Osamu Takasu

Autophagy-Related IRGM Polymorphism Is Associated with Mortality of Patients with Severe Sepsis

Objective Autophagy is the regulated catabolic process for recycling damaged or unnecessary organelles, which plays crucial roles in cell survival during nutrient deficiency, and innate immune defense against pathogenic microorganisms. Autophagy has been also reported to be involved in various conditions including inflammatory diseases. IRGM (human immunity-related GTPase) has an important function in eliminating Mycobacterium tuberculosis from host cells via autophagy. We examined the association between genetic polymorphism and clinical course/outcome in severely septic patients. Methods The study included 125 patients with severe sepsis/septic shock (SS) and 104 non-sepsis patients who were admitted to the intensive care unit (ICU) of Chiba University Hospital between October 2001 and September 2008 (discovery cohort) and 268 SS patients and 454 non-sepsis patients who were admitted to ICUs of five Japanese institutions including Chiba University Hospital between October 2008 and September 2012 (multi-center validation cohort). Three hundred forty seven healthy volunteers who consented to this study were also included. Genotyping was performed for a single-nucleotide polymorphism (SNP) within the coding region of IRGM, IRGM(+313) (rs10065172). Lipopolysaccharide challenge of whole blood from randomly selected healthy volunteers (n = 70) was performed for comparison of IRGM mRNA expression among different genotypes. Results No significant difference in genotypic distributions (CC/CT/TT) at the IRGM(+313) locus was observed among the three subject groups (SS, non-sepsis, and healthy volunteers) in either cohort. When mortality were compared, no significant difference was observed in the non-sepsis group, while TT homozygotes exhibited a significantly higher mortality than the CC+CT genotype category in the SS group for both cohorts (P = 0.043, 0.037). Lipopolysaccharide challenge to whole blood showed a significant suppression of IRGM mRNA expression in TT compared with the CC+CT genotype category (P = 0.019). Conclusions The data suggest that the IRGM(+313), an autophagy-related polymorphic locus, influences outcome in severely septic patients, with the possible involvement of autophagy in sepsis exacerbation.

High D-dimer levels predict a poor outcome in patients with severe trauma, even with high fibrinogen levels on arrival : a multicenter retrospective study

ABSTRACT Elevated D-dimer level in trauma patients is associated with tissue damage severity and is an indicator of hyperfibrinolysis during the early phase of trauma. To investigate the interacting effects of fibrinogen and D-dimer levels on arrival at the emergency department for massive transfusion and mortality in severe trauma patients in a multicenter retrospective study. This study included 519 adult trauma patients with an injury severity score ≥16. Patients with ≥10 units of red cell concentrate transfusion and/or death during the first 24 h were classified as having a poor outcome. Receiver operating characteristic curve analysis for predicting poor outcome showed the optimal cut-off fibrinogen and D-dimer values to be 190 mg/dL and 38 mg/L, respectively. On the basis of these values, patients were divided into four groups: low D-dimer (<38 mg/L)/high fibrinogen (>190 mg/dL), low D-dimer (<38 mg/L)/low fibrinogen (⩽190 mg/dL), high D-dimer (≥38 mg/L)/high fibrinogen (>190 mg/dL), and high D-dimer (≥38 mg/L)/low fibrinogen (⩽190 mg/dL). The survival rate was lower in the high D-dimer/low fibrinogen group than in the other groups. Moreover, the survival rate was lower in the high D-dimer/high fibrinogen group than in the low D-dimer/high fibrinogen and low D-dimer/low fibrinogen groups. High D-dimer level on arrival is a strong predictor of early death or requirement for massive transfusion in severe trauma patients, even with high fibrinogen levels.

Development of a teicoplanin loading regimen that rapidly achieves target serum concentrations in critically ill patients with severe infections

We performed high-dose loading (12 mg/kg every 12 h for 48 h; 4 doses total) of teicoplanin (TEIC) in patients with severe methicillin-resistant Staphylococcus aureus (MRSA) infections, with the goal of achieving target serum concentration (TEICc) ≥ 15 mg/l within 48 h of starting administration. The safety and effectiveness of the fixed, early-stage administration method were evaluated across a range of kidney dysfunction severity levels. TEIC high-dose loading was administered to 106 patients with MRSA infection from February 2010 to February 2013. After high-dose loading, maintenance doses based on therapeutic drug monitoring (TDM) of TEICc were administered via 30-min intravenous drips, every 24 h. Subjects were divided into 4 groups based on kidney function and renal replacement therapy (RRT) status for safety and effectiveness evaluation: group 1 (G1) did not undergo RRT and exhibited creatinine clearance (Ccr; ml/min/m(2)) >50, group 2 (G2) exhibited Ccr ≤ 50, group 3 (G3) underwent continuous RRT (CRRT), and group 4 (G4) underwent intermittent RRT (IRRT). TEICc was measured after 24, 48, 72, and 144 h, immediately before TEIC administration. Target TEICc was reached in all groups, and bacteriological effectiveness and utility were high in G1, G2, and G3. The maximum TEICc (≥ 28.0 mg/l) and serum albumin (≤ 1.84 g/dl) were associated with organ toxicity. Fixed high-dose loading of TEIC achieved the target therapeutic range (≥ 15 mg/l) within 48 h of the start of administration regardless of kidney dysfunction, and exhibited sufficient utility.

Development of Novel Criteria of the “lethal Triad” as an Indicator of Decision Making in Current Trauma Care: A Retrospective Multicenter Observational Study in Japan

Objectives: To evaluate the utility of the conventional lethal triad in current trauma care practice and to develop novel criteria as indicators of treatment strategy. Design: Retrospective observational study. Settings: Fifteen acute critical care medical centers in Japan. Patients: In total, 796 consecutive trauma patients who were admitted to emergency departments with an injury severity score of greater than or equal to 16 from January 2012 to December 2012. Interventions: None. Measurements and Main Results: All data were retrospectively collected, including laboratory data on arrival. Sensitivities to predict trauma death within 28 days of prothrombin time international normalized ratio greater than 1.50, pH less than 7.2, and body temperature less than 35°C were 15.7%, 17.5%, and 15.9%, respectively, and corresponding specificities of these were 96.4%, 96.6%, and 93.6%, respectively. The best predictors associated with hemostatic disorder and acidosis were fibrin/fibrinogen degradation product and base excess (the cutoff values were 88.8 µg/mL and –3.05 mmol/L). The optimal cutoff value of hypothermia was 36.0°C. The impact of the fibrin/fibrinogen degradation product and base excess abnormality on the outcome were approximately three- and two-folds compared with those of hypothermia. Using these variables, if the patient had a hemostatic disorder alone or a combined disorder with acidosis and hypothermia, the sensitivity and specificity were 80.7% and 66.8%. Conclusions: Because of the low sensitivity and high specificity, conventional criteria were unsuitable as prognostic indicators. Our revised criteria are assumed to be useful for predicting trauma death and have the potential to be the objective indicators for activating the damage control strategy in early trauma care.

Long-Term Outcomes of Pancreatic Function Following Pancreatic Trauma

The objective of this study is to retrospectively assess long-term outcomes and late complications of pancreatic trauma. We studied 14 patients with pancreatic trauma who were treated at the Advanced Emergency Medical Service Center, Kurume University Hospital, between 1981 and 2012 and discharged alive. Relevant data were extracted from patient records and a retrospective patient questionnaire and blood test were completed to evaluate pancreatic function. The median patient age at the time of the survey was 49 years; the median post-injury period was 23 years and 5 months. The comorbidity rates for pancreatic endocrine and exocrine dysfunctions were 35.7% and 33.3%, respectively. No new-onset diabetes mellitus (DM) was seen within 3 years of trauma, except in 1 patient who underwent pancreaticoduodenectomy. DM developed >15 years after trauma in 2 patients each in the pancreatectomy and non-pancreatectomy groups. Diarrhea exacerbated by fat intake was seen in 3 and 1 patient in the pancreatectomy and non-pancreatectomy groups, respectively. Both complications were more common in the pancreatectomy group, but without statistical significance. Although post-surgical pancreatic dysfunction may be absent at discharge, treatment for pancreatic trauma should take into account the possibility that pancreatectomy may accelerate DM onset.

Intraperitoneal adipose tissue is strongly related to survival rate in a mouse cecal ligation and puncture model

Cecal ligation and puncture (CLP) models exhibiting polymicrobial sepsis are considered as the gold standard in sepsis research. However, despite meticulous research being conducted in this field, only few treatment drugs are available, indicating that CLP sepsis models do not completely mimic human sepsis models. The greatest flaw in CLP models is abscess formation because the localization of inflammation caused by abscess formation increases the survival rate. Therefore, by resecting intraperitoneal adipose tissue, we developed a mouse CLP model wherein abscess formation was unlikely. Survival rates at 7 days postoperatively were compared using the Kaplan–Meier method for an intraperitoneal adipose tissue resection group (resection group, n=34), an intraperitoneal adipose tissue non‐resection group (non‐resection group, n=35) and a sham group (n=10). Results indicated that the survival rate was significantly higher in the non‐resection group compared with the resection group. Intraperitoneal macroscopic findings in the non‐resection group revealed the localization of inflammation caused by abscesses formation covered in adipose tissue. The survival rate for the sham group was 100%. Measurement of interleukin 6 (IL‐6) indicated that during the 12 h after the creation of the CLP model, the median level of IL‐6 was 1300 (552–3000) pg ml−1 in the non‐resection group (n=19) and 3000 (1224–8595) pg ml−1 in the resection group (n=19). Meanwhile, for the sham group, IL‐6 values were below measurement sensitivity in most cases (9/10 mice). Thus our results suggest that, in CLP models, intraperitoneal adipose tissue has an important role in abscess formation and is strongly related to the survival rate.

Fibrinogen level on admission is a predictor for massive transfusion in patients with severe blunt trauma: Analyses of a retrospective multicentre observational study

INTRODUCTION In the early phase of trauma, fibrinogen (Fbg) plays an important role in clot formation. However, to the best of our knowledge, few studies have analysed methods of predicting the need for massive transfusion (MT) based on Fbg levels using multiple logistic regression. Therefore, the present study aimed to evaluate whether Fbg levels on admission can be used to predict the need for MT in patients with trauma. METHODS We conducted a retrospective multicentre observational study. Patients with blunt trauma with ISS ≥16 who were admitted to 15 tertiary emergency and critical care centres in Japan participating in the J-OCTET were enrolled in the present study. MT was defined as the transfusion of packed red blood cells (PRBC) ≥10 units or death caused by bleeding within 24h after admission. Patients were divided into non-MT and MT groups. Multiple logistic-regression analysis was used to assess the predictive value of the variables age, sex, vital signs, Glasgow Coma Scale (GCS) score, and Fbg levels for MT. We also evaluated the discrimination threshold of MT prediction via receiver operating characteristic curve (ROC) analysis for each variable. RESULTS Higher heart rate (HR; per 10 beats per minutes [bpm]), systolic blood pressure (SBP; per 10mm Hg), GCS, and Fbg levels (per 10mg/dL) were independent predictors of MT (odds ratio [OR] 1.480, 95% confidence interval [CI] 1.326-1.668; OR 0.851, 95% CI 0.789-0.914; OR 0.907, 95% CI 0.855-0.962; and OR 0.931, 95% CI 0.898-0.963, respectively). The optimal cut-off values for HR, SBP, GCS, and Fbg levels were ≥100 bpm (sensitivity 62.4%, specificity 79.8%), ≤120mm Hg (sensitivity 61.5%, specificity 70.5%), ≤12 points (sensitivity 63.3%, specificity 63.6%), and ≤190mg/dL (sensitivity 55.1%, specificity 78.6%), respectively. CONCLUSIONS Our findings suggest that vital signs, GCS, and decreased Fbg levels can be regarded as predictors of MT. Therefore, future studies should consider Fbg levels when devising models for the prediction of MT.

Successful transcatheter lumbar arterial embolization of traumatic hemothorax

Traumatic hemothorax associated with the lumbar artery is extremely rare. In addition to tube thoracostomy, active hemostatic intervention is necessary in life-threatening massive hemothorax cases. Here we report a case of hemothorax resulting from a lumbar arterial injury accompanied by vertebral fracture, which was successfully treated with transcatheter lumbar arterial embolization. Most sources of hemothorax include the lung parenchyma, chest wall, or mediastinum. In cases of life-threatening massive hemothorax not responding to initial tube drainage, urgent surgical intervention is strongly recommended [1]. Furthermore, transcatheter arterial embolization (TAE) has emerged as an effective intervention for hemothorax [2–4]. Here, we report a rare case of traumatic hemothorax related to lumbar arterial injury, which was successfully treated with TAE. A74-year-old man hit by an automobile in his back was transferred to the emergency department. On admission, the patient’s airway was patent, and his respiratory rate was 16 breaths per minute with 96% oxygen saturation on oxygen inhalation. Initial blood pressure was 88/52 mm Hg with a pulse rate of 47 beats per minute. The patient had a Glasgow Coma Scale of 13/ 15 (E3V4M6) without anisocoria. The focused assessment with sonography for trauma was positive in the right intrapleural space, and chest radiograph showed a whole hypolucent area on the right lung field. Contrast-enhanced computed tomography (CT) revealed brain contusion, right hemothorax, and first lumbar vertebral fracture with extravasation of the contrast medium into the retroperitoneum (Fig. 1). Conventional tube drainage was performed for the right hemothorax, with immediate evacuation of 1000 mL of blood. However, bleeding from the chest tube persisted that necessitated blood transfusion to maintain hemodynamic stability. Thus, emergency angiographywas performed followingtracheal intubation. The aortography and selective right first lumbar arteriogram revealed a pseudoaneurysm sac and contrast extravasation (Fig. 2). Transcatheter arterial embolization with gelatin sponge particles and microcoils was performed for the right first lumbar artery, resulting in the complete disappearance of the pseudoaneurysm sac and contrast extravasation. Noncontrast CT image recorded 20 minutes after TAE showed the evidence of hemothorax because of injury to the right first lumbar artery; a high-density area, likely the contrast agent from angiography, extending from the embolic site to the right thoracic cavity via the right crus of diaphragmwasobserved(Fig.3).Thepatientreceived10Uofpackedredblood