Published papers

Oxygen-derived free radicals play important roles in pathophysiological processes in critically ill patients, but the data characterizing relationships between radicals and neuroendocrine system response are sparse. To search the cue to reduce the oxidative cellular damage from the point of view of neuroendocrine system response, we studied the indicators of neuroendocrine and inflammatory responses excreted in urine in 14 burn patients (42.3 ± 31.4 years old, and 32.3 ± 27.6% burn of total body surface area [%TBSA]) during the first seven days post burn. The daily mean amounts of urinary excretion of 8-hydroxy-2′-deoxy-guanosine (8-OHdG), a marker of oxidative cellular damage, were above the upper limit of the standard value during the studied period. The total amount of urinary excretion of 8-OHdG in the first day post burn correlated with burn severity indices: %TBSA (r = 0.63, p = 0.021) and burn index (r = 0.70, p = 0.008). The daily urinary excretion of 8-OHdG correlated with the daily urinary excretion of norepinephrine and nitrite plus nitrate (NOx) during the studied period except day 2 post burn, and correlated with the daily urinary excretion of 17-hydroxycorticosteriod (17-OHCS) in days 2, 3, and 7 post burn. These data suggest that oxidative cellular damage correlates with burn severity and neuroendocrine system response modulates inflammation and oxidative cellular damage. Modulation of neuroendocrine system response and inflammation in the treatment in the early phase of burn may be useful to reduce the oxidative cellular damage and to prevent multiple organ failures in patients with extensive burn. © 2007 Tohoku University Medical Press.

Purpose: Recent studies have shown increased survival benefits when a high fresh frozen plasma (FFP) to packed red blood cell (PRBC) ratio is used during trauma resuscitation. However, some reports have raised questions about the effect of higher FFP:PRBC transfusion ratios. The aim of this study was to examine the efficacy of high FFP:PRBC ratios in injured patients with regard to survival and morbidity in a single tertiary emergency center in Japan. Methods: This study examined severe trauma patients who received 10 or more PRBC units during the first 24 h of admission. We examined the relationship between the FFP:PRBC ratios during the first 6 h and the patient outcome. Results: The severity was similar among all groups. The mortality rate was 44.4 % in the high (>1:1.5), 16.7 % in the middle (1:1.5-1:2) and 33.3 % in the low (<1:2) F:P ratio groups. Only one patient in the high group developed sepsis, and none of the patients developed ARDS. Conclusions: The current results indicate that the FFP:PRBC ratios during the first 6 h after admission might not affect the mortality or morbidity. However, differences between trauma care systems in Japan and other countries, along with other study limitations, necessitate that a subsequent prospective multicenter study be undertaken before any definitive conclusions can be made.

Micafungin (MCFG) concentrations in the plasma and in burn eschar were investigated after daily intravenous infusion (1 h) of MCFG (200 mg) in three patients with severe burns. MCFG treatment was initiated more than 72 h after the burn injuries. The MCFG concentrations in the plasma were determined at the end of the first administration of MCFG, immediately before the second dosing, at the end of the MCFG infusion after at least 4 days from the initial treatment, and immediately before the subsequent dosing using high-performance liquid chromatography. In addition, the trough levels in burn eschar after both the initial administration and repeated administration were measured. The peak and trough levels in the plasma were comparable to or slightly lower than the reported values in healthy volunteers. The mean (range) MCFG concentrations in the burn eschar after initial administration and repeated administration were 1.41 μg/mL (<0.1-3.98 μg/mL) and 6.65 μg/mL (1.10-14.81 μg/mL), respectively. In most cases, the MCFG concentrations in the burn eschar, especially after repeated administration, were higher than the reported MIC 90 of MCFG against the clinically important pathogenic species of Candida and Aspergillus. These results suggest that MCFG is capable of penetrating burn eschar. © 2013 Springer-Verlag.

Bacteria isolated from surgical infections during the period from April 2011 to March 2012 were investigated in a multicenter study in Japan, and the following results were obtained. In this series, 785 strains including 3 1 strains of Candida spp. were isolated from 204 (78.8%) of 259 patients with surgical infections. Five hundred and twenty three strains were isolated from primary infections, and 231 strains were isolated from surgical site infection. From primary infections, anaerobic Gram-negative bacteria were predominant, followed by aerobic Gram-negative bacteria, while from surgical site infection aerobic Gram-positive bacteria were predominant, followed by anaerobic Gram-negative bacteria. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus spp. was highest, followed by Streptococcus spp. and Staphylococcus spp., in this order, from primary infections, while Enterococcus spp. was highest, followed by Staphylococcus spp. from surgical site infection. Among aerobic Gram-negative bacteria, Escherichia coil was the most predominantly isolated from primary infections, followed by Kiebsielia pneumoniae, Pseudomonas aeruginosa and Enterobacter cioacae, in this order, and from surgical site infection, E. coil was most predominantly isolated, followed by F aeruginosa, K. pneumoniae, and E. cioacae. Among anaerobic Gram-positive bacteria, the isolation rate of Eggertheiia lenta was the highest from primary infections, followed by Parvimonas micra, Coilinseila aerofaciens, Lactobaciiius acidophilus and Finegoidia magna, and from surgical site infection, E. ienta was most predominantly isolated, followed by F micra and L. acidophiius, in this order. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroidesfragiiis was the highest from primary infections, followed by Bilophila wadsworthia, Bactero ides thetaiotaomicron, Bacteroides unformis and Bactero ides vuigatus, and from surgical site infection, B. fragiiis was most predominantly isolated, followed by Bactero ides caccae, B. thetaiotaomicron, Bactero ides ovatus and B. wadsworthia, in this order. In this series, vancomycin-resistant MRSA (methicillin-resistant Staphylococcus aureus), vancomycinresistant Enterococcus spp. and multidrug-resistant F aeruginosa were not observed. We should carefully follow up B. wadsworthia which was resistant to various antimicrobial agents, and also Bacteroides spp. which was resistant to many ,lJ-lactams.

In the fields of surgery, emergency and intensive care, patients with various severe underlying diseases often have severe infections with treatment-resistant bacteria, such as methicillin-resistant Staphylococcus aureus(MRSA) and multi-drug resistant Pseudomonas aeruginosa(MDRP). In such cases, fungal infections, especially Candida infection, which occur during the process of treatment and are possibly attributable to antimicrobial use, emerge as a serious problem. In order to improve the outcomes of Candida infection, it is important to consider targeted treatment for serious complications, such as for lesions of the eye, osteomyelitis, septic embolisms, and deep-seated abscesses, as well as to focus on extraction of high-risk patients based on the guidelines and early diagnosis and treatment Although many guidelines recommend echinocandin drugs as the first-line antifungal drugs in these fields, it is necessary to implement a set of multidisciplinary practice guidelines, which we refer to as antifungal stewardship, in order to properly and effectively use antifungal drugs and succeed in antifungal therapy. For implementation of the guidelines, early-stage administration of antifungal drugs needs to be established in preemptive therapy or empiric treatment the loading doses of antifungal drugs and the drug disposition need to be considered, and treatment based on antifungal heterogeneity, which uses the most suitable antifungal drug in terms of the drug properties and suppression of resistant strains, needs to be provided.

Invasive pneumococcal disease (IPD) has a high mortality. Although preventive strategies including vaccination have been established for children, less attention has been devoted to pregnant and postnatal women and to mothers caring for their infants. As a significant number of women have either undergone splenectomy or are in a hyposplenic state and have not received adequate pneumococcal vaccinations, they can potentially develop overwhelming postsplenectomy infections. A 34-year-old woman with an 8-month-old baby, who underwent splenectomy at the age of 10 for benign pancreatic tumor, presented with fever and petechial eruption. Despite extensive treatment, she died 17 h after admission. A 40-year-old woman with a 11-month-old baby, who underwent splenectomy at 2 years of age for hemolytic anemia, was admitted for septic shock and disseminated intravascular coagulation. Despite extensive treatment, she died 2 h after admission. Blood cultures from both women were positive for Streptococcus pneumoniae and neither of them had been vaccinated against the bacterium. IPD rapidly progressed and developed to multiple organ dysfunction syndromes in mothers caring for their infants, particularly those who had undergone splenectomy or were in a hyposplenic state. Thus, routine pneumococcal vaccination is recommended for pregnant women. In addition, we suggest a thorough medical interview and checkup for splenectomy or hyposplenism in prenatal women. © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

Micafungin 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 Candida and Aspergillus species. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Object: This study sought to define hemorrhagic shock from blood pressure and heart rate and then to provide a treatment policy based on response to initial fluid therapy. Materials: This was a prospective clinical observational study conducted in eight hospitals. Subjects were consecutive patients with trauma who met any of the field triage conditions proposed by the Committee on Trauma of the American College of Surgeons. Initial fluid therapy was performed in patients with suspected hemorrhagic shock. Patients who required blood transfusion ≥4 U within 24 hours or interventions for active bleeding within 24 hours were classified into a "bleeding group" (B). A "nonbleeding group" (non-B) comprised patients who did not require blood transfusion ≥4 U or other interventions within 24 hours. Our committee maintained the database of survey items. Four of the hospitals were selected at random to provide training data and that was used in a recursive partitioning analysis to predict the B group. Data on patients in the other four facilities were used for validation. Results: There were a total of 400 patients studied. The training set consisted of 261 patients, 50 of whom were classified into the B group. A total of 94% patients with hemorrhagic shock suspected clinically, shock index at admission (first SI) ≥0.8, and SI at 1 L of fluid resuscitation (second SI) ≥1.0 were assigned to the B group. The non-B group (92%) were patients those whose first SI was <0.8 and base deficits at admission ≥-1.0. Validation data consisted of 139 patients. The sensitivity, specificity, and accuracy of these data to predict the B group were 71%, 93%, and 89%, respectively. Conclusions: Patients whose first SI was ≥0.8 and second SI ≥1.0 would be diagnosed as "nonresponders" by American College of Surgeons. Patients with first SI <0.8 and base deficits ≥-1.0 will not be candidates for the B group. Copyright © 2010 by Lippincott Williams & Wilkins.

The ABLS course sponsored by the ABA has not yet been made available in Japan, although it is strongly desired. During the 3 years between 2006 and 2008, authorized ABLS provider courses were given once a year in Japan as part of preparations to reach an agreement between the ABA and the JSBI for the continuation of ABLS provider courses in Japan. These courses were provided as one of the programs available at the annual meeting of the JSBI. Nine Japanese registered ABLS instructors (including some candidates) acted as lecturers. Two national faculty members and one course coordinator, acting as ABA observers, participated in the first and second courses. In total, 64 physicians (37 emergency physicians, 20 plastic surgeons, 4 intensivists and 3 general surgeons) attended the courses. Course management and instructor behavior were reviewed by the ABA observers and the 64 physicians in attendance using questionnaires. The ABA observers rated the courses as "outstanding" in every aspect (course faculty, facilities, course organization, course conduct, and adherence to ABLS philosophies). The pre-course planning, course conduct, and course evaluations were professional and adhered to the highest educational standards. However, several areas of the ABLS course content may require revision to accommodate differences in standard medical treatment between the United States and Japan. Two percent of the physicians rated the courses as easy, 59% rated the course as moderate, 22% rated the course as slightly difficult, and 6% rated the course as difficult. The courses were generally evaluated as very good by 28% of the physicians and good by 56%. The major opinion regarding the organization of the course in Japan was that the course should have undergone appropriate curriculum changes to accommodate societal differences (including the translation of the course into Japanese) as well as modifications to the disaster management and patient transport sections. Regarding the organization of future ABLS courses in Japan, the active involvement of the JSBI is inevitable. Several areas of the ABLS course content may need to be revised to accommodate differences in standard medical treatment between the United States and Japan. A joint effort between the ABA and the JSBI regarding appropriate curriculum changes to accommodate societal differences as well as modifications to some sections would increase the applicability of the course in Japan. © 2009 Elsevier Ltd and ISBI.

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 vitro for the elucidation of immunologic mechanisms. Unexpectedly, the liver IL-18 decreased transiently after burn injury, and in vivo IL-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-α, and IL-10 was augmented, whereas in vivo IL-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 vivo acceleration of IL-10 production, and could thus be an effective prophylactic strategy against septic complications in critically ill patients. © 2009 by the Shock Society.

Critically ill patients are commonly associated with systemic inflammatory response syndrome (SIRS) and are at a greater risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Under these conditions, large amounts of various cytokines are produced, which either directly or indirectly induce tissue injury and finally organ dysfunctions, through the activation of neutrophils and as a result of release of cytotoxic molecules, especially neutrophil elastase (NE). In the present study, we determined plasma neutrophil elastase-alpha-1 antitrypsin complex (NE-AT) and elastase digests of cross-linked fibrin (e-XDP) in critically ill patients to elucidate the significance of NE in the initiation and progression of ALI and ARDS in the presence or absence of SIRS. We found significantly increased levels of plasma NE-AT in the patients with ARDS, especially when the definition of SIRS was met. Among ALI/ARDS groups, plasma NE-AT, but not e-XDP, correlated significantly with the decrease in PaO2/FIO2 ratio and the duration of ALI/ARDS. Furthermore, NE-AT, but not e-XDP, significantly increased in subgroups whose PaO2/FIO2 ratio decreased by more than 20%. Such correlations and differences between the subgroups were not observed in the non-ALI patients. From these results, we speculate that NE-AT, but not e-XDP, may be predictive of progressive lung injury in the early stage of ALI and ARDS. © 2007 Elsevier Masson SAS. All rights reserved.

Background: Sepsis is an arginine-deficient state and is associated with overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). It has been indicated that low plasma levels of arginine are related to high mortality rates in sepsis. Arginine, however, is also known to be a precursor of NO. Therefore, administration of arginine in septic patients remains controversial. We examined the effects of co-administration of arginine and aminoguanidine, a selective iNOS inhibitor, on sepsis, using rat models. Method: Sepsis was induced in rats by cecal ligation and puncture (CLP). Effects of separate and combined administration of arginine and aminoguanidine were investigated by comparing plasma levels of arginine, expressions of heme oxygenase (HO)-1 and HO-2 in liver and lung, and nitrite + nitrate (NOx) excretion in urine, as well as neuroendocrine responses in urine in the early phase of sepsis. Seven-day survival rates were also examined. Results: A combination of arginine and aminoguanidine recovered the plasma level of arginine at 6 h post-CLP, decreased expression of HO-1 in liver and lung at 24 h post-CLP, decreased urinary excretion of epinephrine, norepinephrine, dopamine, and 17-hydroxycorticosteroid in the first 24 h post-CLP, and increased 7-d survival. Conclusion: It is demonstrated that administration of arginine together with the selective iNOS inhibitor in the early phase of sepsis restores plasma arginine, reduces oxidative stress by probably maintaining NO derived from constitutive NOS, and attenuates neuroendocrine stress responses. This co-administration may be a beneficial treatment approach against sepsis. © 2008 Elsevier Inc. All rights reserved.

Background: We prospectively evaluated whether computed tomographic (CT) scanning and selective laparoscopy (LP) for the diagnosis of blunt bowel injury (BBI) could prevent nontherapeutic laparotomy and delayed diagnosis. Methods: Between April 1994 and May 2002, hemodynamically stable patients suspected of having BBI were enrolled in this study. Patients with hemodynamic instability or solid organ injuries with hemoperitoneum were excluded. All patients underwent a physical examination and contrast CT scanning at admission and once again approximately 12 hours (range, 6-24 hours) after admission. LP was performed under general anesthesia in patients who had local peritoneal signs and indirect CT signs (bowel thickening or isolated intraperitoneal fluid) or in whom abdominal pain or tenderness increased or intraperitoneal fluid increased on the repeat CT scan. The indications for a celiotomy were diffuse peritonitis, pneumoperitoneum on the abdominal CT scan, or bowel perforation visible on LP. Results: During the study period, 399 of 1,074 patients admitted for blunt torso injuries were enrolled in this study. Eleven patients underwent emergency celiotomy and 11 underwent LP immediately after admission to the emergency department. One nontherapeutic laparotomy was performed among the patients who underwent celiotomy. The LPs revealed seven bowel perforations and one mesenteric laceration. After a repeat CT scan, three and seven of the patients underwent laparotomy and LP, respectively. Four bowel perforations were found by LP. The remaining 198 patients were treated conservatively, and no complications related to a delayed BBI diagnosis occurred. Conclusion: CT scanning and selective LP can prevent nontherapeutic laparotomy and delayed diagnosis in patients with suspected BBI. Copyright © 2005 by Lippincott Williams & Wilkins, Inc.

Many patients who experience surgical stress, including burn injury, become susceptible to severe sepsis and septic organ dysfunction, which remains the primary contributor to morbidity and mortality in burn patients. In the present study, we developed a murine model of burn-primed sublethal endotoxemia by producing a 15% BSA full-thickness burn on the dorsum of BALB/c mice under ether anesthesia and administering 10 mg/kg of LPS intravenously on day 11 to model endotoxemia. The prior burn injury in this model induced two-peaked production of cytokines, TNF-α, and macrophage inflammatory protein-2 at 2 and 12 h after LPS administration, and it was associated with increased mortality. We also assessed the effect of pharmacological modulation with cytokine synthesis inhibitors prednisolone and JTE-607 and found that pretreatment with them attenuated later cytokine production and decreased mortality after LPS administration. We speculate that the prior burn injury primed the mice for the secondary insult via cytokine production. These results also suggested that an anticytokine strategy might serve as a novel prophylactic therapy for septic organ dysfunction in burn-primed patients.