Prognostic Significance of Signs of Life in Out-of-Hospital Cardiac Arrest Patients Undergoing Extracorporeal Cardiopulmonary Resuscitation.

OBJECTIVES: Signs of life (SOLs) during cardiac arrest (gasping, pupillary light reaction, or any form of body movement) are suggested to be associated with favorable neurologic outcomes in out-of-hospital cardiac arrest (OHCA). While data has demonstrated that extracorporeal cardiopulmonary resuscitation (ECPR) can improve outcomes in cases of refractory cardiac arrest, it is expected that other contributing factors lead to positive outcomes. This study aimed to investigate whether SOL on arrival is associated with neurologic outcomes in patients with OHCA who have undergone ECPR. DESIGN: Retrospective multicenter registry study. SETTING: Thirty-six facilities participating in the Study of Advanced life support for Ventricular fibrillation with Extracorporeal circulation in Japan II (SAVE-J II). PATIENTS: Consecutive patients older than 18 years old who were admitted to the Emergency Department with OHCA between January 1, 2013, and December 31, 2018, and received ECPR. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were classified into two groups according to the presence or absence of SOL on arrival. The primary outcome was a favorable neurologic outcome (Cerebral Performance Category 1 or 2) at discharge. Of the 2157 patients registered in the SAVE-J II database, 1395 met the inclusion criteria, and 250 (17.9%) had SOL upon arrival. Patients with SOL had more favorable neurologic outcomes than those without SOL (38.0% vs. 8.1%; p < 0.001). Multivariate analysis showed that SOL on arrival was independently associated with favorable neurologic outcomes (odds ratio, 5.65 [95% CI, 3.97-8.03]; p < 0.001). CONCLUSIONS: SOL on arrival was associated with favorable neurologic outcomes in patients with OHCA undergoing ECPR. In patients considered for ECPR, the presence of SOL on arrival can assist the decision to perform ECPR.

Effect of prehospital advanced airway management on out-of-hospital cardiac arrest due to asphyxia: A JAAM-OHCA registry-based observational study in Japan.

Aim: To investigate the relationship between prehospital advanced airway management (AAM) and neurological outcomes in patients with asphyxia-related out-of-hospital cardiac arrest (OHCA). Methods: We retrospectively analyzed data from the Japanese Association for Acute Medicine OHCA registry between June 2014 and December 2017. Patients with asphyxia-related cardiac arrest aged ≥18 years were included. The primary outcome was a 1-month favorable neurological outcome (cerebral performance category [CPC] 1-2). Results: Of the 34,754 patients in the 2014-2017 JAAM-OHCA Registry, 1956 were included in our analysis. Cerebral performance category 1-2 was observed in 31 patients (1.6%), while CPC 3-5 was observed in 1925 patients (98.4%). Although prehospital AAM was associated with unfavorable neurological outcomes (odds ratio [OR], 0.269; 95% confidence interval [CI], 0.114-0.633; p = 0.003) in the univariate analysis, the association was not significant in the multivariate analysis. Compared with the AAM group, the non-AAM group showed increased rates of cardiac arrest after emergency medical service contact (4.3 vs. 7.2%, p = 0.009) and Glasgow Coma Scale ≥4 at hospital admission (1.9% vs. 4.7%, p = 0.004). Among the 903 patients for whom the time to return of spontaneous circulation (ROSC) could be calculated, the time from witnessed cardiac arrest to ROSC was significantly shorter (median, 8.5 vs. 37.0 min; p < 0.001) for those with favorable neurological outcomes than for those without. Conclusion: Prehospital AAM is not associated with improved neurological outcomes among those with asphyxia-related OHCA. However, the time from cardiac arrest to the first ROSC was significantly shorter among those with favorable outcomes.

Dissociated coupling between cerebral oxygen metabolism and perfusion in the prefrontal cortex during exercise: a NIRS study.

Purpose: The present study used near-infrared spectroscopy to investigate the relationships between cerebral oxygen metabolism and perfusion in the prefrontal cortex (PFC) during exercises of different intensities. Methods: A total of 12 recreationally active men (age 24 ± 6 years) were enrolled. They performed 17 min of low-intensity exercise (ExL), followed by 3 min of moderate-intensity exercise (ExM) at constant loads. Exercise intensities for ExL and ExM corresponded to 30% and 45% of the participants' heart rate reserve, respectively. Cardiovascular and respiratory parameters were measured. We used near-infrared time-resolved spectroscopy (TRS) to measure the cerebral hemoglobin oxygen saturation (ScO2) and total hemoglobin concentration ([HbT]), which can indicate the cerebral blood volume (CBV). As the cerebral metabolic rate for oxygen (CMRO2) is calculated using cerebral blood flow (CBF) and ScO2, we assumed a constant power law relationship between CBF and CBV based on investigations by positron emission tomography (PET). We estimated the relative changes in CMRO2 (rCMRO2) and CBV (rCBV) from the baseline. During ExL and ExM, the rate of perceived exertion was monitored, and alterations in the subjects' mood induced by exercise were evaluated using the Profile of Moods Scale-Brief. Results: Three minutes after exercise initiation, ScO2 decreased and rCMRO2 surpassed rCBV in the left PFC. When ExL changed to ExM, cardiovascular variables and the sense of effort increased concomitantly with an increase in [HbT] but not in ScO2, and the relationship between rCMRO2 and rCBV was dissociated in both sides of the PFC. Immediately after ExM, [HbT], and ScO2 increased, and the disassociation between rCMRO2 and rCBV was prominent in both sides of the PFC. While blood pressure decreased and a negative mood state was less prominent following ExM compared with that at rest, ScO2 decreased 15 min after exercise and rCMRO2 surpassed rCBV in the left PFC. Conclusion: Dissociated coupling between cerebral oxidative metabolism and perfusion in the PFC was consistent with the effort required for increased exercise intensity and associated with post-exercise hypotension and altered mood status after exercise. Our result demonstrates the first preliminary results dealing with the coupling between cerebral oxidative metabolism and perfusion in the PFC using TRS.

Long-Term Safety and Efficacy of Mirogabalin for Central Neuropathic Pain: A Multinational, Phase 3, 52-Week, Open-Label Study in Asia.

INTRODUCTION: Central neuropathic pain (CNeP) is difficult to treat and has diverse etiology, including spinal cord injury (CNePSCI), Parkinson's disease (CNePPD), and central post-stroke pain (CPSP). The safety and efficacy of mirogabalin have been demonstrated in short-term trials, including patients with CNePSCI. The objective of our study was to confirm the safety/efficacy of mirogabalin in patients with CNePPD and CPSP, and obtain long-term data for CNePSCI. METHODS: This 52-week, open-label extension of a previous randomized controlled study was conducted across Japan, Korea, and Taiwan. Patients with CNePSCI, CNePPD, or CPSP received twice daily (BID) 5-10 mg mirogabalin for a 4-week titration period, after which the dosage was maintained for 47 weeks at a maximum of 15 mg BID, followed by a 1-week taper period receiving the same dose but only administered once daily. The primary endpoint was safety, assessed primarily by incidence and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed in a post hoc analysis of data obtained by the short-form McGill Pain Questionnaire (SF-MPQ). RESULTS: Of the 210 patients enrolled, 106, 94, and 10 had CNePSCI, CPSP, and CNePPD, respectively. The mean overall age of patients was 62.9 years, and most patients were male and of Japanese ethnicity. TEAEs occurred in 84.8% of patients, the most common being somnolence (16.7%), peripheral edema (12.4%), edema (11.4%), nasopharyngitis (11.0%), and dizziness (7.6%). Most TEAEs were mild. Severe and serious TEAEs occurred in 6.2% and 13.3% of patients, respectively. All patient groups experienced reductions in SF-MPQ visual analog scores for pain: mean ± standard deviation changes from baseline at week 52 were -2.3 ± 21.13 mm (CNePSCI), -17.0 ± 24.99 mm (CPSP), and -17.1 ± 35.32 mm (CNePPD). CONCLUSION: Mirogabalin was generally safe, well tolerated, and effective for treatment of CNeP in this long-term study. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03901352.

Mirogabalin for Central Neuropathic Pain After Spinal Cord Injury: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study in Asia.

BACKGROUND AND OBJECTIVES: Patients with spinal cord injury (SCI) commonly experience central neuropathic pain (CNeP), which is challenging to treat. Mirogabalin is effective for peripheral neuropathic pain, but evidence for CNeP is lacking. METHODS: This randomized, double-blind, placebo-controlled, phase 3 study investigated mirogabalin efficacy and safety for the treatment of CNeP in patients with traumatic SCI. Adult patients from 120 sites throughout Japan, Korea, and Taiwan were randomized (1:1) to receive placebo or mirogabalin (5 mg twice daily [BID] for 1 week, 10 mg BID for 1 week, and 10 or 15 mg BID for 12 weeks). Patients with moderate renal impairment received half the dosage. The primary efficacy endpoint was change from baseline in the weekly average daily pain score (ADPS) at week 14. The secondary endpoints included ADPS responder rates, the Short-Form McGill Pain Questionnaire (SF-MPQ), average daily sleep interference score (ADSIS), and Neuropathic Pain Symptom Inventory (NPSI). Adverse events were monitored for safety. RESULTS: Each treatment group comprised 150 patients. Mirogabalin elicited a statistical and clinically relevant improvement in change from baseline in the weekly ADPS at week 14 (least-squares mean difference [95% CI] vs placebo -0.71 [-1.08 to -0.34], p = 0.0001). Responder rates at week 14 were higher for mirogabalin than those for placebo (odds ratio [95% CI] 1.91 [1.11-3.27] for the ≥30% responder rate; 2.52 [1.11-5.71] for the ≥50% responder rate). Statistical improvements (i.e., least-squares mean difference [95% CI] vs placebo) were also observed in the SF-MPQ (-2.4 [-3.8 to -1.1]), ADSIS -0.71 (-1.04 to -0.38), and NPSI -7.7 (-11.1 to -4.4) scores. Most treatment-emergent adverse events were mild; no serious adverse drug reactions were reported. DISCUSSION: Mirogabalin elicited clinically relevant decreases in pain and was well tolerated, suggesting that mirogabalin is a promising treatment for patients with CNeP due to SCI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03901352); first submitted April 3, 2019; first patient enrolled March 14, 2019; available at clinicaltrials.gov/ct2/show/NCT03901352. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adult patients with CNeP due to traumatic SCI, mirogabalin, 10 or 15 mg BID, effectively improves weekly ADPS at week 14.

Pneumomediastinum as patient self-inflicted lung injury in patients with acute respiratory distress syndrome due to COVID-19: a case series.

Background: In patients with coronavirus disease (COVID-19) due to severe acute respiratory syndrome coronavirus 2 infection, pneumomediastinum has been increasingly reported in cases of noninvasive oxygen therapy, including high-flow nasal cannula, and invasive mechanical ventilation. However, its pathogenesis is still not understood. Case Presentation: We report two cases of pneumomediastinum in acute respiratory distress syndrome (ARDS) caused by COVID-19. In both cases, control of spontaneous breathing with neuromuscular blocking agents resulted in resolution of pneumoperitoneum. Conclusion: The improvement of pneumomediastinum with control of spontaneous breathing suggested patient self-inflicted lung injury as a possible mechanism in this case series. In ARDS cases with pneumomediastinum, in addition to controlling plateau pressure with conventional lung protective ventilation, spontaneous breathing should be controlled if the patient's inspiratory effort is suspected to be strong.

Anti­tumor effects of anti­epileptic drugs in malignant glioma cells.

Patients with glioblastoma frequently suffer epileptic seizures and often require anticonvulsant therapy during the treatment course. The present study investigated four common antiepileptic drugs, perampanel, carbamazepine (CBZ), sodium valproate (VPA) and levetiracetam (LEV), which are expected to have antitumor effects, and determined the most beneficial drug for the treatment of malignant glioma by comparing antitumor effects such as inhibition of cell proliferation and suppression of migration and invasion (using Transwell assays). The inhibition of cell growth was investigated using six malignant glioma cell lines (A­172, AM­38, T98G, U­138MG, U­251MG and YH­13). Significant inhibition of cell proliferation was observed in all six cell lines treated with perampanel, three cell lines treated with CBZ, four cell lines treated with VPA and two cell lines treated with LEV at the therapeutic blood concentration levels for the drugs to be used as antiepileptics. Further antitumor effects in combination with temozolomide were investigated using T98G and U­251MG cell lines, and were confirmed in both cell lines with perampanel and in T98G cells with LEV, but not observed with CBZ and VPA. Cell migration was significantly suppressed in both T98G and U­251MG cell lines with perampanel, but not with CBZ, VPA or LEV. To investigate the mechanisms by which perampanel suppresses the migration of malignant glioma cells, the expression of mRNA related to epithelial­mesenchymal transition following perampanel treatment was analyzed using reverse transcription­quantitative PCR in the T98G and U­251MG cell lines. The expression of Rac1 and RhoA, which constitute the cytoskeleton that enhances cell motility, were reduced in both cell lines. Furthermore, the expression of the mesenchymal marker N­cadherin, which promotes cell migration and infiltration, was decreased, but the expression of the epithelial marker E­cadherin, which strengthens cell­cell adhesion and reduces cell motility, was increased. Furthermore, the expression of matrix metalloproteinase­2, a proteolytic enzyme, was reduced. These effects may reduce cell motility and increase adhesion between cells, suggesting that perampanel treatment suppressed cell migration. In conclusion, the present study suggests that perampanel may be more beneficial in terms of antitumor efficacy than other antiepileptic drugs for the treatment of malignant glioma.

Anti-tumor effects of perampanel in malignant glioma cells.

Glioblastoma has a poor prognosis even after multimodal treatment, such as surgery, chemotherapy and radiation therapy. Patients with glioblastoma frequently develop epileptic seizures during the clinical course of the disease and often require antiepileptic drugs. Therefore, agents with both antiepileptic and antitumoral effects may be very useful for glioblastoma treatment. Perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, is an antiepileptic drug that is widely used for intractable epilepsy. The present study aimed to assess the potential antitumoral effects of perampanel using malignant glioma cell lines. The cell proliferation inhibitory effect was evaluated using six malignant glioma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13). A dose-dependent inhibitory effect of perampanel on cell viability was demonstrated; however, the sensitivity of cells to perampanel varied and further antitumoral effects were demonstrated in combination with temozolomide (TMZ) in certain malignant glioma cells. Furthermore, cell cycle distribution and apoptosis induction analyses were performed in T98G and U-251MG cells using a fluorescence activated cell sorter (FACS) and the expression levels of apoptosis-related proteins were evaluated using western blotting. No significant change was demonstrated in the proportions of cells in the G0/G1, S and G2/M phases under 1.0 µM perampanel treatment, whereas induction of apoptosis was demonstrated using FACS at 10 µM perampanel and western blotting at 1.0 µM perampanel in both glioma cell lines. Overexpression of SERPINE1 may be related to poor prognosis in patients with gliomas. The combination of 1.0 µM perampanel and 5.0 µM tiplaxtinin, a SERPINE1 inhibitor, demonstrated further reduced cell viability in perampanel-resistant U-138MG cells, which have high expression levels of SERPINE1. These results indicated that the antitumor effect of perampanel may not be expected for malignant gliomas with higher expression levels of SERPINE1. The findings of the present study suggested that the antiepileptic drug perampanel may also have an antitumor effect through the induction of apoptosis, which is increased when combined with TMZ in certain malignant glioma cells. These findings also suggested that SERPINE1 expression may be involved in perampanel susceptibility. These results may lead to new therapeutic strategies for malignant glioma.

Estimation of Cerebral Hemodynamics and Oxygenation During Various Intensities of Rowing Exercise: An NIRS Study.

Purpose: This study aimed to investigate changes in cerebral hemodynamics and oxygenation at moderate, heavy, maximal and supramaximal intensities of rowing exercise. It also examined whether these changes reflect alterations in sensation of effort and mood. We also aimed to examine the effects of peak pulmonary oxygen consumption ( V . O2peak ) on cerebral oxygenation. Methods: Eleven rowers, consisting out of six athletes and five recreational rowers [two female; age, 27 ± 9 years; height, 171 ± 7 cm, body mass, 67 ± 9 kg; V . O2peak , 53.5 ± 6.5 mL min-1 kg-1] rowed a 13-min session separated by 10 and 3 min, at 70 (Ex70%) and 80% of V . O2peak (Ex80%), respectively, on a rowing ergometer, followed by three sessions of 1-min supramaximal exercise (ExSp). After a warm-up at 60% of V . O2peak (ExM), seven male rowers performed a 2,000 m all-out test (Ex2000). Cardiovascular and respiratory variables were measured. Cerebral oxygenation was investigated by near-infrared time-resolved spectroscopy (TRS) to measure cerebral hemoglobin oxygen saturation (ScO2) and total hemoglobin concentration ([HbT]) in the prefrontal cortex (PFC) quantitatively. We estimated the relative changes from rest in cerebral metabolic rate for oxygen (rCMRO2) using TRS at all intensities. During Ex70% and Ex80%, ratings of perceived exertion (RPE) were monitored, and alteration of the subject's mood was evaluated using a questionnaire of Positive-and-Negative-Affect-Schedule after Ex70% and Ex80%. Results: When exercise intensity changed from Ex70% to Ex80%, the sense of effort increased while ScO2 decreased. [HbT] remained unchanged. After Ex70% and Ex80%, a negative mood state was less prominent compared to rest and was accompanied by increases in both ScO2 and [HbT]. At termination of Ex2000, ScO2 decreased by 23% compared to rest. Changes in ScO2 correlated with V . O2peak only during Ex2000 (r = -0.86; p = 0.01). rCMRO2 did not decrease at any intensities. Conclusion: Our results suggest that alterations in the sense of effort are associated with oxygenation in the PFC, while positive changes in mood status are associated with cerebral perfusion and oxygen metabolism estimated by TRS. At exhaustion, the cerebral metabolic rate for oxygen is maintained despite a decrease in ScO2.

Pathophysiologic Mechanisms of Hypothermia-Induced Pancreatic Injury in a Rat Model of Body Surface Cooling.

OBJECTIVE: The mechanisms underlying hypothermia-induced pancreatic injury are unclear. Thus, we investigated the pathophysiology of hypothermia-induced pancreatic injury. METHODS: We created a normal circulatory model with body surface cooling in rats. We divided the rats into control (36°C-38°C), mild hypothermia (33°C-35°C), moderate hypothermia (30°C-32°C), and severe hypothermia (27°C-29°C) (n = 5 per group) groups. Then, we induced circulatory failure with a cooling model using high-dose inhalation anesthesia and divided the rats into control (36°C-38°C) and severe hypothermia (27°C-29°C) (n = 5 per group) groups. Serum samples were collected before the introduction of hypothermia. Serum and pancreatic tissue were collected after maintaining the target body temperature for 1 hour. RESULTS: Hematoxylin and eosin staining of the pancreas revealed vacuoles and edema in the hypothermia group. Serum amylase (P = 0.056), lactic acid (P < 0.05), interleukin 1ß (P < 0.05), interleukin 6 (P < 0.05), and tumor necrosis factor α (P = 0.13) levels were suppressed by hypothermia. The circulatory failure model exhibited pancreatic injury. CONCLUSIONS: Hypothermia induced bilateral effects on the pancreas. Morphologically, hypothermia induced pancreatic injury based on characteristic pathology typified by vacuoles. Serologically, hypothermia induced protective effects on the pancreas by suppressing amylase and inflammatory cytokine levels.

Antitumor effects of ribavirin in combination with TMZ and IFN-ß in malignant glioma cells.

The prognosis of gioblastoma, the standard chemotherapy agent for which is temozolomide (TMZ), remains poor despite recent advances in multimodal treatments. Therefore, it is necessary to identify and develop novel therapeutics for this malignant disease. Ribavirin, an anti-viral agent which is one of the standard agents for treatment of chronic hepatitis C in combination with interferon (IFN), was recently revealed to have an antitumor potential towards various tumor cells, including malignant glioma cells. The aim of the present study was to examine the antitumor effect of ribavirin in combination with TMZ and IFN-ß on glioma cells and to evaluate the possibility that such combinations might represent a novel candidate for glioblastoma therapy. The combination of ribavirin with TMZ and IFN-ß displayed a significant cell growth inhibitory effect with a ribavirin dose-dependency, including a relatively low concentration of ribavirin, on not only TMZ-sensitive but also TMZ-resistant malignant glioma cells. The antitumor efficacy of such a combination further indicated a synergistic interaction when assessed by the Chou-Talalay method. Furthermore, flow cytometry analysis suggested that apoptosis induction was one of the possible biological processes underlying the synergistic antitumor effect of these triple combination treatments. Therefore, such combinations may be potentially important in the clinical setting for glioblastoma treatment, although further detailed studies, e.g. on the adverse effects, are required.

IFN­ß sensitizes TRAIL­induced apoptosis by upregulation of death receptor 5 in malignant glioma cells.

Tumor necrosis factor­related apoptosis­inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in cancer cells by binding to its receptors, death receptor 4 (DR4) and DR5, without affecting normal cells, and is therefore considered to be a promising antitumor agent for use in cancer treatment. However, several studies have indicated that most glioma cell lines display resistance to TRAIL­induced apoptosis. To overcome such resistance and to improve the efficacy of TRAIL­based therapies, identification of ideal agents for combinational treatment is important for achieving rational clinical treatment in glioblastoma patients. The main aim of this study was to investigate whether interferon­ß (IFN­ß) (with its pleiotropic antitumor activities) could sensitize malignant glioma cells to TRAIL­induced apoptosis using glioma cell lines. TRAIL exhibited a dose­dependent antitumor effect in all of the 7 types of malignant glioma cell lines, although the intensity of the effect varied among the cell lines. In addition, combined treatment with TRAIL (low clinical dose: 1 ng/ml) and IFN­ß (clinically relevant concentration: 10 IU/ml) in A­172, AM­38, T98G, U­138MG and U­251MG demonstrated a more marked antitumor effect than TRAIL alone. Furthermore, the antitumor effect of the combined treatment with TRAIL and IFN­ß may be enhanced via an extrinsic apoptotic system, and upregulation of DR5 was revealed to play an important role in this process in U­138MG cells. These findings provide an experimental basis to suggest that combined treatment with TRAIL and IFN­ß may offer a new therapeutic strategy for malignant gliomas.

Endoscopic Insertion of Nasojejunal Feeding Tube at Bedside for Critically Ill Patients: Relationship between Tube Position and Intragastric Countercurrent of Contrast Medium.

Background and Oblectives: We evaluated the success rate of endoscopically positioned nasojejunal feeding tubes and the intragastric countercurrent of contrast medium thereafter. METHOD: This retrospective observational study investigated patients who were admitted to a single intensive care unit and required endoscopic placement of a post-pyloric feeding tube between January 2010 and June 2016. The feeding tube was grasped with forceps via a transoral endoscope and inserted into the duodenum or jejunum. Thereafter, we assessed the position of the tube and the intragastric countercurrent using abdominal radiography with contrast medium. RESULTS: The tube tip was inserted at the jejunum and the duodenal fourth portion in 55.8 and 33.6% of patients, respectively. The tip of the inserted tube had moved into the jejunum of 71.7% of patients by the following day. The countercurrent rate was significantly lower among patients with a tube inserted into the duodenal fourth portion or more distal than among those with tubes inserted more proximally (8.4 vs. 45.4%, p = 0.0022). CONCLUSIONS: The endoscopic insertion and positioning of a nasojejunal feeding tube seemed effective because the rate of tube insertion into the duodenal fourth portion or more distal was about 90%. The findings of intragastric countercurrents indicated that feeding tubes should be inserted into the duodenal fourth portion or beyond to prevent vomiting and the aspiration of enteral nutrients.

The prognostic value of agonal respiration in refractory cardiac arrest: a case series of non-shockable cardiac arrest successfully resuscitated through extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Agonal respiration following out-of-hospital cardiac arrest is associated with favorable neurological outcomes. Resuscitation using extracorporeal membrane oxygenation could contribute to achieving favorable neurological outcomes in patients with refractory cardiac arrest. CASE PRESENTATION: We report two cases of refractory cardiac arrest with non-shockable rhythms and agonal respiration; both patients were successfully resuscitated through extracorporeal cardiopulmonary resuscitation (ECPR). Both patients were breathing spontaneously upon arrival. One patient was asystolic and the other experienced pulseless electrical activity followed by ventricular fibrillation. Agonal respiration was observed in both and ECPR was implemented, leading to a favorable neurological outcome at discharge. CONCLUSION: The presence of agonal respiration has the potential to confer a favorable neurological outcome in patients with refractory cardiac arrest if maintained, even when the initial cardiac rhythm is not shockable. In these cases, resuscitation should not be abandoned, and ECPR should be considered.

Successful resuscitation for cardiac arrest due to severe accidental hypothermia accompanied by mandibular rigidity: a case of cold stiffening mimicking rigor mortis.

BACKGROUND: In cases of severe accidental hypothermia, it was recommended that resuscitation should be continued until the patient has rewarmed, as hypothermia itself can preserve cerebral function, and hypothermic cardiac arrest is reversible. During cardiopulmonary resuscitation for normothermic patients, muscle rigidity suggests the initiation of postmortem changes such as rigor mortis and can lead to the termination of resuscitation. Currently, the prognosis of cardiac arrest due to severe accidental hypothermia accompanied by rigidity is unknown. CASE PRESENTATION: A 29-year-old woman was found unresponsive near a snowy mountain trail. Upon discovery, she was found to be in cardiac arrest with an initial asystole rhythm and exhibited mandibular rigidity. On admission, her core temperature was 22 °C. Although cardiac arrest continued, and she showed no response to normal resuscitation, blood gas analysis revealed that her initial serum potassium level was 5.4 mmol/L. Extracorporeal membrane oxygenation (ECMO) for systemic perfusion and rewarming was initiated. After ECMO was introduced, return of spontaneous circulation was achieved. She showed no neurological impairments at discharge. CONCLUSIONS: Muscle rigidity does not rule out the possibility of resuscitation in patients with severe accidental hypothermia under cardiac arrest. Serum potassium levels may assist in deciding whether ECMO should be introduced, even if a patient is in asystole. This knowledge may help emergency physicians to save the lives of such patients.

Efficacy of ribavirin against malignant glioma cell lines: Follow-up study.

Ribavirin, a nucleic acid analog, has been employed as an antiviral agent against RNA and DNA viruses and has become the standard agent used for chronic hepatitis C in combination with interferon-α2a. Furthermore, the potential antitumor efficacy of ribavirin has attracted increasing interest. Recently, we demonstrated a dose-dependent antitumor effect of ribavirin for seven types of malignant glioma cell lines. However, the mechanism underlying the antitumor effect of ribavirin has not yet been fully elucidated. Therefore, the main aim of the present study was to provide further relevant data using two types of malignant glioma cell lines (U-87MG and U-138MG) with different expression of MGMT. Dotted accumulations of γH2AX were found in the nuclei and increased levels of ATM and phosphorylated ATM protein expression were also observed following ribavirin treatment (10 µM of ribavirin, clinical relevant concentration) in both the malignant glioma cells, indicating double-strand breaks as one possible mechanism underlying the antitumor effect of ribavirin. In addition, based on assessements using FACS, ribavirin treatment tended to increase the G0/G1 phase, with a time­lapse, indicating the induction of G0/G1-phase arrest. Furthermore, an increased phosphorylated p53 and p21 protein expression was confirmed in both glioma cells. Additionally, analysis by FACS indicated that apoptosis was induced following ribavirin treatment and caspase cascade, downstream of the p53 pathway, which indicated the activation of both exogenous and endogenous apoptosis in both malignant glioma cell lines. These findings may provide an experimental basis for the clinical treatment of glioblastomas with ribavirin.

Evaluating quality indicators of tertiary care hospitals for trauma care in Japan.

OBJECTIVE: This study examined the associations between trauma mortality and quality of care indicators currently used in Japan. DESIGN: This is a retrospective two-level discrete-time survival analysis. Quality indicators were derived from the 2012-2013 annual hospital survey conducted by the Ministry of Health, Labour and Welfare. Trauma mortality data were derived from the Japan Trauma Data Bank for the period of April 2012 to March 2013. SETTING: Tertiary care centers designated as emergency and critical care centers (ECCCs) in Japan. PARTICIPANTS: The analysis included 12 378 patients aged ≥15 years with blunt trauma and an Injury Severity Score ≥9, registered to the data bank from 91 ECCCs. INTERVENTION: Quality of care indicators examined in the annual hospital survey. MAIN OUTCOME MEASURES: Deaths within 30 days. RESULTS: Of the 12 378 patients, 660 (5%) died within 30 days. Higher indicator score was significantly associated with lower mortality risk (hazard ratio [HR] for the second, third and fourth quartiles vs. lowest quartile 0.61, 0.55 and 0.52, respectively). Factors significantly associated with lower mortality risk were, higher patient volume (HR for the highest vs. lowest quartile, 0.74), director's qualification as specialist (HR 0.57) or consultant (HR 0.58), review of patient arrival process (HR 0.68), triage functions (HR 0.69), availability of psychiatrists (HR 0.75) and operating room being ready 24-h (HR 0.81). CONCLUSIONS: The study identified certain indicators associated with trauma patient mortality. Further refinement of indicators is required to specifically identify what needs changing.

Comparison of registry and government evaluation data to ascertain severe trauma cases in Japan.

Aims: Accurate evaluation of health care quality requires high-quality data, and case ascertainment (confirming eligible cases and deaths) is a foundation for accurate data collection. This study examined the accuracy of case ascertainment from two Japanese data sources. Methods: Using hospital-level data, we investigated the concordance in ascertaining trauma cases between a nationwide trauma registry (the Japan Trauma Data Bank) and annual government evaluations of tertiary hospitals between April 2012 and March 2013. We compared the median values for trauma case volumes, numbers of deaths, and case fatality rates from both data sources, and also evaluated the variability in discrepancies for the intrahospital differences of these outcomes. Results: The analyses included 136 hospitals. In the registry and annual evaluation data, the median case volumes were 120.5 cases and 180.5 cases, respectively; the median numbers of deaths were 11 and 12, respectively; and the median case fatality rates were 8.1% and 6.4%, respectively. There was broad variability in the intrahospital differences in these outcomes. Conclusions: The observed discordance between the two data sources implies that these data sources may have inaccuracies in case ascertainment. Measures are needed to evaluate and improve the accuracy of data from these sources.

Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis: A Randomized Clinical Trial.

Importance: Dexmedetomidine provides sedation for patients undergoing ventilation; however, its effects on mortality and ventilator-free days have not been well studied among patients with sepsis. Objectives: To examine whether a sedation strategy with dexmedetomidine can improve clinical outcomes in patients with sepsis undergoing ventilation. Design, Setting, and Participants: Open-label, multicenter randomized clinical trial conducted at 8 intensive care units in Japan from February 2013 until January 2016 among 201 consecutive adult patients with sepsis requiring mechanical ventilation for at least 24 hours. Interventions: Patients were randomized to receive either sedation with dexmedetomidine (n = 100) or sedation without dexmedetomidine (control group; n = 101). Other agents used in both groups were fentanyl, propofol, and midazolam. Main Outcomes and Measures: The co-primary outcomes were mortality and ventilator-free days (over a 28-day duration). Sequential Organ Failure Assessment score (days 1, 2, 4, 6, 8), sedation control, occurrence of delirium and coma, intensive care unit stay duration, renal function, inflammation, and nutrition state were assessed as secondary outcomes. Results: Of the 203 screened patients, 201 were randomized. The mean age was 69 years (SD, 14 years); 63% were male. Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group (19 patients [22.8%] vs 28 patients [30.8%]; hazard ratio, 0.69; 95% CI, 0.38-1.22; P = .20). Ventilator-free days over 28 days were not significantly different between groups (dexmedetomidine group: median, 20 [interquartile range, 5-24] days; control group: median, 18 [interquartile range, 0.5-23] days; P = .20). The dexmedetomidine group had a significantly higher rate of well-controlled sedation during mechanical ventilation (range, 17%-58% vs 20%-39%; P = .01); other outcomes were not significantly different between groups. Adverse events occurred in 8 (8%) and 3 (3%) patients in the dexmedetomidine and control groups, respectively. Conclusions and Relevance: Among patients requiring mechanical ventilation, the use of dexmedetomidine compared with no dexmedetomidine did not result in statistically significant improvement in mortality or ventilator-free days. However, the study may have been underpowered for mortality, and additional research may be needed to evaluate this further. Trial Registration: clinicaltrials.gov Identifier: NCT01760967.

Neuroprotective effects of silymarin on ischemia-induced delayed neuronal cell death in rat hippocampus.

We examined the effects of silymarin, which was extracted from Silybum marianum, on delayed neuronal cell death in the rat hippocampus. Rats were divided into four groups: sham-operated rats (sham group), rats which underwent ischemic surgery (control group), rats which were treated with silymarin before and after ischemic surgery (pre group), and rats which were treated with silymarin after ischemic surgery only (post group). We performed the ischemic surgery by occluding the bilateral carotid arteries for 20min and sacrificed the rats one week after the surgery. Silymarin was administered orally at 200mg/kg body weight. Smaller numbers of delayed cell deaths were noted in the rat CA1 region of the pre- and post-groups, and no significant difference was observed between these groups. There were few apoptotic cell deaths in all groups. Compared to the control group, significantly fewer cell deaths by autophagy were found in the pre- and post-group. We concluded that silymarin exerts a preservation effect on delayed neuronal cell death in the rat hippocampus and this effect has nothing to do with the timing of administering of silymarin.