The Japanese clinical practice guideline for acute kidney injury 2016.

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention is necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search.

Differential pattern of cell-surface and soluble TREM-1 between sepsis and SIRS.

OBJECTIVE: Triggering receptor expressed on myeloid cells-1 (TREM-1) was reported to play a key roll in amplification of production of inflammatory cytokines. TREM-1 is suggested to be a specific biomarker for sepsis for this reason, but the clinical significance of TREM-1 has not been elucidated. We investigated TREM-1 expression on the cell-surface, and plasma levels of soluble TREM-1 (sTREM-1) in patients with non-infectious systemic inflammatory response syndrome (SIRS) and sepsis admitted to the ICU. METHODS: Thirty-five patients with SIRS and 21 patients with sepsis admitted to ICU were subjected to the study. TREM-1 expressions on the surfaces of monocytes and neutrophils were measured by flow cytometry. Plasma sTREM-1 level and serum interleukin (IL)-6 level were measured. RESULTS: Septic patients had decreased TREM-1 expression, clearly on neutrophils or to a lesser extent on monocyte compared to SIRS patients on ICU admission (neutrophils p<0.001, monocyte p<0.05). TREM-1 expression on neutrophils had a significant inverse correlation with serum IL-6 level (r=-0.64, p<0.0001). Plasma sTREM-1 level in septic patients was significantly higher than that in SIRS patients (p<0.05). Plasma sTREM-1 level positively correlated with severity score and non-survivors had increased plasma sTREM-1 level compared to survivors in all SIRS/sepsis patients (p<0.05). CONCLUSIONS: Patients with sepsis had increased soluble TREM-1 and decreased TREM-1 expression on neutrophil compared to SIRS patients. sTREM-1 may be useful to evaluate disease severity and outcome of patients with SIRS or sepsis.

Urinary neutrophil gelatinase-associated lipocalin and plasma IL-6 in discontinuation of continuous venovenous hemodiafiltration for severe acute kidney injury: a multicenter prospective observational study.

BACKGROUND: Patients with severe acute kidney injury (AKI) who require continuous venovenous hemodiafiltration (CVVHDF) in intensive care unit (ICU) are at high mortality risk. Little is known about clinical biomarkers for risk prediction, optimal initiation, and optimal discontinuation of CVVHDF. METHODS: This prospective observational study was conducted in seven university-affiliated ICUs. For urinary neutrophil gelatinase-associated lipocalin (NGAL) and plasma IL-6 measurements, samples were collected at initiation, 24 h, 48 h after, and CVVHDF discontinuation in adult patients with severe AKI. The outcomes were deaths during CVVHDF and CVVHDF dependence. RESULTS: A total number of 133 patients were included. Twenty-eight patients died without CVVHDF discontinuation (CVVHDF nonsurvivors). Urinary NGAL and plasma IL-6 at the CVVHDF initiation were significantly higher in CVVHDF nonsurvivors than in survivors. Among 105 CVVHDF survivors, 70 patients were free from renal replacement therapy (RRT) or death in the next 7 days after discontinuation (success group), whereas 35 patients died or needed RRT again (failure group). Urinary NGAL at CVVHDF discontinuation was significantly lower in the success group (93.8 ng/ml vs. 999 ng/ml, p < 0.01), whereas no significant difference was observed in plasma IL-6 between the groups. Temporal elevations of urinary NGAL levels during the first 48 h since CVVHDF initiation were observed in CVVHDF nonsurvivors and those who failed in CVVHDF discontinuation. CONCLUSIONS: Urinary NGAL at CVVHDF initiation and discontinuation was associated with mortality and RRT dependence, respectively. The serial changes of urinary NGAL might also help predict the prognosis of patients with AKI on CVVHDF.

Effects of a peripheral cholinesterase inhibitor on cytokine production and autonomic nervous activity in a rat model of sepsis.

PURPOSE: Recently, cholinergic anti-inflammatory pathway manipulation has been proposed as a new strategy to control cytokine production in sepsis. We investigated whether hypercytokinemia can be controlled via this pathway in an animal model of sepsis, with concomitant monitoring of autonomic nervous activity involving heart rate variability (HRV) analysis of electrocardiographic R-R intervals. METHODS: Sixty-eight adult male Sprague-Dawley rats were used (28 for examination of cytokine production and autonomic nervous activity; 40 for survival analysis). Each part of the study involved four animal groups, including two control groups without drug administration. Sepsis was induced by cecal ligation and puncture (CLP). Distigmine bromide, a peripheral, non-selective cholinesterase inhibitor (0.01mg/kg), was administered subcutaneously 90 min after surgery. Continuous electrocardiograms were recorded for 5 min before and after surgery (at intervals of 5h) in CLP and sham-operated animals for HRV analysis. Blood samples were collected 20 h after surgery for serum cytokine and catecholamine assay. RESULTS: On HRV analysis, distigmine inhibited reduction of total power and high-frequency components in CLP animals (P<0.05). Distigmine significantly inhibited cytokine induction (IL-6 and IL-10) (P<0.01) as well as increase in serum levels of noradrenaline and dopamine (P<0.05). Distigmine did not significantly improve CLP animal survival rate. CONCLUSIONS: The cholinesterase inhibitor distigmine inhibited induction of inflammatory cytokines and catecholamines as well as HRV suppression in a rat CLP model, suggesting that an agent modulating the cholinergic anti-inflammatory pathway can control excess cytokine production involved in the pathogenesis of severe sepsis/septic shock.

Correlation between high blood IL-6 level, hyperglycemia, and glucose control in septic patients.

INTRODUCTION: The aim of the present study was to investigate the relationship between the blood IL-6 level, the blood glucose level, and glucose control in septic patients. METHODS: This retrospective observational study in a general ICU of a university hospital included a total of 153 patients with sepsis, severe sepsis, or septic shock who were admitted to the ICU between 2005 and 2010, stayed in the ICU for 7 days or longer, and did not receive steroid therapy prior to or after ICU admission. The severity of stress hyperglycemia, status of glucose control, and correlation between those two factors in these patients were investigated using the blood IL-6 level as an index of hypercytokinemia. RESULTS: A significant positive correlation between blood IL-6 level and blood glucose level on ICU admission was observed in the overall study population (n = 153; r = 0.24, P = 0.01), and was stronger in the nondiabetic subgroup (n = 112; r = 0.42, P < 0.01). The rate of successful glucose control (blood glucose level < 150 mg/dl maintained for 6 days or longer) decreased with increase in blood IL-6 level on ICU admission (P < 0.01). The blood IL-6 level after ICU admission remained significantly higher and the 60-day survival rate was significantly lower in the failed glucose control group than in the successful glucose control group (P < 0.01 and P < 0.01, respectively). CONCLUSIONS: High blood IL-6 level was correlated with hyperglycemia and with difficulties in glucose control in septic patients. These results suggest the possibility that hypercytokinemia might be involved in the development of hyperglycemia in sepsis, and thereby might affect the success of glucose control.

Duration of well-controlled core temperature correlates with neurological outcome in patients with post-cardiac arrest syndrome.

PURPOSE: Detailed procedures for optimal therapeutic hypothermia (TH) have yet to be established. We examined how duration of well-controlled core temperature within the first 24 hours after cardiac arrests (CA) correlated with neurological outcomes of successfully resuscitated out-of-hospital CA (OHCA) patients. METHODS: OHCA patients who survived over 24 hours and treated with TH were included. Core temperature was measured every hour. Physicians intended to maintain temperature at 33 °C ± 1 °C for 24 hours. Cerebral performance categories (CPC) of patients at 6 months were recorded and patients were retrospectively divided into favorable (CPC1,2) and poor (CPC3-5) neurological outcome groups. Total time while the core temperature reached to 33 °C ± 1 °C within the first 24 hours after CA was measured and this duration was defined that of well-controlled temperature. receiver-operating characteristic analysis was performed on duration of well-controlled temperature to select the optimal cutoff value. Neurological outcome predictors were investigated by logistic regression analysis. RESULTS: Fifty-six patients were included. Optimal cutoff value of duration of well-controlled temperature was 18 hours. Ratio of male sex, witnessed by emergency medical service (EMS) personnel, first electrocardiogram as shockable, and duration of well-controlled core temperature ≥ 18 h of favorable neurological outcome group (n = 21) were significantly larger than that of poor neurological outcome group (n = 35). Logistic regression analysis identified "witnessed by EMS", "performed bystander CPR," and "the duration ≥ 18 h" as independent predictors of favorable neurological outcome. CONCLUSION: TH maintained at target temperature of 33 °C ± 1 °C over 18 hours independently correlated with favorable neurological outcome. Therefore, stable core temperature control may improve neurological outcome of successfully resuscitated OHCA.

Outcome prediction in sepsis combined use of genetic polymorphisms - A study in Japanese population.

Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n=123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF -308GA, IL1ß -31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC-AUC=0.68), use of APACHE II score and two genetic parameters (TNF -308 and IL1ß -31) enabled more accurate prediction of ICU mortality (ROC-AUC=0.80). Significant association of two genetic polymorphisms, TNF -308 and IL1ß -31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients.

Comparison of interleukin-6 removal properties among hemofilters consisting of varying membrane materials and surface areas: an in vitro study.

BACKGROUND/AIMS: We sought to identify the most relevant hemofilter for cytokine removal based on the mechanisms of filtration and adsorption. METHODS: Ascites were filtered using four types of hemofilters composed of different membrane materials (polymethyl methacrylate, PMMA, cellulose triacetate, CTA, or polysulfone, PS) and different surface areas (1.0 or 2.1 m(2)) to investigate the rate of interleukin-6 (IL-6) filtration. Next, ascites were perfused through each hemofilter without obtaining a filtrate to study each filter's adsorptive capability. RESULTS: The PMMA hemofilters resulted in a marginal observed IL-6 filtration rates, whereas the CTA and PS hemofilters resulted in highly effective IL-6 filtration. Regarding the IL-6 adsorptive capabilities of the filters, the PMMA hemofilter with a large surface area showed the highest level of IL-6 clearance. CONCLUSION: The present findings suggest that when cytokine removal based on filtration is desired, CTA or PS hemofilters should be selected. When IL-6 removal based on adsorption is desired, a PMMA hemofilter with a large surface area should be selected.

Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia.

INTRODUCTION: Bacteremia is recognized as a critical condition that influences the outcome of sepsis. Although large-scale surveillance studies of bacterial species causing bacteremia have been published, the pathophysiological differences in bacteremias with different causative bacterial species remain unclear. The objective of the present study is to investigate the differences in pathophysiology and the clinical course of bacteremia caused by different bacterial species. METHODS: We reviewed the medical records of all consecutive patients admitted to the general intensive care unit (ICU) of a university teaching hospital during the eight-year period since introduction of a rapid assay for interleukin (IL)-6 blood level to routine ICU practice in May 2000. White blood cell count, C-reactive protein (CRP), IL-6 blood level, and clinical course were compared among different pathogenic bacterial species. RESULTS: The 259 eligible patients, as well as 515 eligible culture-positive blood samples collected from them, were included in this study. CRP, IL-6 blood level, and mortality were significantly higher in the septic shock group (n = 57) than in the sepsis group (n = 127) (P < 0.001). The 515 eligible culture-positive blood samples harbored a total of 593 isolates of microorganisms (Gram-positive, 407; Gram-negative, 176; fungi, 10). The incidence of Gram-negative bacteremia was significantly higher in the septic shock group than in the sepsis group (P < 0.001) and in the severe sepsis group (n = 75, P < 0.01). CRP and IL-6 blood level were significantly higher in Gram-negative bacteremia (n = 176) than in Gram-positive bacteremia (n = 407) (P < 0.001, <0.0005, respectively). CONCLUSIONS: The incidence of Gram-negative bacteremia was significantly higher in bacteremic ICU patients with septic shock than in those with sepsis or severe sepsis. Furthermore, CRP and IL-6 levels were significantly higher in Gram-negative bacteremia than in Gram-positive bacteremia. These findings suggest that differences in host responses and virulence mechanisms of different pathogenic microorganisms should be considered in treatment of bacteremic patients, and that new countermeasures beyond conventional antimicrobial medications are urgently needed.

Efficacy of direct hemoperfusion for the removal of phenobarbital through blood concentration analysis.

AIM: Phenobarbital overdose can cause coma and even death. The consciousness disturbance is often prolonged due to its long half-life. In this study, we investigated the efficacy of direct hemoperfusion (DHP) for the removal of phenobarbital by measuring the blood levels of phenobarbital. METHODS: Study subjects included five patients with phenobarbital poisoning who were transferred to our hospital. Direct hemoperfusion was carried out in three of the five patients (six times in total), and the elimination rate was calculated by measuring the blood levels before and after DHP. Furthermore, the disappearance rate of phenobarbital without DHP was calculated in all five patients (seven times in total) for comparison with the elimination rate. RESULTS: The elimination rate of phenobarbital with DHP was significantly higher than the disappearance rate without DHP．. CONCLUSION: This study suggests that early introduction of DHP should be considered as a treatment option for phenobarbital poisoning.

The effects of body temperature control on cytokine production in a rat model of ventilator-induced lung injury.

BACKGROUND AND PURPOSE: Injurious ventilation with high peak inspiratory pressure (PIP) is known to cause systemic inflammatory response through cytokine production. This study was performed to examine whether body temperature could regulate cytokine production in ventilator-induced lung injury (VILI) model. METHODS: After performing anesthesia, tracheostomy, and catheter insertion, rats were ventilated with 17cmH(2)O of PIP in the low-pressure (LP) group or 35cmH(2)O in the high-pressure (HP) group. Then, each group was divided into three subgroups; hyperthermia (39 degrees C), normothermia (37 degrees C), and hypothermia (34 degrees C) group. Six groups were observed for 6h. RESULTS: Plasma levels of pro-inflammatory cytokines, TNF-a and IL-6 at 1h after the start of observation were highest in 39 degrees C-HP group and were lowest in 34 degrees C-HP group. Furthermore, sustained high plasma levels of IL-6 were observed only in 39 degrees C-HP group. In contrast, plasma levels of anti-inflammatory cytokine, IL-10 at 1h were highest in 34 degrees C-HP group, and lowest in 39 degrees C-HP group. CONCLUSION: The body temperature significantly affects cytokine production in a model of VILI. Body temperature control may be a potentially effective therapeutic modality to regulate cytokine production in VILI.

S-100B and neuron-specific enolase as predictors of neurological outcome in patients after cardiac arrest and return of spontaneous circulation: a systematic review.

INTRODUCTION: Neurological prognostic factors after cardiopulmonary resuscitation (CPR) in patients with cardiac arrest (CA) as early and accurately as possible are urgently needed to determine therapeutic strategies after successful CPR. In particular, serum levels of protein neuron-specific enolase (NSE) and S-100B are considered promising candidates for neurological predictors, and many investigations on the clinical usefulness of these markers have been published. However, the design adopted varied from study to study, making a systematic literature review extremely difficult. The present review focuses on the following three respects for the study design: definitions of outcome, value of specificity and time points of blood sampling. METHODS: A Medline search of literature published before August 2008 was performed using the following search terms: "NSE vs CA or CPR", "S100 vs CA or CPR". Publications examining the clinical usefulness of NSE or S-100B as a prognostic predictor in two outcome groups were reviewed. All publications met with inclusion criteria were classified into three groups with respect to the definitions of outcome; "dead or alive", "regained consciousness or remained comatose", and "return to independent daily life or not". The significance of differences between two outcome groups, cutoff values and predictive accuracy on each time points of blood sampling were investigated. RESULTS: A total of 54 papers were retrieved by the initial text search, and 24 were finally selected. In the three classified groups, most of the studies showed the significance of differences and concluded these biomarkers were useful for neurological predictor. However, in view of blood sampling points, the significance was not always detected. Nevertheless, only five studies involved uniform application of a blood sampling schedule with sampling intervals specified based on a set starting point. Specificity was not always set to 100%, therefore it is difficult to indiscriminately assess the cut-off values and its predictive accuracy of these biomarkers in this meta analysis. CONCLUSIONS: In such circumstances, the findings of the present study should aid future investigators in examining the clinical usefulness of these markers and determination of cut-off values.

Continuous hemodiafiltration in the treatment of reactive hemophagocytic syndrome refractory to medical therapy.

Reactive (or secondary) hemophagocytic syndrome (RHS) is a potentially lethal condition and characterized by hypercytokinemia. Immune modulating drugs sometimes fail to achieve satisfactory control. Therefore we investigate the efficacy of continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter (PMMA-CHDF) for cytokine removal in patients with RHS. Eight consecutive patients who admitted to our ICU with RHS complicating organ failures and refractory to medical therapy were initiated intensive care including PMMA-CHDF. Although remission was achieved in six patients, remaining two patients died of exacerbation of underlying diseases. Changes in blood levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) as indices of cytokine network activation, and serum ferritin level as an index of severity of RHS were investigated during PMMA-CHDF. PMMA-CHDF performed for 3 days significantly reduced blood TNF-alpha level (183+/-159 pg/ml to 84+/-98 pg/ml, p<0.05) and also blood IL-6 level (1113+/-903 pg/ml to 402+/-411 pg/ml, p<0.01). Furthermore, serum ferritin level was significantly decreased 3 days after initiation of PMMA-CHDF (52390+/-65168 ng/ml to 4136+/-2932 ng/ml, p<0.05) although it tended to increase before initiation of PMMA-CHDF. No PMMA-CHDF-related adverse events were observed in any of the patients. PMMA-CHDF was effective to remove cytokine and improved disease severity. Thus, PMMA-CHDF may be an adjunctive treatment in RHS refractory to medical therapy.

Efficacy of high-flow dialysate continuous hemodiafiltration in the treatment of fulminant hepatic failure.

We compared the clinical efficacy of high-flow dialysate continuous hemodiafiltration (HFCHDF) performed as artificial liver support (ALS) in fulminant hepatic failure (FHF) with those of conventional ALS techniques. Ninety patients were divided into non-HFCHDF and HFCHDF groups. Rate of recovery from coma was significantly higher in the HFCHDF group (70.2%) than in the non-HFCHDF group (44.2%) (p<0.01). The excellent recovery rate from coma achieved in patients with FHF by HFCHDF may be due to its enhanced capacity for liver support enabling efficient removal of substances causing hepatic coma from blood. HFCHDF should thus be useful for ALS.

Efficacy of combination therapy of antiviral and immunosuppressive drugs for the treatment of severe acute exacerbation of chronic hepatitis B.

BACKGROUND: Patients with severe exacerbation of chronic hepatitis B, sometimes developing into fulminant liver failure, are at high risk for mortality even with antiviral therapy. The efficacy of immunosuppressive therapy in clinically severe exacerbation of chronic hepatitis B has not been well demonstrated. In this study, we evaluated the efficacy of the early introduction of immunosuppressive therapy in combination with antiviral therapy in such patients. METHODS: Forty-two patients, 29 men and 13 women, were defined as having severe exacerbation of chronic hepatitis B based on our uniform criteria, and were enrolled in this study. Sixteen patients between 1982 and 1996 were analyzed retrospectively. We defined the criteria of severe disease in 1997, and then began to introduce sufficient doses of corticosteroids prospectively. Nucleoside analogs were administered in combination with corticosteroids after 1999. Twenty-six patients between 1997 and 2007 were analyzed prospectively. RESULTS: In the retrospective study between 1982 and 1996, four of 16 (25%) patients recovered. In the prospective study between 1997 and 2007, 17 of 26 (65%) patients recovered; 15 of 17 patients treated with corticosteroids with or without antiviral drugs within 10 days after the diagnosis of severe disease recovered, none of five treated similarly but later than 10 days after the diagnosis recovered, and two of three treated with antiviral drugs recovered. CONCLUSIONS: The early introduction of sufficient doses of corticosteroids and nucleoside analogs could be one option for reversing the potential deterioration of patients with clinically severe, life-threatening exacerbation of chronic hepatitis B.

Current Practices in Acute Blood Purification Therapy in Japan and Topics for Further Study.

Continuous venovenous hemodiafiltration is the modality of choice for acute blood purification therapy at almost all medical institutions in Japan. Nafamostat mesilate, an ultrashort-acting anticoagulant, is widely used for anticoagulation. Due to restrictions imposed by national health insurance, Japanese institutions use an effluent flow rate of 15 mL/kg/h, which is lower than the standard effluent flow rate used in the West. In addition, hemofilters are believed to adsorb cytokines, and thus some institutions also proactively perform continuous renal replacement therapy with a hemofilter at an early stage for cytokine modulation in patients with sepsis. Although some aspects of these Japanese practices differ greatly from Western practices, there has not been much evidence to support current standard methods. Therefore, Japanese researchers must continue working to produce evidence for those methods, at least those that are widely used in Japan.

The Japanese Clinical Practice Guideline for acute kidney injury 2016.

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention are necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016).

BACKGROUND AND PURPOSE: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] 10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine. METHODS: Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members. RESULTS: A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs. CONCLUSIONS: Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016).

Background and Purpose: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 in Japanese. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. Methods: Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ), and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (>66.6%) majority vote of each of the 19 committee members. Results: A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for 5 CQs. Conclusions: Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

Pharmacokinetics of Standard- and Reduced-Dose Recombinant Human Soluble Thrombomodulin in Patients with Septic Disseminated Intravascular Coagulation during Continuous Hemodiafiltration.

INTRODUCTION: Recombinant human soluble thrombomodulin (rTM) is reportedly excreted by the kidneys; therefore, the recommended dose for patients with renal impairment is one-third of the standard dose. The aim of this study was to evaluate whether this reduced dose of rTM achieves effective drug concentrations that are comparable to those of the standard dose in treating sepsis-induced disseminated intravascular coagulation (DIC) during continuous hemodiafiltration (CHDF). METHODS: Eight patients in an intensive care unit were randomized to receive either reduced-dose (0.02 mg/kg, n = 4) or standard-dose (0.06 mg/kg, n = 4) rTM. We evaluated the effect of standard dose in comparison to that of reduced dose on the pharmacokinetics (PKs) of rTM for the sepsis-induced DIC patients receiving CHDF. Patients received rTM during a 30-min infusion for six consecutive days. PK parameters of rTM were analyzed using the one-compartment model. RESULTS: The elimination half-life, clearance (T1/2), and distribution volume of sTM were similar between the reduced and standard doses. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) of sTM were approximately 2.5 times higher with standard-dose daily infusions than that with reduced-dose drip infusions (p = 0.041 and 0.062, respectively). The time when the blood concentration of sTM was >500 ng/mL, i.e., the holding time, was significantly longer with standard-dose infusions than those with reduced dose (p = 0.039). CONCLUSION: rTM displayed dose-dependent PK behavior at clinically relevant doses. During CHDF, effective blood concentration of rTM was not achieved with the reduced dose, and rTM was found to not bioaccumulate. Therefore, this pilot study suggests that reducing the rTM dose is unnecessary, even in sepsis-induced DIC patients who require CHDF. However, we need to perform a definitive study to determine the dosage of rTM for the case.