Angiogenic factors and their soluble receptors predict organ dysfunction and mortality in post-cardiac arrest syndrome

INTRODUCTION: Post-cardiac arrest syndrome (PCAS) often leads to multiple organ dysfunction syndrome (MODS) with a poor prognosis. Endothelial and leukocyte activation after whole-body ischemia/reperfusion following resuscitation from cardiac arrest is a critical step in endothelial injury and related organ damage. Angiogenic factors, including vascular endothelial growth factor (VEGF) and angiopoietin (Ang), and their receptors play crucial roles in endothelial growth, survival signals, pathological angiogenesis and microvascular permeability. The aim of this study was to confirm the efficacy of angiogenic factors and their soluble receptors in predicting organ dysfunction and mortality in patients with PCAS. METHODS: A total of 52 resuscitated patients were divided into two subgroups: 23 survivors and 29 non-survivors. The serum levels of VEGF, soluble VEGF receptor (sVEGFR)1, sVEGFR2, Ang1, Ang2 and soluble Tie2 (sTie2) were measured at the time of admission (Day 1) and on Day 3 and Day 5. The ratio of Ang2 to Ang1 (Ang2/Ang1) was also calculated. This study compared the levels of angiogenic factors and their soluble receptors between survivors and non-survivors, and evaluated the predictive value of these factors for organ dysfunction and 28-day mortality. RESULTS: The non-survivors demonstrated more severe degrees of organ dysfunction and a higher prevalence of MODS. Non-survivors showed significant increases in the Ang2 levels and the Ang2/Ang1 ratios compared to survivors. A stepwise logistic regression analysis demonstrated that the Ang2 levels or the Ang2/Ang1 ratios on Day 1 independently predicted the 28-day mortality. The receiver operating characteristic curves of the Ang2 levels, and the Ang2/Ang1 ratios on Day 1 were good predictors of 28-day mortality. The Ang2 levels also independently predicted increases in the Sequential Organ Failure Assessment (SOFA) scores. CONCLUSIONS: We observed a marked imbalance between Ang1 and Ang2 in favor of Ang2 in PCAS patients, and the effect was more prominent in non-survivors. Angiogenic factors and their soluble receptors, particularly Ang2 and Ang2/Ang1, are considered to be valuable predictive biomarkers in the development of organ dysfunction and poor outcomes in PCAS patients

Quark Mass Hierarchy, FCNC and CP violation in a Seesaw model

The seesaw model of quark masses is studied systematically, focusing on its developments. A framework allowing the top quark mass to be of the order of the electroweak symmetry breaking scale, while the remaining light quarks have much smaller masses, due to the seesaw mechanism, is presented. The violation of the GIM mechanism is shown to be small and the tree level FCNC are suppressed naturally. In this model, there are many particles which could contribute to the FCNC in the one-loop level. Parameters of the model are constrained by using the experimental data on K^0-\bar{K}^0 mixing and \epsilon_K. The rare K meson decays K_{L,S} -> \pi^0 \nu \bar{\nu} and K^+ -> \pi^+ \nu \bar{\nu} are also investigated in the model. In these processes the scalar operators (\bar{s}d)(\bar{\nu}_{\tau}\nu_{\tau}), which are derived from box diagrams in the model, play an important role due to an enhancement factor M_K/m_s in the matrix element . It is emphasized that the K_L decay process through the scalar operator is not the CP violating mode, so B(K_L -> \pi^0 \nu \bar{\nu}) remains non-zero even in the CP conserved limit. The pion energy spectra for these processes are predicted.Comment: 42 pages, 13 figures, psfig.sty is require

The response of antithrombin III activity after supplementation decreases in proportion to the severity of sepsis and liver dysfunction

The decrease in the antithrombin III activity is thought to result from consumption by ongoing coagulation, degradation by neutrophil elastase, capillary leak syndrome, and impaired synthesis. A retrospective data analysis of patients with sepsis was conducted to investigate the response of antithrombin III activity after supplementation in patients with sepsis, and to determine what factors affect the response of antithrombin III activity. The study included 42 sepsis, 75 severe sepsis and 65 septic shock patients, who were administrated antithrombin III. Antithrombin III activity, platelet counts, coagulation and fibrinolytic markers were collected before administration and 24 hr after the supplementation. In the patients with septic shock, the response of antithrombin III activity after supplementation was 0.37 ± 1.21%/IU/kg body weight, which was significantly lower in comparison to those in the patients with sepsis (1.81 ± 1.75 ; P < 0.001) or severe sepsis (1.36 ± 1.65 ; P < 0.001). The patients with liver dysfunction had significantly lower response to antithrombin III activity than that of the patients without liver dysfunction (P < 0.0001). A stepwise multiple-linear regression analysis revealed that the severity of sepsis and liver function were independent predictors for the response to antithrombin III activity. These results suggest that the response to antithrombin III supplementation may be affected by both a systemic inflammation and impaired synthesis in patients with sepsis

Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma : a retrospective observational study

In trauma, hemostatic functions should be maintained appropriately to prevent massive bleeding. This study elucidated the time-dependent changes in platelet count and coagulation variables, and the effects of disseminated intravascular coagulation (DIC) on these changes during the early phase of trauma. Trauma patients with an injury severity score ≥16 were enrolled. The critical levels of platelet count and coagulation variables were defined according to recent trauma guidelines. Massive transfusion was defined as >10 units red cell concentrate. The time from arrival at the emergency department to reaching the critical levels and meeting the criteria for massive transfusion were evaluated. Eighty trauma patients were enrolled; 35 were diagnosed with DIC on arrival. Among all patients, fibrinogen levels reached the critical level earliest among routine coagulation parameters; other routine coagulation parameters deteriorated after the patients met the criteria for massive transfusion. Routine coagulation parameters reached their critical levels earlier in DIC patients than patients without DIC. Massive transfusion was performed more frequently in DIC patients, who met the criteria earlier. During the early phase of trauma, fibrinogen levels deteriorate earlier than other routine coagulation parameters, especially in DIC patients

Insufficient production of urinary trypsin inhibitor for elastase release promotes organ failure following cardiac arrest

To investigate the relationship between the inflammatory responses and post-resuscitation syndrome, we prospectively examined the serial changes of neutrophil elastase (NE), urinary trypsin inhibitor (UTI) and tumor necrosis factor-α (TNF-α) in successfully resuscitated patients following out-of-hospital cardiac arrest. This study included 36 patients with out-of-hospital cardiac arrests that wewere admitted to our intensive care unit after return of spontaneous circulation (ROSC). The twenty-two patients who died within 3 days after ROSC were defined as nonsurvivors. The fourteen patients who survived for more than 3 days after ROSC were defined as survivors. Eight healthy volunteers served as control group. Daily plasma levels of NE, UTI, and TNF-α were measured from days 1 to 5 after ROSC. Persistently high levels of TNF-α and NE were observed in both the survivors and nonsurvivors. In the two groups, the levels of UTI were significantly high and increased as time progressed. NE/UTI ratios were significantly higher in the nonsurvivors than in the survivors, especially on day 1. The nonsurvivors showed statistically higher scores according to the Sequential Organ Failure Assessment and they also had more organ failure than the survivors. In conclusion, an insufficient production of UTI for NE release and persistent high levels of TNF-α may contribute to the pathogenesis of post-resuscitation syndrome following out-of-hospital cardiac arrest

Effects of Rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients : a pilot study

Background: Rikkunshito is a traditional Japanese medicine that has been widely prescribed for patients with various gastrointestinal symptoms. Recently, the prokinetic effects of Rikkunshito in patients with a variety of diseases have attracted attention in Japan. The prokinetic effects of Rikkunshito are believed to result from an increase of active ghrelin, which is most abundant in the stomach and which has a gastrokinetic function. The aim of the present pilot study was to investigate the effects of Rikkunshito on intragastric enteral feeding and plasma ghrelin levels in critically ill patients. Methods: The study population consisted of critically ill patients who were projected to require intragastric tube feeding for more than 7 days. The patients were prospectively assigned to one of two treatment groups and were randomized to receive either Rikkunshito (2.5 g) or metoclopramide (10 mg) every 8 h. All patients received standard enteral nutrition. Patients in both groups were begun on intragastric tube feeding according to our institution’s feeding protocol. Results: All patients were undergoing mechanical ventilation at the time of enrollment. The portions of enteral nutrition provided to the target amount and the quantity of gastric discharge were not statistically significantly different between the two groups. The Rikkunshito group reached 50% of the target amount of enteral feeding significantly earlier than the metoclopramide group, although the proportion of patients in whom enteral feeding was successful did not differ significantly between the two groups. Patients in the Rikkunshito group showed significantly higher plasma levels of active ghrelin compared to those in the metoclopramide group. Conclusions: The administration of Rikkunshito increased the plasma level of active ghrelin, and induced prokinetic effects that were greater than those observed following treatment with metoclopramide in critically ill patients. Trial registration: UMIN0000035

Noble-Collip Drum Trauma Induces Disseminated Intravascular Coagulation But Not Acute Coagulopathy of Trauma-Shock

Background: There are two opposing possibilities for the main pathogenesis of trauma-induced coagulopathy: an acute coagulopathy of trauma shock and disseminated intravascular coagulation with the fibrinolytic phenotype. Objective: The objective of this study was to clarify the main pathogenesis of trauma-induced coagulopathy using a rat model of Noble-Collip drum trauma. Methods: Eighteen rats were divided into the control, trauma 0, and trauma 30 groups. The trauma 0 and 30 groups were exposed to Noble-Collip drum trauma. Blood samples were drawn without, immediately after, and 30 min after Noble-Collip drum trauma in the control, trauma 0, and trauma 30 groups, respectively. Coagulation and fibrinolysis markers were measured. Thrombin generation was assessed according to a calibrated automated thrombogram. Results: Spontaneous thrombin bursts resulting from circulating procoagulants were observed in the nonstimulated thrombin generation assay immediately after trauma. Soluble fibrin levels (a marker of thrombin generation in the systemic circulation) were 50-fold greater in the trauma groups than in the control group. The resultant coagulation activation consumed platelets, coagulation factors, and antithrombin. Endogenous thrombin potential and factor II ratio were significantly negatively correlated with antithrombin levels, suggesting insufficient control of thrombin generation by antithrombin. High levels of active tissue-type plasminogen activator induced hyperfibrin(ogen)olysis. Soluble thrombomodulin increased significantly. However, activated protein C levels did not change. Conclusions: The systemic thrombin generation accelerated by insufficient antithrombin control leads to the consumption of platelets and coagulation factors associated with hyperfibrin(ogen)olysis. These changes are collectively termed disseminated intravascular coagulation with the fibrinolytic phenotype