Shigeki Kushimoto

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.

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.

Validation of extravascular lung water measurement by single transpulmonary thermodilution: human autopsy study

IntroductionGravimetric validation of single-indicator extravascular lung water (EVLW) and normal EVLW values has not been well studied in humans thus far. The aims of this study were (1) to validate the accuracy of EVLW measurement by single transpulmonary thermodilution with postmortem lung weight measurement in humans and (2) to define the statistically normal EVLW values.MethodsWe evaluated the correlation between pre-mortem EVLW value by single transpulmonary thermodilution and post-mortem lung weight from 30 consecutive autopsies completed within 48 hours following the final thermodilution measurement. A linear regression equation for the correlation was calculated. In order to clarify the normal lung weight value by statistical analysis, we conducted a literature search and obtained the normal reference ranges for post-mortem lung weight. These values were substituted into the equation for the correlation between EVLW and lung weight to estimate the normal EVLW values.ResultsEVLW determined using transpulmonary single thermodilution correlated closely with post-mortem lung weight (r = 0.904, P < 0.001). A linear regression equation was calculated: EVLW (mL) = 0.56 × lung weight (g) - 58.0. The normal EVLW values indexed by predicted body weight were approximately 7.4 ± 3.3 mL/kg (7.5 ± 3.3 mL/kg for males and 7.3 ± 3.3 mL/kg for females).ConclusionsA definite correlation exists between EVLW measured by the single-indicator transpulmonary thermodilution technique and post-mortem lung weight in humans. The normal EVLW value is approximately 7.4 ± 3.3 mL/kg.Trial registrationUMIN000002780.

A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis

IntroductionTo validate the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) scoring system in patients with severe sepsis, we conducted a multicenter, prospective study at 15 critical care centers in tertiary care hospitals.MethodsThis study included 624 severe sepsis patients. JAAM DIC was scored on the day of diagnosis of severe sepsis (day 1) and day 4. Scores for disease severity and organ dysfunction were also evaluated.ResultsThe prevalence of JAAM DIC was 46.8% (292/624), and 21% of the DIC patients were scored according to the reduction rate of platelets. The JAAM DIC patients were more seriously ill and exhibited more severe systemic inflammation, a higher prevalence of multiple organ dysfunction syndrome (MODS) and worse outcomes than the non-DIC patients. Disease severity, systemic inflammation, MODS and the mortality rate worsened in accordance with an increased JAAM DIC score on day 1. The Kaplan-Meier curves demonstrated lower 1-year survival in the JAAM DIC patients than in those without DIC (log-rank test P <0.001). The JAAM DIC score on day 1 (odds ratio = 1.282, P <0.001) and the Delta JAAM DIC score (odds ratio = 0.770, P <0.001) were independent predictors of 28-day death. Dynamic changes in the JAAM DIC score from days 1 to 4 also affected prognoses. The JAAM DIC scoring system included all patients who met the International Society on Thrombosis and Haemostasis overt DIC criteria on day 1. The International Society on Thrombosis and Haemostasis scoring system missed a large number of nonsurvivors recognized by the JAAM scoring system.ConclusionsThe JAAM DIC scoring system exhibits good prognostic value in predicting MODS and poor prognosis in patients with severe sepsis and can detect more patients requiring treatment. Conducting repeated daily JAAM scoring increases the ability to predict the patients prognosis.

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

PURPOSE This 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. MATERIALS AND METHODS We 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. RESULTS Concentrations 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. CONCLUSIONS The 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.

The impact of body temperature abnormalities on the disease severity and outcome in patients with severe sepsis: an analysis from a multicenter, prospective survey of severe sepsis

IntroductionAbnormal body temperatures (Tb) are frequently seen in patients with severe sepsis. However, the relationship between Tb abnormalities and the severity of disease is not clear. This study investigated the impact of Tb on disease severity and outcomes in patients with severe sepsis.MethodsWe enrolled 624 patients with severe sepsis and grouped them into 6 categories according to their Tb at the time of enrollment. The temperature categories (≤35.5°C, 35.6–36.5°C, 36.6–37.5°C, 37.6–38.5°C, 38.6–39.5°C, ≥39.6°C) were based on the temperature data of the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring. We compared patient characteristics, physiological data, and mortality between groups.ResultsPatients with Tb of ≤36.5°C had significantly worse sequential organ failure assessment (SOFA) scores when compared with patients with Tb >37.5°C on the day of enrollment. Scores for APACHE II were also higher in patients with Tb ≤35.5°C when compared with patients with Tb >36.5°C. The 28-day and hospital mortality was significantly higher in patients with Tb ≤36.5°C. The difference in mortality rate was especially noticeable when patients with Tb ≤35.5°C were compared with patients who had Tb of >36.5°C. Although mortality did not relate to Tb ranges of ≥37.6°C as compared to reference range of 36.6–37.5°C, relative risk for 28-day mortality was significantly greater in patients with 35.6–36.5°C and ≤35.5°C (odds ratio; 2.032, 3.096, respectively). When patients were divided into groups based on the presence (≤36.5°C, n = 160) or absence (>36.5°C, n = 464) of hypothermia, disseminated intravascular coagulation (DIC) as well as SOFA and APACHE II scores were significantly higher in patients with hypothermia. Patients with hypothermia had significantly higher 28-day and hospital mortality rates than those without hypothermia (38.1% vs. 17.9% and 49.4% vs. 22.6%, respectively). The presence of hypothermia was an independent predictor of 28-day mortality, and the differences between patients with and without hypothermia were observed irrespective of the presence of septic shock.ConclusionsIn patients with severe sepsis, hypothermia (Tb ≤36.5°C) was associated with increased mortality and organ failure, irrespective of the presence of septic shock.Trial registrationUMIN-CTR IDUMIN000008195

Usefulness of the bilateral anterior rectus abdominis sheath turnover flap method for early fascial closure in patients requiring open abdominal management.

BackgroundMany patients requiring conventional open abdominal management need a postoperative intermediate period with a large ventral hernia. This situation, in which the granulated abdominal contents are covered only with a skin graft, carry with it a high risk of enterocutaneous fistula, and the patients ultimately require late-stage abdominal wall reconstruction. Early abdominal wall reconstruction in noncandidates for standard fascial closure has received little attention. In this study we used bilateral anterior rectus abdominis sheath turnover flaps for early fascial closure which, to date, has not been evaluated as a technique for early fascial closure.MethodsEleven trauma and 18 nontrauma cases requiring open abdominal management over a 7-year period were reviewed. Bilateral anterior rectus abdominis sheath turnover flaps were created by longitudinal incisions along the lateral edge of the anterior rectus sheath, which were mobilized medially and approximated. The skin was closed primarily.ResultsTwelve nontrauma and eight trauma patients survived. No enteric fistula or abdominal abscess occurred. Anterior rectus sheath turnover flaps were used in nine of the 18 nontrauma and two of the 11 trauma patients, all of whom were unsuitable for standard fascial closure of prolonged visceral edema; the respective mean intervals from initial laparotomy to fascial closure were 9.4 and 18 days. Of the 11 patients with flaps, ten survived without fascial dehiscence or herniation (maximum follow-up: 65 months).ConclusionsEarly fascial closure using the anterior rectus abdominis sheath turnover flap may reduce the need for skin grafting and subsequent abdominal wall reconstruction. This approach can be considered as an alternative technique in the early management of patients with open abdomen.

Gabexate mesilate, a synthetic protease inhibitor, reduces ischemia/reperfusion injury of rat liver by inhibiting leukocyte activation.

OBJECTIVE To investigate whether gabexate mesilate, a synthetic protease inhibitor with anticoagulant properties, prevents hepatic damage by inhibiting leukocyte activation, we examined its effect on ischemia/reperfusion injury of rat liver in which activated leukocytes play a critical role. DESIGN Prospective, randomized, controlled study. SETTING Research laboratory at a university medical center. SUBJECTS Male Wistar rats weighing 220 to 280 g. INTERVENTIONS Hepatic damage was evaluated by changes in bile flow and serum transaminase concentrations after ischemia/ reperfusion. Rats received continuous intravenous infusions of gabexate mesilate (10 mg/kg/hr) or intravenous administration of an inactive derivative of activated factor X (Xa), a selective inhibitor of thrombin generation (3 mg/kg), immediately before the induction of ischemia in the median and left lobes of the liver. To determine whether gabexate mesilate inhibits leukocyte activation, we examined the effects of gabexate mesilate on hepatic concentrations of tumor necrosis factor-alpha and rat interleukin-8 and on hepatic myeloperoxidase activity after ischemia/reperfusion. MEASUREMENTS AND MAIN RESULTS Hepatic dysfunction, observed after 60 mins of ischemia/reperfusion, showed a reduction in bile flow. The ischemia/reperfusion-induced decrease in bile flow was prevented by administration of gabexate mesilate. Serum transaminase concentrations increased after hepatic ischemia/reperfusion, peaking 12 hrs after reperfusion. Gabexate mesilate significantly inhibited the ischemia/reperfusion-induced increase in serum transaminase levels seen 12 hrs after reperfusion. Although an inactive derivative of factor Xa inhibited the increases in serum levels of fibrin and fibrinogen degradation products 6 hrs after reperfusion, it did not prevent ischemia/ reperfusion-induced liver injury. Hepatic levels of tumor necrosis factor-alpha, rat interleukin-8, and myeloperoxidase were significantly increased after ischemia/reperfusion. These increases were significantly inhibited by gabexate mesilate but unaffected by an inactive derivative of factor Xa. CONCLUSION Gabexate mesilate reduced ischemia/reperfusion-induced hepatic injury not by inhibiting coagulation, but by inhibiting leukocyte activation.

Implementation of the Fifth Link of the Chain of Survival Concept for Out-of-Hospital Cardiac Arrest

Background— The American Heart Association 2010 resuscitation guidelines recommended adding a fifth link (multidisciplinary postresuscitation care in a regional center) to the previous 4 in the chain of survival concept for out-of-hospital cardiac arrest. Our study aimed to determine the effectiveness of this fifth link. Methods and Results— This multicenter prospective cohort study involved all eligible out-of-hospital cardiac arrest patients in the Aizu region (n=1482, suburban/rural, Fukushima, Japan). Proportions of favorable neurological outcomes were evaluated before (January 2006–April 2008) and after (January 2009–December 2010) the implementation of the fifth link. After implementation, all patients were transported directly from the field to the tertiary-level hospital or secondarily from an outlying hospital to the tertiary-level hospital after restoration of circulation. The tertiary hospital provided intensive postresuscitation care, including appropriate hemodynamic and respiratory management, therapeutic hypothermia, and percutaneous coronary intervention. One-month survival with a favorable neurological outcome among all patients treated by emergency medical services providers improved significantly after implementation (4 of 770 [0.5%] versus 21 of 712 [3.0%]; P<0.001). The adjusted odds ratios of favorable neurological outcome were 0.9 (95% confidence interval, 0.7–1.1) for early access to emergency medical care, 3.1 (95% confidence interval, 0.7–14.2) for bystander resuscitation, 14.7 (95% confidence interval, 3.2–67.0) for early defibrillation, 1.0 (95% confidence interval, 1.0–1.1) for early advanced life support, and 7.8 (95% confidence interval, 1.6–39.0) for the fifth link. Conclusion— The proportion of out-of-hospital cardiac arrest patients with a favorable neurological outcome improved significantly after the implementation of the fifth link, which may be an independent predictor of outcome. Clinical Trial Registration— URL: http://www.apps.who.int/trialsearch. Unique identifier: UMIN000001607.

Blunt traumatic rupture of the heart: an experience in Tokyo

The present study was planned to clarify the characteristics of blunt traumatic cardiac rupture. We performed a retrospective analysis of 63 patients with blunt traumatic cardiac rupture during the period from April 1975 through February 1993. Six of nine patients arrived with recordable blood pressure, and injuries were detected by ultrasonography. Three patients underwent pericardiocentesis before surgery. Seven patients survived overall. The hemodynamics in all seven survivors were stabilized within 3 days after cardiac repair. The survival rate among the patients who arrived with blood pressure was 54%. A patient who fell from higher than 6 meters or a pedestrian hit by car and thrown as short a distance as 6.5 meters may have cardiac rupture. Ultrasonography is a useful, quick, and sensitive way to detect the presence of pericardial fluid. We prefer to do pericardiocentesis with a large-bore catheter under ultrasonographic guidance for continuous pericardial drainage rather than to create a subxyphoid pericardial window for cardiac tamponade.