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Background: A rapid 30-minute assay of circulating smooth-muscle myosin heavy-chain protein has been developed as a biochemical diagnostic tool for aortic dissection. Objective: To determine the sensitivity and specificity of this assay. Design: Cross-sectional study. Setting: 8 major cardiovascular centers in Japan. Patients: 95 patients with acute aortic dissection, 48 patients with acute myocardial infarction, and 131 healthy volunteers. Measurements: Levels of circulating smooth-muscle myosin heavy-chain protein. Results: Patients with acute aortic dissection who presented within 3 hours after onset had elevated levels of circulating smooth-muscle myosin heavy-chain protein. In these patients, the assay had a sensitivity of 90.9%, a specificity of 98% compared with healthy volunteers, and a specificity of 83% compared with patients who had acute myocardial infarction; the clinical decision limit was 2.5 (mu)g/L. All patients with proximal lesions had elevated levels of smooth-muscle myosin heavy-chain protein, and only patients with distal lesions had decreased levels (

Eritoran, a synthetic analogue of lipid A, has been shown to bind to TLR4/MD-2 complex and thereby block the interaction of endotoxins with TLR4. We report here the results of a study conducted to assess the single-dose safety and tolerability, as well as the pharmacokinetics and pharmacodynamics, of eritoran infusion in Japanese and Caucasian healthy adult men. Sixty-four men (aged 20–45 years; body mass index 18–30 kg/m2) were randomized into four groups: 4-mg total dose (six Japanese and six Caucasian men); 12-mg total dose (12 Japanese and 12 Caucasian men); 28-mg total dose (six Japanese and six Caucasian men); and placebo (eight Japanese and eight Caucasian men). Eritoran in single doses up to 28 mg over 4 h was well tolerated, with no apparent ethnic differences noted. Plasma concentrations were slightly higher in Japanese versus Caucasian men; these differences were not significant after adjustment for differences in body mass (clearance: approximately 1.2 ml/h/kg; volume of distribution at steady state: approximately 0.07 l/kg). The ex vivo endotoxin inhibitory activity of eritoran was similar in Japanese and Caucasian men. The data do not indicate any need for clinical dose adjustment for possible ethnic-based differences in drug distribution or metabolism.

To investigate treatment effects of thrombomodulin alfa (TM-) in patients with disseminated intravascular coagulation (DIC) having infection as the underlying disease, retrospective subanalysis of a double-blind, randomized controlled phase 3 trial was conducted. In the phase 3 trial, 227 DIC patients (full-analysis set) having infection and/or hematologic malignancy as the underlying disease received either TM- (0.06 mg·kg−1for 30 min once daily) or heparin (8 U·kg−1·h−1for 24 h) for 6 days using the double-dummy method. Among these patients, 147 patients with noninfectious comorbidity leading to severe thrombocytopenia (e.g., hematologic malignancy, or aplastic anemia) were excluded from the present analysis, and 80 patients with infectious disease and DIC were extracted and subjected to the present retrospective subanalysis. Disseminated intravascular coagulation resolution rates were determined using the DIC diagnostic criteria for critically ill patients at 7 days, and mortality rates were evaluated at 28 days. In the TM- and heparin groups, DIC resolution rates were 67.5% (27/40) and 55.6% (20/36), and 28-day mortality rates were 21.4% (9/42) and 31.6% (12/38), respectively. Mortality rates of patients who recovered from DIC were 3.7% (1/27) in the TM- group and 15% (3/20) in the heparin group. These results suggest TM- may be valuable in the treatment of DIC associated with infection.

Previously, we have found that a prior burn insult induces lethal acute lung injury (ALI) and overproduction of proinflammatory cytokines after LPS challenge in mice. The current study was aimed to determine the role of IL-18 in burn-induced LPS hypersensitivity. Except sham group, mice were subjected to a 15% total body surface area full-thickness burn and either untreated or treated with IL-18 alone, IL-18 + anti-IL-10 antibody or IL-18 + isotype immunoglobulin G. LPS was intravenously administered to all mice on the 11th day, and the mice were killed at the indicated time point, or survival was examined. We additionally examined cytokine production by splenic cells in vitrofor the elucidation of immunologic mechanisms. Unexpectedly, the liver IL-18 decreased transiently after burn injury, and in vivoIL-18 supplementation improved survival and ameliorated ALI, as well as reducing the lung contents of all cytokines examined, except IL-10. Neutralization of IL-10 cancelled the protective effect of IL-18. In splenic macrophages obtained from burned mice, the production of macrophage inflammatory protein 2 (MIP-2), TNF-, and IL-10 was augmented, whereas in vivoIL-18 supplementation decreased MIP-2 production, but increased IL-10 production. Furthermore, a physiological concentration of IL-18 directly attenuated MIP-2 production by splenic cells in vitro. Burn injury induces LPS hypersensitivity through augmented production of proinflammatory cytokines by systemic macrophages. IL-18 supplementation is protective for LPS-induced lethal ALI through the direct anti-inflammatory effect on macrophages as well as by in vivoacceleration of IL-10 production, and could thus be an effective prophylactic strategy against septic complications in critically ill patients.

Cardiac dysfunction during hemorrhagic shock (HS) is associated with myocardial ischemia, during which adenosine triphosphate (ATP)-sensitive potassium (KATP) channels can be activated. We investigated the role of KATPchannels in HS-induced myocardial ischemia. Canine HS was induced using an aortic reservoir to maintain the aortic pressure at a constant 40 mmHg. To visualize the myocardial ischemia as a nicotinamide adenine dinucleotide (NADH) - fluorescent area, the beating hearts were rapidly cross-sectioned (120 ms) and freeze-clamped (−190°C) using a sampling device after 10 min of HS. The effect of a KATPchannel blocker, glibenclamide (1 mg/kg, i.v.), on myocardial ischemia was also quantified. Regional myocardial blood flow was measured using heavy element-loaded nonradioactive microspheres. Myocardial ischemia developed in the subendocardium in the HS alone group, whereas it extended through all the cardiac layers in the glibenclamide-treatment group. The coadministration of a KATPchannel opener, cromakalim (50 g/kg, i.v.), with glibenclamide prevented the extension of myocardial ischemia to the subepicardium. Glibenclamide decreased the myocardial ATP concentration selectively in the subepicardium during HS. The HS decreased myocardial blood flow transmurally, and following the administration of glibenclamide, further decreased the blood flow selectively in the subepicardium. These results suggest that KATPchannels are activated during HS, enabling selective subepicardial coronary dilatation and protecting the myocardium from the extension of myocardial ischemia to the subepicardium.

Prostaglandin E2(PGE2) is a potent lipid mediator in a diverse range of biological processes. This study examined the hypertrophic effect of PGE2in primary cultured rat neonatal cardiomyocytes. PGE2increased total protein synthesis in a dose-dependent manner, as measured by [3H]-phenylalanine uptake. PGE2increased the cell size and surface area and induced the reorganization of myofilaments. Phosphorylation of the p42/44 and p38 mitogen-activated protein kinases (MAPK) was also induced by PGE2, and U0126 [a mitogen-activated extracellular signal regulated kinase kinase (MEK) 1/2 inhibitor] significantly inhibited the PGE2-induced protein synthesis. Expression of the hypertrophic marker genes, atrial natriuretic peptide and brain natriuretic peptide, was increased by PGE2, but expression of the α-skeletal actin gene was significantly attenuated. Transcripts for all 4 PGE2receptor subtypes (EP1, EP2, EP3, and EP4) were detected in the cardiomyocytes. AE3-208 (an EP4-selective antagonist) significantly inhibited the α-skeletal actin gene suppression induced by PGE2, whereas SC51322 (an EP1-selective antagonist) did not. In conclusion, PGE2induced hypertrophic changes in cardiomyocytes and attenuated α-skeletal actin gene expression in part via EP4.

ABSTRACTArbekacin is widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus(MRSA). In this study, we have determined the optimal concentration targets of arbekacin for both efficacy and safety. A pharmacokinetic-pharmacodynamic analysis was performed to relate exposure to the drug and clinical cure/improvement or nephrotoxicity. Since we have reported the population pharmacokinetic parameters for arbekacin in the preceding paper (Y. Tanigawara, R. Sato, K. Morita, M. Kaku, N. Aikawa, and K. Shimizu, Antimicrob. Agents Chemother. 50:3754-3762, 2006), individual exposure parameters, such as area under the concentration-time curve (AUC), peak concentration (Cmax), AUC/MIC, Cmax/MIC, and trough concentration (Cmin) were estimated by the Bayesian method. Logistic regression was used to describe the relationship between exposure to the drug and the probability of clinical cure/improvement or nephrotoxicity. For the clinical efficacy analysis, 174 patients confirmed to have an MRSA infection were evaluated. The Cmax, Cmin, and AUC of arbekacin were associated with the probability of clinical cure/improvement during monotherapy. It was shown that the probability of cure/improvement rose when the Cmaxof arbekacin was increased, with an odds ratio of 6.7 for a change in Cmaxfrom 7.9 to 12.5 μg/ml (P= 0.037). For the nephrotoxic risk analysis, 333 patients were included, regardless of whether a pathogen was identified. Logistic regression analysis revealed Cminand AUC as risk factors of nephrotoxicity (P< 0.005). The estimated probabilities of arbekacin-induced nephrotoxicity were 2.5, 5.2, and 13.1% when the Cminvalues were 1, 2, and 5 μg/ml, respectively. The present findings are useful for optimizing the individual dose of arbekacin for the treatment of MRSA-infected patients.

ABSTRACTArbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus(MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CLCR), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CLCR+ (26.5/age) (CLCR< 80 ml/min) and CL (liter/h) = 0.0130 CLCR+ 0.0342WT + (26.5/age) (CLCR≥ 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.

The endothelin-1 (ET-1) is known to cause myocardial ischemia; however, whether this effect is entirely dependent on vasoconstriction is uncertain. The aim of this study was to characterize the myocardial ischemia after the intracoronary administration of endothelin-1, and compare it with that induced by coronary stenosis.

One year after the release of the Japanese “Guidelines for the Diagnosis and Treatment of Deep-Seated Mycosis” we conducted a survey of clinicians to determine the extent to which the new guidelines had penetrated clinical practice, and compared these results with those of a previous survey. The responses to the current survey regarding the diagnosis and treatment had changed from those of the previous survey to reflect the new recommendations, showing that the guidelines have had an effect on clinical practice. However, the current survey highlights a need to provide more practical information in the guidelines for use in the clinical settings. In particular, physicians expect the guidelines to proactively provide more information about the features of both current and new drugs. In addition, an effective drug against the genus Aspergillus is eagerly awaited. However, because it is difficult to differentiate among filamentous fungi, there is a need for a drug with broad-spectrum coverage against filamentous fungi. Investigation of combination therapy consequently becomes necessary. Definitive diagnoses of invasive fungal infection are too scarce at the national level. The cooperation of clinicians for organizing more definitive diagnoses would be appreciated when the guidelines are revised.

Abstract The clinical significance of serum procalcitonin (PCT) for discriminating between bacterial infectious disease and nonbacterial infectious disease (such as systemic inflammatory response syndrome (SIRS)), was compared with the significance of endotoxin, ß-D-glucan, interleukin (IL)-6, and C-reactive protein (CRP) in a multicenter prospective study. The concentrations of PCT in patients with systemic bacterial infection and those with localized bacterial infection were significantly higher than the concentrations in patients with nonbacterial infection or noninfectious diseases. In addition, PCT, endotoxin, IL-6, and CRP concentrations were significantly higher in patients with bacterial infectious disease than in those with nonbacterial infectious disease (P < 0.001, P < 0.005, P < 0.001, and P < 0.001, respectively). The cutoff value of PCT for the discrimination of bacterial and nonbacterial infectious diseases was determined to be 0.5?ng/ml, which was associated with a sensitivity of 64.4% and specificity of 86.0%. Areas under the receiver operating characteristic curves (POCs) were 0.84 for PCT, 0.60 for endotoxin, 0.77 for IL-6, and 0.78 for CRP in the combined group of patients with bacterial infectious disease and those with nonbacterial infectious disease, and the area under the ROC for PCT was significantly higher than that for endotoxin (P < 0.001). In patients diagnosed with bacteremia based on clinical findings, the positive rate of diagnosis with PCT was 70.2%, while that of blood culture was 42.6%. PCT is thus essential for discriminating bacterial infection from SIRS, and is superior in this respect to conventional serum markers and blood culture.

To elucidate the involvement of hepatocyte growth factor (HGF) in systemic inflammatory response syndrome (SIRS) and sepsis, we investigated the plasma levels of HGF, as well as those of various proinflammatory and anti-inflammatory cytokines, in 50 patients who visited our emergency department (ED). The patients were divided into four groups, depending on the existence of SIRS and infection: group 1 (G1), no infection and no SIRS; group 2 (G2), infection and no SIRS; group 3 (G3), no infection and SIRS; and group 4 (G4), infection and SIRS (e.g., sepsis). We found that plasma HGF levels in G4 were significantly higher than those in the groups without infection (G1 and G3). However, the correlations between HGF and other cytokines were comparatively low compared with those between any other pairs of cytokines, suggesting independent regulation of HGF production in vivo. High plasma HGF was significantly correlated with the presence of infection and with serum total bilirubin (TB) level on multivariate logistic regression analysis. Considering HGF’s known functions, we speculated that high plasma HGF levels may indicate the occurrence or necessity for tissue protection and regeneration after acute systemic insults in sepsis.

Disseminated candidiasis is difficult to diagnose and treat, and often becomes life-threatening in critically ill patients. However, guidelines or consensus views regarding the management of disseminated candidiasis do not exist in Japan. To develop feasible guidelines in Japan, we studied the current status of antifungal treatment in critically ill patients in Japan. From April 1999 to January 2000, critically ill patients from either surgical wards or critical care/intensive care units of 26 teaching hospitals were studied, using a prospective enrollment protocol. Patient enrollment criteria included persistent fever(≧38°C) for 3 days or more despite antibacterial agent administration. Data were entered at each institution and managed centrally using Clinware software. Of the 200 patients in the study, 68 (34%) received antifungal agents. Factors associated with antifungal treatment in the 68 patients included: central venous or pulmonary artery catheter, re-surgery, carbapenem or cephem administration, prolonged antibacterial agent administration, and high body temperature. Proven or probable disseminated candidiasis was presumed or diagnosed by culture in 34 patients, and by clinical signs and/or serological tests in 34 patients. Fungi isolated from blood included Candida albicans(57%), C. tropicalis(14%), C. parapsilosis(7%), C. glabrata(7%), and others (14%). Treatment patterns were as follows: 65 patients (96%) were treated with fluconazole (60 as monotherapy and 5 with amphotericin B); 2 patients, with miconazole; and 1 patient, with amphotericin B. Excluding 6 unevaluable cases, antifungal treatment was efficacious in 75% (21/28) of the patients with positive fungal culture and in 68% (23/34) of patients diagnosed by other means.

Objectives:To study the proportion and characteristics of potential candidates for the intravenous administration of tissue plasminogen activator (IV‐tPA) among patients with cerebral infarction in a Japanese emergency department (ED). Methods:A retrospective observational study was performed using patients who had been transported by ambulance between August 1988 and April 2000 to an urban ED of a university hospital located in the Tokyo metropolitan area. Potential candidates for IV‐tPA were identified using the criteria of the National Institute of Neurological Disorders and Stroke (NINDS) study. Results:Of all 30,064 patients transported by ambulance, 526 were diagnosed as having cerebral infarction. Among them, 190 patients arrived at the ED within two hours of symptom onset (early ED arrivers). In comparison of their demographics with late ED arrivers (n = 319), atrial fibrillation, male gender, and consciousness disturbance were related with early ED arrivers, while aging and diabetes were related with late ED arrivers. As to the stroke subtype, patients with an embolic infarction accounted for 76.8% among early ED arrivers. Application of exclusion criteria identified 114 patients, who were suitable for the thrombolysis treatment, indicating that the proportion of potential IV‐tPA candidates was 21.7% among all cerebral infarction patients and 0.38% among all ED patients. Conclusions:The number of potential IV‐tPA candidates among patients transported to the ED by ambulance in Japan was substantial, where the proportion of embolic infarction cases was extremely high.

Abstract: When a large volume of coagulum remains in the body cavity after trauma or surgery, secondary fibrinolysis occurs, which disturbs the hemostatic balance and results in rebleeding. To better understand this condition, we conducted a clinical study on patients with and without coagula and an experimental study on fibrinolytic activity in a rat model. The results of the clinical study showed that when coagula existed in the body cavity, the blood levels of the fibrin degradation products D-dimer and fibrinopeptide Bβ15–42 remained high compared with when subjects were under similar stress but without the presence of coagula. In the experimental studies, fibrinolytic activity of the omentum, measured by the fibrin plate method, was higher in rats with hemoperitoneum. This suggests that increased fibrinolytic activity may lead to rebleeding from the area of transient hemostasis when coagulum is present in the body cavity.

Although dopamine is one of the most widely used vasoactive agents, its postoperative thermogenic and metabolic effects have not been studied. In this study, the effects of low-dose dopamine, given at 5 µ/kg/min, on resting energy expenditure (REE), metabolism, and plasma catecholamine levels were examined in eight postsurgical patients. Dopamine infusion increased REE from 1,839 ± 171 kcal/day to 2,071 ±170 kcal/day, and it decreased to 1,867 ± 141 kcal/day after cessation of the infusion. Dopamine also increased the plasma levels of glucagon from 109.4 ± 8.7 pg/ml to 132.5 ±8.0 pg/ml, and it decreased to 102.9 ± 11.1 pg/ml after cessation of the infusion. The plasma levels of dopamine before, during, and after the infusion were 116.1 ± 18.3, 161.1 ±25.6, and 121.4 ± 17.2 ng/ml, respectively. Insulin and glucose were affected by dopamine, but changes in their plasma levels did not parallel the dopamine levels. Epinephrine and norepinephrine were increased by the infusion of dopamine and continued to increase even after its cessation. The results of this study revealed that low-dose dopamine increased REE in postsurgical patients and that this might be associated with the concomitant increase in plasma glucagon.

Hypovolemia, low cardiac output, and systemic vasoconstriction are major etiologic factors in acute renal failure occurring in the early postburn period, and elevated levels of stress-related hormones (catecholamines, angiotensin, aldosterone, and vasopressin) are implicated in the mechanism. By counteracting the effects of the hormones, atrial natriuretic polypeptide (ANP) regulates the renal response to burns. ANP was elevated after burns, protecting the kidneys by increasing renal blood flow and urine output. In pulmonary acid injury, increased ANP levels were associated with natriuresis which was reduced by administration of anti-ANP serum. Exogenous ANP given to dogs under constant norepinephrine infusion resulted in improvement of hemodynamic and renal parameters. To prevent tubular damage due to hemoglobinuria, a haptoglobin preparation is administered to patients with extensive third-degree burns. With sufficient fluid replacement, these new treatments will reduce the incidence of acute renal failure in the early postburn period.

In hemorrhagic shock (HS), nitric oxide synthase (NOS) inhibitor is known to increase blood pressure and prolong survival time. On the other hand, NOS inhibitor decreases coronary flow and worsens myocardial ischemia. Therefore, we hypothesized that the beneficial effect of NOS inhibitor is attributable to the increased coronary perfusion pressure and that it outcompetes the coronary vasodilating effects of nitric oxide. To investigate the direct effect of NOS inhibitor on the regulation of coronary circulation and the induction of myocardial ischemia in HS, we used a canine model at a constant aortic pressure of 40 mmHg with an aortic reservoir. In seven dogs, intravenous administration of Nω-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg) at 10 min after induction of HS increased both systemic and coronary vascular resistances and further increased the serum catecholamine concentration at 10 min after L-NAME. In another 14 dogs, the beating hearts were rapidly cross-sectioned (120 ms) and freeze clamped (-190°C) by a specially developed sampling device after 10 min of HS. Transmurally distributed myocardial ischemia was visualized by the enhanced reduced nicotinamide adenine dinucleotide fluorescence, which was significantly increased with L-NAME (n = 7). Chemical analysis revealed a decrease in the myocardial ATP concentration with L-NAME in the subendocardial ischemic region in HS. In conclusion, with the use of an aortic reservoir to keep the aortic pressure constant in HS, NOS blockade significantly worsened myocardial ischemia by decreasing coronary flow and augmenting the serum catecholamine concentration.

Abstract: A prospective clinical study was performed on 293 patients, in order to elucidate the abnormalities in acid-base balance following general surgery. Six arterial blood gas and pH determinations were taken from each patient before surgery and on postoperative days zero, one, three, five and seven. A total of 1699 determinations were obtained. Although the majority of patients (87.5 per cent) had a normal acid-base balance before surgery, a postoperative metabolic alkalosis was seen in 50.5 per cent of the patients. However, there was an extremely low incidence of other postoperative acid-base abnormalities, apart from a transient increase in metabolic acidosis on the operative day. A significantly high mortality rate (32.3 per cent) was observed in 31 patients who had continuous metabolic alkalosis during the postoperative period. An excessive bicarbonate load resulting from the administration of fresh frozen plasma following surgery was strongly suggested as one of the major causes of postoperative metabolic alkalosis. Further investigation is required to elucidate the mechanism of the generation of metabolic alkalosis induced by the postoperative bicarbonate load in surgical patients.

ABSTRACTMicafungin concentrations in plasma and burn eschar after daily intravenous infusion (1 h) of micafungin (200 to 300 mg) were investigated for six patients with severe burns. Micafungin treatment was initiated more than 72 h after the burn injuries. The peak and trough levels in the plasma after the initial administration and repeated administrations for more than 4 days were comparable with or slightly lower than the reported values for healthy volunteers. Micafungin concentrations in the plasma and burn eschar were between 3.6 and >1,000 times higher than the reported MIC90s of micafungin against clinically important Candidaand Aspergillusspecies.

The frequency of “talk and deteriorate” in the emergency department (ED), subsequent deterioration of patients with seemingly “mild” head injury at the time of presentation, is summarized. Among the 1,073 patients with minor head injury treated in the last 5 years, five patients (0.5%) deteriorated in the ED. All of the five patients had experienced transient loss of consciousness (LOC) before presentation. Deterioration had occurred during treatment of trivial associated injuries in four-fifths of the cases. Computed tomography (CT) scans revealed four acute epidural hematomas and one cerebellar contusion. Retrospectively, immediate brain CT shortly after their arrival may have revealed the presence of traumatic intracranial hematomas before deterioration. Although routine use of CT scans in patients with mild head injury has been controversial, the authors conclude that CT scans shouldbe taken if patients have experienced transient LOC to prevent or reduce the occurrence of deteriolation in ED. (Am J Emerg Med 2000;18:810-811. Copyright © 2000 by W.B. Saunders Company)

Sepsis is a serious medical condition that requires rapidly administered, appropriate antibiotic treatment. Conventional methods take three or more days for final pathogen identification and antimicrobial susceptibility testing. We organized a prospective observational multicenter study in three study sites to evaluate the diagnostic accuracy and potential clinical utility of the SeptiFast system, a multiplex pathogen detection system used in the clinical setting to support early diagnosis of bloodstream infections.

Background: Thrombomodulin is a thrombin receptor on the endothelial cell surface that plays an important role in the regulation of intravascular coagulation. Recombinant human soluble thrombomodulin (ART-123) is composed of the active, extracellular domain of thrombomodulin. ART-123 has been shown to have a wider safety margin than other anticoagulants and to have a favorable antithrombotic profile with less bleeding in animal and in vitro experiments. ART-123 is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. Objective: We conducted a multicenter, double-blind, randomized parallel-group trial to compare the efficacy and safety of ART-123 to those of heparin for the treatment of disseminated intravascular coagulation (DIC) associated with infection or hematologic malignancy. Methods: DIC was diagnosed according to the diagnostic criteria established by the Japanese Ministry of Health and Welfare. DIC patients were assigned to receive ART-123 (0.06 mg/kg for 30 min, once a day) or heparin sodium (8 units/kg/h for 24 h) for six days using a double dummy method. The primary efficacy endpoint was DIC resolution rate (rate of recovery from DIC). The secondary endpoints included clinical course of bleeding symptoms, and mortality at 28 days. Results: 234 DIC patients were randomized (117 in each arm). DIC resolution rate was 66.1% for the ART-123 group and 49.9% for the heparin group (difference 16.2%; 95% CI 3.3–29.1), thus demonstrating that ART-123 is significantly superior to heparin for the improvement of DIC. Patients in the ART-123 group also showed more marked improvement in clinical course of bleeding symptoms (p=0.0271) and the disappearance rate of bleeding symptoms in the ART-123 group was higher than that in the heparin group (35.2% vs 20.9%; difference 14.3%). The incidence of bleeding-related adverse events up to 7 days after the start of administration was lower in the ART-123 group than in the heparin group (43.1% vs 56.5%; difference; -13.4%; p=0.0487). The mortality rate at 28 days in the ART-123 group was 22.0% vs 25.5% in the heparin group (difference -3.4%; p=0.5396). Although no significant differences were seen, 28-day mortality for the ART-123 group was slightly lower. The mortality rate of patients with DIC secondary to infection in the ART-123 and heparin groups was 28.0% (14/50) and 34.6% (18/52), respectively, indicating a 6.6% lower mortality in the ART-123 group. Conclusion: When compared with low-dose heparin, ART-123 more significantly improves DIC and alleviates bleeding symptoms in DIC patients. The incidence of bleeding-related adverse events is significantly lower with ART-123 than with heparin. Because of its safety and efficacy, ART-123 appears to be a first-line agent in the management of DIC.

Critical care is a young specialty. It emerged less than 50 years ago in response to new technologies that could prolong the survival of patients who previously would have died. The diseases that posed this threat to life were varied and the original practitioners of critical care came from a variety of medical backgrounds, and created a multidisciplinary specialty. As it continues to evolve, however, the participation and influence of surgeons is waning.

The clinical significance of serum procalcitonin (PCT) for discriminating between bacterial infectious disease and nonbacterial infectious disease (such as systemic inflammatory response syndrome (SIRS)), was compared with the significance of endotoxin, β-d-glucan, interleukin (IL)-6, and C-reactive protein (CRP) in a multicenter prospective study. The concentrations of PCT in patients with systemic bacterial infection and those with localized bacterial infection were significantly higher than the con-centrations in patients with nonbacterial infection or noninfectious diseases. In addition, PCT, endotoxin, IL-6, and CRP concentrations were significantly higher in patients with bacterial infectious disease than in those with nonbacterial infectious disease (P<0.001, P<0.005, P<0.001, and P<0.001, respectively). The cutoff value of PCT for the discrimination of bacterial and nonbacterial infectious diseases was determined to be 0.5ng/ml, which was associated with a sensitivity of 64.4% and specificity of 86.0%. Areas under the receiver operating characteristic curves (POCs) were 0.84 for PCT, 0.60 for endotoxin, 0.77 for IL-6, and 0.78 for CRP in the combined group of patients with bacterial infectious disease and those with nonbacterial infectious disease, and the area under the ROC for PCT was significantly higher than that for endotoxin (P<0.001). In patients diagnosed with bacteremia based on clinical findings, the positive rate of diagnosis with PCT was 70.2%, while that of blood culture was 42.6%. PCT is thus essential for discriminating bacterial infection from SIRS, and is superior in this respect to conventional serum markers and blood culture.

Objective: The aim was to clarify the role of serotonin (5-hydroxytryptamine, 5-HT) in monocrotaline induced pulmonary hypertension. Methods: Plasma 5-HT levels, pulmonary capillary platelet count, and vascular responsiveness to 5-HT were evaluated in the model. The effects of the selective 5-HT2 receptor antagonist, DV- 7028, on the development of pulmonary hypertension were also investigated. Results: Plasma 5-HT was raised 12 h to 3 d after monocrotaline administration (60 mg·kg−1), coinciding with accumulation of platelets in the pulmonary circulation. Isolated pulmonary arteries showed hyperreactivity to 5-HT at 14 and 21 d after monocrotaline. Administration of DV-7028 (20 mg·kg−1·d−1) attenuated the increase in pulmonary arterial pressure, right ventricular hypertrophy, and medial thickening of the pulmonary arteries. Conclusions: The present study suggests that 5-HT released from platelets contributes to the initiation and progression of monocrotaline induced pulmonary hypertension. Cardiovascular Research 1993;27:1619-1623