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Purpose This trial was conducted to confirm the non-inferiority of remimazolam versus propofol in the induction and maintenance of general anesthesia in surgical patients. Methods Surgical patients (n = 375) were randomized to remimazolam started at 6 or 12 mg/kg/h by continuous intravenous (IV) infusion until the loss of consciousness (LoC), followed by 1 mg/kg/h to be adjusted as appropriate until the end of surgery or IV propofol administered as a slow bolus of 2.0-2.5 mg/kg until LoC followed by 4-10 mg/kg/h until the end of surgery. Efficacy was measured via the combined primary endpoint of no intraoperative awakening/recall, no need for rescue sedatives, and no body movements. Adverse events and adverse drug reactions (ADRs) were monitored for safety. Results Efficacy rates were 100% in all treatment groups, and the non-inferiority of remimazolam was demonstrated [95% confidence interval (- 0.0487; 0.0250)]. The time to LoC was longer in the remimazolam 6 (p < 0.0001) and 12 mg/kg/h (p = 0.0149) groups versus propofol. The time to extubation was longer in both remimazolam groups versus the propofol group (p [less than or equal to] 0.0001). The incidence of ADRs was similar in the remimazolam groups (39.3% and 42.7%, respectively) compared with the propofol group (61.3%). Decreased blood pressure occurred in 20.0% and 24.0% of patients treated with 6 and 12 mg/kg/h remimazolam, respectively, compared with 49.3% of patients receiving propofol. Injection site pain was reported in 18.7% of propofol patients but not in those receiving remimazolam. Conclusions This trial demonstrated that remimazolam was well tolerated and non-inferior to propofol with regard to efficacy as a sedative hypnotics for general anesthesia. Clinical trial registration This trial is registered with the Japan Pharmaceutical Information Center - Clinical Trials Information (JapicCTI). JapicCTI number: 121973, Author(s): Matsuyuki Doi [sup.1], Kiyoshi Morita [sup.2], Junzo Takeda [sup.3], Atsuhiro Sakamoto [sup.4], Michiaki Yamakage [sup.5], Toshiyasu Suzuki [sup.6] Author Affiliations: (1) grid.471533.7, 0000 0004 1773 3964, Department of Anesthesiology [...]

Purpose We evaluated the safety and efficacy of long-term administration of dexmedetomidine in patients in the intensive care unit (ICU). Primary endpoint was the incidence of hypotension, hypertension, and bradycardia. Secondary endpoints were withdrawal symptoms, rebound effects, the duration of sedation with Richmond Agitation-Sedation Scale (RASS) [less than or equal to] 0 relative to the total infusion time of dexmedetomidine, and the dose of additional sedatives or analgesics. Methods Dexmedetomidine 0.2-0.7 µg/kg/h was continuously infused for maintaining RASS ≤ 0 in patients requiring sedation in the ICU. Safety and efficacy of shortterm ([less than or equal to] 24 h) and long-term (> 24 h) dexmedetomidine administration were compared. Seventy-five surgical and medical ICU patients were administered dexmedetomidine. The incidence of hypotension, hypertension, and bradycardia that occurred after 24 h (long-term) was not significantly different from that occurring within 24 h (short-term) (P = 0.546, 0.513, and 0.486, respectively). Regarding withdrawal symptoms, one event each of hypertension and headache occurred after the end of infusion, but both were mild in severity. Increases of mean arterial blood pressure and heart rate after terminating the infusion of dexmedetomidine were not associated with the increasing duration of its infusion. The ratio of duration with RASS [less than or equal to] 0 was ≥ 85 % until day 20, except day 9 (70 %) and day 10 (75 %). There was no increase in the dose of additional sedatives or analgesics after the first 24-h treatment period. Conclusions Long-term safety of dexmedetomidine compared to its use for 24 h was confirmed. Dexmedetomidine was useful to maintain an adequate sedation level (RASS ≤ 0) during long-term infusion. Keywords Dexmedetomidine * Long term * Sedation * Intensive care unit * Withdrawal, Introduction The importance of optimizing the levels of sedation in critical care has been increasingly recognized [1]. Many intensive care experts are focusing on maintaining a targeted 'ideal' sedation level [...]

Purpose Atrial natriuretic peptide (ANP) has been known to be protective against hepatic ischemia/reperfusion injury. The purpose of this study was to verify the hypothesis that ANP conserves microvascular circulation and reduces ischemia-reperfusion injury in the in vivo rabbit model. Methods With IRB approval, 30 male Japanese white rabbits under pentobarbital anesthesia were studied. These animals were randomly assigned to the following three groups (n = 10 each): control, ANP, and sham group. Animals in the ANP group received continuous infusion of ANP at 0.1 µg/kg/min throughout the study period. Animals in control and ANP groups underwent 90 min of partial hepatic ischemia by clamping the right hepatic artery and portal vein. Descending aortic blood flow (AoF) was monitored with a transit-time ultrasound flowmeter. Hepatic tissue microvascular blood flow (HTBF) at both right (ischemic) and left (nonischemic) lobe was intermittently evaluated with the hydrogen clearance method. After 180 min of reperfusion, hepatic injury was determined with serum AST and ALT. Galactose clearance of reperfused right lobe was also measured as an indicator of hepatic metabolic function. Histopathological change and the number of apoptotic hepatocytes were also evaluated. Results Systemic hemodynamic data including mean arterial pressure, heart rate, and AoF did not differ among the three groups during the study period. ANP attenuated ischemia-induced right HTBF decrease. ANP also suppressed histopathological degeneration, apoptosis, and decline in galactose clearance after reperfusion. Conclusions ANP attenuated hepatic microvascular dysfunction and hepatocyte injury after reperfusion without significant hemodynamic change. Keywords Atrial natriuretic peptide * Ischemia-reperfusion * Liver injury * Tissue microvascular blood flow, Introduction Attenuation or prevention of hepatic ischemia-reperfusion injury is an important clinical challenge in several settings such as liver surgery, liver transplantation, and shock state. The liver has several unique [...]

The present study was conducted to evaluate the efficacy and safety of BLM-240 (desflurane) in comparison to sevoflurane in Japanese patients. A total of 216 patients were enrolled in this randomized comparative study at 15 medical institutions. The patients received either BLM-240 with 50-70 % [N.sub.2]O in [O.sub.2] (n = 111), BLM-240 with 30 % [O.sub.2] in air (n = 55), or sevoflurane with 50-70 % [N.sub.2]O in [O.sub.2] (n = 50). Efficacy was evaluated by an efficacy rate based on an efficacy evaluation criteria and recovery time to extubation from the discontinuation of the anesthetics. Safety was evaluated by incidence of adverse drug reactions (ADR) and other clinical indicators. The efficacy rate of BLM-240 was 98.8 % (164/166 patients), indicating that BLM-240 is effective as an anesthetic. Time from discontinuation of anesthetic delivery to extubation was 9.7 [+ or -] 0.6 min in the BLM-240/[N.sub.2]O group and 14.3 [+ or -] 0.9 min in the sevoflurane/[N.sub.2]O group, meeting the pre-defined non-inferiority criteria of BLM-240 to sevoflurane. There was no statistically significant difference in the incidence of total ADR between the BLM-240 group (62.0 %) and sevoflurane group (48.0 %). The results indicate that BLM-240 is an effective and safe inhalation anesthetic in Japanese patients. Keywords Desflurane * Sevoflurane * Inhalation * Anesthetic, BLM-240 (desflurane) has been widely used in clinical practice outside of Japan as a volatile inhaled anesthetic in a variety of surgeries including ambulatory, cardiovascular, geriatric and pediatric surgeries [1-4]. [...]

Enhancement of the endotoxin recognition pathway by ventilation with a large tidal volume in rabbits. Am J Physiol Lung Cell Mol Physiol 286:L1114-L1121, 2004. First published November 2l, 2003; 10.1152/ajplung.00296.2003.--Ventilation with a small tidal volume ([V.sub.t]) is associated with better clinical outcomes than with a large [V.sub.t], particularly in critical settings, including acute lung injury. To determine whether [V.sub.t] influences the lipopolysaccaharide (LPS) recognition pathway, we studied CD 14 expression in rabbit lungs and the release of TNF-[alpha] by cultured alveolar macrophages after 240 min of ventilation with a large (20 ml/kg) vs. a small (5 ml/kg) [V.sub.t]. We also applied small or large [V.sub.t] to lungs instilled with 50 [micro]g/kg of LPS. The alveolar macrophages collected after large V, ventilation revealed a 20-fold increase in LPS-induced TNF-[alpha] release compared with those collected after small [V.sub.t] ventilation, whereas TNF-[alpha] was undetectable without LPS stimulation. In animals ventilated with a large [V.sub.t], the expression of CD14 mRNA in whole lung homogenates and the expression of CD14 protein on alveolar macrophages, assessed by immunohistochemistry, were both significantly increased in the absence of LPS stimulation. A large [V.sub.t] applied to LPS-instilled lungs increased the pulmonary albumin permeability and TNF-[alpha] release into the plasma. These results suggest that mechanical stress caused by a large [V.sub.t] sensitizes the lungs to endotoxin, a phenomenon that may occur partially via the upregulation of CD14. acute lung injury; ventilator-induced lung injury

Elevation of KL-6, a lung epithelial'cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 286:L1088-L1094, 2004. First published September 5, 2003; 10.1152/ajplung.00420.2002.--KL-6 is a pulmonary epithelial mucin more prominently expressed on the surface membrane of alveolar type II cells when these cells are proliferating, stimulated, and/or injured. We hypothesized that high levels of KL-6 in epithelial lining fluid and plasma would reflect the severity of lung injury in patients with acute lung injury (ALI). Epithelial lining fluid was obtained at onset (day' 0) and day 1 of acute respiratory distress syndrome (ARDS)/ALI by bronchoscopic microsampling procedure in 35 patients. On day 0, KL-6 and albumin concentrations in epithelial lining fluid were significantly higher than in normal controls (P < 0.001), and the concentrations of KL-6 in epithelial lining fluid (P < 0.002) and in plasma (P < 0.0001) were higher in nonsurvivors than in survivors of ALI/ARDS. These observations were corroborated by the immunohistochemical localization of KL-6 protein expression in the lungs of nonsurvivors with ALI and KL-6 secretion from cultured human alveolar type II cells stimulated by proinflammatory cytokines. Because injury to distal lung epithelial ceils, including alveolar type II cells, is important in the pathogenesis of ALI, the elevation of KL-6 concentrations in plasma and epithelial lining fluid could be valuable indicators for poor prognosis in clinical ALL alveolar type II cell; pulmonary edema; microsampling