Shuji Shimazaki

Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial

Summary.  Background: Soluble thrombomodulin is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. Objectives: We conducted a multicenter, double‐blind, randomized, parallel‐group trial to compare the efficacy and safety of recombinant human soluble thrombomodulin (ART‐123) to those of low‐dose heparin for the treatment of disseminated intravascular coagulation (DIC) associated with hematologic malignancy or infection. Methods: DIC patients (n = 234) were assigned to receive ART‐123 (0.06 mg kg−1 for 30 min, once daily) or heparin sodium (8 U kg−1  h−1 for 24 h) for 6 days, using a double‐dummy method. The primary efficacy endpoint was DIC resolution rate. The secondary endpoints included clinical course of bleeding symptoms and mortality rate at 28 days. Results: DIC was resolved in 66.1% of the ART‐123 group, as compared with 49.9% of the heparin group [difference 16.2%; 95% confidence interval (CI) 3.3–29.1]. Patients in the ART‐123 group also showed more marked improvement in clinical course of bleeding symptoms (P = 0.0271). The incidence of bleeding‐related adverse events up to 7 days after the start of infusion was lower in the ART‐123 group than in the heparin group (43.1% vs. 56.5%, P = 0.0487). Conclusions: When compared with heparin therapy, ART‐123 therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients.

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.

The role of interventional radiology in the management of blunt renal injury : A practical protocol

OBJECTIVE The purpose of this study was to evaluate the efficacy of a protocol designed to minimize the need for surgery in the management of severe blunt renal injury. METHODS Forty-six of 752 trauma patients had evidence of renal injury on computed tomographic (CT) scan. Two patients required emergency laparotomy, and the remaining 44 patients were classified by CT scan grade using the American Association for the Surgery of Trauma classification system. Patients with CT scan grade 3 or over underwent renal angiography. RESULTS Twenty-one patients had a high-grade injury on CT scan (> or =3). Eight had angiographic evidence of extravasation from renal arterial branches and underwent transarterial embolization. One patient with a grade 5 injury had extravasation from a main renal vein and underwent immediate laparotomy. This was the only patient who required surgery for renal injury. CONCLUSION Surgery can be avoided in most cases of blunt renal injury. Hemodynamic instability and injury to main renal veins remain indications for surgical exploration.

The usefulness of transcatheter arterial embolization for patients with blunt polytrauma showing transient response to fluid resuscitation.

BACKGROUND This study aimed to determine whether nonsurgical management using transcatheter arterial embolization (TAE) is safe for patients with blunt multiple trauma who transiently respond to the initial fluid resuscitation. METHODS Contrast computed tomography was performed for patients with blunt abdominal injuries, excluding those who did not respond to initial fluid resuscitation. Angiography was performed for patients with injuries showing contrast extravasation or solid organ injury classified, according to the American Association for the Surgery of Trauma, as grade 3 or higher on computed tomography. Transcatheter arterial embolization was performed when angiography showed arterial extravasation. The protocol was abandoned for any patients who became profoundly hypotensive (with systolic blood pressure 60 mm Hg or lower) during computed tomography or angiography. RESULTS Between January 2000 and December 2002, 269 patients with blunt abdominal injuries underwent TAE immediately after admission. Of these patients, 41 had injuries in at least two regions and underwent TAE for these regions. Among them, 22 patients were hemodynamically stable or showed rapid response to fluid resuscitation. The nonsurgical treatment was successful in all these cases. The remaining 19 patients (Injury Severity Score, 37.3 +/- 8.2), who showed a transient response, were the subjects of this study. Of these patients, 15 underwent TAE for injuries in two regions (13 pelvic fractures, 7 splenic injuries, 6 hepatic injuries, 3 facial bleeding, and 1 renal injury), and 4 patients underwent TAE for injuries in three regions (4 had splenic injuries, 3 hepatic injuries, 2 renal injuries, 2 pelvic fractures, and 1 facial bleeding). For all these patients, TAE was successfully performed. Before TAE, the systolic blood pressure was 79.9 +/- 8.4 mm Hg, and the shock index was 1.45 +/- 0.25 mm Hg. After TAE, the corresponding values were 120.6 +/- 19.3 mm Hg and 0.87 +/- 0.16 mm Hg, respectively (p < 0.001). The rate of fluid administration required after TAE (214.2 +/- 139.3 mL/hour) was significantly less than that required before TAE (1244.2 +/- 347.1 mL/hour; range, 632-1,728 mL/hour) (p < 0.001). The deaths of two patients were classified as nonpreventable on the basis of the Trauma and Injury Severity Score (TRISS), and their respective probabilities of survival were determined to be 0.13 and 0.03. CONCLUSION Nonsurgical management using TAE can be performed safely even for patients with blunt multiple trauma who are in hemorrhagic hypotension if their hemodynamics are improved by resuscitation with 2 L of fluid.

Predictors of Death in Patients with Life-threatening Pelvic Hemorrhage after Successful Transcatheter Arterial Embolization

OBJECTIVE The purpose of this study was to determine predictors of death in patients with pelvic fracture whose pelvic arterial hemorrhage is controlled successfully by transcatheter arterial embolization (TAE). METHODS From January 1996 to December 2000, 61 patients with a pelvic fracture who had pelvic arterial hemorrhage were treated at our Level I trauma center according to a protocol that assigns a high priority to diagnostic and therapeutic angiography within the algorithm. Angiography is performed before laparotomy in patients with hemoperitoneum, who can be stabilized by fluid resuscitation, and otherwise afterward. External fixation was performed immediately after TAE in the angiography suite. Predictors of outcome were determined retrospectively by univariate and multivariate analysis using anatomic and physiologic parameters. RESULTS Forty-eight patients survived and 13 died. TAE successfully controlled pelvic arterial hemorrhage in all patients. Predictors of death included posterior pelvic arterial injury and an elevated Acute Physiology and Chronic Health Evaluation II score (odds ratio, 15.6 and 23.9, respectively). Need for fluid requirements to achieve hemodynamic stability were higher in nonsurvivors than in survivors. Outcome did not correlate with the type of fracture or the Injury Severity Score. CONCLUSION Application of angiography as a therapeutic intervention in patients with pelvic arterial bleeding may reduce the need for surgery, thereby avoiding or minimizing this additional trauma.

Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial.

To investigate treatment effects of thrombomodulin alfa (TM-&agr;) in patients with disseminated intravascular coagulation (DIC) having infection as the underlying disease, retrospective subanalysis of a double-blind, randomized controlled phase 3 trial was conducted. In the phase 3 trial, 227 DIC patients (full-analysis set) having infection and/or hematologic malignancy as the underlying disease received either TM-&agr; (0.06 mg·kg−1 for 30 min once daily) or heparin (8 U·kg−1·h−1 for 24 h) for 6 days using the double-dummy method. Among these patients, 147 patients with noninfectious comorbidity leading to severe thrombocytopenia (e.g., hematologic malignancy, or aplastic anemia) were excluded from the present analysis, and 80 patients with infectious disease and DIC were extracted and subjected to the present retrospective subanalysis. Disseminated intravascular coagulation resolution rates were determined using the DIC diagnostic criteria for critically ill patients at 7 days, and mortality rates were evaluated at 28 days. In the TM-&agr; and heparin groups, DIC resolution rates were 67.5% (27/40) and 55.6% (20/36), and 28-day mortality rates were 21.4% (9/42) and 31.6% (12/38), respectively. Mortality rates of patients who recovered from DIC were 3.7% (1/27) in the TM-&agr; group and 15% (3/20) in the heparin group. These results suggest TM-&agr; may be valuable in the treatment of DIC associated with infection.

The efficacy and limitations of transarterial embolization for severe hepatic injury.

BACKGROUND The efficacy of transarterial embolization (TAE) for severe blunt hepatic injury has been reported. We performed a prospective study evaluating the efficacy and the limitation of TAE from January 1996 to December 2000. METHODS All patients with blunt abdominal injury who could be stabilized by fluid resuscitation underwent computed tomographic (CT) scan examinations. Patients with CT scan evidence of hepatic injury were classified into five grades according to CT scan findings on the basis of the injury scale of the American Association for the Surgery of Trauma (Mirvis classification). All patients with CT scan grade 3 to 5 injury underwent angiography. When angiography showed extravasation of contrast medium extending from hepatic arterial branches, TAE was performed. RESULTS Of 612 patients with blunt abdominal trauma, 51 had CT scan grade 3 to 5 injury. Thirty-seven of these patients had a CT scan grade 3 injury and 18 underwent TAE. One of 19 patients who did not undergo TAE developed a delayed hemorrhage on day 6 and required a laparotomy. All 13 patients with a CT scan grade 4 injury had angiographic findings of the extravasation. TAE was successful in 11 patients and unsuccessful in 2. Five patients with a CT scan grade 4 injury required laparotomy. One developed a delayed hemorrhage on day 4. The remaining four patients had a major venous injury (a right lobectomy was performed in two with inferior vena cava injury, and a gauze packing in two with hepatic venous injury). One patient with a CT scan grade 5 injury underwent immediate laparotomy after TAE. Laparotomy revealed inferior vena cava injury and a right lobectomy was performed. Only two patients who underwent a lobectomy died of an uncontrollable hemorrhage. All CT scans of patients with hepatic venous or inferior vena cava injury showed a large low-density area (> or = 10 cm) with involvement of these vessels. The volumes of fluid resuscitation needed from admission until TAE ranged from 2,109 to 2,638 mL/h. CONCLUSION It was considered that the combination of the presence of a CT scan grade 4 or 5 lesion and the fluid requirements of more than 2,000 mL/h to maintain normotension indicated the absolute necessity of surgery. We felt that these patients were not candidates for TAE, and should undergo immediate laparotomy.

An outcome study of out-of-hospital cardiac arrest using the Utstein template—a Japanese experience

Publication of the Utstein style template has made it possible to evaluate and compare national, regional, and hospital based Emergency Medical Services. This research was a national investigation to present outcome data for out-of-hospital cardiac arrest (OHCA) patients in Japan. 3029 OHCA patients who were transported to 10 Emergency and Critical Care Medical Center from November 1997 to April 1999 were recorded according to the Utstein style and the outcome evaluated by logistic regression analysis. Among 3029 OHCA patients, 109 were found dead. The remaining 2920 patients who underwent cardiopulmonary resuscitation (CPR) by emergency medical technicians (EMT) were included in this study. Among these patients, 1294 were considered of primary cardiac origin patients by the EMT and 722 of these patients suffered a witnessed cardiac arrest. Bystander CPR were performed in 28.4% of these witnessed patients and the discharge rate was 3.5% overall and 11.4% in witnessed VF/VT. Outcome analysis showed that a discharge rate in witnessed primary cardiac arrest was 30% in prehospital resuscitation which was 7.5 times higher than in-hospital emergency room resuscitation groups (4.0%). The longer the interval between an emergency telephone call and defibrillation, the lower the 1 month survival rate, which reached almost 0% at 30 min. Follow up evaluation after discharge revealed that the survival rate rapidly decreased from 24 h to 3 months, then became a plateau in primary cardiac patients was rapidly decreased from 24 h to 1 month, then became a near plateau in non-cardiac origin group. To improve the resuscitation rate in the prehospital phase, a prehospital medical control system should be developed with expansion of on scene techniques by Japanese paramedics such as tracheal intubation, administration of emergency drugs and early defibrillation with standing orders. Education and motivation of first responders will be needed and every effort should be concentrated on improving bystander CPR rate.

Body fluid changes during hypertonic lactated saline solution therapy for burn shock.

The body fluid changes of 12 burn patients treated with Hypertonic Lactate Saline solution (HLS group) were compared with 26 burn patients receiving isotonic therapy (iso Na group). 1) Total infusion volume during the first 48 hours postburn in the HLS group was only one-half to two-thirds of that in the iso Na group, although the sodium loads were nearly equal. 2) HLS therapy maintained sufficient functional extracellular fluid volume (f-ECFV) in the shock period and protected the excess increase of f-ECFV in the postresuscitative period, in contradistinction to the iso Na group. In this paper, some clinical problems such as a rapid shift of ECF water into the ICF space and hypernatremia following HLS administration are discussed.

SIRS-associated coagulopathy and organ dysfunction in critically ill patients with thrombocytopenia.

Backgrounds: Coagulopathy and thrombocytopenia often occur in critically ill patients, and disseminated intravascular coagulation (DIC) can lead to multiple organ dysfunction and a poor outcome. However, the relation between coagulopathy and systemic inflammatory response has not been thoroughly clarified. Thus, we evaluated coagulative activity, organ dysfunction, and systemic inflammatory response syndrome (SIRS) in critically ill patients with thrombocytopenia and examined the balance between coagulopathy and systemic inflammation. Patients and Methods: Two hundred seventy-three patients, who were admitted to 13 critical care centers in Japan and fulfilled the criteria of platelet count of less than 150•109/L, were included. Coagulative variables (platelet count, fibrin/fibrinogen degradation products, and DIC scores), organ dysfunction index (Sequential Organ Failure Assessment [SOFA] score), and SIRS score in each patient were evaluated for 4 consecutive days after fulfilling the above entry criteria. The effect of SIRS on coagulopathy and organ dysfunction was evaluated in these patients. Results: Both the maximum SIRS score and entry SIRS score had significant relation to the maximum SOFA score during the observation period. Coagulation disorders indicated by the minimum platelet count, maximum DIC scores, and positivity for DIC worsened gradually with increases in SIRS scores. Both the minimum platelet count and maximum DIC scores were significantly correlated with the maximum SOFA score, indicating that a relation exists between coagulopathy and organ dysfunction. Conclusions: In critically ill patients with thrombocytopenia, coagulopathy and organ dysfunction progress with significant mutual correlation, depending on the increase in SIRS scores. The SIRS-associated coagulopathy may play a critical role in inducing organ dysfunction after severe insult.