Naoshi Takeyama

A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis

IntroductionTo validate the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) scoring system in patients with severe sepsis, we conducted a multicenter, prospective study at 15 critical care centers in tertiary care hospitals.MethodsThis study included 624 severe sepsis patients. JAAM DIC was scored on the day of diagnosis of severe sepsis (day 1) and day 4. Scores for disease severity and organ dysfunction were also evaluated.ResultsThe prevalence of JAAM DIC was 46.8% (292/624), and 21% of the DIC patients were scored according to the reduction rate of platelets. The JAAM DIC patients were more seriously ill and exhibited more severe systemic inflammation, a higher prevalence of multiple organ dysfunction syndrome (MODS) and worse outcomes than the non-DIC patients. Disease severity, systemic inflammation, MODS and the mortality rate worsened in accordance with an increased JAAM DIC score on day 1. The Kaplan-Meier curves demonstrated lower 1-year survival in the JAAM DIC patients than in those without DIC (log-rank test P <0.001). The JAAM DIC score on day 1 (odds ratio = 1.282, P <0.001) and the Delta JAAM DIC score (odds ratio = 0.770, P <0.001) were independent predictors of 28-day death. Dynamic changes in the JAAM DIC score from days 1 to 4 also affected prognoses. The JAAM DIC scoring system included all patients who met the International Society on Thrombosis and Haemostasis overt DIC criteria on day 1. The International Society on Thrombosis and Haemostasis scoring system missed a large number of nonsurvivors recognized by the JAAM scoring system.ConclusionsThe JAAM DIC scoring system exhibits good prognostic value in predicting MODS and poor prognosis in patients with severe sepsis and can detect more patients requiring treatment. Conducting repeated daily JAAM scoring increases the ability to predict the patients prognosis.

The impact of body temperature abnormalities on the disease severity and outcome in patients with severe sepsis: an analysis from a multicenter, prospective survey of severe sepsis

IntroductionAbnormal body temperatures (Tb) are frequently seen in patients with severe sepsis. However, the relationship between Tb abnormalities and the severity of disease is not clear. This study investigated the impact of Tb on disease severity and outcomes in patients with severe sepsis.MethodsWe enrolled 624 patients with severe sepsis and grouped them into 6 categories according to their Tb at the time of enrollment. The temperature categories (≤35.5°C, 35.6–36.5°C, 36.6–37.5°C, 37.6–38.5°C, 38.6–39.5°C, ≥39.6°C) were based on the temperature data of the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring. We compared patient characteristics, physiological data, and mortality between groups.ResultsPatients with Tb of ≤36.5°C had significantly worse sequential organ failure assessment (SOFA) scores when compared with patients with Tb >37.5°C on the day of enrollment. Scores for APACHE II were also higher in patients with Tb ≤35.5°C when compared with patients with Tb >36.5°C. The 28-day and hospital mortality was significantly higher in patients with Tb ≤36.5°C. The difference in mortality rate was especially noticeable when patients with Tb ≤35.5°C were compared with patients who had Tb of >36.5°C. Although mortality did not relate to Tb ranges of ≥37.6°C as compared to reference range of 36.6–37.5°C, relative risk for 28-day mortality was significantly greater in patients with 35.6–36.5°C and ≤35.5°C (odds ratio; 2.032, 3.096, respectively). When patients were divided into groups based on the presence (≤36.5°C, n = 160) or absence (>36.5°C, n = 464) of hypothermia, disseminated intravascular coagulation (DIC) as well as SOFA and APACHE II scores were significantly higher in patients with hypothermia. Patients with hypothermia had significantly higher 28-day and hospital mortality rates than those without hypothermia (38.1% vs. 17.9% and 49.4% vs. 22.6%, respectively). The presence of hypothermia was an independent predictor of 28-day mortality, and the differences between patients with and without hypothermia were observed irrespective of the presence of septic shock.ConclusionsIn patients with severe sepsis, hypothermia (Tb ≤36.5°C) was associated with increased mortality and organ failure, irrespective of the presence of septic shock.Trial registrationUMIN-CTR IDUMIN000008195

Beneficial effects of the heme oxygenase-1/ carbon monoxide system in patients with severe sepsis/septic shock

PurposeWe evaluated the relations among the arterial carbon monoxide (CO) concentration, heme oxygenase (HO)-1 expression by monocytes, oxidative stress, plasma levels of cytokines and bilirubin, and the outcome of patients with severe sepsis or septic shock.MethodsThirty-six patients who fulfilled the criteria for severe sepsis or septic shock and 21 other patients without sepsis during their stay in the intensive care unit were studied. HO-1 protein expression by monocytes, arterial CO, oxidative stress, bilirubin, and cytokines were measured.ResultsArterial blood CO, cytokine, and bilirubin levels, and monocyte HO-1 protein expression were higher in patients with severe sepsis/septic shock than in non-septic patients. Increased HO-1 expression was related to the arterial CO concentration and oxidative stress. There was a positive correlation between survival and increased HO-1 protein expression or a higher CO level.ConclusionsArterial CO and monocyte HO-1 protein expression were increased in critically ill patients, particularly those with severe sepsis or septic shock, suggesting that oxidative stress is closely related to HO-1 expression. The HO-1/CO system may play an important role in sepsis.

Epidemiology of severe sepsis in Japanese intensive care units: a prospective multicenter study.

Severe sepsis is a leading cause of morbidity and mortality in the intensive care unit (ICU). We conducted a prospective multicenter study to evaluate epidemiology and outcome of severe sepsis in Japanese ICUs. The patients were registered at 15 general critical care centers in Japanese tertiary care hospitals when diagnosed as having severe sepsis. Of 14,417 patients, 624 (4.3%) were diagnosed with severe sepsis. Demographic and clinical characteristics at enrollment (Day 1), physiologic and blood variables on Days 1 and 4, and mortality were evaluated. Mean age was 69.0 years, and initial mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were 23.4 and 8.6, respectively. The 28-day mortality was 23.1%, and overall hospital mortality was 29.5%. SOFA score and disseminated intravascular coagulation (DIC) score were consistently higher in nonsurvivors than survivors on Days 1 and 4. SOFA score, DIC score on Days 1 and 4, and hospital mortality were higher in patients with than without septic shock. SOFA score on Days 1 and 4 and hospital mortality were higher in patients with than without DIC. Logistic regression analyses showed age, presence of septic shock, DIC, and cardiovascular dysfunction at enrollment to be predictors of 28-day mortality and presence of comorbidity to be an additional predictor of hospital mortality. Presence of septic shock or DIC resulted in approximately twice the mortality of patients without each factor, whereas the presence of comorbidity may be a significant predictor of delayed mortality in severe sepsis.

Apheresis of activated leukocytes with an immobilized polymyxin B filter in patients with septic shock.

In this study, we examined the effects of direct hemoperfusion through filters with immobilized polymyxin B (PMX-DHP) on leukocyte function and plasma levels of cytokines in patients with septic shock. We found that PMX-DHP caused increased expression of C-X-C chemokine receptor 1 (CXCR1) and CXCR2, along with decreased expression of CD64 and CD11b, by circulating neutrophils in patients with septic shock. Plasma levels of cytokines, including interleukin 6 (IL-6), IL-8, IL-10, and high-mobility group box 1, were elevated in patients with septic shock compared with healthy controls, but cytokine levels were not altered by PMX-DHP. These results suggest that PMX-DHP influences neutrophils via a mechanism that does not involve cytokine. Ex vivo perfusion of heparinized blood from patients with sepsis and septic shock through PMX filters in a laboratory circuit caused a significant decrease in neutrophil and monocyte counts. After 120 min of perfusion, neutrophils, monocytes, and lymphocytes were decreased by 78%, 70%, and 10%, respectively, compared with baseline values. Flow cytometric analysis indicated that activated neutrophils with high levels of CD11b/CD64 expression and low levels of CXCR1/CXCR2 expression showed preferential adhesion to PMX filters. Neutrophils isolated from the blood after ex vivo PMX perfusion caused less damage to an endothelial cell monolayer than cells from sham-treated blood, whereas neutrophil phagocytosis of opsonized Escherichia coli was unaffected. These results indicate that PMX-DHP selectively removes activated neutrophils and reduces the ability of circulating cells to cause endothelial damage. Selective removal of activated neutrophils using PMX-DHP may improve the systemic inflammatory response in patients with septic shock.

Neutrophil extracellular traps in patients with sepsis.

BACKGROUND Release of neutrophil extracellular traps (NETs) has been identified as an important aspect of innate immunity. We examined whether sepsis had any influence on ex vivo generation of NETs by neutrophils. MATERIALS AND METHODS We isolated neutrophils from consecutive patients with sepsis (n = 17) and without sepsis (n = 18) admitted to the intensive care unit. Neutrophils were activated by incubation with phorbol-12-myristate-13-acetate (PMA) to induce release of NETs, and NET formation was assessed by measuring the extracellular DNA level. Immunolabeling and fluorescence imaging were also performed. Extracellular killing of bacteria by NETs was studied by co-culture of Escherichia coli and neutrophils in the presence of a phagocytosis inhibitor. To assess in vivo NET formation, plasma levels of cell-free DNA and histones were measured. RESULTS After stimulation with PMA, neutrophils isolated from septic patients released 4.08 ± 1.02% of their total DNA, whereas neutrophils from nonseptic patients released 29.06 ± 2.94% (P = <0.0001). Immunofluorescent staining of released DNA, elastase, and myeloperoxidase also revealed similar results. Neutrophils from nonseptic patients showed effective extracellular killing of E coli through NETs, whereas neutrophils from septic patients did not (P < 0.001). Plasma levels of cell-free DNA and histones were higher in septic patients than nonseptic patients (P < 0.001). CONCLUSIONS The ex vivo generation of NETs is downregulated in neutrophils isolated from patients with sepsis. However, it is unclear whether in vivo NET formation is also impaired during sepsis, so further investigation is necessary.

A multicenter, prospective evaluation of quality of care and mortality in Japan based on the Surviving Sepsis Campaign guidelines

To elucidate the standard Surviving Sepsis Campaign (SSC) guidelines-based quality of care and mortality related to severe sepsis in Japan, we conducted a multicenter, prospective, observational study using a new web-based database between June 1, 2010, and December 31, 2011. A total of 1104 patients with severe sepsis were enrolled from 39 Japanese emergency and critical care centers. All-cause hospital mortality was 29.3% in patients with severe sepsis and 40.7% in patients with septic shock. Pulmonary, renal, hepatic, and hematological dysfunctions were associated with significantly higher mortality, and hematological dysfunction, especially coagulopathy, was associated with the highest odds ratio for mortality. Compliance with severe sepsis bundles in our study was generally low compared with that in a previous international sepsis registry study, and glycemic control was associated with lowest odds ratio for mortality. Despite higher complication rates of multiple organ dysfunction syndrome and low compliance with severe sepsis bundles on the whole, mortality in our study was similar to that in the international sepsis registry study. From these results, we concluded that our prospective multicenter study was successful in evaluating SSC guidelines-based standard quality of care and mortality related to severe sepsis in Japan. Although mortality in Japan was equivalent to that reported worldwide in the above-mentioned international sepsis registry study, compliance with severe sepsis bundles was low. Thus, there is scope for improvement in the initial treatment of severe sepsis and septic shock in Japanese emergency and critical care centers.

Role of Plasma Proteins in Pharmacokinetics of Micafungin, an Antifungal Antibiotic, in Analbuminemic Rats

ABSTRACT There were no significant differences in the pharmacokinetics of micafungin and expression of hepatic multidrug resistance-associated protein 2 (ABCC2/Mrp2) between analbuminemic and Sprague-Dawley rats. Micafungin bound strongly to high-density lipoprotein (HDL) and moderately to gamma globulin. These results suggest that HDL and gamma globulin contribute to the pharmacokinetics of micafungin.

Time to Initiation of Treatment with Polymyxin B Cartridge Hemoperfusion in Septic Shock Patients

Background: We investigated whether early initiation of hemoperfusion with a polymyxin B cartridge (PMX) after the diagnosis of septic shock could improve the clinical outcome. Methods: A prospective, open-labeled, multicenter cohort study was performed at intensive care units in Japan. 41 patients received PMX within 6 h after the diagnosis of septic shock (early group) and 51 patients were treated after 6 h (late group). Results: The early group had a significantly shorter duration of ventilator support and also had a lower catecholamine requirement. PMX was effective for improvement of hypotension, hypoperfusion, the sequential organ failure assessment score, and pulmonary oxygenation regardless of the timing of its initiation. The 28-day mortality rate did not differ between the two groups. Conclusions: Early initiation of PMX shortened the duration of ventilator support and also reduced the catecholamine requirement, so early treatment of septic shock should achieve a better outcome.

Selective expansion of the CD14(+)/CD16(bright) subpopulation of circulating monocytes in patients with hemophagocytic syndrome.

Overproduction of proinflammatory cytokines is characteristic of hemophagocytic syndrome (HPS), a highly lethal inflammatory disease. Peripheral blood monocytes include two distinct subpopulations according to surface antigen expression: a major type, CD14+/CD16− (classical monocytes), and a minor type, CD14+/CD16bright (proinflammatory monocytes). Among peripheral blood monocytes from HPS patients, CD14+/CD16bright cells were increased, together with lipopolysaccharide-induced production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. By three-color immunofluorescence, CD14+/CD16bright monocytes exhibited more intense human leukocytic antigen DR than CD14+/CD16− monocytes, consistent with greater maturity. Serum IL-6, TNF-α, and IL-8 were increased in HPS patients. A sensitive inflammatory marker, neutrophil CD64 expression, also was significantly elevated in HPS patients. In conclusion, expansion of proinflammatory monocytes and increased expression of neutrophil CD64 appeared to be important in the pathophysiology of HPS. Expansion of CD14+/CD16bright monocytes and neutrophil CD64 expression could serve as indicators of the inflammatory state in HPS.