Kazuma Yamakawa

Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study

IntroductionCross-talk between the coagulation system and inflammatory reactions during sepsis causes organ damage followed by multiple organ dysfunction syndrome or even death. Therefore, anticoagulant therapies have been expected to be beneficial in the treatment of severe sepsis. Recombinant human soluble thrombomodulin (rhTM) binds to thrombin to inactivate coagulation, and the thrombin-rhTM complex activates protein C to produce activated protein C. The purpose of this study was to examine the efficacy of rhTM for treating patients with sepsis-induced disseminated intravascular coagulation (DIC).MethodsThis study comprised 65 patients with sepsis-induced DIC who required ventilatory management. All patients fulfilled the criteria of severe sepsis and the International Society on Thrombosis and Haemostasis criteria for overt DIC. The initial 45 patients were treated without rhTM (control group), and the following 20 consecutive patients were treated with rhTM (0.06 mg/kg/day) for six days (rhTM group). The primary outcome measure was 28-day mortality. Stepwise multivariate Cox regression analysis was used to assess which independent variables were associated with mortality. Comparisons of Sequential Organ Failure Assessment (SOFA) score on sequential days between the two groups were analyzed by repeated measures analysis of variance.ResultsCox regression analysis showed 28-day mortality to be significantly lower in the rhTM group than in the control group (adjusted hazard ratio, 0.303; 95% confidence interval, 0.106 to 0.871; P = 0.027). SOFA score in the rhTM group decreased significantly in comparison with that in the control group (P = 0.028). In the post hoc test, SOFA score decreased rapidly in the rhTM group compared with that in the control group on day 1 (P < 0.05).ConclusionsWe found that rhTM administration may improve organ dysfunction in patients with sepsis-induced DIC. Further clinical investigations are necessary to evaluate the effect of rhTM on the pathophysiology of sepsis-induced DIC.

Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis.

BACKGROUND: Respiratory dysfunction associated with severe sepsis is a serious condition leading to poor prognosis. Activation of coagulation is a consequence of and contributor to ongoing lung injury in severe sepsis. The purpose of this study was to examine the efficacy of recombinant human soluble thrombomodulin (rhTM), a novel anticoagulant agent, for treating patients with sepsis-induced disseminated intravascular coagulation (DIC) in terms of mortality and respiratory dysfunction. METHODS: This study comprised 86 consecutive patients with sepsis-induced DIC who required ventilator management. The initial 45 patients were treated without rhTM (control group), and the following 41 patients were given rhTM (0.06 mg/kg/d) for 6 days (rhTM group). Patients were followed up for 90 days after study entry. Sequential Organ Failure Assessment (SOFA) score and lung injury score were recorded until 7 days after entry. RESULTS: The baseline characteristic of severity of illness was significantly higher in the rhTM group than in the control group. Nevertheless, 90-day mortality rate in the rhTM group was significantly lower than that in the control group (37% vs. 58%, p = 0.038). There was a significant difference in the serial change of SOFA score from baseline to day 7 between the two groups (p = 0.009). Both the respiratory component of the SOFA score and the lung injury score in the rhTM group were significantly lower compared with the control group (p = 0.034 and p < 0.001, respectively). CONCLUSIONS: rhTM may have a significant beneficial effect on mortality and respiratory dysfunction in patients with sepsis-induced DIC. LEVEL OF EVIDENCE: III, therapeutic study.

Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta‐analysis

Although recombinant human soluble thrombomodulin (rhTM) is a widely used novel anticoagulant agent for disseminated intravascular coagulation (DIC) in Japan, its clinical efficacy in sepsis‐induced DIC has not been demonstrated convincingly.

Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta‐analysis of randomized controlled trials

Essentials Most anticoagulant therapy has failed to demonstrate a survival benefit in the overall sepsis population. We conducted separate meta‐analyses of anticoagulant therapy in three different populations. Survival benefit was observed only in the septic disseminated intravascular coagulation (DIC) population. Further randomized controlled trials should focus on specific populations with septic DIC.

Benefit profile of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis.

IntroductionThe safety and efficacy of recombinant human soluble thrombomodulin (rhTM) have been demonstrated, with promising evidence suggestive of efficacy for patients with severe sepsis involving coagulopathy in a phase IIb randomized controlled trial. However, the benefit profiles of rhTM have not been elucidated. The purpose of this study was to explore whether patients with greater disease severity, determined according to the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores, would experience treatment benefit from rhTM administration.MethodsThis was a post hoc, subgroup analysis of a multicenter retrospective cohort study conducted in three Japanese tertiary referral hospitals. Patients with sepsis-induced disseminated intravascular coagulation (DIC) who required ventilator management were included. We stratified patients into several strata according to disease severity, determined by APACHE II and SOFA scores, using classification and regression trees for survival data. Intervention effects, expressed as hazard ratios (HR), were analyzed using Cox regression analysis adjusted for a propensity model to detect subgroup heterogeneity of the effects of rhTM on in-hospital mortality.ResultsParticipants were 162 patients with sepsis-induced DIC; 68 of these patients received rhTM and 94 did not. After adjusting for imbalances, rhTM administration was significantly associated with reduced mortality in high-risk patients (APACHE II: 24 to 29; HR: 0.281; 95% confidence interval (CI): 0.093 to 0.850; P = 0.025). A similar nonsignificant tendency was observed in the very high-risk subset (APACHE II: ≥30; HR: 0.529; 95% CI: 0.202 to 1.387; P = 0.195) but was not evident in the moderate-risk subset of patients (APACHE II: <24; HR: 0.814; 95% CI: 0.351 to 1.884; P = 0.630). A similar tendency was observed in analysis of SOFA scores (moderate-risk subset (SOFA: <11), P = 0.368; high-risk subset (SOFA: ≥11), P = 0.042).ConclusionsSurvival benefit was observed with rhTM treatment in sepsis-induced DIC and high risk of death according to baseline APACHE II and SOFA scores.

Recombinant human soluble thrombomodulin and mortality in sepsis-induced disseminated intravascular coagulation : a multicentre retrospective study

Recombinant human soluble thrombomodulin (rhTM) is a novel class of anticoagulants for treating disseminated intravascular coagulation (DIC). Although rhTM is widely used in clinical settings throughout Japan, there is limited clinical evidence supporting the use of rhTM in patients with sepsis-induced DIC. Furthermore, rhTM is not approved for DIC treatment in other countries. This study aimed to clarify the survival benefits of rhTM administration in critically ill patients. Data from 3,195 consecutive adult patients who were admitted to 42 intensive care units for the treatment of severe sepsis or septic shock between January 2011 and December 2013 were retrospectively analysed, and 1,784 patients were diagnosed with DIC based on the scoring algorithm from the Japanese Association for Acute Medicine DIC (n = 645, rhTM group; n = 1,139, control group). Propensity score matching created 452 matched pairs, and logistic regression analysis revealed a significant association between rhTM administration and lower in-hospital all-cause mortality in the propensity score-matched groups (odds ratio, 0.757; 95 % confidence interval, 0.574-0.999, p = 0.049). Inverse probability of treatment weighted and quintile-stratified analyses also revealed significant associations between rhTM administration and lower in-hospital all-cause mortality. Survival time in the propensity score-matched rhTM group was significantly longer than that in the propensity score-matched control group (hazard ratio, 0.781; 95 % confidence interval, 0.624-0.977, p = 0.03). Bleeding complications were not more frequent in the rhTM groups. In conclusion, this study demonstrated that rhTM administration is associated with reduced in-hospital all-cause mortality among patients with sepsis-induced DIC.

Impact on survival of whole-body computed tomography before emergency bleeding control in patients with severe blunt trauma

IntroductionWhole-body computed tomography (CT) has gained importance in the early diagnostic phase of trauma care. However, the diagnostic value of CT for seriously injured patients is not thoroughly clarified. This study assessed whether preoperative CT beneficially affected survival of patients with blunt trauma who required emergency bleeding control.MethodsThis retrospective study was conducted from January 2004 to December 2010 in two tertiary trauma centers in Japan. The primary inclusion criterion was patients with blunt trauma who required emergency bleeding control (surgery or transcatheter arterial embolization). CT before emergency bleeding control was performed at the attending physicians discretion based on individual patient condition (for example, hemodynamic stability or certain abnormalities in the primary survey). We assessed covariates associated with 28-day mortality with multivariate logistic regression analysis and evaluated standardized mortality ratio (SMR, ratio of observed to predicted mortality by Trauma and Injury Severity Score (TRISS) method) in two subgroups of patients who did or did not undergo CT.ResultsThe inclusion criterion was fulfilled by 152 patients with a median Injury Severity Score of 35.3. During the early resuscitation phase, 132 (87%) patients underwent CT and 20 (13%) did not. Severity of injury was significantly higher in the non-CT versus CT group patients. Observed mortality rate was significantly lower in the CT versus non-CT group (18% vs. 80%, P <0.001). Multivariate adjustment for the probability of survival (Ps) by TRISS method confirmed CT as an independent predictor for 28-day mortality (adjusted OR, 7.22; 95% CI, 1.76 to 29.60; P = 0.006). In the subgroup with less severe trauma (TRISS Ps ≥50%), SMR in the CT group was 0.63 (95% CI, 0.23 to 1.03; P = 0.066), indicating no significant difference between observed and predicted mortality in the CT group. In contrast, in the subgroup with more severe trauma (TRISS Ps <50%), SMR was 0.65 (95% CI, 0.41 to 0.90; P = 0.004) only in the CT group, whereas the difference between observed and predicted mortality was not significant in the non-CT group, suggesting a possible beneficial effect of CT on survival only in trauma patients at high risk of death.ConclusionCT performed before emergency bleeding control might be associated with improved survival, especially in severe trauma patients with TRISS Ps of <50%.

Systemic involvement of high-mobility group box 1 protein and therapeutic effect of anti-high-mobility group box 1 protein antibody in a rat model of crush injury.

ABSTRACT Patients with crush injury often present systemic inflammatory response syndrome and fall into multiple organ failure. The mechanism by which the local tissue damage induces distant organ failure is still unclear. We focused on high-mobility group box 1 protein (HMGB1) as one of the damage-associated molecular pattern molecules that cause systemic inflammation in crush injury. We investigated involvement of HMGB1 and the effects of treatment with anti-HMGB1 antibody in a rat model of crush injury. Both hindlimbs of rats were compressed for 6 h and then released. In the crush injury group, the level of serum HMGB1 peaked at 3 h after releasing compression, followed by the increasing in the serum levels of interleukin 6 and tumor necrosis factor &agr;. Hematoxylin-eosin staining showed substantial damage in the lung 24 h after the crush injury, with upregulation of the expression of receptor for advanced glycation end products, as revealed by immunohistochemical analysis. Intravenous administration of anti-HMGB1 antibody improved survival (n = 20 each group) and significantly suppressed serum levels of HMGB1, interleukin 6, and tumor necrosis factor &agr; compared with the untreated crush injury group (n = 6–9 each group). Histological findings of lung damage were ameliorated, and the expression of receptor for advanced glycation end products was hampered by the treatment. These results indicate that HMGB1 is released in response to damage immediately after crush injury and acts as a proinflammatory mediator. Administration of anti-HMGB1 antibody reduced inflammatory reactions and improved survival by blocking extracellular HMGB1. Thus, HMGB1 appears to be a therapeutic target, and anti-HMGB1 antibody may become a promising novel therapy against crush injury to prevent the progression to multiple organ failure.

Platelet mitochondrial membrane potential correlates with severity in patients with systemic inflammatory response syndrome.

BACKGROUND The role of mitochondrial dysfunction has not been thoroughly clarified in the pathogenesis of critically ill patients. The objective of this study was to investigate mitochondrial membrane potential (&Dgr;&PSgr;m) and apoptosis in circulating platelets in patients with systemic inflammatory response syndrome (SIRS). METHODS This prospective observational study was conducted from May 2011 to February 2012. Criteria for inclusion were adult patients with SIRS. We used mitochondrial indicator JC-1 in conjunction with flow cytometry to measure &Dgr;&PSgr;m and annexin V to evaluate apoptosis in peripheral blood platelets. &Dgr;&PSgr;m was expressed as the percentage of platelets with altered &Dgr;&PSgr;m. Severity of illness was assessed by SIRS score, Acute Physiology and Chronic Health Evaluation II score, and Sequential Organ Failure Assessment score. RESULTS This study was composed of 36 patients who met the inclusion criteria and 12 healthy controls. Causes of SIRS were sepsis in 13, trauma in 13, and others in 10 patients. Platelet &Dgr;&PSgr;m depolarization was significantly enhanced in patients with SIRS versus that in controls (median [interquartile range], 10.6% [8.1–12.6%] vs. 7.1% [6.1–8.0%]; p < 0.001). The percentage of apoptotic platelets was significantly higher in patients with SIRS than in controls (8.7% [5.5–13.5%] vs. 5.4% [3.9–7.0%]; p = 0.006). Interestingly, &Dgr;&PSgr;m depolarization increased significantly with the increase in SIRS scores (p < 0.001). There was a significant correlation between &Dgr;&PSgr;m depolarization and severity of illness, as indicated by Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, and serum lactate levels (all, p < 0.05). CONCLUSION We demonstrated that &Dgr;&PSgr;m depolarization and apoptosis were enhanced in circulating platelets in patients with SIRS. Our findings suggest that &Dgr;&PSgr;m depolarization may be associated with the progression of SIRS. LEVEL OF EVIDENCE Diagnostic study, level III.

Electrical Vagus Nerve Stimulation Attenuates Systemic Inflammation and Improves Survival in a Rat Heatstroke Model

This study was performed to gain insights into novel therapeutic approaches for the treatment of heatstroke. The central nervous system regulates peripheral immune responses via the vagus nerve, the primary neural component of the cholinergic anti-inflammatory pathway. Electrical vagus nerve stimulation (VNS) reportedly suppresses pro-inflammatory cytokine release in several models of inflammatory disease. Here, we evaluated whether electrical VNS attenuates severe heatstroke, which induces a systemic inflammatory response. Anesthetized rats were subjected to heat stress (41.5°C for 30 minutes) with/without electrical VNS. In the VNS-treated group, the cervical vagus nerve was stimulated with constant voltage (10 V, 2 ms, 5 Hz) for 20 minutes immediately after completion of heat stress. Sham-operated animals underwent the same procedure without stimulation under a normothermic condition. Seven-day mortality improved significantly in the VNS-treated group versus control group. Electrical VNS significantly suppressed induction of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 in the serum 6 hours after heat stress. Simultaneously, the increase of soluble thrombomodulin and E-selectin following heat stress was also suppressed by VNS treatment, suggesting its protective effect on endothelium. Immunohistochemical analysis using tissue preparations obtained 6 hours after heat stress revealed that VNS treatment attenuated infiltration of inflammatory (CD11b-positive) cells in lung and spleen. Interestingly, most cells with increased CD11b positivity in response to heat stress did not express α7 nicotinic acetylcholine receptor in the spleen. These data indicate that electrical VNS modulated cholinergic anti-inflammatory pathway abnormalities induced by heat stress, and this protective effect was associated with improved mortality. These findings may provide a novel therapeutic strategy to combat severe heatstroke in the critical care setting.