Kohji Okamoto

TG13 diagnostic criteria and severity grading of acute cholecystitis (with videos)

Since its publication in 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) have been widely adopted. The validation of TG07 conducted in terms of clinical practice has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. Discussion by the Tokyo Guidelines Revision Committee concluded that acute cholecystitis should be suspected when Murphy’s sign, local inflammatory findings in the gallbladder such as right upper quadrant abdominal pain and tenderness, and fever and systemic inflammatory reaction findings detected by blood tests are present but that definite diagnosis of acute cholecystitis can be made only on the basis of the imaging of ultrasonography, computed tomography or scintigraphy (HIDA scan). These proposed diagnostic criteria provided better specificity and accuracy rates than the TG07 diagnostic criteria. As for the severity assessment criteria in TG07, there is evidence that TG07 resulted in clarification of the concept of severe acute cholecystitis. Furthermore, there is evidence that severity assessment in TG07 has led to a reduction in the mean duration of hospital stay. As for the factors used to establish a moderate grade of acute cholecystitis, such as leukocytosis, ALP, old age, diabetes, being male, and delay in admission, no new strong evidence has been detected indicating that a change in the criteria used in TG07 is needed. Therefore, it was judged that the severity assessment criteria of TG07 could be applied in the updated Tokyo Guidelines (TG13) with minor changes. TG13 presents new standards for the diagnosis, severity grading and management of acute cholecystitis.Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

TG13: Updated Tokyo Guidelines for the management of acute cholangitis and cholecystitis

In 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were first published in the Journal of Hepato-Biliary-Pancreatic Surgery. The fundamental policy of TG07 was to achieve the objectives of TG07 through the development of consensus among specialists in this field throughout the world. Considering such a situation, validation and feedback from the clinicians’ viewpoints were indispensable. What had been pointed out from clinical practice was the low diagnostic sensitivity of TG07 for acute cholangitis and the presence of divergence between severity assessment and clinical judgment for acute cholangitis. In June 2010, we set up the Tokyo Guidelines Revision Committee for the revision of TG07 (TGRC) and started the validation of TG07. We also set up new diagnostic criteria and severity assessment criteria by retrospectively analyzing cases of acute cholangitis and cholecystitis, including cases of non-inflammatory biliary disease, collected from multiple institutions. TGRC held meetings a total of 35 times as well as international email exchanges with co-authors abroad. On June 9 and September 6, 2011, and on April 11, 2012, we held three International Meetings for the Clinical Assessment and Revision of Tokyo Guidelines. Through these meetings, the final draft of the updated Tokyo Guidelines (TG13) was prepared on the basis of the evidence from retrospective multi-center analyses. To be specific, discussion took place involving the revised new diagnostic criteria, and the new severity assessment criteria, new flowcharts of the management of acute cholangitis and cholecystitis, recommended medical care for which new evidence had been added, new recommendations for gallbladder drainage and antimicrobial therapy, and the role of surgical intervention. Management bundles for acute cholangitis and cholecystitis were introduced for effective dissemination with the level of evidence and the grade of recommendations. GRADE systems were utilized to provide the level of evidence and the grade of recommendations. TG13 improved the diagnostic sensitivity for acute cholangitis and cholecystitis, and presented criteria with extremely low false positive rates adapted for clinical practice. Furthermore, severity assessment criteria adapted for clinical use, flowcharts, and many new diagnostic and therapeutic modalities were presented. The bundles for the management of acute cholangitis and cholecystitis are presented in a separate section in TG13.Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

Expert consensus for the treatment of disseminated intravascular coagulation in Japan

The present report from The Japanese Society of Thrombosis and Hemostasis provides an expert consensus for the treatment of disseminated intravascular coagulation (DIC) in Japan. Disseminated intravascular coagulation (DIC) may be classified as follows: asymptomatic type, marked bleeding type, and organ failure type. Although treatment of DIC is important, adequate treatment differs according to type of DIC. In asymptomatic DIC, low molecular weight heparin (LMWH), synthetic protease inhibitor (SPI), and antithrombin (AT) are recommended, although these drugs have not yet been proved to have a high degree of effectiveness. Unfractionated heparin (UFH) and danaparoid sodium (DS) are sometimes administrated in this type, but their usefulness is not clear. In the marked bleeding type, LMWH, SPI, and AT are recommended although these drugs do not have high quality of evidence. LMWH, UFH, and DS are not recommended in case of life threatening bleeding. In case of severe bleeding, SPI is recommended since it does not cause a worsening of bleeding. Blood transfusions, such as fresh frozen plasma and platelet concentrate, are also required in cases of life threatening bleeding. In the organ failure type, including sepsis, AT has been recommended based on the findings of several clinical trials. DIC is frequently associated with thrombosis and may thus require strong anticoagulant therapy, such as LMWH, UFH, and DS.

Proteolytic Cleavage of High Mobility Group Box 1 Protein by Thrombin-Thrombomodulin Complexes

Objective—High mobility group box 1 protein (HMGB1) was identified as a mediator of endotoxin lethality. We previously reported that thrombomodulin (TM), an endothelial thrombin-binding protein, bound to HMGB1, thereby protecting mice from lethal endotoxemia. However, the fate of HMGB1 bound to TM remains to be elucidated. Methods and Results—TM enhanced thrombin-mediated cleavage of HMGB1. N-terminal amino acid sequence analysis of the HMGB1 degradation product demonstrated that thrombin cleaved HMGB1 at the Arg10-Gly11 bond. Concomitant with the cleavage of the N-terminal domain of HMGB1, proinflammatory activity of HMGB1 was significantly decreased (P<0.01). HMGB1 degradation products were detected in the serum of endotoxemic mice and in the plasma of septic patients with disseminated intravascular coagulation (DIC), indicating that HMGB1 could be degraded under conditions in which proteases were activated in the systemic circulation. Conclusions—TM not only binds to HMGB1 but also aids the proteolytic cleavage of HMGB1 by thrombin. These findings highlight the novel antiinflammatory role of TM, in which thrombin–TM complexes degrade HMGB1 to a less proinflammatory form.

TG13 flowchart for the management of acute cholangitis and cholecystitis

We propose a management strategy for acute cholangitis and cholecystitis according to the severity assessment. For Grade I (mild) acute cholangitis, initial medical treatment including the use of antimicrobial agents may be sufficient for most cases. For non-responders to initial medical treatment, biliary drainage should be considered. For Grade II (moderate) acute cholangitis, early biliary drainage should be performed along with the administration of antibiotics. For Grade III (severe) acute cholangitis, appropriate organ support is required. After hemodynamic stabilization has been achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. In patients with Grade II (moderate) and Grade III (severe) acute cholangitis, treatment for the underlying etiology including endoscopic, percutaneous, or surgical treatment should be performed after the patient’s general condition has been improved. In patients with Grade I (mild) acute cholangitis, treatment for etiology such as endoscopic sphincterotomy for choledocholithiasis might be performed simultaneously, if possible, with biliary drainage. Early laparoscopic cholecystectomy is the first-line treatment in patients with Grade I (mild) acute cholecystitis while in patients with Grade II (moderate) acute cholecystitis, delayed/elective laparoscopic cholecystectomy after initial medical treatment with antimicrobial agent is the first-line treatment. In non-responders to initial medical treatment, gallbladder drainage should be considered. In patients with Grade III (severe) acute cholecystitis, appropriate organ support in addition to initial medical treatment is necessary. Urgent or early gallbladder drainage is recommended. Elective cholecystectomy can be performed after the improvement of the acute inflammatory process.Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey.

Objective:To survey the natural history of disseminated intravascular coagulation (DIC) in patients diagnosed according to the Japanese Association for Acute Medicine (JAAM) DIC scoring system in a critical care setting. Design:Prospective, multicenter study during a 4-month period. Setting:General critical care center in a tertiary care hospital. Patients:All patients were enrolled when they were diagnosed as DIC by the JAAM DIC scoring system. Interventions:None. Measurements and Main Results:Platelet counts, prothrombin time ratio, fibrinogen, and fibrin/fibrinogen degradation products were measured, and the systemic inflammatory response syndrome criteria met by the patients were determined following admission. Of 3,864 patients, 329 (8.5%) were diagnosed with DIC and the 28-day mortality rate was 21.9%, which was significantly different from that of the non-DIC patients (11.2%) (p < .0001). The progression of systemic inflammation, deterioration of organ function, and stepwise increase in incidence of the International Society on Thrombosis and Haemostasis (ISTH) DIC and its scores all correlated with an increase in the JAAM DIC score as demonstrated by the patients on day 0. There were significant differences in the JAAM DIC score and the variables adopted in the scoring system between survivors and nonsurvivors. The logistic regression analyses showed the JAAM DIC score and prothrombin time ratio on the day of DIC diagnosis to be predictors of patient outcome. The patients who simultaneously met the ISTH DIC criteria demonstrated twice the incidence of multiple organ dysfunction (61.1 vs. 30.5%, p < .0001) and mortality rate (34.4 vs. 17.2%, p = .0015) compared with those without the ISTH DIC diagnosis. Conclusions:This prospective survey demonstrated the natural history of DIC patients diagnosed by the JAAM DIC diagnostic criteria in a critical care setting. The study provides further evidence of a progression from the JAAM DIC to the ISTH overt DIC.

High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice

Islet transplantation for the treatment of type 1 diabetes mellitus is limited in its clinical application mainly due to early loss of the transplanted islets, resulting in low transplantation efficiency. NKT cell-dependent IFN-gamma production by Gr-1(+)CD11b(+) cells is essential for this loss, but the upstream events in the process remain undetermined. Here, we have demonstrated that high-mobility group box 1 (HMGB1) plays a crucial role in the initial events of early loss of transplanted islets in a mouse model of diabetes. Pancreatic islets contained abundant HMGB1, which was released into the circulation soon after islet transplantation into the liver. Treatment with an HMGB1-specific antibody prevented the early islet graft loss and inhibited IFN-gamma production by NKT cells and Gr-1(+)CD11b(+) cells. Moreover, mice lacking either of the known HMGB1 receptors TLR2 or receptor for advanced glycation end products (RAGE), but not the known HMGB1 receptor TLR4, failed to exhibit early islet graft loss. Mechanistically, HMGB1 stimulated hepatic mononuclear cells (MNCs) in vivo and in vitro; in particular, it upregulated CD40 expression and enhanced IL-12 production by DCs, leading to NKT cell activation and subsequent NKT cell-dependent augmented IFN-gamma production by Gr-1(+)CD11b(+) cells. Thus, treatment with either IL-12- or CD40L-specific antibody prevented the early islet graft loss. These findings indicate that the HMGB1-mediated pathway eliciting early islet loss is a potential target for intervention to improve the efficiency of islet transplantation.

Surgical stress induces endotoxin hyporesponsiveness and an early decrease of monocyte mCD14 and HLA-DR expression during surgery.

It is generally accepted that major surgery is associated with severe alterations of the host-defense mechanisms. We investigated the effect of surgical stress on the immune system. Specifically, we studied the relationship between perioperative lipopolysaccharide (LPS) hyporesponsiveness and monocyte human leukocyte antigen-DR (HLA-DR) and CD14 expression during the perioperative period in 20 patients who underwent partial gastrectomy. This study demonstrated that surgical stress rapidly depressed monocyte mCD14 and HLA-DR expression in comparison with preanesthesia levels. Monocyte mCD14 expression recovered to preoperative levels on the first postoperative day, and monocyte HLA-DR expression recovered by the seventh postoperative day. Consistent with our previous study, LPS-induced tumor necrosis factor (TNF)-&agr; production ex vivo was significantly suppressed from the beginning of the operation. On the contrary, the plasma interleukin-10 concentration started to increase after the surgical incision was made. LPS hyporesponsiveness was least at the end of the operation and returned to preoperative levels on the first postoperative day. In conclusion, the present study demonstrated that LPS responsiveness, plasma interleukin-10 concentration, and monocytes mCD14 and HLA-DR expression altered from the early period of surgery. These alterations may be related to the impairment of the immune system during the perioperative period.

Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia.

Objective: In addition to the hyperactivation of the inflammatory cytokines, high-mobility group box-1 protein (HMGB1), recently identified as a lethal late-phase mediator is suspected to be closely correlated with the development of sepsis. Therefore, the therapeutic efficacy of recombinant human soluble thrombomodulin (ART-123) administration on the production of inflammatory cytokines and the plasma level of HMGB1 was investigated in experimental endotoxemia. Design: Prospective, comparative, experimental study. Setting: Laboratory animal research center at a university. Subjects: Male Sprague-Dawley rats (250–300 g). Interventions: Endotoxemia was induced in rats by a bolus intravenous injection of lipopolysaccharide (LPS) at a dosage of 4 mg/kg (LPS group). ART-123 (1 mg/kg) was administered as a bolus injection 30 minutes before or 4 hours after injection of LPS (ART-123 pretreated/treated group). As a control, an equal volume of physiologic saline was administered instead of LPS and ART-123 (control group). Measurements and Main Results: Rats were randomly divided into ART-123 pretreated group, ART-123 treated group, and LPS group, respectively. After the injection of LPS, the levels of inflammatory cytokines and thrombin–antithrombin III complex, plasma HMGB1 concentrations, liver immunohistochemical and histopathologic characteristics, liver dysfunction, and survival rate were examined. The increased levels of inflammatory cytokines and plasma HMGB1 induced by LPS in this rat model were improved by the administration of ART-123; additionally, reduced liver dysfunction and increased survival rate were observed. Conclusions: This study demonstrated that ART-123 inhibits the expression of inflammatory cytokines and decreases the plasma HMGB1 levels in experimental endotoxemia. In addition, ART-123 administration markedly reduced liver dysfunction and mortality even with delayed treatment of ART-123. The use of ART-123 may therefore be a beneficial treatment for septic patients.

Evaluation of New Japanese Diagnostic Criteria for Disseminated Intravascular Coagulation in Critically Ill Patients

New Japanese diagnostic criteria were prepared for disseminated intravascular coagulation (DIC) in critically ill patients and their usefulness was compared with the criteria of the International Society of Thrombosis and Haemostasis (ISTH) and those of the Japan Ministry of Health and Welfare (JMHW). In a retrospective study of patients with platelet counts of less than 150 × 103/mL, 52 cases (33.3%), 66 cases (42.3%), and 101 cases (64.7%) were diagnosed as DIC by the ISTH, JMHW, and new Japanese DIC criteria, respectively. The DIC state as diagnosed by the new Japanese DIC criteria included both DIC states as diagnosed by ISTH or JMHW criteria. Some DIC states diagnosed by the JMHW criteria included those diagnosed by ISHT criteria but this was not universal. The mortality of DIC as diagnosed by the ISTH or JMHW criteria was markedly high, compared to that for DIC diagnosed by the new Japanese criteria. The mortality of patients without DIC by ISTH was also high when they were diagnosed as DIC by the new Japanese criteria. The frequency of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection. The mortality of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection, and the mortality of overt-DIC by ISTH diagnostic criteria was also high in patients without infection.