Long-term delayed emergence after remimazolam-based general anesthesia: a case report.

BACKGROUND: Remimazolam is an ultra-short-acting benzodiazepine anesthetic that is antagonized by flumazenil, and it is typically expected to be applied in anesthesia with the purpose of ensuring early postoperative recovery. We report a case of long-term delayed emergence with re-sedation even after three times of flumazenil administration. CASE PRESENTATION: A 71-year-old man was scheduled for a robotic-assisted laparoscopic radical prostatectomy for prostate cancer. We used remimazolam for anesthetic induction and maintenance. The intraoperative bispectral index (BIS) was 30-50. Flumazenil was administered as patient emergence was delayed after surgery; however, re-sedation was observed. This finding persisted till 12 h after surgery, and the patient awakened on postoperative day 2. CONCLUSIONS: Remimazolam is a short-acting anesthetic, but long-term delayed emergence with re-sedation may occur even after flumazenil administration. Anesthesia using remimazolam requires anesthesia management that takes into account the individual differences in sensitivity and metabolism, with BIS as the indicator.

Vitamin E-Coated Polysulfone Membrane-Based Hemodiafiltration Attenuates Inflammation in a Rat Model of Lipopolysaccharide-Induced Systemic Inflammation.

BACKGROUND: Acute blood purification (ABP) therapy is used regularly in the clinical setting and reportedly alleviates organ failure associated with severe systemic inflammatory responses, leading to reduced mortality. The present study aimed to determine whether there is a difference in efficacy between polysulfone (PS) membranes, which are currently used regularly in the clinical setting, and vitamin E-coated polysulfone (VEPS) membranes, which are anticipated to exhibit the antioxidant and anti-inflammatory properties of vitamin E. METHODS: Male Wistar rats (n=15/group) were intravenously administered 10 mg/kg of lipopolysaccharide (LPS) to establish a systemic inflammatory response model. Six hours after LPS administration, hemodiafiltration (HDF) was performed for 30 minutes using a PS or VEPS membrane under general anesthesia. Blood was collected at various time points, lung tissue was evaluated histologically, and 24-hour survival was assessed. RESULTS: The rats in the VEPS group tended to have a higher survival rate than those in the PS group when undergoing HDF, although the difference was not significant. With respect to lung tissue, the inflammatory response was suppressed to a greater extent in the VEPS group than the PS group. Serum interleukin (IL)-6 levels were reduced at an early stage, plasma antioxidant activity was increased, and oxidative stress was reduced in the VEPS group compared to the PS group. CONCLUSION: Relative to PS membrane-based HDF, the survival rate tended to improve and inflammation was subdued earlier due to the antioxidant activity and early attenuation of inflammation associated with VEPS membrane-based HDF.

Pharmacokinetics of ceftriaxone in patients undergoing continuous renal replacement therapy.

BACKGROUND: The duration of time for which the serum levels exceed the minimum inhibitory concentration (MIC) is an important pharmacokinetics (PK)/pharmacodynamics (PD) parameter correlating with efficacy for the antibiotic, ceftriaxone (CTRX). However, no reports exist regarding the PK or PD in patients undergoing continuous renal replacement therapy (CRRT). The purpose of this study was to examine the PK and safety of CTRX in patients undergoing CRRT in order to establish safer and more effective regimens. METHODS: CTRX (1 g once a day) was intravenously administered four or more times to nine patients undergoing CRRT. Blood was collected after administration to measure CTRX concentrations in serum and the filtration fraction of CRRT by high-performance liquid chromatography. In addition to calculating PK parameters from serum CTRX, we (a) estimated by simulation CTRX concentrations when the dose interval was extended to once every 2 or 3 days, (b) calculated CTRX clearance via CRRT from CTRX concentrations in the filtration fraction, and (c) assessed the safety of CTRX use. RESULTS: Total body clearance and the half-life of CTRX were 7.46 mL/min (mean) and 26.5 h, respectively, in patients undergoing CRRT. CTRX was found in the filtration fraction, and the estimated clearance by CRRT was about 70% of total body clearance. Simulations revealed that even when the dose interval is increased to 2 or 3 days, CTRX would retain its efficacy. CONCLUSIONS: Our findings suggest that, depending on the condition of patients undergoing CRRT, CTRX could be used safely against pathogens with a CTRX MIC ≤2 µg/mL, even when extending the dose interval.

Should nicorandil infusion be adapted in dialysis-dependent patients undergoing continuous renal replacement therapy after cardiac surgery?

In this report, we studied whether plasma concentration of nicorandil is maintained effectively and safely in dialysis-dependent patients with stage 5 chronic kidney disease (CKD5D) undergoing continuous renal replacement therapy (CRRT). Participants consisted of 10 patients undergoing CRRT after cardiac surgery. CRRT was performed with an effluent flow rate of either 600 mL/h (low-flow group; n = 5) or 1800 mL/h (high-flow group; n = 5). Nicorandil was infused intravenously at 0.1 mg/kg/h for more than 15 h starting 8 h before and 7 h after the start of CRRT. Plasma nicorandil concentrations were measured from arterial blood lines 1 h before and 7 h after CRRT initiation. Nicorandil clearance by CRRT was also calculated 1 h after CRRT initiation. Nicorandil plasma concentrations before and 7 h after CRRT initiation were 68.0 ng/mL and 74.6 ng/mL, respectively. Nicorandil clearance 1 h after CRRT initiation was 20.2 mL/min. Increasing the effluent flow rate from 600 mL/h to 1800 mL/h tended to increase nicorandil clearance. When nicorandil was infused intravenously during CRRT at 0.1 mg/kg/h in patients with CKD5D, plasma nicorandil concentrations were maintained within an effective concentration range.

Removal of 17 cytokines, HMGB1, and albumin by continuous hemofiltration using a cellulose triacetate membrane: an ex vivo study.

BACKGROUND: Hemofiltration is often used to treat critically ill patients with renal failure and septic shock. Although hemofiltration has been reported to remove humoral mediators such as cytokines, most studies have investigated the removal of only limited kinds of cytokines. Here, we assessed the removal of 17 cytokines, HMGB1, and albumin by continuous hemofiltration (CHF) with a cellulose triacetate membrane (2.1 m(2) or 1.1 m(2)). METHODS: The subjects were six healthy volunteers. We collected 400 mL blood into containers with heparin. After adding 1 mg/mL lipopolysaccharide, the blood was incubated at 39°C for 12 h and then filtered through a closed hemofiltration circuit (1 or 2 L/h). Sixty and 240 min after beginning hemofiltration, samples were collected from the outlet (arterial) side, inlet (venous) side, and filtrate port. Blood levels of cytokines, HMGB1, and albumin were determined at each time point. RESULTS: Increasing the flow rate significantly increased cytokine clearance. Increasing the membrane area of the hemofilter significantly changed the sieving coefficient of only five cytokines (IL-1ß, IL-6, MCP-1, MIP-1ß, HMGB1). For many cytokines, the sieving coefficient did not decline during the 240-min CHF procedure. CONCLUSION: Although all 17 cytokines, HMGB1, and albumin were detected in the filtrate, the SC and clearance varied widely. For numerous cytokines, clearance increased with the higher filtration flow rate. We demonstrated that CHF removed many cytokines and HMGB1, but was inefficient at removing albumin.

Effect of hemopurification rate on doripenem pharmacokinetics in critically ill patients receiving high-flow continuous hemodiafiltration.

  Hemopurification is an effective therapy for acute kidney injury, defined as creatinine clearance less than 30 ml/min, which occurs frequently in the intensive care unit. These critically ill patients often have severe infectious complications and are thus often treated with antibiotics. However, the effect of hemopurification on the pharmacokinetics of antibiotics is not well understood. In this study, we investigated the pharmacokinetics of doripenem (DRPM) in critically ill patients with accompanying renal dysfunction undergoing continuous hemodiafiltration by high-volume filtration/high-flow dialysis (high-flow CHDF) and compared it to the pharmacokinetics of DRPM during conventional CHDF. We studied 8 patients (2 in the high-flow group and 6 in the conventional group) in whom DRPM was administered while performing CHDF for acute kidney injury. DRPM (250 mg) was intravenously infused over 1 h. For the conventional group, CHDF was performed at a blood flow rate (Q(B)) of 100 ml/min, dialysate flow rate (Q(D)) of 500 ml/h, and filtration flow rate (Q(F)) of 300 ml/h. For the high-flow group, CHDF was performed at a blood flow rate (Q(B)) of 100 ml/min, dialysate flow rate (Q(D)) of 1500 ml/h, and filtration flow rate (Q(F)) of 900 ml/h. For both groups, a polysulfonehemofilter with a membrane area of 1.0 m(2) was used. Mean half-life, total body clearance, and clearance via hemodiafiltration of DRPM were 2.9 h, 118 ml/min, and 41.9 ml/min, respectively, in the high-flow group, and 7.9 h, 58 ml/min, and 13.5 ml/min in the conventional group. Clearance via hemodiafiltration increased approximately 3-fold by tripling the hemopurification rate. Therefore, CHDF parameters greatly affected DRPM pharmacokinetics in patients receiving CHDF. These results suggest that clearance via hemodiafiltration increases proportionally to the hemopurification rate. Thus, it is reasonable to conclude that DRPM dose must be increased to 1.0-1.5 g/day when performing high-flow CHDF.

The antioxidant EPC-K1 attenuates renal ischemia-reperfusion injury in a rat model.

BACKGROUND: Acute kidney injury (AKI) occurs frequently in the intensive care unit. A primary cause is renal ischemia/reperfusion (I/R) injury, during which excess reactive oxygen species (ROS) are produced. ROS subsequently damage renal cells, leading to the development of AKI. Here, we investigated whether renal I/R injury could be attenuated by the antioxidant EPC-K1. METHODS: We divided male Wistar rats into the following three groups: (1) a renal I/R group, (2) an EPC-K1 + renal I/R group and (3) a control group. Rats were sacrificed 24 h after treatment (I/R or sham). To measure oxidative stress in renal tissue, histological examinations were performed and serum levels of blood urea nitrogen (BUN) and creatinine were measured. The antioxidant action of EPC-K1 was also evaluated in RAW264.7 cells stimulated with antimycin A. RESULTS: Serum BUN and creatinine levels were elevated in the I/R group; however, this increase was significantly attenuated by EPC-K1 in the EPC-K1 + I/R group. Renal tissue injury was also significantly lower in the EPC-K1 + I/R group compared with the I/R group. In vitro experiments showed that EPC-K1 significantly attenuated the generation of ROS induced by antimycin A. CONCLUSION: In our study, EPC-K1 was able to attenuate AKI due to renal I/R by reducing oxidative stress. These results suggest that EPC-K1 may be effective against various types of I/R injury.

Continuous hemodiafiltration therapy ameliorates LPS-induced systemic inflammation in a rat model.

BACKGROUND: Systemic inflammation can result in multiple organ dysfunction syndrome, a potentially life-threatening condition. Some reports suggest that continuous hemodiafiltration can effectively remove proinflammatory cytokines from circulation during systemic inflammation. In the present study, we investigated whether continuous hemodiafiltration therapy could prevent LPS-induced systemic inflammation and improve survival in a rat model. MATERIALS AND METHODS: Male Wistar rats were injected with lipopolysaccharide (LPS; 7.5 mg/kg body weight), and 6 h later were treated with either single-pass hemofiltration (C group), continuous hemofiltration (CHF group), continuous hemodiafiltration (CHDF group), or mock filtration (Control group). We performed histologic examinations of lung and liver tissues, determined serum cytokine levels, and survival rates for each treatment group, and compared cytokine removal between CHF and CHDF therapies. RESULTS: Histologic examination revealed significant reduction in inflammation in lung and liver tissues harvested 24 h after CHDF compared with the Control group. Likewise, LPS-induced serum TNF-α and IL-6 levels decreased with continuous hemodiafiltration along with a significant improvement in survival. After 30 min of treatment, both CHF and CHDF removed significant amounts of TNF-α and IL-6 from the blood. However, serum cytokine levels measured before and after filtration were not significantly different. CONCLUSIONS: Continuous hemodiafiltration therapy lowered inflammatory cytokines and increased survival rates in a rat model of systemic inflammation. Therefore, continuous hemodiafiltration may be a potential therapy for use against various systemic inflammatory diseases.

Filtration leukocytapheresis therapy ameliorates lipopolysaccharide-induced systemic inflammation in a rat model.

BACKGROUND: Systemic inflammation, which is associated with various conditions such as sepsis, pneumonia, and trauma, can lead to multiple organ dysfunction syndrome. Systemic inflammation can be life-threatening and is often associated with conditions seen in the intensive care unit. Leukocytes exert a proinflammatory effect and damage various tissues during systemic inflammation. The purpose of this study was to determine whether leukocytapheresis therapy can prevent lipopolysaccharide (LPS)-induced systemic inflammation in a rat model. MATERIALS AND METHODS: Male Wistar rats weighing 250 to 300 g were used for all experiments. Rats received an LPS injection, followed 6 h later by filtration leukocytapheresis or mock treatment for 30 min under sevoflurane anesthesia. Systemic inflammation was induced in rats by intravenous LPS injection (7.5 mg/kg) followed by filtration leukocytapheresis. Following blood filtration, we evaluated lung and liver histology, serum cytokine levels, and survival rate of rats for each treatment group. RESULTS: Histologic examination revealed markedly reduced inflammatory injury in lung and liver tissue harvested from rats 24 h after leukocytapheresis therapy compared with mock treatment. LPS-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 secretion was also inhibited by leukocytapheresis therapy. Moreover, survival was significantly increased in rats treated with high-efficiency leukocytapheresis compared to mock-treated rats (P<0.05). CONCLUSIONS: Taken as a whole, our findings indicate that filtration leukocytapheresis therapy protects against LPS-induced systemic inflammation. Therefore, leukocytapheresis shows potential as a new therapy for various systemic inflammatory diseases.

Gabexate mesilate inhibits the expression of HMGB1 in lipopolysaccharide-induced acute lung injury.

High mobility group box 1 (HMGB1) is an important late mediator of acute lung injury. Gabexate mesilate (GM) is a synthetic protease inhibitor with some anti-inflammatory action. We aimed to evaluate the effect of GM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats. Prior to the injection of LPS to induce lung injury, rats were administered saline or GM. Injury to the lung and expression of HMGB1, plasminogen activator inhibitor-1 (PAI-1), and protease-activated receptor-2 (PAR-2) were examined. In an accompanying in vitro study, we performed LPS stimulation under GM administration in a mouse macrophage cell line and measured the quantity of HMGB1 and cytokines in the supernatant, and cell signal in the cells. Histologic examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the GM+LPS group compared wih the LPS group. Furthermore, LPS-induced increases in PAI-1 and PAR-2 activity and in plasma HMGB1 concentrations were lower in the rats given both GM and LPS than in the rats given LPS alone. Release of HMGB1 and cytokines from the cell after the administration of LPS were decreased by GM. Phosphorylation of IκB was inhibited by GM. GM may have inhibited PAI-1 and PAR-2, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. This indicates that GM can inhibit lung injury induced by LPS in rats. GM is a candidate for use in novel strategies to prevent or minimize lung injury in sepsis.

Effective control of paroxysmal tachycardia with landiolol hydrochloride during cesarean section in a patient with hypertrophic obstructive cardiomyopathy.

Hypertrophic obstructive cardiomyopathy (HOCM) involves marked hypertrophy of cardiac muscle, resulting in myocardial ischemia and arrhythmia because of left ventricular diastolic dysfunction. In perioperative management of HOCM, hemodynamic stabilization is required, by prevention of arrhythmia and tachycardia and maintenance of preload and afterload. Here, we describe anesthesia management during cesarean section in a patient complicated by HOCM. The patient was a 27-year-old woman who underwent elective cesarean section scheduled at 36 weeks of pregnancy given her history of HOCM. She was managed with spinal anesthesia with monitoring of invasive blood pressure and arterial pressure cardiac output. Administration of landiolol hydrochloride was initiated, because of paroxysmal tachycardia after delivery. Approximately 5 min after initiation of administration, her heart rate decreased gradually and blood pressure rose. Circulatory dynamics stabilized and landiolol was discontinued 3 h after she was admitted to the intensive care unit. Her circulatory dynamics remained stable after discontinuation of landiolol, and she was moved to a general ward on the following day. She was discharged on postoperative day 14, with her child.

The effect of landiolol on cerebral blood flow in patients undergoing off-pump coronary artery bypass surgery.

PURPOSE: To examine the effect of landiolol on cerebral blood flow in patients with normal or deteriorated cardiac function. METHODS: Thirty adult patients who were diagnosed with angina pectoris and who underwent elective off-pump coronary artery bypass surgery were studied. Patients were divided into two groups, one with a preoperative left ventricular ejection fraction (EF) of 50% or higher (normal EF group; n = 15) and the other with an EF of less than 50% (low EF group; n = 15). The mean cerebral blood flow velocity (Vmca) and pulsatility index (PI) in the middle cerebral artery were recorded using transcranial Doppler ultrasonography (TCD). Individual hemodynamic data were obtained using a pulmonary arterial catheter. RESULTS: In both groups, landiolol produced a significant decrease in heart rate (HR), which then returned to baseline 15 min after administration was completed. A significant decrease in mean arterial pressure occurred in the low EF group, but the decrease was within 30% of the baseline. In the normal EF group, there was no decrease in cardiac index (CI), whereas in the low EF group, CI significantly decreased along with the decrease in HR. There were no significant differences in Vmca and PI between the two groups. CONCLUSION: Continuous administration of landiolol at a dose of 0.04 mg/kg/min after 1 min rapid i.v. administration at a dose of 0.125 mg/kg/min decreases HR without causing aggravation of CBF during treatment of intraoperative tachycardia in patients with normal and deteriorated cardiac function.

Doripenem pharmacokinetics in critically ill patients receiving continuous hemodiafiltration (CHDF).

Objectives of the prospective, open-label study were to investigate pharmacokinetics of doripenem and determine appropriate doripenem regimens during continuous hemodiafiltration (CHDF) in critically ill patients with renal failure (creatinine clearance <30 ml/min) in the intensive care unit at a university hospital in Japan. Six patients received intravenous (IV) administration of 250 mg of doripenem every 12 or 24 hours during CHDF (dialysis rate, 500 ml/h; hemofiltration rate, 300 ml/h) via a polysulfone hemofilter. Doripenem concentrations in pre- and post-membrane blood (plasma) samples collected at specified times during one dosing interval were measured in order to calculate pharmacokinetic parameters and clearance via hemodiafiltration. Mean half-life (+/-standard deviation) of doripenem was 7.9+/-3.7 hours. Total body clearance of doripenem was 58.0+/-12.7 ml/min, including clearance of 13.5+/-1.6 ml/min via CHDF. An IV dose of 250 mg of doripenem every 12 hours during CHDF provided adequate plasma concentrations for critically ill patients with renal failure, without resulting in accumulation upon steady-state. Thus, under the conditions tested, CHDF appeared to have little effect on doripenem clearance. Therefore, the blood level of doripenem can be satisfactorily controlled by adjustment of doripenem dose and dosing interval, in accordance with residual renal function in patients receiving CHDF.

The impact of oxidative stress levels on the clinical effectiveness of sivelestat in treating acute lung injury: an electron spin resonance study.

BACKGROUND: Sivelestat, a neutrophil elastase inhibitor, has been used to treat acute lung injury (ALI) with varying levels of clinical success. Variable baseline levels of oxidative stress in patients with ALI have been proposed as one explanation for inconsistent results. METHODS: Using a bedside electron spin resonance spectrometer, we evaluated electron spin resonance signal intensities of serum ascorbyl free radicals supplemented with dimethyl sulfoxide (AFR/DMSO) in patients with ALI. RESULTS: We found a positive correlation between AFR/DMSO and ascorbate levels, suggesting that serum AFR/DMSO measurements may serve as a surrogate for real-time assessments of oxidative stress. Levels of AFR/DMSO in patients with ALI were significantly lower than those found in healthy controls. Stratified analyses revealed that baseline AFR/DMSO levels were significantly lower in patients with ALI who failed to respond to sivelestat compared with those who did respond. CONCLUSIONS: Our results suggest that the clinical efficacy of sivelestat is dependent on baseline oxidative stress levels.

Anesthetic management of a patient with hyperthyroidism due to hydatidiform mole.

Secondary hyperthyroidism can often complicate gestational trophoblastic disease, a malignant uterine cancer. We report here the perioperative management of hyperthyroidism due to hydatidiform mole. A 53-year-old woman underwent emergency surgery due to suspicion of hydatidiform mole. Tachycardiac atrial fibrillation was detected by electrocardiography at the preoperative examination. No abnormalities were found in blood count, coagulation, biochemical tests, chest radiographs, or respiratory function. General anesthesia with nitrous oxide, oxygen, and sevoflurane, combined with fentanyl and 1% mepivacaine, was administered intermittently from an epidural catheter. Intraoperative events included hypotension and tachycardia, although in general, tachycardia was prevented with antiarrhythmic agents and transfusion with a plasma expander and crystalloid fluid. Hyperthyroidism was highly suspected from the patient's clinical course and was confirmed by high levels of preoperative serum free triiodothyronine (T3) and thyroxine (T4). The patient became euthyroid within a few days after mole evacuation and did not require an antiarrhythmic agent after her return to the inpatient ward.

[Anesthesia management of geriatric patients with arterial pressure-based cardiac output monitoring FloTrac sensor for emergency surgery].

In cases of emergency surgery for geriatric patients, immediate anesthesia induction and careful intraoperative management is necessary without sufficient preoperative information. We report anesthesia management of a 96-year and a 90-year old patients with FloTrac sensor which is an arterial pressure-based cardiac output monitoring device and is able to manage critical patients effectively and safely during anesthesia.

Antagonist of the type-1 ANG II receptor prevents against LPS-induced septic shock in rats.

PURPOSE: Type 1 angiotensin II (AT1) receptor antagonists have anti-inflammatory effects in vitro and in patients. The purpose of this study was to investigate whether losartan (LOS), an AT1 receptor antagonist, reduces lung damage by inhibiting the induction of high mobility group box 1 (HMGB1) protein and cytokines by lipopolysaccharide (LPS; serotype: O127:B8) in a rat model. METHODS: We used male Wistar rats. Control group rats received a 0.9% NaCl solution. The LOS + LPS group rats received LOS (50 mg kg(-1)) before LPS (7.5 mg kg(-1)) administration. LPS group rats received injection of LPS (7.5 mg kg(-1)). MEASUREMENTS AND RESULTS: We performed immunohistochemistry, ELISA, and western blot analysis to examine the suppressive effects of LOS on LPS-induced cytokine induction. Plasma concentrations of cytokines (IL-6 and TNF-alpha) and HMGB1 (p < 0.05) were markedly reduced in the LOS + LPS group compared to the LPS group. LOS also inhibited the LPS-mediated decrease in angiotensin-converting enzyme 2 (ACE2) activity (p < 0.05). Immunohistochemical analysis revealed positive staining for ACE2 in lungs from both control and LOS + LPS groups. The intensity and degree of ACE2 labeling in lung tissue sections from the LPS group were markedly reduced compared to the control and LOS + LPS groups (p < 0.05). Additionally, RAW264.7 murine macrophages were stimulated with LPS, with or without simultaneous LOS treatment, resulting in inhibition of IkappaB phosphorylation. CONCLUSIONS: Treatment with LOS improved lung injury in an endotoxin shock model system by an anti-inflammatory action that inhibits reduction of ACE2.

Effects of an angiotensin-converting enzyme inhibitor on the inflammatory response in in vivo and in vitro models.

OBJECTIVE: Sepsis remains a major health threat in intensive care medicine. The renin-angiotensin system (ACE) affects inflammatory responses. In addition, angiotensin-converting enzyme inhibitors act to ameliorate lung injury. To investigate whether the widely used ACE inhibitor enalapril, used to treat hypertension, could inhibit secretion of cytokines and high-mobility group box 1 (HMGB1) protein, thus reducing lung damage in a rat model of lipopolysaccharide (LPS)-induced sepsis. DESIGN: Randomized, prospective animal study. SETTING: University medical center research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: LPS was administered intravenously to rats, with or without intraperitoneal pretreatment with enalapril. In addition, mouse macrophage RAW264.7 cells were stimulated with LPS, with and without simultaneous enalapril treatment. MEASUREMENTS AND MAIN RESULTS: Histologic examination showed marked reduction of interstitial congestion, edema, inflammation, and hemorrhage in lung tissue harvested 12 hours after treatment with both agents compared with LPS administration alone. Plasma concentration of angiotensin II was strongly induced by LPS; this induction was inhibited by the enalapril pretreatment. Likewise, LPS-induced secretion of proinflammatory cytokines and HMGB1 protein was inhibited by enalapril. The presence of HMGB1 protein in the lung was examined directly by immunohistochemistry; the number of stained cells was significantly lower in LPS-treated animals that also received enalapril. In the in vitro studies, enalapril administration inhibited the phosphorylation of IkappaB. CONCLUSIONS: The ACE inhibitor enalapril blocked the LPS-induced inflammatory response and protected against the acute lung injury normally associated with endotoxemia in this rat sepsis model. Given these results, enalapril is a strong candidate as a therapeutic agent for sepsis.

[Cardiac anesthesia induction by low target plasma concentration setting of propofol using target-controlled infusion].

BACKGROUND: Propofol-anesthesia administerd using target-controlled infusion (TCI) has been proposed for cardiac surgery. But, moderate target concentration of propofol during induction using TCI has not been studied in detail. METHODS: Thirty patients scheduled for cardiac surgery under cardiopulmonary bypass (CPB) and TCI propofol anesthesia were randomly divided into two groups to receive a computer-controlled infusion of propofol with target concentrations of 1.5 or 2.0 micro/g x ml(-1) [1.5 microg x ml(-1) group (n=15) and 2.0 microg x ml(-1) group (n=15)]. Mean arterial pressure (MAP), heart rate (HR) and bispectral index scale (BIS) values were recorded at 5 time points during induction of anesthesia. RESULTS: MAP was significantly lower in 2.0 microg x ml(-1) group compared with 1.5 microg x ml(-1) group. In both groups, a rise of BIS value did not occur during tracheal intubation. CONCLUSIONS: We have demonstrated that propofol TCI at a target concentration of 1.5 microg x ml(-1) is effective for hemodynamic stability during induction of anesthesia in patients for cardiac surgery under CPB.

Danaparoid sodium inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats.

INTRODUCTION: Systemic inflammatory mediators, including high mobility group box 1 (HMGB1), play an important role in the development of sepsis. Anticoagulants, such as danaparoid sodium (DA), may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesised that DA would act as an inhibitor of systemic inflammation and prevent endotoxin-induced acute lung injury in a rat model. METHODS: We used male Wistar rats. Animals in the intervention arm received a bolus of 50 U/kg of DA or saline injected into the tail vein after lipopolysaccharide (LPS) administration. We measured cytokine (tumour necrosis factor (TNF)alpha, interleukin (IL)-6 and IL-10) and HMGB1 levels in serum and lung tissue at regular intervals for 12 h following LPS injection. The mouse macrophage cell line RAW 264.7 was assessed following stimulation with LPS alone or concurrently with DA with identification of HMGB1 and other cytokines in the supernatant. RESULTS: Survival was significantly higher and lung histopathology significantly improved among the DA (50 U/kg) animals compared to the control rats. The serum and lung HMGB1 levels were lower over time among DA-treated animals. In the in vitro study, administration of DA was associated with decreased production of HMGB1. In the cell signalling studies, DA administration inhibited the phosphorylation of IkappaB. CONCLUSION: DA decreases cytokine and HMGB1 levels during LPS-induced inflammation. As a result, DA ameliorated lung pathology and reduces mortality in endotoxin-induced systemic inflammation in a rat model. This effect may be mediated through the inhibition of cytokines and HMGB1.