Pyridoxine Has a Potential to Prevent the Appearance of Pigmented Spots: Effects on the Phagocytosis and Differentiation of Keratinocytes.

Pyridoxine (VB6) is a vitamin that is essential to maintain the homeostasis of the human body by contributing to various metabolic reactions. In the skin, although some studies have shown that VB6 is involved in regulating homeostasis through the attenuation of intracellular oxidative stress, there are few reports regarding the effects of VB6 on the prevention or improvement of skin aging. Thus, we conducted this study to determine the potential anti-skin pigmentation effect of VB6 focusing on the phagocytosis of melanosomes (MSs) by keratinocytes. The phagocytosis of MSs by keratinocytes is activated by oxidative stress and is an important factor of skin pigmentation and the eventual appearance of pigmented spots. First, we confirmed the antioxidant property of VB6 that enhanced the expression of several intracellular antioxidants via nuclear erythroid factor 2-related factor 2 (Nrf2). Although the incorporation of fluorescent beads (FBs), which are used as pseudo-MSs, into keratinocytes was increased under higher oxidation conditions caused by UVB and by the depletion of intracellular glutathione, treatment with VB6 suppressed the increased incorporation of FBs into those keratinocytes via Nrf2 activation. Furthermore, VB6 restored the decreased expression of differentiation marker proteins in keratinocytes caused by FB incorporation. Taken together, the results show that VB6 has the potential to prevent the appearance of pigmented spots by suppressing the activation of phagocytosis in keratinocytes caused by oxidative stress, and by restoring the differentiation of keratinocytes disrupted by FB incorporation.

Clinical Features of Early Stage COVID-19 in a Primary Care Setting.

Background: The coronavirus disease 2019 (COVID-19) pandemic remains a global healthcare crisis. Nevertheless, the majority of COVID-19 cases involve mild to moderate symptoms in the early stages. The lack of information relating to these cases necessitates further investigation. Methods: Patients visiting the outpatient clinic at the Kamagaya General Hospital were screened by interview and body temperature check. After initial screening, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was suspected in 481 patients who then underwent blood tests and the loop-mediated isothermal amplification (LAMP) test for SARS-CoV-2. Clinical characteristics between positive and negative SARS-CoV-2 groups were compared. Further, the novel predictive value of routine blood test results for SARS-CoV-2 infection was evaluated using ROC analysis. Results: A total of 15,560 patients visited our hospital during the study period. After exclusion and initial screening by interview, 481 patients underwent the LAMP test and routine blood tests. Of these patients, 69 (14.3%) were positive for SARS-CoV-2 and diagnosed with COVID-19 (positive group), and 412 (85.7%) were negative (negative group). The median period between the first onset of symptoms and visit to our hospital was 3.4 and 2.9 days in the negative and positive groups, respectively. Cough (p = 0.014), rhinorrhea (p = 0.039), and taste disorders (p < 0.001) were significantly more common in the positive group, while gastrointestinal symptoms in the negative group (p = 0.043). The white blood cell count (p < 0.001), neutrophil count (p < 0.001), and percentage of neutrophils (p < 0.001) were higher in the negative group. The percentage of monocytes (p < 0.001) and the levels of ferritin (p < 0.001) were higher in the positive group. As per the predictive values for COVID-19 using blood tests, the values for the area under the curve for the neutrophil-to-monocyte ratio (NMR), white blood cell-to-hemoglobin ratio (WHR), and the product of the two (NMWH) were 0.857, 0.837, and 0.887, respectively. Conclusion: Symptoms in early stage COVID-19 patients were similar to those in previous reports. Some blood test results were not consistent with previous reports. NMR, WHR, and NMWH are novel diagnostic scores in early-stage mild-symptom COVID-19 patients in primary care settings.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016)

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (JSSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 in Japanese. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within eachteam were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ), and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a twothirds (>66.6%) majority vote of each of the 19 committee members. A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in additionto ratings of the strengths of the recommendation and its supporting evidence were also added to each recommendation statement.We conducted meta-analyses for 29 CQs. Thirty seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for 5 CQs.Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

Disseminated intravascular coagulation with increased fibrinolysis during the early phase of isolated traumatic brain injury.

BACKGROUND: There is evidence to demonstrate that the coagulopathy which occurs in patients with traumatic brain injury coincides with disseminated intravascular coagulation (DIC). We hypothesized that DIC with increased fibrinolysis during the early stage of isolated traumatic brain injury (iTBI) affects the outcome of the patients and that hypoperfusion contributes to hyperfibrinolysis in the DIC. METHODS: This retrospective study included 92 patients with iTBI who were divided into DIC and non-DIC groups according to the Japanese Association Acute Medicine DIC scoring system. The DIC patients were subdivided into those with and without hyperfibrinolysis. The platelet counts and global markers of coagulation and fibrinolysis were measured. Systemic inflammatory response syndrome (SIRS), organ dysfunction (assessed by the Sequential Organ Failure Assessment score), tissue hypoperfusion (assessed by the lactate levels) and the transfusion volume were also evaluated. The outcome measure was all-cause hospital mortality. RESULTS: DIC patients showed consumption coagulopathy, lower antithrombin levels and higher fibrin/fibrinogen degradation products (FDP) and D-dimer levels than non-DIC patients. All of the DIC patients developed SIRS accompanied by organ dysfunction and required higher blood transfusion volumes, leading to a worse outcome than non-DIC patients. These changes were more prominent in DIC with hyperfibrinolysis. A higher FDP/D-dimer ratio suggests that DIC belongs to the fibrinolytic phenotype and involves fibrin(ogen)olysis. The mean blood pressures of the patients with and without DIC on arrival were identical. Hypoperfusion and the lactate levels were not identified as independent predictors of hyperfibrinolysis. CONCLUSIONS: DIC, especially DIC with hyperfibrinolysis, affects the outcome of patients with iTBI. Low blood pressure-induced tissue hypoperfusion does not contribute to hyperfibrinolysis in this type of DIC.

Fibrin/fibrinogen degradation products (FDP) at hospital admission predict neurological outcomes in out-of-hospital cardiac arrest patients.

OBJECTIVE: This study aimed to test the hypothesis that coagulation, fibrinolytic markers and disseminated intravascular coagulation (DIC) score (International Society on Thrombosis and Haemostasis) at hospital admission of out-of-hospital cardiac arrest (OHCA) patients can predict neurological outcomes 1 month after cardiac arrest. METHODS: In this retrospective, observational analysis, data were collected from the Sapporo Utstein Registry and medical records at Hokkaido University Hospital. We included patients who experienced OHCA with successful return of spontaneous circulation (ROSC) between 2006 and 2012 and were transferred to Hokkaido University Hospital. From medical records, we collected information about the following coagulation and fibrinolytic factors at hospital admission: platelet count; prothrombin time; activated partial thromboplastin time; plasma levels of fibrinogen, D-dimer, fibrin/fibrinogen degradation products (FDP), and antithrombin; and calculated DIC score. Favorable neurological outcomes were defined as a cerebral performance category 1-2. RESULTS: We analyzed data for 315 patients. Except for fibrinogen level, all coagulation variables, fibrinolytic variables, and DIC score were associated with favorable neurological outcomes. In the receiver operating characteristic curve analysis, FDP level had the largest area under the curve (AUC; 0.795). In addition, the AUC of FDP level was larger than that of lactate level. CONCLUSIONS: All of the coagulation and fibrinolytic markers, except for fibrinogen level, and DIC score at hospital admission, were associated with favorable neurological outcomes. Of all of the variables, FDP level was most closely associated with favorable neurological outcomes in OHCA patients who successfully achieved ROSC.

Disseminated intravascular coagulation with the fibrinolytic phenotype predicts the outcome of patients with out-of-hospital cardiac arrest.

BACKGROUND: We tested the hypothesis that disseminated intravascular coagulation (DIC) during the early phase of post-cardiopulmonary resuscitation (CPR) is associated with systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS) and affects the outcome of out-of-hospital cardiac arrest (OHCA) patients. METHODS: A review of the computer-based medical records of OHCA patients was retrospectively conducted and included 388 patients who were divided into DIC and non-DIC patients based on the Japanese Association for Acute Medicine DIC diagnostic criteria. DIC patients were subdivided into two groups: those with and without hyperfibrinolysis. Pre-hospital factors, platelet count, coagulation and fibrinolysis markers and lactate levels within 24 h after resuscitation were evaluated. The outcome measure was all-cause hospital mortality. RESULTS: DIC patients exhibited lower platelet counts, prolonged prothrombin time, decreased levels of fibrinogen and antithrombin associated with increased fibrinolysis than those without DIC. DIC patients more frequently developed SIRS and MODS, followed by worse outcomes than non-DIC patients. The same changes were observed in DIC patients with hyperfibrinolysis who showed a higher prevalence of MODS, leading to worse outcome than those without hyperfibrinolysis. Logistic regression analyses showed that lactate levels predicted hyperfibrinolysis and DIC is an independent predictor of patient death. Survival probabilities of DIC patients during hospital stay were significantly lower than non-DIC patients. The area under the receiver operating characteristic curve of DIC for the prediction of death was 0.704. CONCLUSIONS: The fibrinolytic phenotype of DIC during the early phase of post-CPR more frequently results in SIRS and MODS, especially in patients with hyperfibrinolysis, and affects the outcome of OHCA patients.

The response time threshold for predicting favourable neurological outcomes in patients with bystander-witnessed out-of-hospital cardiac arrest.

OBJECTIVE: It is well established that the period of time between a call being made to emergency medical services (EMS) and the time at which the EMS arrive at the scene (i.e. the response time) affects survival outcomes in patients who experience out-of-hospital cardiac arrest (OHCA). However, the relationship between the response time and favourable neurological outcomes remains unclear. We therefore aimed to determine a response time threshold in patients with bystander-witnessed OHCA that is associated with positive neurological outcomes and to assess the relationship between the response time and neurological outcomes in patients with OHCA. METHODS: This study was a retrospective, observational analysis of data from 204,277 episodes of bystander-witnessed OHCA between 2006 and 2012 in Japan. We used classification and regression trees (CARTs) and receiver operating characteristic (ROC) curve analyses to determine the threshold of response time associated with favourable neurological outcomes (Cerebral Performance Category 1 or 2) 1 month after cardiac arrest. RESULTS: Both CARTs and ROC analyses indicated that a threshold of 6.5min was associated with improved neurological outcomes in all bystander-witnessed OHCA events of cardiac origin. Furthermore, bystander cardiopulmonary resuscitation (CPR) prolonged the threshold of response time by 1min (up to 7.5min). The adjusted odds ratio for favourable neurological outcomes in patients with OHCA who received care within ≤6.5min was 1.935 (95% confidential interval: 1.834-2.041, P<0.001). CONCLUSIONS: A response time of ≤6.5min was closely associated with favourable neurological outcomes in all bystander-witnessed patients with OHCA. Bystander CPR prolonged the response time threshold by 1min.

[The clinical condition and treatment of diseases associated with sudden death].

The Hokkaido Medical Society is a group of doctors and medical researchers in Hokkaido. Its purpose is to contribute to medicine and to the improvement of medical treatment. This symposium was carried out in order to inform citizens about the condition known as sudden death. We hypothesize that the incidence of sudden death tends to increase in line with the incidence of metabolic syndrome. Approximately four hundred patients were transported to our hospital by ambulance in a state of cardiopulmonary arrest (CPA) last year. The number of CPA patients who are treated in our hospital has increased in comparison to the previous decade. The theme of this year is "The clinical condition and treatment of diseases associated with sudden death" in view of the above mentioned situation. In 2015, it was reported that sudden death occurred in an American pilot and that the co-pilot was forced to make an emergency landing. Interestingly, sudden death can ever sometimes occur in pilots who undergo regular physical examinations. Numerous diseases and conditions are associated with sudden death, including: acute myocardial infarction, irregular pulse, cardiac insufficiency, cerebrovascular disease, aortic dissection and choking. We are of the opinion that the frequency of sudden death is very high in the fields of emergency medicine, cardiovascular medicine, cardiovascular surgery and neurosurgery. In this symposium, we presented and explained the condition that is known as sudden death and the current state of treatment of sudden death in emergency medicine, cardiovascular medicine, cardiovascular surgery and neurosurgery departments of the Hokkaido University Graduate School of Medicine in October, 2015. We hope that the symposium will help the citizen audience to understand the condition and treatment of sudden death, and also to help prevent sudden death.

Activated protein C does not increase in the early phase of trauma with disseminated intravascular coagulation: comparison with acute coagulopathy of trauma-shock.

We hypothesized that activated protein C does not increase in disseminated intravascular coagulation (DIC) after trauma and that the same is true for acute coagulopathy of trauma-shock (ACOTS). Activated protein C levels were prospectively measured in 57 trauma patients: 30 with DIC and 27 without DIC. Normal to more decreased activated protein C levels were observed in DIC patients than in the controls and non-DIC patients. The activated protein C levels in ACOTS patients were similar to those in DIC patients. In conclusion, activated protein C does not increase in either DIC or ACOTS in the early phase of trauma.

Should laryngeal tubes or masks be used for out-of-hospital cardiac arrest patients?

OBJECTIVE: Few studies have compared airway management via laryngeal masks (LM) or laryngeal tubes (LT) in patients with out-of-hospital cardiac arrest (OHCA). This study evaluated whether LT insertion by emergency medical service (EMS) personnel affected ventilation and outcomes in OHCA patients (vs. the standard LM treatment). METHODS: This prospective, cluster-randomized, and open-label study evaluated data that were collected by the Sapporo Fire Department between June 2012 and January 2013. We selected the 14 EMS teams that treated the greatest number of OHCA patients in Sapporo, Japan during 2011, and randomized the teams into Groups A and B. In the first study period (June 2012 to September 2012), Group A treated OHCA patients via LT and Group B treated OHCA patients via LM. In the second period (October 2012 to January 2013), Group A treated OHCA patients via LM and Group B treated OHCA patients via LT. If necessary, both groups were allowed to use an esophageal obturator airway (EOA) kit. The primary endpoints were time from cardiopulmonary resuscitation to device insertion and the rate of successful pre-hospital ventilation. The secondary endpoints were return of spontaneous circulation and survival and favorable neurological outcomes at 1 month after cardiac arrest. RESULTS: LT was used in 148 OHCA patients and LM was used in 165 OHCA patients. Our intention-to-treat analyses revealed no significant differences in the primary and secondary outcomes of the LT- and LM-treated groups. CONCLUSION: Prehospital advanced airway management via LT provides similar outcomes to those of LM in OHCA patients.

Effects of prehospital epinephrine administration on neurological outcomes in patients with out-of-hospital cardiac arrest.

BACKGROUND: To determine if the effects of epinephrine administration on the outcome of out-of-hospital cardiac arrest (OHCA), patients are associated with the duration of cardiopulmonary resuscitation (CPR) performed by Emergency Medical Service (EMS) personnel. METHODS: This retrospective, nonrandomized, observational analysis used the All-Japan Utstein Registry, a prospective, nationwide population-based registry of all OHCA patients transported to the hospital by EMS staff as the data source. We stratified all OHCA patients for quartile of EMSs' CPR duration. Group 1 consisted of patients who fell under the 25th percentile of EMSs' CPR duration (under 15 min); group 2, patients who fell into the 25th to 50th percentile (between 15 and 19 min); group 3, patients who fell into the 50th to 75th percentile (between 20 and 26 min); and group 4, patients who fell at or above the 75th percentile (over 26 min). The primary endpoint was a favorable neurological outcome 1 month after cardiac arrest. The secondary endpoints were ROSC before arrival at the hospital and 1-month survival. RESULTS: A total of 383,811 patients aged over 18 years who had experienced OHCA between 2006 and 2010 in Japan, when stratified for quartile of EMSs' CPR duration, the epinephrine administration increased the rate of return of spontaneous circulation (ROSC) approximately tenfold in all groups. However, the beneficial effects of epinephrine administration on 1-month survival disappeared in patients on whom EMSs' CPR had been performed for more than 26 min, and the beneficial effects of epinephrine administration on neurological outcomes were observed only in patients on whom EMSs' CPR had been performed between 15 and 19 min (odds ratio, 1.327, 95 % confidence intervals, 1.017-1.733 P = 0.037). CONCLUSIONS: Epinephrine administration is associated with an increase of ROSC and with improvement in the neurological outcome on which EMSs' CPR duration is performed between 15 and 19 min.

Pharmacokinetics and the optimal regimen for levofloxacin in critically ill patients receiving continuous hemodiafiltration.

The aim of this study was to establish the pharmacokinetics of levofloxacin (LVFX) and determine the optimal dose of this drug in critically ill patients receiving continuous hemodiafiltration (CHDF). The results of in vivo and in vitro studies showed the pharmacokinetics of LVFX total clearance (CLtotal) according to the creatinine clearance (CLCre), dialysate flow (QD), and ultrafiltrate flow (QF), to be as follows: CLtotal (l/h) = 0.0836 × CLCre (ml/min) + 0.013 × body weight (kg) + 0.94(QD + QF) (l/h). The optimal dose of LVFX was expressed by the following formula: 50 × CLtotal. These results demonstrate that the usual dose of LVFX (500 mg) was sufficient for the patients evaluated in this study.

Rapid evaluation of fibrinogen levels using the CG02N whole blood coagulation analyzer.

Rapid evaluation of fibrinogen (Fbg) levels is essential for maintaining homeostasis in patients with massive bleeding during severe trauma and major surgery. This study evaluated the accuracy of fibrinogen levels measured by the CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) using heparinized blood drawn for blood gas analysis (whole blood-Fbg). A total of 100 matched pairs of heparinized blood samples and citrated blood samples were simultaneously collected from patients in the intensive care unit. Whole blood-Fbg results were compared with those of citrated plasma (standard-Fbg). The whole blood coagulation analyzer measured fibrinogen levels within 2 minutes. Strong correlations between standard-Fbg and whole blood-Fbg were observed (ρ = 0.91, p < 0.001). Error grid analysis showed that 88% of the values were clinically acceptable, and 12% were in a range with possible effects on clinical decision-making; none were in a clinically dangerous range without appropriate treatment. Using a fibrinogen cutoff value of 1.5 g/L for standard-Fbg, the area under the receiver operating characteristic curve of whole blood-Fbg was 0.980 (95% confidence interval 0.951-1.000, p < 0.001). The whole blood coagulation analyzer can rapidly measure fibrinogen levels in heparinized blood and could be useful in critical care settings where excessive bleeding is a concern.

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.

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.

Effects of protease activated receptor (PAR)2 blocking peptide on endothelin-1 levels in kidney tissues in endotoxemic rat mode.

AIMS: Septic shock, the severe form of sepsis, is associated with development of progressive damage in multiple organs. Kidney can be injured and its functions altered by activation of coagulation, vasoactive-peptide and inflammatory processes in sepsis. Endothelin (ET)-1, a potent vasoconstrictor, is implicated in the pathogenesis of sepsis and its complications. Protease-activated receptors (PARs) are shown to play an important role in the interplay between inflammation and coagulation. We examined the time-dependent alterations of ET-1 and inflammatory cytokine, such as tumor necrosis factor (TNF)-α in kidney tissue in lipopolysaccharide (LPS)-induced septic rat model and the effects of PAR2 blocking peptide on the LPS-induced elevations of renal ET-1 and TNF-α levels. MAIN METHODS: Male Wistar rats at 8 weeks of age were administered with either saline solution or LPS at different time points (1, 3, 6 and 10h). Additionally, we treated LPS-administered rats with PAR2 blocking peptide for 3h to assess whether blockade of PAR2 has a regulatory role on the ET-1 level in septic kidney. KEY FINDINGS: An increase in ET-1 peptide level was observed in kidney tissue after LPS administration time-dependently. Levels of renal TNF-α peaked (around 12-fold) at 1h of sepsis. Interestingly, PAR2 blocking peptide normalized the LPS-induced elevations of renal ET-1 and TNF-α levels. SIGNIFICANCE: The present study reveals a distinct chronological expression of ET-1 and TNF-α in LPS-administered renal tissues and that blockade of PAR2 may play a crucial role in treating renal injury, via normalization of inflammation, coagulation and vaso-active peptide.

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: UMIN00000356.

Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock.

BACKGROUND: We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC. METHODS: We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction. RESULTS: Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients. CONCLUSION: Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed.

Massive amounts of tissue factor induce fibrinogenolysis without tissue hypoperfusion in rats.

Trauma-induced tissue factor (TF) release into the systemic circulation is considered to play an important role in the development of disseminated intravascular coagulation (DIC) immediately after severe trauma. However, the relationship between TF and hyperfibrinolysis, especially fibrinogenolysis, has been unclear. A total of 18 rats were divided into three groups: (a) the control group was infused with normal saline; (b) the low-dose group was infused with 4 U/kg TF; and (c) the high-dose group was infused with 16 U/kg TF. Arterial blood was drawn immediately and 2 and 4 h after the start of TF infusion. At each sampling point, arterial blood gases, platelet counts, and coagulation variables were measured. The fibrinogen degradation products were evaluated by a Western blot analysis. Hypotension, hypoxemia, and lactic acidosis were not observed in any of the three groups. In proportion to the doses of TF, the platelet counts, coagulation, and fibrinolysis variables deteriorated in line with DIC. The α2-plasmin inhibitor levels significantly decreased in the high-dose group compared with the other groups. The amounts of fibrinogen degradation products increased in proportion to the doses of TF. The plasmin-α2-plasmin inhibitor complex level in the high-dose group increased more than that of the other groups. In conclusion, TF can induce DIC associated with fibrinolysis and fibrinogenolysis without tissue hypoperfusion. The decrease in the α2-plasmin inhibitor level and the significant increase in the plasmin level may be the two main factors underlying the pathogenesis of hyperfibrin(ogen)olysis after TF administration.