Published papers

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 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.

Objectives The mortality of severe sepsis has markedly decreased since the implementation of the Surviving Sepsis Campaign guidelines. The next logical step is to examine the necessity of individualized management guidelines for targeted therapy against specific bacteria. Streptococcus pneumoniae is the leading cause of community-acquired severe sepsis; however, little is known regarding the prognostic factors in adult patients with S pneumoniae sepsis. We aimed to identify prognostic factors in patients with S pneumoniae sepsis and to explore a subgroup of patients at high risk for death with detailed Sequential Organ Failure Assessment (SOFA) score analysis. Methods We retrospectively reviewed the records of patients with S pneumoniae infection treated between 1st January 2006 and 31st July 2012. We identified prognostic factors for 28-day mortality using univariate and multivariate logistic regression models. Results Of 171 patients (median age, 72 years) with S pneumoniae infection who were included in this study, the 28-day mortality was 17% (29/171). The SOFA score (odds ratio, 2.25; 95% confidence interval, 1.60-3.18; P

Objective The aim of this study was to compare the values of a noninvasive blood pressure (NIBP) measurement during cuff inflation (inflationary NIBP) and deflationary NIBP measurements and to verify whether inflationary NIBP is equivalent to conventional deflationary NIBP and is acceptable for clinical use in the emergency room (ER). Materials and methods A total of 2981 NIBP data points were collected from 175 patients (age, 56.5± 22.2 years; range, 7-92 years) who had been treated in the resuscitation area of the ER at Keio University Hospital. The data points were obtained using two alternate algorithms with a standard monitor (BSM-6000). One algorithm consisted of continuous inflationary and deflationary measurements in a single cycle (dual algorithm, 1502 data points); this algorithm was used to verify the success rate and the precision of the data. The second algorithm (1479 data points) consisted of only conventional deflationary measurements and was used to verify the duration of the measurement cycle. Results The success rate of the inflationary NIBP (completed using only the inflationary method) was 69.0%. Failures in the inflationary measurements were caused by arrhythmia and/or body motions. The mean difference and SD of the systolic pressure and the diastolic pressure between inflationary NIBP and deflationary NIBP were-0.6± 8.8 and 3.5± 7.5 mmHg, respectively. The confidence intervals were-0.6 (95% confidence interval=-1.1 to-0.1) and 3.5 (95% confidence interval=3.0 to 4.0) mmHg. The coefficients of correlation were 0.96 and 0.93. Inflationary NIBP was capable of determining the NIBP more quickly compared with deflationary NIBP (average of 15.9 vs. 34.2 s; P

Background: Daptomycin is recommended for complicated skin and skin-structure infections. However, information on the penetration of daptomycin into skin is limited. Therefore, the aim of this in vivo investigation was to determine the pharmacokinetics and skin penetration of daptomycin in rats. Materials and methods: Concentrations of daptomycin were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis was conducted to estimate the rate and extent of daptomycin penetration from the systemic circulation into skin tissue. Since protein binding of daptomycin in rat serum was 89.3%, the free maximum concentration (Cmax) and free area under the curve from time 0 to infinity (AUC0-∞) for plasma were calculated as follows: fCmax,plasma = (1 - 0.893) × Cmax,plasma, fAUC0-∞,plasma = (1 - 0.893) × AUC0-∞,plasma. Results: The following values (mean ± standard deviation) were obtained: 0.06±0 L/h/kg for total clearance (CLtotal), 0.44±0.06 hours for elimination-rate constant, 1.58±0.23 hours for half-life, 0.14±0.02 L/kg for steady-state volume distribution, and 2.28±0.33 hours for mean residence time. Time to Cmax was 3.0 hours for plasma and skin tissue. Cmax and AUC0-∞ for plasma were 175.8±5.1 μg/mL and 811.8±31.9 μg × h/mL, respectively. Cmax and AUC0-∞ for skin tissue were 19.1±1.7 μg/mL and 113.9±21.8 μg × h/mL, respectively. Furthermore, fCmax and fAUC0-∞ for plasma were 18.8 μg/mL and 86.9 μg × h/mL, respectively. The degrees of skin-tissue penetration, defined as the Cmax, skin tissue/fCmax, plasma ratio andAUC0-∞, skin tissue/fAUC0-∞, plasma ratio, were 1.0 and 1.3, respectively. Conclusion: Daptomycin exhibited good penetration into skin tissue, supporting its use for the treatment of complicated skin and skin-structure infections. However, further studies are needed in infected patients in order to investigate the relationship between the antimicrobial efficacy of daptomycin and its drug concentrations in skin tissues.

Aim: To clarify whether quantitative assessment of pupillary light reflexes (PLR) can predict the outcome of post-cardiac arrest (CA) patients during the first 72 h after the return of spontaneous circulation (ROSC). Methods: Fifty adults resuscitated after non-traumatic out-of-hospital CA (OHCA) (mean age 64.1 years old, 36 males) were enrolled in four emergency hospitals. PLR was sequentially measured at 0, 6, 12, 24, 48, and 72 h after ROSC by an automated portable infrared pupillometry. PLR values for each time point were compared between both survivors and non-survivors, and patients with either favourable (Cerebral Performance Category (CPC) 1 or 2) or unfavourable neurological outcomes. Results: Twenty-three patients survived for 90 days after CA, and 13 patients achieved favourable neurological outcomes. The PLR values of the survivors and patients with favourable neurological outcomes were consistently greater than those of non-survivors (P < 0.001) and those with unfavourable neurological outcomes (P < 0.001), respectively. The change in PLR over time was not statistically different between the outcome groups. The 0-hour PLR best predicted both 90-day survival (AUC = 0.82, cutoff 3%, sensitivity 0.87, specificity 0.80) and favourable neurological outcomes (AUC = 0.84, cutoff 6%, sensitivity 0.92, specificity 0.74). No patient with a 6-hour PLR less than 3% survived for 90 days after CA. Conclusions: Quantitatively measured PLR was consistently greater in survivors and patients with favourable neurological outcomes during the 72 h after ROSC. Quantitative assessment of PLR at as early as 0 h has a potential role for prognostication in post-CA patients.

Background: Hydrogen gas inhalation (HI) reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model of acute myocardial infarction (AMI). We designed a prospective, open-label, rater-blinded clinical pilot study in patients experiencing ST-elevated MI (STEMI). Methods and Results: The 20 patients with an initial diagnosis of STEMI were assigned to either an HI group (1.3% H2 with 26% oxygen) or a control group (26% oxygen). There were no HI-related severe adverse events. In the full analysis set, the cardiac salvage index as evaluated using cardiac magnetic resonance imaging at 7 days after primary percutaneous coronary intervention (PCI), showed no significant between-group difference (HI: 50.0±24.3%; control: 60.1±20.1%; P=0.43). However, the improvement from day 7 in the HI group was numerically greater than that in the control group in some of the surrogate outcomes at 6-month follow-up, including the LV stroke volume index (HI: 9.2±7.1 mL/m2; control: -1.4±7.2 mL/m2; P=0.03) and the LV ejection fraction (HI: 11.0%±9.3%; control: 1.7%±8.3%; P=0.11). Conclusions: The first clinical study has shown that HI during PCI is feasible and safe and may also promote LV reverse remodeling at 6 months after STEMI. The study was not powered to test efficacy and a further large-scale trial is warranted. (Clinical trials registration: UMIN00006825).

Limited clinical evidence demonstrates the effectiveness of direct retroperitoneal pelvic packing for hemorrhage control in pelvic fractures due to the difficulty in measuring pressure on the pelvic walls within the pelvic cavity after retroperitoneal pelvic packing. Using a cadaver model, the authors aimed to assess whether retroperitoneal pelvic packing generates pressure that exceeds the venous return and arterial pressure in the pelvis. The pressure on the pelvic wall was measured in 5 fresh Japanese cadavers. Sensors were placed at 4 points on the pelvic wall, and the pressure at each point was measured after the insertion of each of 3 sponges, per the procedure originally described for direct retroperitoneal pelvic packing. In each specimen, the average pressure across all 4 points on the pelvic wall increased with the addition of each sponge, reaching 12.3±4.5 mm Hg when all 3 sponges were inserted. Furthermore, the pressure at the pelvic floor and posterior pelvic brim increased significantly, whereas the pressure at the anterior and middle pelvic brim increased nonsignificantly. The results of this study suggest that retroperitoneal pelvic packing provides pressure on the pelvic wall that exceeds the venous pressure and is thus effective for the control of venous hemorrhage in pelvic fractures. Currently, the recommended procedure combines external fixation for venous bleeding, transcatheter arterial embolization, and pelvic packing; however, the authors' results suggest that pelvic packing alone may be effective for controlling venous hemorrhage in pelvic fracture.

Objective: A high plasma level of remnant-like particle cholesterol (RLP-C), which is equivalent to triglyceride-rich lipoprotein remnant, is an important coronary risk marker. RLP-C level is high, independent of other plasma lipids, in patients with chronic kidney disease (CKD) undergoing hemodialysis. The effect of teneligliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, on plasma levels of RLP-C in patients with diabetes mellitus and CKD under hemodialysis was studied. Methods: Teneligliptin 20 mg/day was administered to 15 patients with diabetes and CKD undergoing hemodialysis for 12 weeks. Ten patients with diabetes and CKD undergoing hemodialysis were allocated to the control group. Blood was sampled following a 12-h fast. Fasting plasma glucose (FPG), C-peptide, triglyceride, low-density lipoprotein (LDL)-cholesterol (C), high-density lipoprotein (HDL)-C, RLP-C, apolipoprotein (apo) B, oxidized LDL, lipoprotein lipase, and glycated hemoglobin (HbA1c) were measured. Results: HbA1c decreased in the teneligliptin group but significantly increased in the control group. FPG and RLP-C significantly decreased in the teneligliptin group. Plasma lipoprotein-related parameters except RLP-C were not affected by teneligliptin treatment. Conclusion: Teneligliptin treatment significantly reduced plasma levels of RLP-C, FPG, and HbA1c in patients with diabetes with CKD who are undergoing hemodialysis.

Background: A reduction in mortality with the early use of tranexamic acid has been demonstrated in severely injured patients who are bleeding. However, the modest treatment effect with no reduction in blood transfusion has raised concerns. The aim of the present study was to estimate the effectiveness of regular use of tranexamic acid in severely injured patients. Methods: This multicentre observational study used retrospectively collected data from consecutive injured patients (Injury Severity Score at least 16) treated in 15 Japanese academic institutions in 2012. A propensity score-matched analysis compared patients who did or did not receive tranexamic acid administration within 3 h of injury. Study outcomes included 28-day all-cause and cause-specific mortality, and need for blood transfusion. Results: Of 796 eligible subjects, 281 were treated with tranexamic acid. Propensity score matching selected a total of 500 matched subjects (250 in each group). Tranexamic acid administration was associated with lower 28-day mortality (10·0 versus 18·4 per cent; difference −8·4 (95 per cent c.i. –14·5 to −2·3) per cent) and lower 28-day mortality from primary brain injury (6·0 versus 13·2 per cent; difference −7·2 (−12·3 to −2·1) per cent). However, there was no significant difference between groups in the need for blood transfusion (33·2 versus 34·8 per cent; difference −1·6 (−9·9 to 6·7) per cent). Conclusion: Early tranexamic acid use was associated with reduced mortality in severely injured patients, in particular those with a primary brain injury.

We evaluated the efficacy and safety of levofloxacin (LVFX) injection 500 mg once-daily by intravenous infusion for 3 days to 14 days in patients with the secondary infections of injury, burns, or surgical wounds, acute cholecystitis, or acute cholangitis. The utility of sequential therapies, from LVFX injection to LVFX oral agent, for the treatment of surgical infection was evaluated. Additionally, the drug penetration into gallbladder bile and duct bile after administrating 500 mg of LVFX by injection was determined in patients with biliary tract infections. Clinical efficacy: The clinical efficacy rate at test of cure (primary endpoint) was 90.0% (9/10) in patients with the secondary infections of injury, burns or surgical wounds. All five patients with acute cholecystitis and all three patients with acute cholangitis were evaluated as cured. Microbiological efficacy: The microbiological efficacy rate at test of cure was 90.0% (9/10) in patients with the secondary infections of injury, burns or surgical wounds. Three (out of five) patients with acute cholecystitis and three patients with acute cholangitis were evaluated as demonstrating microbial eradication. Pharmacokinetics: The concentration of LVFX in gallbladder bile and duct bile after administrating LVFX injections was measured in two patients with acute cholecystitis (gallbladder bile) and four patients with acute cholangitis (duct bile). The LVFX concentration in gallbladder bile 3 h after starting infusion in the two patients was 13.9 μg/mL and 24.5 μg/mL, respectively. The gallbladder bile to plasma concentration ratios were 1.78 and 2.16, respectively. The mean value of the LVFX concentration in duct bile 3 h after starting infusion in the four patients was 12.0 jig/mL (range: 9.0 μg/mL-15.6 μg/mL). The mean value of duct bile to plasma concentration ratio was 1.82 (range: 1.37-2.31). Safety: The incidence rates of adverse events (AEs) and adverse drug reactions (ADRs) were 63.6% (14/ 22) and 13.6% (3/22), respectively. The severities of all ADRs were mild, and all patients who had any ADRs recovered. From these results, LVFX injection 500 mg once-daily was shown to be useful for the treatment of the secondary infections of injury, burns, or surgical wounds, acute cholecystitis, and acute cholangitis, and it was demonstrated that there were no significant problems with its safety.