武山 直志

Introduction: Abnormal 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. Methods: We 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. Results: Patients with Tb of ≤36.5°C had significantly worse sequential organ failure assessment (SOFA) scores when compared with patients with Tb &gt 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 &gt 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 &gt 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 (&gt 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. Conclusions: In 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 registration: UMIN-CTR ID UMIN000008195. © 2013 Kushimoto et al. licensee BioMed Central Ltd.

Introduction: To 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. Methods: This 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. Results: The 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. Conclusions: The 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 patient's prognosis.

Objective: Impaired fibrinolysis is associated with a higher incidence of both multiple organ dysfunction and mortality in the intensive care unit (ICU). Plasminogen activator inhibitor (PAI)-1 is the chief inhibitor of fibrinolysis. We investigated the influence of the 4G/5G polymorphism (rs1799768) of the PAI-1 gene on the plasma PAI-1 level and the outcome of critically ill patients. Methods: In 41 consecutive patients admitted to the ICU, PAI-1 gene polymorphism was assessed, plasma PAI-1 and arterial lactate concentrations were measured and clinical severity scores were recorded. Results: Homozygotes for the 4G allele had higher plasma levels of PAI-1 antigen. The mean +/- SD PAI-1 antigen level was 193.31 +/- 167.93 ng/ml for the 4G/4G genotype, 100.67 +/- 114.16 ng/ml for the 4G/5G genotype and 0.43 +/- 0.53 ng/ml for the 5G/5G genotype. There was a significant correlation between plasma PAI-1 and arterial lactate concentrations, as well as between PAI-1 and severity scores. The mortality rate was 63, 33 and 0% for patients with the 4G/4G, 4G/5G and 5G/5G genotypes, respectively. Conclusions: These results demonstrate that the 4G/5G polymorphism of the PAI-1 gene affects the plasma PAI-1 concentration, which could impair fibrinolysis and cause organ failure, and thus the presence of the 4G allele increases the risk of death. Copyright (C) 2011 S. Karger AG, Basel

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. Copyright (C) 2012 S. Karger AG, Basel

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.

Background. Immunosuppression after burn injury increases the risk of sepsis and multiple organ failure. We examined changes of immune function in mice after burn injury and investigated the immunostimulatory effect of oligodeoxynucleotides containing CpG motifs. Materials and Methods. Male BALB/c mice (8-10 wk old) received a full-thickness burn to 20% of their body surface area, after which the immunological parameters of splenic macrophages were evaluated. To assess the immunostimulatory effect of oligodeoxynucleotide treatment, splenic macrophages harvested from burned mice were incubated with oligodeoxynucleotides. Then cytokine production and major histocompatibility complex class H antigen expression were measured. To assess the in vivo effect of oligodeoxynucleotides, intraperitoneal administration was done on day 4 after burn injury, and class II antigen expression by splenic macrophages was measured 10 d later. Results. Class II antigen expression and the synthesis of cytokines (interleukin-12, tumor necrosis factor-alpha, interleukin-6, and interleukin-1) by splenic macrophages were significantly reduced after burn injury, while incubation of splenic macrophages from burned mice with oligodeoxynucleotides partially enhanced the production of interleukin-12, tumor necrosis factor-a, interleukin-6, and interleukin-1. In addition, intraperitoneal administration of oligodeoxynucleotides enhanced class II antigen expression by splenic macrophages. Conclusions. The reduction of class II antigen expression and synthesis of cytokines (interleukin-12, tumor necrosis factor-a, interleukin-6, and interleukin-1) by splenic macrophages after burn injury was partially reversed by oligodeoxynucleotide treatment. Therefore, immunostimulatory oligodeoxynucleotides may be a potential treatment for post-burn immunosuppression. (C) 2010 Elsevier Inc. All rights reserved

救急集中治療領域で扱う重症疾患は 臓器不全を併発する場合が多く，しばしば高額な医療費が費やされる。また集中治療を要する患者は単一疾患でないこと，全身性の複雑な病態を呈する場合が多いことなどより，治療効果の評価や施設間での比較に際しては，患者対象を層別化する重症度評価法が必要である。ICUにおける死亡率は不全臓器数と各臓器不全の程度に左右されるため，臓器機能障害度指標も重要となる。本稿では年代別に3種類の総合的全身重症度指標と4種類の多臓器不全重症度指標を示すとともに，4種類の個別疾患・臓器重症度指標に関して概説する。正確な重症度判定は，発症早期の重症例の検出と適切な治療法の選択へと繋がり，救命率の向上に寄与する。

We 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. Thirty-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. Arterial 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. Arterial 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.