Agonal breathing upon hospital arrival as a prognostic factor in patients experiencing out-of-hospital cardiac arrest.

Background: Agonal breathing is a relatively common symptom that follows cardiac arrest when the brainstem function is preserved. Agonal breathing is associated with favorable survival in patients experiencing out-of-hospital cardiac arrest (OHCA). While previous studies focused on agonal breathing observed in the pre-hospital setting for all study subjects, we focused on agonal breathing observed upon hospital arrival. In this multicenter prospective study, we aimed to assess the prognosis of patients exhibiting agonal breathing upon hospital arrival were compared. We hypothesized that agonal breathing at hospital arrival would be associated with favorable neurological outcomes among patients with OHCA. Methods: The data on incidence of agonal breathing were prospectively collected for all evaluable participants in a multicenter, observational study in Japan (SOS-KANTO [Survey of Survivors after Out-of-Hospital Cardiac Arrest in Kanto Area] 2017 Study). Groups with and without agonal breathing were compared upon hospital arrival. Propensity-score with inverse probability of treatment weighting (IPTW) analysis was performed to adjust for confounding factors. The primary outcome was a favorable neurological outcome (Cerebral Performance Category 1-2) at 1 month. Results: A total of 6,457 participants out of the 9,909 registered in SOS-KANTO 2017 (in which 42 facilities participated) were selected for the current study. There were 128 patients (2.0%) in the with-agonal breathing group and 6,329 (98.0%) in the withoutagonal breathing group. The primary outcome was 1.1% in the with-agonal breathing group and 0.6% in the without-agonal breathing group (risk difference, 0.55; 95% confidence interval, 0.23-0.87) after IPTW analysis. Conclusion: In this multicenter prospective study, agonal breathing at hospital arrival was significantly associated with better neurological outcomes and increased survival at 1 month. Thus, agonal breathing at hospital arrival may be a useful prognostic predictor for patients experiencing OHCA.

Risk factors for the need for advanced care among prescription and over-the-counter drug overdose patients.

Aim: Prescription drug and over-the-counter (OTC) drug overdose is a major problem in emergency departments in Japan, and some need advanced care which is more than observation. We aimed to identify the prehospital risk factors for the need of advanced care among overdose patients. Methods: This was a single-center retrospective cohort study. We included overdoses patients of prescription drugs or OTC drugs, who admitted to our hospital between 2016 and 2021. We grouped them into advanced care and non-advanced care. The main outcome was the need for advanced care. We performed a multiple logistic regression analysis, calculated the PAV score (Paracetamol use, Alcohol use, abnormal Vital signs on scene) and performed a receiver operating characteristic (ROC) analysis. Results: There were 229 subjects. The logistic regression analysis revealed that alcohol, paracetamol, and the abnormal vital signs on scene were associated with advanced care (alcohol-odds ratio [OR]: 2.95; 95% confidence interval [CI]: 1.29-6.75; paracetamol-OR: 5.47; 95% CI: 2.18-13.71; abnormal vital signs-OR: 4.61, 95% CI: 2.07-10.27). The rate of advanced care in the high PAV score (2 and 3) group was statistically higher than that in the low PAV score (0-1) group (p = 0.04). Area under the ROC curve of the PAV score was 0.72 (95% CI, 0.65-0.80). Conclusion: Alcohol, paracetamol use and abnormal vital signs on scene might be risk factors for advanced care among prescription drugs or OTC drugs overdose patients, and the PAV score may predict the need for advanced care.

Changes Over 7 Years in Temperature Control Treatment and Outcomes After Out-of-Hospital Cardiac Arrest: A Japanese, Multicenter Cohort Study.

Temperature control is the only neuroprotective intervention suggested in current international guidelines for patients with return of spontaneous circulation after cardiac arrest, but the prevalence of temperature control therapy, temperature settings, and outcomes have not been clearly reported. We aimed to investigate changes over 7 years in provision of temperature control treatment among out-of-hospital cardiac arrest (OHCA) patients in Kanto region, Japan. Data of all adult OHCA patients who survived for more than 24 hours in the prospective cohort studies, SOS-KANTO 2012 (conducted from 2012 to 2013) and SOS-KANTO 2017 (conducted from 2019 to 2021), in Japan were included. We compared the prevalence of temperature control and the proportion of mild (≥35°C) and moderate (from 32°C to 34.9°C) hypothermia between the two study groups. We also performed a Cox regression analysis to evaluate 30-day mortality adjusted by temperature control therapy (none, moderate hypothermia, or mild hypothermia), age, sex, past medical history, witnessed status, bystander cardiopulmonary resuscitation, initial rhythm, location of arrest, and dataset (SOS-KANTO 2012 or 2017). We analyzed data from 2936 patients (n = 1710, SOS-KANTO 2012; n = 1226, SOS-KANTO 2017). Use of temperature control was lower (45.3% vs. 41.4%, p = 0.04), moderate hypothermia was lower (p < 0.01), and mild hypothermia was higher (p < 0.01) in SOS-KANTO 2017 compared with SOS-KANTO 2012. The survival rate was significantly higher for patients with mild (p < 0.01) and moderate (p < 0.01) hypothermia compared with those who did not receive temperature control therapy. Overall, the incidence of moderate hypothermia decreased and that of mild hypothermia increased and the use of temperature control decreased between the two studies conducted 7 years apart in the Kanto area, Japan. Temperature control management might improve survival of patients with OHCA.

Impact of the COVID-19 pandemic on prehospital and in-hospital treatment and outcomes of patients after out-of-hospital cardiac arrest: a Japanese multicenter cohort study.

BACKGROUND: In the chain of survival for Out-of-hospital cardiac arrest (OHCA), each component of care contributes to improve the prognosis of the patient with OHCA. The SARS-CoV-2 (COVID-19) pandemic potentially affected each part of care in the chain of survival. The aim of this study was to compare prehospital care, in-hospital treatment, and outcomes among OHCA patients before and after the COVID-19 pandemic. METHODS: We analyzed data from a multicenter prospective study in Kanto area, Japan, named SOS-KANTO 2017. We enrolled patients who registered during the pre-pandemic period (September 2019 to December 2019) and the post-pandemic period (June 2020 to March 2021). The main outcome measures were 30-day mortality and the proportion of favorable outcomes at 1 month, and secondary outcome measures were changes in prehospital and in-hospital treatments between the pre- and post-pandemic periods. RESULTS: There were 2015 patients in the pre-pandemic group, and 5023 in the post-pandemic group. The proportion of advanced airway management by emergency medical service (EMS) increased (p < 0.01), and EMS call-to-hospital time was prolonged (p < 0.01) in the post- versus pre-pandemic group. There were no differences between the groups in defibrillation, extracorporeal membrane oxygenation, or temperature control therapy (p = 0.43, p = 0.14, and p = 0.16, respectively). Survival rate at 1 month and favorable outcome rate at 1 month were lower (p = 0.01 and p < 0.01, respectively) in the post- versus pre-pandemic group. CONCLUSION: Survival rate and favorable outcome rate 1 month after return of spontaneous circulation of OHCA worsened, EMS response time was prolonged, and advanced airway management by EMS increased in the post- versus pre-pandemic group; however, most prehospital and in-hospital management did not change between pre- and post-COVID-19 pandemic.

Evaluation of clinical response to empirical antimicrobial therapy on day 7 and mortality in the intensive care unit: sub-analysis of the DIANA study Japanese data.

It is not clear whether evaluating the clinical response to antibiotic use at day 7 among critically ill patients accurately predicts outcomes. We aimed to evaluate the relationship between clinical response to the initial empiric therapy on day 7 and mortality. Methods: The determinants of antimicrobial use and de-escalation in critical care (DIANA) study was an international, multicenter, observational study on antibiotic use in the intensive care unit (ICU). ICU patients ages over 18 years in whom an empiric antimicrobial regimen in Japan was initiated were included. We compared patients who were evaluated as cured or improved ("effective") 7 days after starting antibiotic treatment with patients who were evaluated as deteriorated ("failure"). Results: Overall, 217 (83%) patients were in the effective group, and 45 (17%) were in the failure group. Both the infection-related mortality rate in the ICU and the in-hospital infection-related mortality rate in the effective group were lower than those in the failure group (0% versus 24.4%; P < 0.01 and 0.5% versus 28.9%; P < 0.01, respectively). Conclusion: Assessment of efficacy of empiric antimicrobial treatment on day 7 may predict a favorable outcome among patients suffering from infection in the ICU.

Utility of a Compatibility Chart for Continuous Infusions in the Intensive Care Unit.

BACKGROUND: In the intensive care unit (ICU), multiple intravenous drugs are often administered through the same catheter line, greatly increasing the risk of drug incompatibility. We previously developed a compatibility chart including 27 drugs and have used it to avoid drug incompatibilities in the ICU. This retrospective study evaluated the utility of this chart by analyzing prescriptions and incidents of incompatibilities in an ICU. METHODS: We analyzed 257 ICU prescriptions of two or more continuous infusions on the same day during the period between March 2016 and February 2017 and investigated the rate of compliance with the compatibility chart. Drug combinations were classified as "compatible," "tolerable compatible," "incompatible," and "no data." For all combinations, the compliance rate was defined as the ratio of compatible and tolerable compatible combinations. Additionally, using our hospital incident report database, we analyzed 27,117 injections administered in the ICU between March 2016 and February 2017 and investigated incidents related to incompatibility. RESULTS: Three hundred infusion combinations were identified in the prescriptions. The compliance rate was 97% (n = 293). Of the 113 combinations judged to be tolerable compatible, 98% (n = 111) consisted of three or more continuous medications injected through the same intravenous line. Of the two incidents related to incompatibility in the incident report database, the combination "nicardipine and furosemide" was defined as incompatible in the compatibility chart. CONCLUSIONS: The high rate of compliance with the compatibility chart suggested it was useful in preventing drug incompatibility.

Effect of angioembolization for isolated complex pelvic injury: A post-hoc analysis of a nationwide multicenter trauma database in Japan.

BACKGROUND AND IMPORTANCE: Complex pelvic injuries are among the types of trauma with the highest mortality. Treatment strategies should be based on the hemodynamic status, the anatomical type of fracture, and the associated injuries. Combination therapies, including preperitoneal pelvic packing, temporary mechanical stabilization, resuscitative endovascular balloon occlusion of the aorta, and angioembolization, are recommended for pelvic injuries. OBJECTIVE: To investigate the effect of urgent angioembolization alone on severe pelvic injury-associated mortality. DESIGN, SETTINGS, AND PARTICIPANTS: We used the Japan Trauma Data Bank database, a multicenter observational study, to retrospectively identify adult patients with isolated blunt pelvic injuries (Abbreviated Injury Scale [AIS] score: 3-5) from 2004 to 2018. OUTCOME MEASURES AND ANALYSIS: The primary outcome measure was in-hospital mortality. We subdivided patients into two groups, those who underwent urgent angioembolization and non-urgent angioembolization, and compared their mortality rates. We performed multiple imputation and multivariable analyzes to compare the mortality rates between groups after adjusting for known potential confounding factors (age, sex, Glasgow Coma Scale score, systolic blood pressure on hospital arrival, Injury Severity Score, pelvic AIS score, laparotomy, resuscitative endovascular balloon occlusion of the aorta, and external fixation) and for within-hospital clustering using the generalized estimating equation. MAIN RESULTS: We analyzed 4207 of 345,932 trauma patients, of whom 799 underwent urgent angioembolization. The in-hospital mortality rate was significantly higher in the urgent embolization group than in the non-urgent embolization group (7.4 vs. 4.0%; p < 0.01). However, logistic regression analysis revealed that the mortality rates of patients with urgent angioembolization significantly decreased after adjusting for factors independently associated with mortality (odds ratio: 0.60; 95% confidence interval: 0.37-0.96; p = 0.03). CONCLUSION: Urgent angioembolization may be an effective treatment for severe pelvic injury regardless of the pelvic AIS score and the systolic blood pressure on hospital arrival.

Association between mortality and age among mechanically ventilated COVID-19 patients: a Japanese nationwide COVID-19 database study.

BACKGROUND: Only a few studies have reported the association between age and mortality in COVID-19 patients who require invasive mechanical ventilation (IMV). We aimed to evaluate the effect of age on COVID-19-related mortality among patients undergoing IMV therapy. METHODS: This cohort study was conducted using the COVID-19 Registry Japan database, a nationwide multi-centre study of hospitalized patients with laboratory-confirmed COVID-19. Of all 33,808 cases registered between 1 January 2020 to 28 February 2021, we analysed 1555 patients who had undergone IMV. We evaluated mortality rates between age groups using multivariable regression analysis after adjusting for known potential components, such as within-hospital clustering, comorbidities, steroid use, medication for COVID-19, and vital signs on admission, using generalized estimation equation. RESULTS: By age group, the mortality rates in the IMV group were 8.6%, 20.7%, 34.9%, 49.7% and 83.3% for patients in their 50s, 60s, 70s, 80s, and 90s, respectively. Multivariable analysis showed that compared with those for patients aged < 60 years, the odds ratios (95% confidence interval) of death were 2.6 (1.6-4.1), 6.9 (4.2-11.3), 13.2 (7.2-24.1), 92.6 (16.7-515.0) for patients in their 60s, 70s, 80s, and 90s, respectively. CONCLUSIONS: In this cohort study, age had a great effect on mortality in COVID-19 patients undergoing IMV, after adjusting for variables independently associated with mortality. This study suggested that age was associated with higher mortality and that preventing progression to severe COVID-19 in elderly patients may be a great public health issue.

Ultra-Early Induction of General Anesthesia for Reducing Rebleeding Rates in Patients with Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Rebleeding of aneurysmal subarachnoid hemorrhage (aSAH) is one of the significant risk factors for poor clinical outcome. The rebleeding risk is the highest during the acute phase with an approximate rebleeding rate of 9-17% within the first 24 h. Theoretically, general anesthesia can stabilize a patient's vital signs; however, its effectiveness as initial management for preventing post-aSAH rebleeding remains unclear. The purpose of this study was to determine the feasibility and safety of ultra-early general anesthesia induction for reducing the rebleeding rates among patients with aSAH. MATERIALS AND METHODS: We retrospectively evaluated patients with aSAH who were admitted to our department between January 2013 and December 2019. All the patients underwent ultra-early general anesthesia induction as initial management regardless of their severity. We evaluated the rebleeding rate before definitive treatment, factors influencing rebleeding, and general anesthesia complications. RESULTS: We included 191 patients with two-third of them having a poor clinical grade (World Federation of Neurological Society [WFNS] grade IV or V). The median duration from admission to general anesthesia induction was 22 min. Rebleeding before definitive treatment occurred in nine patients (4.7%). There were significant differences in the Glasgow Coma Scale score (p = 0.047), WFNS grade (p = 0.02), and dissecting aneurysm (p <0.001) between the rebleeding and non-rebleeding patients. There were no cases of unsuccessful tracheal intubation or rebleeding during general anesthesia induction. CONCLUSION: Ultra-early general anesthesia induction could be performed safely in patients with aSAH, regardless of the WFNS grade; moreover, it resulted in lower rebleeding rate than that reported in previous epidemiological reports.

Blood concentration of levetiracetam after bolus administration in patients with status epilepticus.

PURPOSE: We aimed to evaluate the blood concentration of levetiracetam (LEV), as a second-line drug, in patients with status epilepticus (SE) in an emergency clinical setting. METHODS: We prospectively evaluated 20 consecutive patients with SE admitted to our department between July 2017 and July 2019. LEV (2500 mg) was administered via bolus infusion after diazepam infusion, followed by 500 mg every 12 h for 48 h and then 500 mg orally. The primary outcomes were LEV blood concentration 15 min, 12 h, 48 h, and 96 h after administration and the proportion of patients showing trough LEV concentration within the therapeutic range. The secondary outcomes were the discontinuation of apparent convulsive seizure, epileptic wave on electroencephalogram, tracheal intubation, adverse events related to blood parameters, and abnormal findings in vital signs examination. RESULTS: Median blood LEV (2500 mg) concentration at 15 min after administration was 81.6 µg/mL. The median trough concentration after 12, 48, and 96 h was 28.8, 10.5, and 9.1 µg/mL, respectively. Moreover, 95% of patients had trough concentration above the lower limit of the therapeutic blood concentration (>12 µg/mL) after 12 h. Regarding secondary outcomes, endotracheal intubation, seizure suppression, and abnormal electroencephalogram findings were observed in approximately 40%, 90%-95%, and 41% of patients, respectively. No abnormal findings were noted in blood tests and vital sign examination, although the AST/ALT levels increased in 10% of the patients. CONCLUSION: After bolus administration of 2500 mg, the blood LEV concentration reached the therapeutic window in patients with early-stage SE.

Validation of sepsis-induced coagulopathy score in critically ill patients with septic shock: post hoc analysis of a nationwide multicenter observational study in Japan.

Coagulation disorder is a major cause of death in sepsis patients. Recently, sepsis-induced coagulopathy (SIC) scoring was developed as a new criterion for coagulopathy-associated sepsis. We aimed to evaluate the accuracy of the SIC score for predicting the prognosis of septic shock. We analyzed data from a multicenter observational study conducted from 2011 to 2013. We grouped the participants into those who did and did not use vasopressors, and compared the in-hospital mortality rates of SIC and non-SIC patients. Patients who needed vasopressors were considered to have septic shock. We performed survival analysis adjusted by factors independently associated with mortality. SIC developed in 66.4% of patients who used vasopressors and 42.2% of patients who did not. The in-hospital mortality difference between the SIC and non-SIC groups was statistically significant in those who needed vasopressors (35.8% vs 27.9%, p < 0.01). Cox regression analysis indicated that SIC was significantly correlated with mortality risk in patients who used vasopressors (hazard ratio [HR] 1.39; 95% confidence interval [CI] 1.13-1.70; p < 0.01), but not in those who did not (HR 1.38; 95% CI 0.81-2.34; p = 0.23). In conclusion, the SIC score might be a good diagnostic indicator of fatal coagulopathy among sepsis patients who need vasopressors.

Early versus late surgery after cervical spinal cord injury: a Japanese nationwide trauma database study.

BACKGROUND: The management of cervical spinal cord injury (SCI) has changed drastically in the last decades, and surgery is the primary treatment. However, the optimum timing of early surgical treatment (within 24 h or 72 h after injury) is still controversial. We sought to determine the optimum timing of surgery for cervical SCI, comparing the length of the intensive care unit (ICU) stay and in-hospital mortality in patients who underwent surgical treatments (decompression and stabilization) for cervical SCI within 24 h after injury and within 7 days after injury. METHODS: This was a retrospective cohort study using Japan Trauma Data Bank (JTDB) which is a nationwide, multicenter database. We selected adult isolated cervical SCI patients who underwent operative management within 7 days after injury, between 2004 and 2015. The main outcome measures were the length of ICU stay and in-hospital mortality. We grouped the patients into two, based on the time from onset of injury to surgery, an early group (within 24 h) and a late group (from 25 h to 7 days). Next, we performed multivariable analyses for analyzing the relevance between the timing of surgery and the length of ICU stay after adjusting for baseline characteristics using propensity score. We also performed the Cox survival analyses to evaluate in-hospital mortality. RESULTS: From 236,698 trauma patients registered in JTDB, we analyzed 514 patients. The early group comprised 291 patients (56.6%), and the late group comprised 223 (43.4%). The length of ICU stay did not differ between the two groups (early, 10 days; late, 11 days; p = 0.29). There was no significant difference for length of ICU stay between the early and late group even after adjustment by multivariate analysis (p = 0.64). There was no significant difference in in-hospital mortality between the two groups (the early group 3.8%, the late group 2.2%, p = 0.32), and no significant difference was found in the Cox survival analysis. CONCLUSIONS: Our study showed that neither the length of ICU stay nor in-hospital mortality after spinal column stabilization or spinal cord decompression for cervical SCI significantly differed according to the timing of surgery between 24 h and 7 days.

Early antibiotics administration during targeted temperature management after out-of-hospital cardiac arrest: a nationwide database study.

BACKGROUND: Patients resuscitated after cardiac arrest are reportedly at high risk for infection and sepsis, especially those treated with targeted temperature management (TTM). There is, however, limited evidence suggesting that early antibiotic use improves patient outcomes. We examined the hypothesis that early treatment with antibiotics reduces mortality in patients with cardiac arrest receiving TTM. METHODS: We identified 2803 patients with cardiogenic out-of-hospital cardiac arrest (OHCA) that were treated with TTM and were admitted to 371 hospitals that contribute to the Japanese Diagnosis Procedure Combination inpatient database between July 2007 and March 2013. Of these, 1272 received antibiotics within the first 2 days (antibiotics) and 1531 did not (control). We generated 802 propensity score-matched pairs. RESULTS: There was no significant difference in 30-day mortality between the groups (control vs. antibiotics; 33.0 % vs. 29.9 %; difference, 3.1 %; 95 % confidence interval [CI], -1.4 to 7.7 %, p = 0.18). Analysis using the hospital antibiotics prescribing rate as an instrumental variable showed that antibiotic use was not significantly associated with a reduction in 30-day mortality (6.6 %, CI 95 %, -0.5 to 13.7 %, p = 0.28). A subgroup analysis of patients who required extracorporeal membrane oxygenation (ECMO) indicated a significant difference in 30-day mortality between the 2 groups (62.9 % vs. 43.5 %; difference 19.3 %, CI 95 %, 5.9 to 32.7 %, p = 0.005). In the instrumental variable model, the estimated reduction in 30-day mortality associated with antibiotics was 18.2 % (CI 95 %, 21.3 to 34.4 %, p = 0.03) in ECMO patients. CONCLUSIONS: Although there was no significant association between the use of antibiotics and mortality after overall cardiogenic OHCA treated with TTM, antibiotics may be beneficial in patients who require ECMO.

Amiodarone Compared with Lidocaine for Out-Of-Hospital Cardiac Arrest with Refractory Ventricular Fibrillation on Hospital Arrival: a Nationwide Database Study.

PURPOSE: The latest resuscitation guidelines recommend the use of amiodarone in adult patients with out-of-hospital cardiac arrest (OHCA) and refractory ventricular fibrillation (VF) to improve the rates of return of spontaneous circulation. However, there is limited evidence to suggest that amiodarone is superior to lidocaine with respect to survival at discharge. The purpose of the present study was to evaluate the hypothesis that amiodarone is superior to lidocaine with regard to the rate of survival to hospital discharge for OHCA patients with VF/pulseless VT (pVT) on hospital arrival. METHODS: Using the Japanese Diagnosis Procedure Combination inpatient database, we identified 3951 patients from 795 hospitals who experienced cardiogenic OHCA and had refractory ventricular fibrillation on hospital arrival between July 2007 and March 2013. The patients were categorized into amiodarone (n = 1743) and lidocaine (n = 2208) groups, from which 801 propensity score-matched pairs were generated. RESULTS: There was no significant difference in the rate of survival to hospital discharge between the amiodarone and lidocaine groups (15.2 % vs. 17.1 %; difference, -1.9 %; 95 % CI, -5.5 to 1.7) in propensity score-matched analyses. Cox regression analyses did not indicate significant in-hospital mortality differences between the amiodarone and lidocaine groups for the propensity score-matched groups (hazard ratio, 1.05; 95 % CI, 0.94 to 1.17). CONCLUSIONS: The present nationwide study suggested that there was no significant difference in the rate of survival to hospital discharge between cardiogenic OHCA patients with persistent ventricular fibrillation on hospital arrival treated with amiodarone or lidocaine.

Fasudil, a Rho-kinase inhibitor, attenuates lipopolysaccharide-induced vascular hyperpermeability and colonic muscle relaxation in guinea pigs.

BACKGROUND: Rho-associated coiled coil-forming protein kinase (Rho-kinase), a downstream target effector of the small GTP-binding protein Rho, plays a key role in cell adhesion, motility, and contraction. The goal of the present study was to determine the role of the Rho/Rho-kinase signal pathway in the pathogenesis of lipopolysaccharide (LPS)-induced vascular hyperpermeability using the Rho-kinase inhibitor fasudil. METHODS: To evaluate plasma leakage, fasudil (3 or 10 mg/kg) or saline was intravenously administered 30 min before LPS injection. LPS (100, 300, and 1,000 µg/0.1 mL/site) and saline (0.1 mL/site) were administered intracutaneously in the dorsum of guinea pigs. Vascular permeability was measured on the dorsal skin by the local accumulation of Evans Blue dye after intracutaneous injection of LPS (100-1000 µg/site) from Escherichia coli. For the measurement of colonic muscle tension, fasudil (3 mg/kg) or saline was intravenously administered 30 min before LPS injection. LPS (1 mg/kg) was administered intravenously. RESULTS: Dye leakage in the skin increased significantly 2 h after the injection of LPS. This LPS-induced dye leakage was significantly suppressed by fasudil (3 and 10 mg/kg). LPS caused a transient decrease in colonic muscle tension, which peaked 2.5 h after the injection. This decrease in muscle tension was significantly suppressed by pretreatment with fasudil (3 mg/kg). CONCLUSIONS: The Rho/Rho-kinase pathway might play an important role in the pathogenesis of LPS-induced endotoxemia, and fasudil could attenuate LPS-induced microvascular permeability, leading to inhibition of endotoxemia.

The novel selective toll-like receptor 4 signal transduction inhibitor tak-242 prevents endotoxaemia in conscious Guinea-pigs.

1. TAK-242 is a novel compound that suppresses nitric oxide and cytokine production by selectively inhibiting intracellular signals from toll-like receptor (TLR)-4. In the present study, we investigated the effectiveness of TAK-242 against sepsis using an endotoxaemia model in conscious and unrestricted guinea-pigs. Measures examined included muscle tension paralysis of the intestine, blood pressure, high morbidity group box (HMGB)-1 levels and survival rate. 2. Tension of the longitudinal muscle of the colon was monitored continuously by telemetry. Arterial blood pressure was monitored via a carotid artery catheter. TAK-242 was administered intravenously through a jugular vein catheter. Guinea-pigs were divided into a control group, given vehicle (placebo emulsion), and the experimental group, administered 3 or 10 mg/kg TAK-242, 1 h before administration of 10 mg/kg lipopolysaccharide (LPS). 3. In the control group, the tension of the longitudinal muscle of the colon decreased in a time-dependent manner and blood pressure was reduced, with maximal effects observed 1-3 h after administration of LPS. In the TAK-242-treated group, LPS-induced relaxation of the intestine and hypotension were significantly inhibited. In the control group, HMGB-1 levels were increased after LPS administration and this reaction was significantly blocked in the TAK-242-treated group. Importantly, survival rate was increased after TAK-242 treatment. 4. In conlusion, the results of the present study show that TAK-242 inhibited the symptoms associated with endotoxaemia in a guinea-pig model of sepsis and that it may, therefore, be an effective treatment for sepsis.

Continuous infusion of sivelestat sodium hydrate prevents lipopolysaccharide-induced intestinal paralysis and hypotension in conscious guinea-pigs.

1. Sivelestat sodium hydrate (sivelestat), a neutrophil elastase inhibitor, is used to treat acute lung injury associated with systemic inflammatory response syndrome, but its effects have not been described for endotoxaemia. In the present study, we examined the effects of a continuous infusion of sivelestat on intestinal mechanical activity and blood pressure using an endotoxaemic model in conscious, unrestrained guinea-pigs. 2. Guinea-pigs underwent laparotomy while anaesthetized and were implanted with a force transducer sutured onto the taenia caecum. With this transducer, changes in tension in the intestinal longitudinal muscle were measured continuously via telemetry. Catheters were inserted into the carotid artery and jugular vein, were tunnelled subcutaneously and were accessed from the back of the neck. These catheters were connected to a cannula swivel and were used to monitor arterial pressure as well as to administer drugs i.v. in conscious, unrestrained guinea-pigs. Twenty hours after surgery, guinea-pigs received a single dose of lipopolysaccharide (LPS; 0.3 mg/kg, i.p.) 10 min after the start of a continuous 2 h i.v. infusion of sivelestat (30 mg/kg per h) or vehicle (saline). Elastase activity before and after sivelestat or vehicle administration was measured spectrometrically using a specific synthetic substrate. 3. We confirmed that intestinal longitudinal muscle tension decreased 2-3 h after LPS administration in the control group, with a concurrent decline in blood pressure. In guinea-pigs treated with sivelestat, the LPS-induced decreases in muscle tension and blood pressure were significantly reduced. In LPS-treated control guinea-pigs, serum elastase activity was elevated and this increase was significantly attenuated by administration of sivelestat. 4. The findings from the present study suggest that sivelstat can effectively reduce intestinal dysfunction and attenuate LPS-induced decreases in blood pressure in endotoxaemia.