNA levels of tumor necrosis factor­α, interleukin­1ß (IL­1ß), C­X­C motif chemokine ligand 11, C­C motif chemokine ligand (CCL17), CCL22 and suppressor of cytokine signaling 3 were decreased, and mRNAs levels of arginase­1 (Arg1) and nitric oxide synthase 2 (iNOS) were increased, in LPS­tolerant macrophages compared with LPS­activated macrophages. Furthermore, western blot analysis demonstrated that the protein levels of phosphorylated (p)­PKR were significantly decreased in the LPS­tolerant cells. PKR activation with rotenone (10 µM) abrogated endotoxin tolerance by increasing the levels of the IL­1ß, CCL17 and CCL22 mRNAs and decreasing the levels of the Arg1 and iNOS mRNAs. Furthermore, western blotting demonstrated that AKT was markedly inactivated in endotoxin­tolerant cells, as indicated by reduced p­AKT levels. However, levels of p­AKT were markedly increased following rotenone­induced PKR activation in endotoxin­tolerant cells. Ly294002 (10 µM), a phosphatidylinositol­4,5­bisphosphate 3­kinase (PI3K)/AKT signaling inhibitor, partially reversed the rotenone­induced alleviation of endotoxin tolerance. These results demonstrated that PKR inhibition mediated endotoxin tolerance in macrophages, and these effects were partially mediated by PI3K/AKT signaling. PKR may be a potential target for the treatment of endotoxin tolerance in patients with sepsis.