Increasing angiotensin-converting enzyme (ACE) 2/ACE axes ratio alleviates early pulmonary vascular remodeling in a porcine model of acute pulmonary embolism with cardiac arrest.

BACKGROUND: Acute pulmonary embolism (APE) with cardiac arrest (CA) is characterized by high mortality in emergency due to pulmonary arterial hypertension (PAH). This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme (ACE) 2-angiotensin (Ang) (1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor (AT1) axis (ACE2/ACE axes) ratio on pulmonary artery lesion after return of spontaneous circulation (ROSC). METHODS: To establish a porcine massive APE with CA model, autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg (1 mmHg=0.133 kPa). Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation. Pigs were divided into four groups of five pigs each: control group, APE-CA group, ROSC-saline group, and ROSC-captopril group, to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril. RESULTS: Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells. Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor (VEGF) in the APE-CA group compared with the control group. Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC. Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax) ratio and decreasing cleaved caspase-3 expression. CONCLUSION: Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.

The effect of hemodialysis on N-terminal pro-brain natriuretic peptide: A systematic review and meta-analysis.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-pro BNP) increases in patients with heart failure and renal failure. Hemodialysis is a useful treatment to these patients. The aim of this study was to conduct a systematic and meta-analysis to evaluate the influence of hemodialysis on NT-pro BNP concentration. METHODS: Relevant studies were identified by searching in PubMed, Medline, Embase, OVID, Web of Science, China Biology Medicine (CBM) and Google Scholar. Standard errors of mean difference along with its 95% CI were calculated to assess the association of hemodialysis and NT-pro BNP concentration. Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were explored. RESULTS: Individual patient data was obtained from 270 participants in seven articles suffered from chronic renal failure with regular hemodialysis, which was standard normal distribution. A fixed effects model suggested a pooled mean difference of 79.265 (95% CI: -331.172-489.702) without heterogeneity (Q = 0.70 df = 6 p = 0.994 I2 = 0.0%). The adults group estimated a MD of 209.958 (95% CI: -3080.76-3500.67; p = 0.900) with no heterogeneity (Q = 0.70 df = 4 p = 0.983 I2 = 0.0%). In the four articles whose data were not standard normal distribution, hemodiafiltration protocols were similar; three articles reported increasing and one decreasing in NT-proBNP concentration. CONCLUSIONS: Finding of this systematic review and meta-analysis demonstrated that NT-pro BNP may not been influenced by hemodialysis, and it could not been used to determine if heart failure is improving in patients with renal failure who are treated with hemodialysis.

Protective effect of extracorporeal membrane oxygenation on intestinal mucosal injury after cardiopulmonary resuscitation in pigs.

The present study aimed to explore the protective effects of extracorporeal membrane oxygenation (ECMO) on intestinal mucosal injury following cardiopulmonary resuscitation (CPR), and to assess the potential mechanisms involved. A total of 24 healthy adult domestic pigs were selected as the study subjects. A ventricular fibrillation model was induced through programmed electric stimulation. Subsequently, the animals were randomly divided into conventional CPR and CPR+ECMO groups (n=12 per group). The mortality and hemodynamic parameters of the two groups were compared. The expression levels of inflammatory cytokines in the serum and intestinal mucosa were detected by ELISAs. The intestinal mucosa was subjected to hematoxylin and eosin, and immunohistochemical staining, followed by electron microscopy, to assess the degree of apoptosis and necrosis. The animals in both groups recovered from the programmed ventricular fibrillation. In the CPR group, two animals died at 2 h and two more animals died a further 2 h later, resulting in a 33.3% mortality rate, whereas no cases of mortality were observed in the CPR+ECMO group. Compared with the animals in the CPR group, the hemodynamic parameters of the animals in the CPR+ECMO group revealed significantly improved outcomes. Multiple inflammatory factors (tumor necrosis factor α, interleukin-1 and interleukin-6), myeloperoxidase and malondialdehyde levels were decreased, whereas Na/Ca-ATPase and superoxide dismutase levels were elevated in the intestinal mucosa of animals in the CPR+ECMO group compared with those in the CPR group. Additionally, pathological staining demonstrated that the intestinal mucosa tissue in the CPR+ECMO group exhibited less apoptosis, necrosis and inflammatory cell infiltration, which was further supported by a decrease in Bax expression and an increase in Bcl-2 expression. Overall, ECMO after CPR reduced the intestinal mucosal barrier injury after spontaneous circulation recovery, and the mechanism involved decreased inflammation and apoptosis.

ECMO attenuates inflammation response and increases ATPase activity in brain of swine model with cardiac arrest compared with CCPR.

Extracorporeal membrane oxygenation (ECMO) could increase survival rate and neurological outcomes of cardiac arrest (CA) patients compared with conventional cardiopulmonary resuscitation (CCPR). Currently, the underlying mechanisms how ECMO improves neurological outcomes of CA patients compared with CCPR have not been revealed. A pig model of CA was established by ventricular fibrillation induction and then underwent CCPR or ECMO. Survival and hemodynamics during the 6 h after return of spontaneous circulation (ROSC) were compared. The levels of inflammatory cytokines and Ca2+-ATPase and NA+-K+-ATPase activities were detected. Brain tissues histology and ultra-microstructure in CCPR and ECMO groups were also examined. Results suggested that ECMO significantly improved the survival of pigs compared with CCPR. Heart rate (HR) decreased while cardiac output (CO) increased along with the time after ROSC in both ECMO and CCPR groups. At each time point, HR in ECMO groups was lower than that in CCPR group while CO and mean arterial pressure in ECMO group was higher than CCPR group. In ECMO group, lower levels of IL-1, IL-1ß, IL-6, TNFα, and TGFß, especially IL-1, IL-6, TNFα, and TGFß, were found compared that in CCPR group while no difference of IL-10 between the two groups was observed. Similar with the results from enzyme-linked immunosorbent assay, decreased expressions of IL-6 and TGFß were also identified by Western blotting. And Ca2+-ATPase and NA+-K+-ATPase activities were increased by ECMO compared with CCPR. Hematoxylin and eosin staining and ultra-microstructure examination also revealed an improved inflammation situation in ECMO group compared with CCPR group.

Imbalance of angiotensin-converting enzymes affects myocardial apoptosis during cardiac arrest induced by acute pulmonary embolism in a porcine model.

Acute pulmonary embolism (APE) with cardiac arrest (CA) is associated with a high mortality rate. Even upon return of the spontaneous circulation (ROSC), APE­CA survivors are prone to myocardial cell apoptosis, a key cellular mechanism that induces heart failure. A recent study by our group discovered a post­resuscitation imbalance in the serum angiotensin­converting enzyme (ACE)2/ACE axis of the renin­angiotensin system (RAS), as well as regressive cardiac function in a porcine model of APE­CA. However, it has remained elusive how this imbalance in the ACE2/ACE axis affects myocardial cell apoptosis. In the present study, western blot and immunohistochemical analyses demonstrated that the RAS was only activated in the left myocardium, as evidenced by a decreased ACE2/ACE ratio following APE­CA and ROSC, but not the right myocardium. Ultrastructural analysis confirmed myocardial apoptosis in the left and right myocardium. Furthermore, B­cell lymphoma 2 (Bcl­2)­associated X protein (Bax) and caspase­3 levels were elevated and Bcl­2 levels were decreased in the left myocardium following APE­CA and ROSC. Treatment with the ACE inhibitor captopril for 30 min after initiation of ROSC prevented the increase in Bax and the decrease in Bcl­2 in the left myocardium compared with that in saline­treated pigs. Captopril also inhibited the activation of extracellular signal­regulated kinase (ERK)1/2 in the left myocardium. The results of the present study suggest that an imbalance in the ACE2/ACE axis has an important role in myocardial apoptosis following APE­CA, which may be attributed to decreased ERK1/2 activation. In addition, it was indicated that captopril prevents apoptosis in the left myocardium after ROSC.

Venoarterial Extracorporeal Membrane Oxygenation Increased Immune Function of Spleen and Decreased Reactive Oxygen Species During Post-Resuscitation.

We aimed to investigate the effect of venoarterial extracorporeal membrane oxygenation (VA-ECMO) on immune function of the spleen and reactive oxygen species (ROS) during post-resuscitation in a porcine model. After 8 min of untreated ventricular fibrillation and 6 min of basic life support, pigs were randomized into two groups: Group 1 received VA-ECMO and Group 2 received conventional cardiopulmonary resuscitation. After successful return of spontaneous circulation, the hemodynamic status was determined and blood samples were collected at 0, 1, 2, 4, and 6 h. Surviving pigs were euthanized 6 h after return of spontaneous circulation, their spleens were harvested and the T-cells were separated. Then, we investigated immune function parameters of the spleen and ROS levels. VA-ECMO increased the return of spontaneous circulation and 6 h survival rate after return of spontaneous circulation. Compared with the conventional cardiopulmonary resuscitation group, the VA-ECMO group showed increased superoxide dismutase and decreased malondialdehyde and ROS levels. Furthermore, VA-ECMO was associated with a high rate of CD4+ and CD4+/CD8+, high levels of interleukin 2, interferon γ, and interferon γ/interleukin 4, as well as high proliferation of lymphocytes. The apoptotic rate of T-cells was lower in the VA-ECMO group than it was in the conventional cardiopulmonary resuscitation group. VA-ECMO increased immune function of spleen and decreased ROS levels during post-resuscitation. Further research is expected to illustrate whether the differences in immune responses are due to ROS or some other perfusion related effect on spleen.

Gut Microbiota Disruption in Septic Shock Patients: A Pilot Study.

BACKGROUND The composition of the intestinal microbiota and its effect on septic shock patients in the intensive care unit (ICU) is unknown. In the present study we explored the hypothesis that bacterial diversity is decreased in septic shock patients and that this diversity may be improved by use of probiotics or enteral nutrition. MATERIAL AND METHODS A total of 15 stool samples were collected prospectively from septic shock patients in the ICU, while 15 samples from healthy subjects served as controls. Bacterial DNA was submitted for 16S rDNA gene sequencing. The relationship between intestinal microbiota and prognosis was evaluated. RESULTS Significantly lower bacterial diversity was found in septic shock patients compared with healthy subjects (p<0.05). However, there was no difference in bacterial diversity in the presence or absence of probiotics (p=0.59), enteral nutrition (p=0.59), or in-hospital death (p=0.93) in septic shock patients. A high abundance of Proteobacteria and Fusobacteria was observed in most septic shock patients, whereas low abundance was observed in healthy subjects (mean relative proportion: 23.71% vs. 3.53%, p<0.05; 1.27% vs. 0.12%, p=0.59). CONCLUSIONS Bacterial diversity was decreased, and 1 or 2 rare bacterial species were overgrown in septic shock patients. Bacterial diversity was not improved by use of probiotics or enteral nutrition. The small sample size of our study limits the interpretation of results.

Extracorporeal Membrane Oxygenation Improving Survival and Alleviating Kidney Injury in a Swine Model of Cardiac Arrest Compared to Conventional Cardiopulmonary Resuscitation.

BACKGROUND: Acute kidney injury (AKI) frequently occurs in cardiopulmonary resuscitation patients. Studies comparing the effects of extracorporeal membrane oxygenation (ECMO) with conventional cardiopulmonary resuscitation (CCPR) on AKI were rare. This study aimed to compare the effects of ECMO with those of CCPR on survival rate and AKI and explore the underlying mechanisms in a swine model of cardiac arrest (CA). METHODS: Sixteen male pigs were treated with ventricular fibrillation to establish CA model and then underwent CCPR (CCPR group, n = 8) or ECMO during cardiopulmonary resuscitation (ECPR group, n = 8). The study endpoints were 6 h after return of spontaneous circulation (ROSC) or death. Serum and urine samples were collected at baseline and during the 6 h after ROSC. The biomarkers of AKI were detected by enzyme-linked immunosorbent assay. The apoptosis of renal tubular epithelial cells was discovered by transmission electron microscope (TEM) and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Apoptosis-related genes were detected by immune-staining and Western blotting. Data were compared by Student's t-test. RESULTS: All pigs in ECPR group were successfully resuscitated with a higher 6-h survival rate (8/8) compared to CCPR group (6/8). The expressions of AKI biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), tissue inhibitor of metalloproteinase2 (TIMP2), insulin-like growth factor-binding protein 7 (IGFBP7), liver fatty acid-binding protein (LFABP), and kidney injury molecule1 (Kim-1) were all increased along with the time after ROSC in both groups and lower in ECPR group compared with CCPR group. Especially, products of urinary TIMP and IGFBP levels (TIMP*IGFBP) were significantly lower at ROSC4 (0.58 ± 0.10 ng2/ml2 vs. 1.18 ± 0.38 ng2/ml2, t = 4.33, P = 0.003) and ROSC6 (1.79 ± 0.45 ng2/ml2 vs. 3.00 ± 0.44 ng2/ml2, t = 5.49, P < 0.001); urinary LFABP was significantly lower at ROSC6 (0.74 ± 0.06 pg/ml vs. 0.85 ± 0.11 pg/ml, t = 2.41, P = 0.033); and urinary Kim-1 was significantly lower at ROSC4 (0.66 ± 0.09 pg/ml vs. 0.83 ± 0.06 pg/ml, t = 3.99, P = 0.002) and ROSC6 (0.73 ± 0.12 pg/ml vs. 0.89 ± 0.08 pg/ml, t = 2.82, P = 0.016). Under light microscope and TEM, the morphological injures in renal tissues were found to be improved in ECPR group. Moreover, apoptosis was also alleviated in ECPR group. CONCLUSIONS: Compared with CCPR, ECMO improves survival rate and alleviates AKI in a swine model of CA. The mechanism of which might be via downregulating AKI biomarkers and apoptosis in kidney.

Association of serum biomarkers with outcomes of cardiac arrest patients undergoing ECMO.

BACKGROUND: Recently, a series of studies have been conducted to investigate the association of the common biochemical biomarkers, such as serum lactate and creatinine, with clinical outcomes in cardiac arrest patients treated with extracorporeal membrane oxygenation (ECMO), however, the results were not consistent and the sample size of primary studies is limited. In the present study, we performed a systematic review and meta-analysis to summarize the associations. METHODS: Relevant studies in English databases (PubMed, ISI web of science, and Embase) and Chinese databases (Wanfang and CNKI) up to January 2018 were systematically searched. Crude ORs or HRs from the included studies were extracted and pooled to summarize the associations of lactate and creatinine with clinical outcomes including survival and neurological outcomes in ECMO treated cardiac arrest patients. RESULTS: 17 papers containing 903 cases were included in the present meta-analysis study. After pooling all the eligible studies, we identified the significant associations of high lactate level with poor survival (N=13, OR=1.335, 95%CI=1.167-1.527, P<0.001) and poor neurological outcome (N=2, HR=1.058, 95%CI=1.020-1.098, P=0.002) in CA patients treated with ECMO and a slight significant association of high creatinine with poor survival was also found (N=7, OR=1.010, 95%CI=1.002-1.018, P=0.015). CONCLUSIONS: High serum lactate level was associated with poor survival and poor neurological outcome in CA patients treated with ECMO. Further well-designed studies with larger sample size should be conducted to confirm the results.

Association between ACE2/ACE balance and pneumocyte apoptosis in a porcine model of acute pulmonary thromboembolism with cardiac arrest.

Acute pulmonary embolism (APE) is frequently reported in patients with cardiac arrest (CA) in emergency care. Pneumocyte apoptosis is commonly observed in the lungs following an APE. An important pathological mechanism evoking apoptosis during a lipopolysaccharide­induced acute lung injury is the angiotensin­converting enzyme 2 (ACE2)/ACE imbalance. The present study uses a porcine model to examine the anti­apoptotic effects of captopril on APE­CA and the return of spontaneous circulation (ROSC). Pigs were randomly assigned into four groups: Control, APE­CA, ROSC­saline, and ROSC­captopril. Surviving pigs were euthanized at 6 h and lungs were isolated for analysis using several biochemical assays. Compared with the control group, the ACE2/ACE ratio was lower in the APE­CA and ROSC pigs. In addition, APE­CA pigs had higher Bcl­2­associated X protein (Bax) and cleaved caspase­3 levels, and lower B­cell lymphoma­2 (Bcl­2) level compared to control pigs. Captopril treatment reduced lung apoptosis, as demonstrated by lower TUNEL­positive cells, higher Bcl­2, and lower cleaved caspase­3 protein levels in the lung. Notably, the ACE2/ACE ratio was positively correlated with Bcl­2 protein levels and Bcl­2/Bax ratio. In conclusion, captopril has a protective effect against lung apoptosis following ROSC and that maintaining the balance of the ACE2/ACE axis is important for inhibiting pulmonary apoptosis during APE.

Efficacy of vasopressin-epinephrine compared to epinephrine alone for out of hospital cardiac arrest patients: A systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to conduct a meta-analysis to evaluate the efficacy of vasopressin-epinephrine compared to epinephrine alone in patients who suffered out-of-hospital cardiac arrest (OHCA). METHODS: Relevant studies up to February 2017 were identified by searching in PubMed, EMBASE, the Cochrane Library, Wanfang for randomized controlled trials(RCTs) assigning adults with cardiac arrest to treatment with vasopressin-epinephrine (VEgroup) vs adrenaline (epinephrine) alone (E group). The outcome point was return of spontaneous circulation (ROSC) for patients suffering from OHCA. Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were explored. RESULTS: Individual patient data were obtained from 5047 participants who experienced OHCA in nine studies. Odds ratios (ORs) were calculated using a random-effects model and results suggested that vasopressin-epinephrine was associated with higher rate of ROSC (OR=1.67, 95% CI=1.13-2.49, P<0.00001, and total I2=83%). Subgroup showed that vasopressin-epinephrine has a significant association with improvements in ROSC for patients from Asia (OR=3.30, 95% CI=1.30-7.88); but for patients from other regions, there was no difference between vasopressin-epinephrine and epinephrine alone (OR=1.07, 95% CI=0.72-1.61). CONCLUSION: According to the pooled results of the subgroup, combination of vasopressin and adrenaline can improve ROSC of OHCA from Asia, but patients from other regions who suffered from OHCA cannot benefit from combination of vasopressin and epinephrine.

Variations of Postresuscitation Lung Function after Thrombolysis Therapy in a Cardiac Arrest Porcine Model Caused by Pulmonary Thromboembolism.

BACKGROUND: Study of lung function in survivor from cardiac arrest (CA) caused by pulmonary thromboembolism (PTE) was rare. The aim of this study was to investigate the variations of postresuscitation lung function after thrombolysis treatment in a CA porcine model caused by PTE. METHODS: After 2 min of untreated CA, pigs of 10-12 weeks with a weight of 30 ± 2 kg (n = 24) were treated with recombinant human tissue plasminogen activator (50 mg). Cardiopulmonary resuscitation (CPR) and ventilation were initiated after drug administration. Pulmonary function and arterial blood gas parameters were measured at baseline, return of spontaneous circulation (ROSC) immediately, and 1 h, 2 h, 4 h, and 6 h after ROSC. RESULTS: The dynamic lung compliance decreased significantly at ROSC immediately and 1 h after ROSC compared to baseline (21.86 ± 2.00 vs. 26.72 ± 2.20 ml/mmHg and 20.38 ± 1.31 vs. 26.72 ± 2.20 ml/mmHg, respectively; P < 0.05; 1 mmHg = 0.133 kPa). Compared with baseline, airway resistance increased significantly at ROSC immediately and 1 h after ROSC (P < 0.05). Respiratory index also increased after ROSC and showed significant differences among baseline, ROSC immediately, and 2 h after ROSC (P < 0.05). Oxygen delivery decreased at ROSC immediately compared to baseline (P < 0.05). The oxygenation index decreased significantly at any time after ROSC compared to baseline (P < 0.05). Extravascular lung water index and pulmonary vascular permeability index (PVPI) showed significant differences at ROSC immediately compared to baseline and 1 h after ROSC (P < 0.05); PVPI at ROSC immediately was also different from 6 h after ROSC (P < 0.05). Ventilation/perfusion ratios increased after ROSC (P < 0.05). Histopathology showed fibrin effusion, bleeding in alveoli, and hemagglutination in pulmonary artery. CONCLUSIONS: Lung function remains abnormal even after CPR with thrombolysis therapy; it is essential to continue anticoagulation and symptomatic treatment after ROSC.

Efficacy and Safety of Combination Therapy of Shenfu Injection and Postresuscitation Bundle in Patients With Return of Spontaneous Circulation After In-Hospital Cardiac Arrest: A Randomized, Assessor-Blinded, Controlled Trial.

OBJECTIVES: Postresuscitation care bundle treatment after return of spontaneous circulation in patients experiencing in-hospital cardiac arrest can improve patients' survival and quality of life. The aim of the study was to evaluate the efficacy and safety of combined therapy of Shenfu injection and postresuscitation care bundle in these patients. DESIGN: Prospective, randomized, controlled clinical study. SETTING: Fifty hospitals in China. PATIENTS: Adult patients had experienced in-hospital cardiac arrest between 2012 and 2015. INTERVENTIONS: Based on the standardized postresuscitation care bundle treatment, patients were randomized to a Shenfu injection group (Shenfu injection + postresuscitation care bundle) or control group (postresuscitation care bundle) for 14 days or until hospital discharge. In the Shenfu injection group, 100 mL Shenfu injection was additionally administered via continuous IV infusion, bid. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day survival after randomization. The secondary outcomes included 90-day survival as well as the duration of mechanical ventilation and the hospital stay and the total cost of hospitalization. Of 1,022 patients enrolled, a total of 978 patients were allocated to the two groups: the control (n = 486) and Shenfu injection (n = 492) groups. The Shenfu injection group had a significantly greater 28-day survival rate (42.7%) than the control group (30.1%). Also, the Shenfu injection group had a significantly higher survival rate at 90 days (39.6%) than the control group (25.9%). Compared with patients in the control group, patients in the Shenfu injection group had lower risks of 28-day mortality (hazard ratio, 0.61; 95% CI, 0.43-0.89; p = 0.009) and 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79; p = 0.002). In the Shenfu injection group, the duration of mechanical ventilation (8.6 ± 3.2 vs 12.7 ± 7.9 d; p < 0.001) and the hospital stay (8.7 ± 5.9 vs 13.2 ± 8.1 d; p < 0.001) were significantly less than in the control group. Irreversible brain damage was the main cause of death in both groups. No serious drug-related adverse event was recorded. CONCLUSIONS: This study demonstrates that Shenfu injection in combination with conventional postresuscitation care bundle treatment is effective at improving clinical outcomes in patients with return of spontaneous circulation after in-hospital cardiac arrest.

Risk indicators for venous thrombosis in first-degree relatives of patients with recurrent venous thromboembolism in Chinese.

Having encountered several subjects with venous thromboembolism (VTE) in 1 family in which 1 proband has recurrent VTE (rVTE), we aimed to assess the risk of VTE in first-degree relatives, especially the children of individuals with rVTE, and to investigate the association of endothelial nitric oxide synthase (eNOS) G894T polymorphism between Chinese persons with rVTE and their offspring.We collected information about family histories and blood samples from 126 individuals with rVTE who had presented to our institute from 2003 to 2014, and 126 population-based controls and the first-degree relatives of subjects in these 2 groups. We tested blood samples for heritable thrombophilia and calculated odds ratios (ORs) and kappa coefficients.First-degree relatives of individuals with rVTE patients had a statistically significant risk of developing VTE (OR 2.62, 95% confidence interval [CI] 1.61-4.26, P < 0.001). For siblings, the OR was 2.72 (95% CI 1.56-4.73, P < .001). Moreover, for each year that the patient was older, the OR was 0.98 (95% CI 0.97-0.99, P = 0.03). One (11.2%) of the 9 individuals who had the same eNOS G894T polymorphism as their probands had a history of VTE, whereas none of the 17 relatives without the same polymorphism had developed VTE. The associations between patients and their children were statistically significant for VTE (kappa = 0.23, P < 0.001) and for eNOS G894T (kappa = 0.03, P = 0.04).In this case-controlled study, we demonstrated a higher risk of VTE among first-degree relatives of individuals with rVTE, especially in siblings of younger subjects with rVTE. We also found that eNOS G894T polymorphism may be a predictor of VTE in offspring of individuals with rVTE.

Captopril improves postresuscitation hemodynamics protective against pulmonary embolism by activating the ACE2/Ang-(1-7)/Mas axis.

Acute pulmonary embolism (APE) has a very high mortality rate, especially at cardiac arrest and even after the return of spontaneous circulation (ROSC). This study investigated the protective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on postresuscitation hemodynamics, in a porcine model of cardiac arrest established by APE. Twenty-nine Beijing Landrace pigs were infused with an autologous thrombus leading to cardiac arrest and subjected to standard cardiopulmonary resuscitation and thrombolysis. Ten resuscitated pigs were randomly and equally apportioned to receive either captopril (22.22 mg/kg) infusion or the same volume saline, 30 min after ROSC. Hemodynamic changes and ACE-Ang II-angiotensin II type 1 receptor (AT1R) and ACE2/Ang-(1-7)/Mas receptor axis levels were determined. APE was associated with a decline in mean arterial pressure and a dramatic increase in pulmonary artery pressure and mean right ventricular pressure. After ROSC, captopril infusion was associated with significantly lower mean right ventricular pressure and systemic and pulmonary vascular resistance, faster heart rate, and higher Ang-(1-7) levels, ACE2/ACE, and Ang-(1-7)/Ang II, compared with the saline infusion. The ACE2/Ang-(1-7)/Mas pathway correlated negatively with external vascular lung water and pulmonary vascular permeability and positively with the right cardiac index. In conclusion, in a pig model of APE leading to cardiac arrest, captopril infusion was associated with less mean right ventricular pressure overload after resuscitation, compared with saline infusion. The reduction in systemic and pulmonary vascular resistance associated with captopril may be by inhibiting the ACE-Ang II-AT1R axis and activating the ACE2/Ang-(1-7)/Mas axis.

Study of Cardiac Arrest Caused by Acute Pulmonary Thromboembolism and Thrombolytic Resuscitation in a Porcine Model.

BACKGROUND: The success rate of resuscitation in cardiac arrest (CA) caused by pulmonary thromboembolism (PTE) is low. Furthermore, there are no large animal models that simulate clinical CA. The aim of this study was to establish a porcine CA model caused by PTE and to investigate the pathophysiology of CA and postresuscitation. METHODS: This model was induced in castrated male pigs (30 ± 2 kg; n = 21) by injecting thrombi (10-15 ml) via the left external jugular vein. Computed tomographic pulmonary angiography (CTPA) was performed at baseline, CA, and return of spontaneous circulation (ROSC). After CTPA during CA, cardiopulmonary resuscitation (CPR) with thrombolysis (recombinant tissue plasminogen activator 50 mg) was initiated. Hemodynamic, respiratory, and blood gas data were monitored. Cardiac troponins T, cardiac troponin I, creatine kinase-MB, myoglobin, and brain natriuretic peptide (BNP) were measured by enzyme-linked immunosorbent assay. Data were compared between baseline and CA with paired-sample t-test and compared among different time points for survival animals with repeated measures analysis of variance. RESULTS: Seventeen animals achieved CA after emboli injection, while four achieved CA after 5-8 ml more thrombi. Nine animals survived 6 h after CPR. CTPA showed obstruction of the pulmonary arteries. Mean aortic pressure data showed occurrence of CA caused by PTE (Z = -2.803, P = 0.002). The maximal rate of mean increase of left ventricular pressure (dp/dtmax) was statistically decreased (t = 6.315, P = 0.000, variation coefficient = 0.25), and end-tidal carbon dioxide partial pressure (PetCO2) decreased to the lowest value (t = 27.240, P = 0.000). After ROSC (n = 9), heart rate (HR) and mean right ventricular pressure (MRVP) remained different versus baseline until 2 h after ROSC (HR, P = 0.036; MRVP, P = 0.027). Myoglobin was statistically increased from CA to 1 h after ROSC (P = 0.036, 0.026, 0.009, respectively), and BNP was increased from 2 h to 6 h after ROSC (P = 0.012, 0.014, 0.039, respectively). CONCLUSIONS: We established a porcine model of CA caused by PTE. The dp/dtmaxand PetCO2may be important for the occurrence of CA, while MRVP may be more important in postresuscitation.

Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients: a prospective cohort study.

BACKGROUND: Septic shock is a major healthcare problem with a high mortality rate that might be caused by immunosuppression. Programmed cell death receptor-1 (PD-1) and programmed cell death receptor ligand-1 (PD-L1), which are co-inhibitory receptor molecules, participate in sepsis-induced immunosuppression. In this study, we investigated which PD-1-related molecules can be used to evaluate the risk stratification and prognosis of septic patients. Furthermore, we explored the prognostic significance of a combination of ideal predictors and conventional clinical risk parameters in septic shock patients. METHODS: In total, 29 healthy controls, 59 septic patients, and 76 septic shock patients were enrolled in this study. Considering that the focus of the research was on the second phase of sepsis, blood samples were obtained at days 3-4 after the onset of systemic inflammatory response syndrome (SIRS). PD-1 and PD-L1 expression were measured on circulating CD4(+) T cells, CD8(+) T cells, and monocytes (PD-L1 only) by flow cytometry. RESULTS: Our results showed that only monocyte PD-L1 expression gradually increased, based on the increasing severity of disease (P < 0.001). Similarly, multivariate logistic regression analysis showed that only monocyte PD-L1 expression was an independent predictor of 28-day mortality in septic shock patients. Area under the receiver operating characteristic curve analysis of the combination of monocyte PD-L1 expression and conventional clinical risk parameters indicated a more significant prognostic ability than analysis of each parameter alone. CONCLUSION: Our study demonstrated that, among PD-1-related molecules, only monocyte PD-L1 expression after 3-4 days of sepsis was associated with risk stratification and mortality in septic patients. Furthermore, measurement of monocyte PD-L1 expression was a promising independent prognostic marker for septic shock patients.

Prognostic Value of Dynamic Monitoring of Cellular Immunity and HMGB1 in Severe Sepsis: Delayed Chronic Inflammation may be the Leading Cause of Death in Late Severe Sepsis.

BACKGROUND: Sepsis is a life-threatening response to infection with a high mortality rate. In order to explore the prognostic value of dynamic monitoring of cellular immunity during late severe sepsis, we assessed levels of Tlymphocyte subsets, the human leukocyte antigen D-related (HLA-DR), and the high mobility group box-1 (HMGB1) protein. METHODS: Study participants included 247 consecutive severe sepsis patients who were admitted to Beijing ChaoYang Hospital's Emergency Intensive Care Unit. Patients were divided into survivors and non-survivors based on 90-day survival rates, and clinical data were collected. T-lymphocyte subsets on days 1 and 7, HLA-DR on days 1 and 12, and HMGB1 on days 1, 3, 5, 7, and 12 were analyzed. RESULTS: Counts of CD3+, CD3+CD4+, and CD3+CD8+ T cells on day 1 in non-survivors were lower than those in survivors. By day 7, counts of all three types of T cells had increased in both survivors and non-survivors, but CD3+ and CD3+CD8+ T cells remained lower in non-survivors than in survivors. There was no significant difference in HLA-DR levels between survivors and non-survivors on day 1, but HLA-DR levels increased in survivors and decreased in non-survivors by day 12. In contrast, over days 1 - 12, HMGB1 levels increased in non-survivors and decreased in survivors. CONCLUSIONS: Patients with severe sepsis present with cellular immune dysfunction and persistent chronic inflammation, both of which may lead to death in the late phase of severe sepsis. Dynamic monitoring of indicators of cellular immunity and HMGB1 is useful for evaluating the immune status, chronic inflammation processes, and prognoses of patients with severe sepsis.

Prognostic significance of the angiopoietin-2/angiopoietin-1 and angiopoietin-1/Tie-2 ratios for early sepsis in an emergency department.

INTRODUCTION: This study was performed to assess the early diagnostic, risk stratification, and prognostic value of the angiopoietin-2/angiopoietin-1 ratio (Ang-2/Ang-1) and angiopoietin-1/tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 ratio (Ang-1/Tie-2) and to compare these factors with procalcitonin (PCT) and the Mortality in Emergency Department Sepsis (MEDS) score in patients with early sepsis in the emergency department (ED). METHODS: Consecutive patients with sepsis (n = 440) were enrolled in this study. They fulfilled the systemic inflammatory response syndrome (SIRS) criteria and were admitted to the ED of Beijing Chao-yang Hospital between August 2014 and February 2015. The control group consisted of 55 healthy blood donors. The patients were categorized into four groups: SIRS, sepsis, severe sepsis, and septic shock. Serum Ang-1, Ang-2, Tie-2, and PCT were measured, and the MEDS score was calculated upon ED arrival. The prognostic values of Ang-2/Ang-1, Ang-1/Tie-2, Ang-1, Ang-2, and Tie-2 were compared with the PCT and MEDS scores. All patients were followed for 28 days. RESULTS: Upon admission, the median levels of the serum Ang-2 level and Ang-2/Ang-1 ratio increased and the serum Ang-1 levels and Ang-1/Tie-2 ratios decreased with the severity of sepsis. The areas under the receiver operating characteristic curves of the Ang-2/Ang-1 and Ang-1/Tie-2 ratios were greater than those of the Ang-1, Ang-2, and PCT levels and MEDS scores in the diagnosis and prediction of 28-day mortality due to sepsis. Ang-2/Ang-1 was significantly higher and Ang-1/Tie-2 was significantly lower in nonsurvivors than in survivors at the 28-day follow-up examination. Ang-2/Ang-1, Ang-1/Tie-2, and MEDS score were found to be independent predictors of 28-day mortality in patients with sepsis. The levels of serum Ang-1, Ang-2, and Tie-2 were positively correlated with each other. The ratios of Ang-2/Ang-1 and Ang-1/Tie-2 were positively and negatively correlated, respectively, with the MEDS score in every septic group. CONCLUSIONS: The Ang-2/Ang-1 and Ang-1/Tie-2 ratios are valuable for risk stratification in patients with sepsis and are associated with the poor clinical outcome of early sepsis in the ED.