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This survey of bile replacement (BR) was conducted on patients with external biliary drainage to assess the current status of indication and implementation protocol of BR with special reference to infection control.A 12-item questionnaire regarding the performance of perioperative BR was sent to 124 institutions in Japan.BR was performed in 29 institutions, and the indication protocol was introduced in 19. BR was performed preoperatively in 11 institutions, pre- and postoperatively in 12, and postoperatively in 6. The methods used for BR administration included oral intake (n = 10), nasogastric tube (n = 1), enteral nutrition tube (n = 3), oral intake and enteral nutrition tube (n = 6), oral intake or nasogastric tube (n = 2), nasogastric tube and enteral nutrition tube (n = 2), and oral intake or nasogastric tube and enteral nutrition tube (n = 5). In 10 of 29 institutions, isolation of multidrug-resistant organisms and a high bacterial load were considered contraindications for the use of BR. Seven institutions experienced environmental contamination.Given the different implementation of BR among institutions, the appropriate indication and protocols for BR should be established for infection control.

Introduction The objective of this cohort study was to investigate whether the revised post-Cardiac Arrest Syndrome for Therapeutic hypothermia score (rCAST), which we previously developed as a prognostic score for adult patients with post-cardiac arrest syndrome (PCAS), is also applicable to pediatric patients. Methods Pediatric PCAS patients were included from an out-of-hospital cardiac arrest (OHCA) registry of the Japanese Association for Acute Medicine (JAAM). We validated the predictive accuracy of the rCAST for the neurological outcomes at 30 and 90 days. We also evaluated the probability of a good neurological outcome in each of the three specified severity categories based on the rCAST (low severity: ≤5.5; moderate severity: 6.0–14.0; high severity: ≥14.5). Results Among the 737 pediatric patients with OHCA, the data of 179 pediatric PCAS patients in whom return of spontaneous circulation was achieved were analyzed. The areas under the curve (AUC) of the rCAST for predicting the neurological outcomes at 30 days and 90 days were 0.95 (95% CI: 0.90–0.99) and 0.96 (0.91–1.00), respectively. The proportions of patients with a good neurological outcome at 30 days were 100% (12/12) in the low severity group, 36.1% (13/36) in the moderate severity group, and 2.3% (3/131) in the high severity group. Conclusions The AUC of the rCAST for pediatric PCAS patients was found to be greater than 0.9 in the external validation, which corresponds to excellent predictive accuracy. There was no patient with good neurological outcome among the patients with more than 17.0 points (extremely high severity group).

This study retrospectively analyzed data from the Medical Information Mart for Intensive Care-III critical care database to determine whether visually-assessed right ventricular (RV) dysfunction was associated with clinical outcomes in septic shock patients. Associations between visually-assessed RV dysfunction by echocardiography and in-hospital mortality, lethal arrhythmia, and hemodynamic indicators to determine the prognostic value of RV dysfunction in patients with septic shock were analyzed. Propensity score analysis showed RV dysfunction increased risk of in-hospital death in patients with septic shock (adjusted odds ratio [OR], 2.15; 95% confidence interval [CI], 1.99–2.32; PPPP

Cumulative evidence has established that macrophages orchestrate inflammatory responses that crucially contribute to the pathogenesis of insulin-resistant obesity and type 2 diabetes. In the present study, we examined the impact of hyperglycemia on macrophage pro-inflammatory responses under an inflammatory stimulus. To conduct this study, RAW264.7 macrophages were cultured under normal- (5.5 mM) or high-glucose (22 or 40 mM) conditions for 7 days and stimulated with lipopolysaccharide (LPS). Long-term exposure to high glucose significantly enhanced the increase in the production of pro-inflammatory cytokines, including tumor necrosis-α, interleukin (IL)-1β, and IL-6, when macrophages were stimulated with LPS. The LPS-induced increases in inducible nitric oxide (NO) synthase (iNOS) expression and NO production were also significantly enhanced by long-term exposure of macrophages to high glucose. Treatment with N-acetyl-l-cysteine, a widely used thiol-containing antioxidant, blunted the enhancement of the LPS-induced upregulation of pro-inflammatory cytokine production, iNOS expression, and NO production in macrophages. When intracellular reactive oxygen species (ROS) were visualized using the fluorescence dye 5-(and-6)-chloromethyl-2′,7′-dichlorofluorescein diacetate, acetyl ester, a significant increase in ROS generation was found after stimulation of macrophages with LPS, and this increased ROS generation was exacerbated under long-term high-glucose conditions. LPS-induced translocation of phosphorylated nuclear factor-κB (NF-κB), a transcription factor regulating many pro-inflammatory genes, into the nucleus was promoted under long-term high-glucose conditions. Altogether, the present results indicate that a long-term high-glucose environment can enhance activation of NF-κB in LPS-stimulated macrophages possibly due to excessive ROS production, thereby leading to increased macrophage pro-inflammatory responses.

The acute respiratory distress syndrome (ARDS) is an important cause of respiratory failure in critically ill patients and may become a life-threatening condition where inflammation of the lungs may begin in one lung but eventually affects both, leading to damage to the alveoli and surrounding small blood vessels. ARDS is particularly characterized by noncardiogenic pulmonary edema caused by an increase in pulmonary capillary permeability. Several clinical disorders can precipitate in ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. The most common cause of ARDS is sepsis, which is a serious and widespread infection of the bloodstream and is now defined as life-threatening organ dysfunction due to a dysregulated reponse of the host to infection. In sepsis, a number of vascular hyperpermeable factors, such as histamine, nitric oxide, thromboxane A

A 37-year-old man diagnosed with diffuse large B-cell lymphoma two weeks previously, visited our emergency department with sudden dyspnea. He had a severe respiratory failure with saturated percutaneous oxygen at 80% (room air). Chest radiography showed a large amount of left pleural effusion. After 1000 mL of the effusion was urgently drained, reexpansion pulmonary edema (RPE) occurred. Despite ventilator management, oxygenation did not improve and venovenous extracorporeal membrane oxygenation (VV-ECMO) was initiated in the intensive care unit. The next day, contrast-enhanced computed tomography showed a massive thrombus in the right pulmonary artery, at this point the presence of pulmonary thromboembolism (PTE) was revealed. Fortunately, the patient’s condition gradually improved with anticoagulant therapy and VV-ECMO support. VV-ECMO was successfully discontinued on day 4, and chemotherapy was initiated on day 8. We speculated the following mechanism in this case: blood flow to the right lung significantly reduced due to acute massive PTE, and blood flow to the left lung correspondingly increased, which could have caused RPE in the left lung. Therefore, our observations suggest that drainage of pleural effusion when contralateral blood flow is impaired due to acute PTE may increase the risk of RPE.

We treated two patients with COVID-19 pneumonia requiring mechanical ventilation. Case 1 was a 73-year-old Japanese man. Computed tomography (CT) revealed ground-glass opacities in both lungs. He had severe respiratory failure with a partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen ratio (P/F ratio) of 203. Electrocardiogram showed a heart rate (HR) of 56 beats/min, slight ST depression in leads II, III, and aVF, and mild saddle-back type ST elevation in leads V1 and V2. High-sensitivity cardiac troponin T (cTnT) level was slightly elevated. Despite a high fever and hypoxemia, his HR remained within 50-70 beats/min. Case 2 was a 52-year-old Japanese woman. CT revealed ground-glass opacities in the lower left lung. Electrocardiogram showed a HR of only 81 beats/min, despite a body temperature of 39.2 °C, slight ST depression in leads V4, V5, V6, and a prominent U wave in multiple leads. She had an elevated cTnT and a P/F ratio of 165. Despite a high fever and hypoxemia, her HR remained within 50-70 beats/min. Both patients had a poor compensatory increase in their HR, despite their critical status. Relative bradycardia could be a cardiovascular complication and is an important clinical finding in patients with COVID-19. .

Drug interactions are significant in anesthesiology because drug combinations can potentially possess novel properties. The pharmacological advantages of a new combination of the benzodiazepine receptor agonist JM-1232(-) and propofol were investigated in mice. Male adult mice were administered JM-1232(-) or propofol or combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis, and the time until recovery of the reflex was measured as hypnosis time. After determining the ED50, doses double and triple the ED50 of propofol were injected with JM-1232(-) to compare hypnosis time. The injections were repeated four times, and the hypnosis times were compared. Flumazenil was administered separately immediately after the last dose was injected. The ED50 values ([95% confidence interval]) for hypnosis were 3.76 [3.36-4.10] for JM-1232(-) and 9.88 [8.03-11.58] mg kg-1 for propofol. Co-administration of 0.5 and 1 mg kg-1 JM-1232(-) reduced the ED50 values of propofol to 1.76 [1.21-2.51] and 1.00 [0.46-1.86] mg kg-1, respectively. The drug combination for hypnosis produced a supra-additive interaction. Hypnosis time was significantly shorter in the groups given the mixtures compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with the hypnotic alone. Flumazenil completely restored the recovery time after anesthesia. The combination of JM-1232(-) and propofol showed a supra-additive interaction, and the reduced hypnotic dose contributed to a faster recovery even after multiple injections.

Sepsis is a major clinical challenge with unacceptably high mortality. The signal transducers and activators of transcription (STAT) family of transcription factors is known to activate critical mediators of cytokine responses, and, among this family, STAT3 is implicated to be a key transcription factor in both immunity and inflammatory pathways. We investigated whether in vivo introduction of synthetic double-stranded STAT3 decoy oligodeoxynucleotides (ODNs) can provide benefits for reducing organ injury and mortality in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. We found that STAT3 was rapidly activated in major end-organ tissues following CLP, which was accompanied by activation of the upstream kinase JAK2. Transfection of STAT3 decoy ODNs downregulated pro-inflammatory cytokine/chemokine overproduction in CLP mice. Moreover, STAT3 decoy ODN transfection significantly reduced the increases in tissue mRNAs and proteins of high mobility group box 1 (HMGB1) and strongly suppressed the excessive elevation in serum HMGB1 levels in CLP mice. Finally, STAT3 decoy ODN administration minimized the development of sepsis-driven major end-organ injury and led to a significant survival advantage in mice after CLP. Our results suggest a critical role of STAT3 in the sepsis pathophysiology and the potential usefulness of STAT3 decoy ODNs for sepsis gene therapy.

Vascular endothelial growth factor (VEGF) is a prime regulator of vascular permeability. Acute lung injury (ALI) is characterized by high-permeability pulmonary edema in addition to refractory hypoxemia and diffuse pulmonary infiltrates. In this study, we examined whether VEGF can be implicated as a pulmonary vascular permeability factor in sepsis-associated ALI. We found that a great increase in lung vascular leak occurred in mice instilled intranasally with lipopolysaccharide (LPS), as assessed by IgM levels in bronchoalveolar lavage fluid. Treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced this hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. However, this was not solely attributable to excessive levels of intrapulmonary VEGF. Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Furthermore, a significant rise in plasma VEGF levels was observed in CLP-induced septic mice. The increase in VEGF released from HPMECs after LPS/IFN-γ challenge was completely blocked by either specific inhibitor of mitogen-activated protein kinase (MAPK) subgroups. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways.

Cumulative evidence has established that macrophages orchestrate inflammatory responses that crucially contribute to the pathogenesis of insulin-resistant obesity and type 2 diabetes. In the present study, we examined the impact of hyperglycemia on macrophage pro-inflammatory responses under an inflammatory stimulus. To conduct this study, RAW264.7 macrophages were cultured under normal- (5.5 mM) or high-glucose (22 or 40 mM) conditions for 7 days and stimulated with lipopolysaccharide (LPS). Long-term exposure to high glucose significantly enhanced the increase in the production of pro-inflammatory cytokines, including tumor necrosis-α, interleukin (IL)-1β, and IL-6, when macrophages were stimulated with LPS. The LPS-induced increases in inducible nitric oxide (NO) synthase (iNOS) expression and NO production were also significantly enhanced by long-term exposure of macrophages to high glucose. Treatment with N-acetyl-L-cysteine, a widely used thiol-containing antioxidant, blunted the enhancement of the LPS-induced upregulation of pro-inflammatory cytokine production, iNOS expression, and NO production in macrophages. When intracellular reactive oxygen species (ROS) were visualized using the fluorescence dye 5-(and-6)-chloromethyl-2',7'-dichlorofluorescein diacetate, acetyl ester, a significant increase in ROS generation was found after stimulation of macrophages with LPS, and this increased ROS generation was exacerbated under long-term high-glucose conditions. LPS-induced translocation of phosphorylated nuclear factor-κB (NF-κB), a transcription factor regulating many pro-inflammatory genes, into the nucleus was promoted under long-term high-glucose conditions. Altogether, the present results indicate that a long-term high-glucose environment can enhance activation of NF-κB in LPS-stimulated macrophages possibly due to excessive ROS production, thereby leading to increased macrophage pro-inflammatory responses.

In sepsis-associated coagulopathies and disseminated intravascular coagulation, relative platelet reductions may reflect coagulopathy severity. However, limited evidence supports their clinical significance and most sepsis-associated coagulopathy criteria focus on the absolute platelet counts. To estimate the impact of relative platelet reductions and absolute platelet counts on sepsis outcomes. A multicenter retrospective observational study was performed using the eICU Collaborative Research Database, comprising 335 intensive care units (ICUs) in the United States. Patients with sepsis and an ICU stay > 2 days were included. Estimated effects of relative platelet reductions and absolute platelet counts on mortality and coagulopathy-related complications were evaluated. Overall, 26,176 patients were included. Multivariate mixed-effect logistic regression analysis revealed marked in-hospital mortality risk with larger platelet reductions between days one and two, independent from the resultant absolute platelet counts. The adjusted odds ratio (OR) [95% confidence intervals (CI)] for in-hospital mortality was 1.28[1.23–1.32], 1.86[1.75–1.97], 2.99[2.66–3.36], and 6.05[4.40–8.31] for 20–40%, 40–60%, 60–80%, and > 80% reductions, respectively, when compared with a P P P P

Introduction There are no established risk classification for post-cardiac arrest syndrome (PCAS) patients at the Emergency Department (ED) undergoing targeted temperature management (TTM). The aim of this study was to externally validate a simplified version of our prognostic score, the “post-Cardiac Arrest Syndrome for Therapeutic hypothermia score” (revised CAST [rCAST]) and estimate the predictive accuracy of the risk classification based on it. Methods For the external validation, we used data from an out-of-hospital cardiac arrest (OHCA) registry of the Japanese Association for Acute Medicine (JAAM), which is a multicenter, prospective registry of OHCA patients across Japan. Eligible patients were PCAS patients treated with TTM at 33–36 °C between June 2014 and December 2015. We validated the accuracy of rCAST for predicting the neurological outcomes at 30 and 90 days. Results Among the 12,024 OHCA patients, the data of 460 PCAS patients treated by TTM were eligible for the validation. The areas under the curve of rCAST for predicting the neurological outcomes at 30 and 90 days were 0.892 and 0.895, respectively. The estimated sensitivity and specificity of the risk categories for the outcomes were as follows: 0.95 (95% CI: 0.92–0.98) and 0.47 (0.40–0.55) for the low (rCAST: ≤5.5), 0.62 (0.56–0.68) and 0.48 (0.40–0.55) for the moderate (rCAST: 6.0–14.0), and 0.57 (0.51–0.63) and 0.95 (0.91–0.98) for the high severity category (rCAST: ≥14.5). Conclusions The rCAST was useful for predicting the neurological outcomes with high accuracy in PCAS patients, and the three grades was developed for a risk classification based on the rCAST.

Objectives The optimal target temperature during targeted temperature management for patients after cardiac arrest remains under debate. The aim of this study was to evaluate the association between targeted temperature management at lower target temperatures and the neurologic outcomes among patients classified by the severity of postcardiac arrest syndrome. Design A multicenter observational study from the out-of-hospital cardiac arrest registry of the Japanese Association for Acute Medicine, which is a nationwide prospective registry of out-of-hospital cardiac arrest patients. Setting A total of 125 critical care medical centers or hospitals with an emergency care department across Japan. Patients A total of 1,111 out-of-hospital cardiac arrest patients who had received targeted temperature management. Measurements and main results We divided all 1,111 postcardiac arrest syndrome patients treated with targeted temperature management into two groups: those who received targeted temperature management at a lower target temperature (33-34°C) and those who received targeted temperature management at a higher target temperature (35-36°C). In regard to classification of the patients, we divided the patients into three categories of severity (low, moderate, and high severities) using the risk classification tool, post-Cardiac Arrest Syndrome for Therapeutic hypothermia, which was previously validated. The primary outcome was the percentage of patients with a good neurologic outcome at 30 days, and the secondary outcome was the survival rate at 30 days. Multivariate analysis showed that targeted temperature management at 33-34°C was significantly associated with a good neurologic outcome and survival at 30 days in the moderate severity (odds ratio, 1.70 [95% CI, 1.03-2.83] and 1.90 [95% CI, 1.15-3.16], respectively), but not in the patients of low or high severity (pinteraction = 0.033). Propensity score analysis also showed that targeted temperature management at 33-34°C was associated with a good neurologic outcome in the moderate-severity group (p = 0.022). Conclusions Targeted temperature management at 33-34°C was associated with a significantly higher rate of a good neurologic outcome in the moderate-severity postcardiac arrest syndrome group, but not in the low- or high-severity group.

Supplemental Digital Content is available in the text., Objectives: Abnormal secretion of catecholamines is well known to cause delirium. In particular, disturbances of catecholamine balance can cause ICU-acquired delirium. The aim of this study was to evaluate the association between the serum levels of catecholamines and the risk of occurrence of ICU-acquired delirium separately in patients who had/had not received exogenous catecholamines before ICU admission. Design: A secondary analysis of the data of 81 patients enrolled in our previous randomized clinical trial. Setting: ICU of an academic hospital. Patients: ICU patients in whom the serum levels of catecholamines were measured at ICU admission. Interventions: None. Measurements and Main Results: We evaluated the association between the serum levels of catecholamines measured at ICU admission and the risk of ICU-acquired delirium separately in patients who had received exogenous catecholamines at ICU admission (Ex[+] group) and those who had not received exogenous catecholamines (Ex[–] group). The serum levels of norepinephrine measured at ICU admission were significantly associated with the risk of ICU-acquired delirium in the Ex(–) group (odds ratio, 2.58; 95% CI, 1.02–6.52; p = 0.046), but not in the Ex(+) group (odds ratio, 1.02; 95% CI, 0.88–1.18; p = 0.823). Furthermore, there was a statistically significant interaction effect between the serum levels of norepinephrine and the use/nonuse of exogenous catecholamines at ICU admission in relation to the risk of occurrence of ICU-acquired delirium (pinteraction = 0.017). Conclusions: The serum levels of norepinephrine measured at admission were associated with the risk of occurrence of ICU-acquired delirium in patients who had not received exogenous catecholamines at ICU admission, whereas no such association was observed in those who had received exogenous catecholamines previously. Thus, the association between the serum levels of catecholamines measured at admission and the risk of ICU-acquired delirium differed between patients who had/had not received exogenous catecholamines at ICU admission.

Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat ischemic symptoms of peripheral vascular disease. Ample evidence has suggested that cilostazol also exhibits an anti-inflammatory effect, but its anti-inflammatory mechanism is not fully understood. Here, we showed that cilostazol specifically inhibited expression of cytokines, which are induced by nuclear factor-κB (NF-κB) activation, in RAW264.7 macrophage cells stimulated with different Toll-like receptor (TLR) ligands. Cilostazol was found to significantly reduce TLR-4 and TLR-3 ligands-stimulated NF-κB transcriptional activity, which was quantified by luciferase reporter assays. However, cilostazol was without effect on IκBα degradation and NF-κB p65 phosphorylation and nuclear translocation after challenge with the TLR-4 ligand lipopolysaccharide (LPS). Cilostazol did not also prevent the LPS-induced increase in phosphorylated levels of the mitogen-activated protein kinase (MAPK) family. On the other hand, using chromatin immunoprecipitation assays, we demonstrated that cilostazol reduced the LPS-induced transcriptional activities of interleukin-6 and tumor necrosis factor-α by preventing the recruitment of NF-κB p65 to these gene promoters. When cilostazol was given to mice by oral gavage daily for 7 days, LPS-induced aberrant pro-inflammatory cytokine production and end-organ tissue injury were significantly reduced. The results of this study suggest that cilostazol is capable of directly interrupting DNA binding activity of NF-κB proteins from the TLR signaling pathways. The therapy to specifically intervene in this pathway may be potentially beneficial for the prevention of different inflammatory disorders.

Objectives: To clarify the relationship between mobility disability at the time of discharge from the ICU and clinical factors evaluated at ICU admission in septic patients. Design: A single-center, retrospective, observational study. Setting: Ten-bed, the emergency and medical ICU. Patients: We analyzed the data of septic patients who were admitted to our ICU between September 2012 and September 2016 and received early rehabilitation. Interventions: None. Measurements and Main Results: The patients were categorized into two groups based on their scores on the ICU mobility scale at the time of discharge from the ICU: the mobility disability group (ICU mobility scale score < 9) and the no mobility disability group (ICU mobility scale score ≥ 9). Of the 110 eligible patients, 63 met the inclusion criteria; of these, 46 patients (73%) were classified into the mobility disability group, and 17 patients (27%) were classified into the no mobility disability group. The age (median, 72 vs 64 yr; p = 0.024), prevalence of patients with clinical frailty scale scores of greater than or equal to 5 (54% vs 12%; p = 0.003), Sequential Organ Failure Assessment score (median, 9.0 vs 6.0; p = 0.006) and rate of vasopressin use (26% vs 0%; p = 0.026) were significantly higher in the mobility disability group as compared with the no mobility disability group. Among the candidate variables for which values recorded before/at the time of ICU admission were available, the clinical frailty scale score was identified as the only independent, statistically significant predictor of mobility disability at ICU discharge (odds ratio, 7.77; 95% CI, 1.37–44.21; p = 0.021). The positive predictive value and negative predictive value of clinical frailty scale scores greater than or equal to 5 for mobility disability at ICU discharge were 92.6% and 41.7%, respectively. Conclusions: The clinical frailty scale score was associated with increased mobility disability at ICU discharge in septic patients receiving early rehabilitation.

Despite advances in overall medical care, sepsis and its sequelae continue to be an embarrassing clinical entity with an unacceptably high mortality rate. The central reason for high morbidity and high mortality of sepsis and its sequelae is the lack of an effective treatment. Previous clinical trials have largely failed to identify an effective therapeutic target to improve clinical outcomes in sepsis. Thus, the key goal favoring the outcome of septic patients is to devise innovative and evolutionary therapeutic strategies. Gene therapy can be considered as one of the most promising novel therapeutic approaches for nasty disorders. Since a number of transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), play a pivotal role in the pathophysiology of sepsis that can be characterized by the induction of multiple genes and their products, sepsis may be regarded as a gene-related disorder and gene therapy may be considered a promising novel therapeutic approach for treatment of sepsis. In this review article, we provide an up-to-date summary of the gene-targeting approaches, which have been developed in animal models of sepsis. Our review sheds light on the molecular basis of sepsis pathology for the development of novel gene therapy approaches and leads to the conclusion that future research efforts may fully take into account gene therapy for the treatment of sepsis.

Supplemental Digital Content is available in the text., Objectives: Occurrence of delirium in the ICU is associated with a longer stay in the ICU. To examine whether the use of ramelteon, a melatonin agonist, can prevent delirium and shorten the duration of ICU stay of critically ill patients. Design: A single-center, triple-blinded, randomized placebo-controlled trial. Setting: ICU of an academic hospital. Patients: Eligible patients were ICU patients who could take medicines orally or through a nasogastric tube during the first 48 hours of admission. Interventions: The intervention group received ramelteon (8 mg/d), and the control group received placebo (1 g/d of lactose powder) at 20:00 hours every day until discharge from the ICU. Measurements and Main Results: A total of 88 subjects were randomized to the ramelteon group (45 subjects) or the placebo group (43 subjects). As the primary endpoint, there was a trend toward decrease in the duration of ICU stay (4.56 d) in the ramelteon group compared with the placebo group (5.86 d) (p = 0.082 and p = 0.028 before and after adjustments). As the secondary endpoints, statistically significant decreases in the occurrence rate (24.4% vs 46.5%; p = 0.044) and duration (0.78 vs 1.40 d; p = 0.048) of delirium were observed in the ramelteon group. The nonintubated patients of the ramelteon group showed statistically significantly fewer awakenings per night and a higher proportion of nights without awakenings. Conclusions: Ramelteon tended to decrease the duration of ICU stay as well as decreased the occurrence rate and duration of delirium statistically significantly.

Introduction The aim of this study was to evaluate the differential effects of mild therapeutic hypothermia (MTH) in post-cardiac arrest syndrome (PCAS) patients depending on the presence/absence of hypoxic encephalopathy (HE) in the early brain CT images obtained before the initiation of MTH. Methods We conducted a retrospective review of the data of a total of 129 patients with PCAS who were treated by MTH (34 °C) or normothermia treatment (NT) (35 °C or 36 °C), and had undergone brain CT examination prior to the initiation of these treatments. We divided the subjects into 4 groups, namely, the HE(−)/MTH, HE(−)/NT, HE(+)/MTH, and HE(+)/NT groups, for evaluating the interaction effect between the two variables. Then, we compared the neurological outcomes between the HE(−)/MTH and HE(−)/NT groups by multivariate logistic analysis. Good outcome was defined as a Cerebral Performance Category score of ≤2 at 30 days. Results The percentages of subjects with a good outcome in the HE(−)/MTH and HE(−)/NT group were 68.9% (42/61) and 36.1% (13/36), respectively (p = .003), while those in the HE(+)/MTH and HE(+)/NT groups were lower, at 7.4% (2/27) and 20.0% (1/5), respectively (p = .410), suggesting a statistically significant interaction effect between the two variables (pinteraction = 0.002). In the HE(−) group, MTH was associated with a higher odds ratio of a good outcome as compared to NT (OR 6.80, 95% CI 1.19–38.96, p = .031). Conclusions The effect of MTH in patients with PCAS differed depending on the presence/absence of evidence of HE on the early CT images.

Levosimendan and milrinone may be used in place of dobutamine to increase cardiac output in septic patients with a low cardiac output due to impaired cardiac function. The effects of the two inotropic agents on cardiac inflammation and left ventricular (LV) performance were examined in mice with cecal ligation and puncture (CLP)-induced sepsis. CLP mice displayed significant cardiac inflammation, as indicated by highly increased pro-inflammatory cytokines and neutrophil infiltration in myocardial tissues. When continuously given, levosimendan prevented but milrinone exaggerated cardiac inflammation, but they significantly reduced the elevations in plasma cardiac troponin-I and heart-type fatty acid-binding protein, clinical markers of cardiac injury. Echocardiographic assessment of cardiac function showed that the effect of levosimendan, given by an intravenous bolus injection, on LV performance was impaired in CLP mice, whereas milrinone produced inotropic responses equally in sham-operated and CLP mice. A lesser effect of levosimendan on LV performance after CLP was also found in spontaneously beating Langendorff-perfused hearts. In ventricular myocytes isolated from control and CLP mice, levosimendan, but not milrinone, caused a large increase in the L-type calcium current. This study represents that levosimendan and milrinone have cardioprotective properties but provide different advantages and drawbacks to cardiac inflammation/dysfunction in sepsis.

Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up-regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS-stimulated MG6 cells. Furthermore, the LPS-induced up-regulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in LPS-stimulated MG cells. In mice with cecal ligation and puncture-induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up-regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE.

Objectives Inflammation and apoptosis are decisive mechanisms for the development of end-organ injury in sepsis. Activator protein-1 may play a key role in regulating expression of harmful genes responsible for the pathophysiology of septic end-organ injury along with the major transcription factor nuclear factor-κB. We investigated whether in vivo introduction of circular dumbbell activator protein-1 decoy oligodeoxynucleotides can provide benefits for reducing septic end-organ injury. Design Laboratory and animal/cell research. Settings University research laboratory. Subjects Male BALB/c mice (8-10 wk old). Interventions Activator protein-1 decoy oligodeoxynucleotides were effectively delivered into tissues of septic mice in vivo by preparing into a complex with atelocollagen given 1 hour after surgery. Materials and main results Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Activator protein-1 decoy oligodeoxynucleotide transfection inhibited abnormal production of proinflammatory and chemotactic cytokines after cecal ligation and puncture. Histopathologic changes in lung, liver, and kidney tissues after cecal ligation and puncture were improved by activator protein-1 decoy oligodeoxynucleotide administration. When activator protein-1 decoy oligodeoxynucleotides were given, apoptosis induction was strikingly suppressed in lungs, livers, kidneys, and spleens of cecal ligation and puncture mice. These beneficial effects of activator protein-1 decoy oligodeoxynucleotides led to a significant survival advantage in mice after cecal ligation and puncture. Apoptotic gene profiling indicated that activator protein-1 activation was involved in the up-regulation of many of proapoptotic and antiapoptotic genes in cecal ligation and puncture-induced sepsis. Conclusions Our results indicate a detrimental role of activator protein-1 in the sepsis pathophysiology and the potential usefulness of activator protein-1 decoy oligodeoxynucleotides for the prevention and treatment of septic end-organ failure.

Fulminant myocarditis (FM) causes rapid onset severe heart failure requiring inotropes or mechanical circulatory support. Myocarditis is sometimes associated with pericardial effusion, however, how this effusion affects the hemodynamics in patients with FM under venoarterial extracorporeal membrane oxygenation (VA-ECMO) management has not been fully reported. We show a case of FM presenting with cardiac tamponade during VA-ECMO management. A 64-year-old female diagnosed as having FM showed a rapid hemodynamic collapse and that led to the application of VA-ECMO. Although her left ventricular ejection fraction did not improve despite proper hemodynamics management for several days, a pericardial effusion accumulated gradually. Apparent elevation of right atrial pressure and reduction of blood pressure were not observed, however, we performed pericardiocentesis because we were not able to wean off VA-ECMO. After the drainage of pericardial effusion, the blood pressure and cardiac output elevated as did the left ventricular ejection fraction. We successfully removed VA-ECMO and the patient was discharged without any complications. This is a case report in which a cardiac tamponade under VA-ECMO did not show typical signs and pericardiocentesis contributed to withdrawal of a VA-ECMO system. .

Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. Elevations of plasma cardiac troponin-I showed cardiac injury in CLP mice. Noninvasive echocardiographic assessment of cardiac function revealed that despite preserved left ventricular function in the presence of fluid replacement, the dobutamine inotropic response was significantly impaired in CLP mice compared with sham-operated controls. By contrast, milrinone exerted inotropic effects in sham-operated and CLP mice in an equally effective manner. Surface expression levels of β1-adrenoceptors and α-subunits of three main G protein families in the myocardium were unaffected by CLP-induced sepsis. Plasma cAMP levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support. NEW & NOTEWORTHY Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis without changes in cardiac β1-adrenoceptor signaling as a result of cAMP breakdown achieved by upregulated phosphodiesterase 4D.

Pericytes are believed to originate from either mesenchymal or neural crest cells. It has recently been reported that pericytes play important roles in the central nervous system (CNS) by regulating blood-brain barrier homeostasis and blood flow at the capillary level. However, the origin of CNS microvascular pericytes and the mechanism of their recruitment remain unknown. Here, we show a new source of cerebrovascular pericytes during neurogenesis. In the CNS of embryonic day 10.5 mouse embryos, CD31+F4/80+ hematopoietic lineage cells were observed in the avascular region around the dorsal midline of the developing midbrain. These cells expressed additional macrophage markers such as CD206 and CD11b. Moreover, the CD31+F4/80+ cells phagocytosed apoptotic cells as functionally matured macrophages, adhered to the newly formed subventricular vascular plexus, and then divided into daughter cells. Eventually, these CD31+F4/80+ cells transdifferentiated into NG2/PDGFRβ/desmin-expressing cerebrovascular pericytes, enwrapping and associating with vascular endothelial cells. These data indicate that a subset of cerebrovascular pericytes derive from mature macrophages in the very early phase of CNS vascular development, which in turn are recruited from sites of embryonic hematopoiesis such as the yolk sac by way of blood flow.

The host stress hormone norepinephrine (NE), also called noradrenaline, is reported to augment bacterial growth and pathogenicity, but few studies have focused on the effect of NE on the activity of antimicrobials. The aim of this study was to clarify whether NE affects antimicrobial activity against multidrug-resistant Acinetobacter baumannii (MDR-AB). Time–kill studies of tigecycline (TIG) and colistin (COL) against MDR-AB as well as assays for factors contributing to antibiotic resistance were performed using MDR-AB clinical strains both in the presence and absence of 10 µM NE. In addition, expression of three efflux pump genes ( adeB , adeJ and adeG ) in the presence and absence of NE was analysed by quantitative reverse transcription PCR. Viable bacterial cell counts in TIG-supplemented medium containing NE were significantly increased compared with those in medium without NE. In contrast, NE had little influence on viable bacterial cell counts in the presence of COL. NE-supplemented medium resulted in an ca. 2 log increase in growth and in bacterial cell numbers adhering on polyurethane, silicone and polyvinylchloride surfaces. Amounts of biofilm in the presence of NE were ca. 3-fold higher than without NE. Expression of the adeG gene was upregulated 4–6-fold in the presence of NE. In conclusion, NE augmented factors contributing to antibiotic resistance and markedly reduced the in vitro antibacterial activity of TIG against MDR-AB. These findings suggest that NE treatment may contribute to the failure of TIG therapy in patients with MDR-AB infections.

Tachycardia and atrial fibrillation frequently occur in patients being treated for sepsis or septic shock and have a poor prognosis. Treatments for tachyarrhythmias are often ineffective or contraindicated in this setting. We aimed to investigate the efficacy and safety of landiolol, an ultra-short-acting β-blocker, for treating sepsis-related tachyarrhythmias.We did a multicentre, open-label, randomised controlled trial at 54 hospitals in Japan. Patients admitted to the intensive care units who received conventional treatment for sepsis, according to clinical guidelines for the management of sepsis, and who subsequently developed a tachyarrhythmia, were enrolled. The main inclusion criteria were 20 years of age or older, diagnosis of sepsis according to Third International Consensus Definitions for Sepsis and Septic Shock criteria, administration of catecholamine necessary to maintain mean arterial pressure at 65 mm Hg or more for at least 1 h, and heart rate of 100 beats per min (bpm) or more maintained for at least 10 min without a change in catecholamine dose with diagnosis of atrial fibrillation, atrial flutter, or sinus tachycardia. Only patients who developed these symptoms and signs within 24 h before randomisation, and within 72 h after entering an intensive care unit, were prospectively assigned to receive conventional sepsis therapy alone (control group) or conventional sepsis therapy plus landiolol (landiolol group) in an open-label manner. Landiolol hydrochloride was intravenously infused at an initial dose of 1 μg/kg per min within 2 h after randomisation and the dose could be increased per study protocol to a maximum of 20 μg/kg per min. Patients in both groups received conventional therapy (Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock 2016), including respiratory and fluid resuscitation, antimicrobials, and catecholamines. The treating physicians were required to stabilise the patient's haemodynamic status before randomisation. Randomisation was done using a central randomisation system and dynamic allocation with the minimisation method by institution, heart rate at randomisation (≥100 to120 bpm or ≥120 bpm), and age (70 years or ≥70 years). The primary outcome was the proportion of patients with heart rate of 60-94 bpm at 24 h after randomisation. Patients without heart rate data at 24 h after randomisation were handled as non-responders. The primary outcome was analysed using the full analysis set on an as-assigned basis, while safety was analysed using the safety analysis set according to the treatment received. This study was registered with the Japan Pharmaceutical Information Center Clinical Trials Information database, number JapicCTI-173767.Between Jan 16, 2018 and Apr 22, 2019, 151 patients were randomly assigned, 76 to the landiolol group and 75 to the control group. A significantly larger proportion of patients in the landiolol group had a heart rate of 60-94 bpm 24 h after randomisation than in the control group (55% [41 of 75] vs 33% [25 of 75]), with a between-group difference of 23·1% (95% CI 7·1-37·5; p=0·0031). Adverse events were observed in 49 (64%) of 77 patients in the landiolol group and in 44 (59%) of 74 in the control group, with serious adverse events (including adverse events leading to death) in nine (12%) of 77 and eight (11%) of 74 patients. Serious adverse events related to landiolol occurred in five (6%) of 77 patients, including blood pressure decreases in three patients (4%) and cardiac arrest, heart rate decrease, and ejection fraction decrease occurred in one patient each (1%).Landiolol resulted in significantly more patients with sepsis-related tachyarrhythmia achieving a heart rate of 60-94 bpm at 24 h and significantly reduced the incidence of new-onset arrhythmia. Landiolol was also well tolerated, but it should be used under appropriate monitoring of blood pressure and heart rate owing to the risk of hypotension in patients with sepsis and septic shock.Ono Pharmaceutical Co.

Background Drug interactions are significant in anesthesiology because drug combinations can potentially possess novel properties. The pharmacological advantages of a new combination of the benzodiazepine receptor agonist JM-1232(-) and propofol were investigated in mice.Methods Male adult mice were administered JM-1232(-) or propofol or combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis, and the time until recovery of the reflex was measured as hypnosis time. After determining the ED50, doses double and triple the ED50 of propofol were injected with JM-1232(-) to compare hypnosis time. The injections were repeated four times, and the hypnosis times were compared. Flumazenil was administered separately immediately after the last dose was injected.Results The ED50 values ([95% confidence interval]) for hypnosis were 3.76 [3.36–4.10] for JM-1232(-) and 9.88 [8.03–11.58] mg kg-1 for propofol. Co-administration of 0.05 and 0.1 mg kg-1 JM-1232(-) reduced the ED50 values of propofol to 1.76 [1.21–2.51] and 1.00 [0.46–1.86] mg kg-1, respectively. The drug combination for hypnosis produced a supra-additive interaction. Hypnosis time was significantly shorter in the groups given the mixtures compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with the hypnotic alone. Flumazenil completely restored the recovery time after anesthesia.Conclusions The combination of JM-1232(-) and propofol showed a supra-additive interaction, and the reduced hypnotic dose contributed to a faster recovery even after multiple injections.