Daisuke Kudo

Plasma mitochondrial DNA levels in patients with trauma and severe sepsis: Time course and the association with clinical status☆

PURPOSEnThis study aimed to investigate the serial changes in plasma levels of mitochondrial DNA (mtDNA) in patients with trauma and severe sepsis and the mechanism of increase in mtDNA levels and the association between the levels and severity.nnnMATERIALS AND METHODSnWe conducted a prospective observational study of patients with trauma having injuries with an Abbreviated Injury Scale score of 3 or higher (n = 37) and patients with severe sepsis (n = 23). The mtDNA concentrations in clarified plasma were measured using real-time quantitative polymerase chain reaction.nnnRESULTSnConcentrations of mtDNA peaked on the day of admission (day 1) in patients with trauma, whereas they increased on day 1 and remained constant until day 5 in patients with sepsis. The mtDNA levels on day 1 correlated with the maximal levels of creatinine phosphokinase in patients with trauma (R(2) = 0.463, P < .05) but not in patients with sepsis (R(2) = 0.028, P = .43). The mtDNA levels on day 1 were significantly higher in nonsurvivors compared with survivors of trauma (P < .05) but not sepsis.nnnCONCLUSIONSnThe levels of mtDNA were elevated during traumatic injury and severe sepsis, although time course and prognostic significance differed between the groups, suggesting that the mechanisms of mtDNA release into plasma differ.

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; 95u2009% 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; 95u2009% 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.

Benefit profile of anticoagulant therapy in sepsis: a nationwide multicentre registry in Japan

BackgroundLittle evidence supports anticoagulant therapy as effective adjuvant therapy to reduce mortality overall in sepsis. However, several studies suggest that anticoagulant therapy may reduce mortality in specific patients. This study aimed to identify a subset of patients with high benefit profiles for anticoagulant therapy against sepsis.MethodsThis post hoc subgroup analysis of a nationwide multicentre retrospective registry was conducted in 42 intensive care units in Japan. Consecutive adult patients with sepsis were included. Treatment effects of anticoagulants, e.g. antithrombin, recombinant thrombomodulin, heparin, and protease inhibitors, were evaluated by stratifying patients according to disseminated intravascular coagulation (DIC) and Sequential Organ Failure Assessment (SOFA) score. Intervention effects of anticoagulant therapy on in-hospital mortality and bleeding complications were analysed using Cox regression analysis stratified by propensity scores.ResultsParticipants comprised 2663 consecutive patients with sepsis; 1247 patients received anticoagulants and 1416 received none. After adjustment for imbalances, anticoagulant administration was significantly associated with reduced mortality only in subsets of patients diagnosed with DIC, whereas similar mortality rates were observed in non-DIC subsets with anticoagulant therapy. Favourable associations between anticoagulant therapy and mortality were observed only in the high-risk subset (SOFA score 13–17; adjusted hazard ratio 0.601; 95xa0% confidence interval 0.451, 0.800) but not in the subsets of patients with sepsis with low to moderate risk. Although the differences were not statistically significant, there was a consistent tendency towards an increase in bleeding-related transfusions in all SOFA score subsets.ConclusionsThe analysis of this large database indicates anticoagulant therapy may be associated with a survival benefit in patients with sepsis-induced coagulopathy and/or very severe disease.Trial registrationUniversity Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000012543). Registered on 10 December 2013.

Involvement of high mobility group box 1 and the therapeutic effect of recombinant thrombomodulin in a mouse model of severe acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is accompanied by severe lung inflammation induced by various diseases. Despite the severity of the symptoms, therapeutic strategies have been ineffective. High mobility group box 1 (HMGB1), which was identified originally as a DNA binding protein, has been proposed as a mediator of acute lung injury. In addition to its anti‐coagulant activity, recombinant thrombomodulin (rTM) possesses an ability to suppress the inflammatory response through neutralizing HMGB1. T regulatory (Treg) cells in the lungs are reported to modify innate immune responses during resolution of acute lung injury. In the present study, we investigated the therapeutic effect of rTM, and the contribution of Treg cells to this effect, in a mouse model of severe ARDS. C57BL/6 mice received sequential intratracheal administration of α‐galactosylceramide (α‐GalCer) and lipopolysaccharide (LPS), which resulted in the development of severe ARDS. HMGB1 levels in the lungs increased to a higher level in ARDS mice compared to those in mice treated with LPS alone. HMGB1 was expressed in the infiltrating neutrophils and macrophages in lungs. Treg cells were reduced significantly in the lungs of ARDS mice compared to those in mice treated with LPS alone. rTM administration prolonged the survival time and ameliorated the development of ARDS, which was associated with increased Treg cells and synthesis of interleukin (IL)‐10 and transforming growth factor (TGF)‐β in the lungs. These results suggest that HMGB1 is involved in the development of severe ARDS and rTM shows therapeutic effects through promoting the accumulation of Treg cells at the inflammatory sites.

Antithrombin Supplementation and Mortality in Sepsis-induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study

ABSTRACT Supplemental doses of antithrombin (AT) are widely used to treat sepsis-induced disseminated intravascular coagulation (DIC) in Japan. However, evidence on the benefits of AT supplementation for DIC is insufficient. This multicenter retrospective observational study aimed to clarify the effect of AT supplementation on sepsis-induced DIC using propensity score analyses. Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (nu200a=u200a715, AT group; nu200a=u200a1,069, control group). Inverse probability of treatment-weighted propensity score analysis indicated a statistically significant association between AT supplementation and lower in-hospital all-cause mortality (nu200a=u200a1,784, odds ratio [95% confidence intervals]: 0.748 [0.572–0.978], Pu200a=u200a0.034). However, quintile-stratified propensity score analysis (nu200a=u200a1,784, odds ratio: 0.823 [0.646–1.050], Pu200a=u200a0.117) and propensity score matching analysis (461 matching pairs, odds ratio: 0.855 [0.649–1.125], Pu200a=u200a0.263) did not show this association. In the early days after intensive care unit admission, the survival rate was statistically higher in the propensity score-matched AT group than in the propensity score-matched control group (Pu200a=u200a0.007). In DIC patients without concomitant heparin administration, similar results were observed. In conclusion, AT supplementation may be associated with reduced in-hospital all-cause mortality in patients with sepsis-induced DIC. However, the statistical robustness of this connection was not strong. In addition, although the number of transfusions needed in patients with AT supplementation increased, severe bleeding complications did not.

Early-phase changes of extravascular lung water index as a prognostic indicator in acute respiratory distress syndrome patients

BackgroundThe features of early-phase acute respiratory distress syndrome (ARDS) are leakage of fluid into the extravascular space and impairment of its reabsorption, resulting in extravascular lung water (EVLW) accumulation. The current study aimed to identify how the initial EVLW values and their change were associated with mortality.MethodsThis was a post hoc analysis of the PiCCO Pulmonary Edema Study, a multicenter prospective cohort study that included 23 institutions. Single-indicator transpulmonary thermodilution-derived EVLW index (EVLWi) and conventional prognostic factors were prospectively collected over 48xa0h after enrollment. Associations between 28-day mortality and each variable including initial (on day 0), mean, maximum, and Δ (subtracting day 2 from day 0) EVLWi were evaluated.ResultsWe evaluated 192 ARDS patients (median age, 69xa0years (quartile, 24xa0years); Sequential Organ Failure Assessment (SOFA) score on admission, 10 (5); all-cause 28-day mortality, 31%). Although no significant differences were found in initial, mean, or maximum EVLWi, Δ-EVLWi was significantly higher (i.e., more reduction in EVLWi) in survivors than in non-survivors (3.0 vs. −0.3xa0mL/kg, pu2009=u20090.006). Age, maximum, and Δ-SOFA scores and Δ-EVLW were the independent predictors for survival according to the Cox proportional hazard model. Patients with Δ-EVLWiu2009>u20092.8 had a significantly higher incidence of survival than those with Δ-EVLWiu2009≤u20092.8 (log-rank test, χ2u2009=u20097.08, pu2009=u20090.008).ConclusionsDecrease in EVLWi during the first 48xa0h of ARDS may be associated with 28-day survival. Serial EVLWi measurements may be useful for understanding the pathophysiologic conditions in ARDS patients. A large multination confirmative trial is required.

Body temperature abnormalities in non-neurological critically ill patients: a review of the literature

Body temperature abnormalities, which occur because of several infectious and non-infectious etiologies, are among the most commonly noted symptoms of critically ill patients. These abnormalities frequently trigger changes in patient management. The purpose of this article was to review the contemporary literature investigating the definition and occurrence of body temperature abnormalities in addition to their impact on illness severity and mortality in critically ill non-neurological patients, particularly in patients with severe sepsis. Reports on the influence of fever on outcomes are inconclusive, and the presence of fever per se may not contribute to increased mortality in critically ill patients. In patients with severe sepsis, the impacts of elevated body temperature and hypothermia on mortality and the severity of physiologic decline are different. Hypothermia is significantly associated with an increased risk of mortality. In contrast, elevated body temperature may not be associated with increased disease severity or risk of mortality. In patients with severe sepsis, the effect of fever and fever control on outcomes requires further research.

Micafungin Concentrations in the Plasma and Burn Eschar of Severely Burned Patients

ABSTRACT 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.

Hemodynamic reactions in patients with hemorrhagic shock from blunt trauma after initial fluid therapy.

OBJECTnThis 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.nnnMATERIALSnThis 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.nnnRESULTSnThere 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.nnnCONCLUSIONSnPatients 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.

High D-dimer levels predict a poor outcome in patients with severe trauma, even with high fibrinogen levels on arrival : a multicenter retrospective study

ABSTRACT Elevated D-dimer level in trauma patients is associated with tissue damage severity and is an indicator of hyperfibrinolysis during the early phase of trauma. To investigate the interacting effects of fibrinogen and D-dimer levels on arrival at the emergency department for massive transfusion and mortality in severe trauma patients in a multicenter retrospective study. This study included 519 adult trauma patients with an injury severity score ≥16. Patients with ≥10 units of red cell concentrate transfusion and/or death during the first 24u200ah were classified as having a poor outcome. Receiver operating characteristic curve analysis for predicting poor outcome showed the optimal cut-off fibrinogen and D-dimer values to be 190u200amg/dL and 38u200amg/L, respectively. On the basis of these values, patients were divided into four groups: low D-dimer (<38u200amg/L)/high fibrinogen (>190u200amg/dL), low D-dimer (<38u200amg/L)/low fibrinogen (⩽190u200amg/dL), high D-dimer (≥38u200amg/L)/high fibrinogen (>190u200amg/dL), and high D-dimer (≥38u200amg/L)/low fibrinogen (⩽190u200amg/dL). The survival rate was lower in the high D-dimer/low fibrinogen group than in the other groups. Moreover, the survival rate was lower in the high D-dimer/high fibrinogen group than in the low D-dimer/high fibrinogen and low D-dimer/low fibrinogen groups. High D-dimer level on arrival is a strong predictor of early death or requirement for massive transfusion in severe trauma patients, even with high fibrinogen levels.