Effectiveness of early administration of tranexamic acid in patients with severe trauma.

BACKGROUND: A reduction in mortality with the early use of tranexamic acid has been demonstrated in severely injured patients who are bleeding. However, the modest treatment effect with no reduction in blood transfusion has raised concerns. The aim of the present study was to estimate the effectiveness of regular use of tranexamic acid in severely injured patients. METHODS: This multicentre observational study used retrospectively collected data from consecutive injured patients (Injury Severity Score at least 16) treated in 15 Japanese academic institutions in 2012. A propensity score-matched analysis compared patients who did or did not receive tranexamic acid administration within 3 h of injury. Study outcomes included 28-day all-cause and cause-specific mortality, and need for blood transfusion. RESULTS: Of 796 eligible subjects, 281 were treated with tranexamic acid. Propensity score matching selected a total of 500 matched subjects (250 in each group). Tranexamic acid administration was associated with lower 28-day mortality (10·0 versus 18·4 per cent; difference -8·4 (95 per cent c.i. -14·5 to -2·3) per cent) and lower 28-day mortality from primary brain injury (6·0 versus 13·2 per cent; difference -7·2 (-12·3 to -2·1) per cent). However, there was no significant difference between groups in the need for blood transfusion (33·2 versus 34·8 per cent; difference -1·6 (-9·9 to 6·7) per cent). CONCLUSION: Early tranexamic acid use was associated with reduced mortality in severely injured patients, in particular those with a primary brain injury.

Risk factors for surgical site infection following orthopaedic surgery for fracture by trauma: a nested case-control study.

BACKGROUND: Surgical site infection (SSI) is associated with higher medical expenses and lower patient quality of life. AIM: To identify specific modifiable risk factors for SSI after orthopaedic surgery for fractures caused by trauma. METHODS: This nested case-control study used a nationwide trauma registry, the Japan Trauma Data Bank (JTDB) database. Patient data from 280 hospitals between January 2004 and May 2019 were retrieved from the JTDB. Patients with SSI and identified patients without SSI as control subjects were included, using propensity score matching adjusted for unmodifiable factors. Risk factors associated with SSI after orthopaedic trauma surgery were assessed using multi-level mixed-effects logistic regression models. FINDINGS: In total, 15,910 patients were included in the analysis. Of these patients, 377 (2.4%) had SSI. After propensity score matching, 258 patients with SSI and 2580 matched patients without SSI were selected. In the multi-level mixed-effects logistic regression analysis, blood transfusion within 24 h (odds ratio (OR): 1.51; 95% confidence interval (CI): 1.06-2.13) was a significant risk factor for SSI following orthopaedic fracture surgery. The OR (95% CI) values for external fixation, transcatheter arterial embolization, and tourniquet for SSI following orthopaedic fracture surgery were 1.40 (0.96-2.03), 1.66 (0.81-3.38), and 2.99 (0.60-14.87), respectively. CONCLUSION: These findings highlight the necessity of exercising caution when implementing blood transfusion within 24 h as a risk factor associated with SSI following orthopaedic trauma surgery.

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 (T(reg)) 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 T(reg) 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. T(reg) 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 T(reg) cells and synthesis of interleukin (IL)-10 and transforming growth factor (TGF)-ß 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 T(reg) cells at the inflammatory sites.

The precision of PiCCO® measurements in hypothermic post-cardiac arrest patients.

The aim of the present study was to determine the precision of the PiCCO(®) system for post-cardiac arrest patients who underwent therapeutic hypothermia. The precision of the measurements for cardiac output, global end-diastolic volume, extravascular lung water and the pulmonary vascular permeability index was assessed using the least significant change; this was regarded as precise when less than 15%. A total of 462 measurement sets were prospectively performed on 88 patients following successful resuscitation after cardiac arrest. Using the mean value of three injections for a measurement, the least significant change for the cardiac output, global end-diastolic volume, extravascular lung water and pulmonary vascular permeability index measurements were found to be 7.8%, 8.5%, 7.8% and 12.1%, respectively. No significant differences between hypothermia (n=150) and non-hypothermia (n=312) were found. The PiCCO-derived variables were found to be precise for post-cardiac arrest patients even under conditions of varying body temperature.

Role of neutrophils in spinal cord injury in the rat.

Activated neutrophils are thought to be involved in tissue injury through the release of various inflammatory mediators. To understand the role of neutrophils in spinal cord injury, the effects of nitrogen mustard-induced leukocyte depletion and the administration of an anti-P-selectin monoclonal antibody on motor disturbances observed following spinal cord compression were examined in rats. Spinal cord injury was induced by applying a 20-g weight for 20 min at the level of the 12th thoracic vertebra, resulting in motor disturbances of the hindlimbs 24 h postcompression. Motor disturbances, evaluated using Tarlov's index, an inclined-plane test and climbing ability, were markedly attenuated in rats with nitrogen mustard-induced leukocytopenia. Administration of the anti-P-selectin monoclonal antibody, by which adhesion of activated neutrophils to endothelial cells may be inhibited, also attenuated motor disturbances. Histological examination revealed that intramedullary hemorrhages observed 24 h after compression at the 12th thoracic vertebra of the spinal cord were significantly attenuated in leukocytopenic animals and those which received the anti-P-selectin monoclonal antibody. The accumulation of neutrophils at the site of compression, as evaluated by measuring the tissue myeloperoxidase activity, significantly increased with time following the compression, peaking at 3 h postcompression. Spinal cord myeloperoxidase activity did not increase in sham-operated animals. Leukocyte depletion and administration of the anti-P-selectin monoclonal antibody both reduced the accumulation of neutrophils in the damaged spinal cord segment 3 h postcompression. These observations strongly suggest that activated neutrophils play an important role in compression-induced thoracic spinal cord injury and that a P-selectin-mediated interaction between activated neutrophils and endothelial cells may be a critical step in endothelial cell injury leading to spinal cord injury.

Pulmonary vascular injury induced by hemorrhagic shock is mediated by P-selectin in rats.

To investigate whether the P-selectin-mediated leukocyte adhesion to the endothelial cells is involved in pulmonary vascular injury after hemorrhagic shock, we examined the effect of an anti-P-selectin monoclonal antibody (MAb PB1.3) on the pulmonary accumulation of leukocytes and the subsequent pulmonary vascular injury observed after hemorrhagic shock in rats. Two hours after hemorrhagic shock, pulmonary accumulation of leukocytes, as evaluated by measuring myeloperoxidase activity, began to increase and peaked after 6 hours. Pulmonary vascular injury, as evaluated by the extravascular leakage of 125I-albumin, was significantly increased 6 hours after hemorrhagic shock. MAb PB1.3 significantly prevented both the pulmonary accumulation of leukocytes and subsequent pulmonary vascular injury. MAb PNB1.6, an anti-P-selectin monoclonal antibody incapable of inhibiting P-selectin-mediated leukocyte adhesion, did not prevent either of these effects. These observations strongly suggest that the pulmonary sequestration of leukocytes and the subsequent pulmonary vascular injury after hemorrhagic shock are mediated by P-selectin.

Implications of excessive fibrinolysis and alpha(2)-plasmin inhibitor deficiency in patients with severe head injury.

OBJECTIVE: To evaluate the involvement of the fibrinolytic system, especially focused on alpha(2)-plasmin inhibitor, in patients with head injury. METHODS: This study consisted of 47 patients with isolated blunt head trauma in whom blood sampling could be initiated within 3 hours after injury. Patients were divided into two groups according to Glasgow Outcome Scale score status at 3 months after injury. In Group 1 patients (n = 26), the outcome was characterized as good recovery or moderate disability; in Group 2 patients (n = 21), the outcome was characterized as severe disability, vegetative state, or death. RESULTS: Concentrations of thrombin-antithrombin III complex were greater than 100 microg/L in 39 of 47 patients, and concentrations in Group 2 patients were elevated significantly beyond the concentrations in Group 1 patients. Activities of alpha(2)-plasmin inhibitor in Group 2 were significantly lower than in Group 1 (P < 0.0001). In Group 1 patients, alpha(2)-plasmin inhibitor activity was greater than 60%, while in all but four Group 2 patients, the inhibitor was reduced to less than 60% of normal activity within 3 hours of injury. All patients with alpha(2)-plasmin inhibitor activity less than 60% showed a marked bleeding tendency and/or severe brain edema. Using sandwich enzyme-linked immunosorbent assay, fibrinogen degradation product and fibrin degradation product were measured separately. A significant correlation was apparent between thrombin-antithrombin III complex and fibrinogen degradation product, as well as between the complex and fibrin degradation product. Marked decreases in alpha(2)-plasmin inhibitor were noted only in patients with thrombin-antithrombin III complex concentrations exceeding 500 microg/L. CONCLUSION: Fibrinolysis and fibrinogenolysis may be involved according to the degree of coagulation activation in the pathophysiology of severe head injury. Decreased activity of alpha(2)-plasmin inhibitor indicated poor prognosis and may be an exacerbating factor in the acute phase of head trauma.

[SIRS (systemic inflammatory response syndrome): clinical entity, definitions, and the significance].

The clinical entity, definitions, and the significance of SIRS (systemic inflammatory response syndrome) were reviewed. The term, SIRS was proposed to define sepsis and its sequelae clearly in 1991, in order to make early detection of the disease possible, and to improve the ability to compare innovative potential diagnostic and therapeutic modalities by standardizing terms. Although the criteria of SIRS is not strict and too sensitive, SIRS has been shown to be useful as a warning sign of severe condition in clinical setting. We also discussed about a new concept, CARS (compensatory anti-inflammatory response syndrome), which was characterized as anti-inflammatory mediators-dominant condition, in this issue.

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.

Role of granulocyte elastase in the formation of hemorrhagic shock-induced gastric mucosal lesions in the rat.

OBJECTIVE: To investigate the mechanism by which activated leukocytes induce gastric mucosal lesions, we examined whether granulocyte elastase is involved in the formation of such lesions in a rat model of hemorrhagic shock. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory at a university medical center. SUBJECTS: Male Wistar rats, weighing 220 to 280 g. INTERVENTIONS: Animals were subjected to hemorrhagic shock by phlebotomy. ONO-5046, a granulocyte elastase inhibitor (300 mg/kg ip), was administered 30 mins before or after phlebotomy. The effects of antithrombotic substances and tranexamic acid on hemorrhagic shock-induced gastric mucosal lesions also were examined. The effects of granulocyte elastase on the thrombomodulin activity and 35S-glycosaminoglycan content of endothelial cells were examined, using cultured human umbilical vein endothelial cells.

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.

Role of granulocyte elastase in ischemia/reperfusion injury of rat liver.

OBJECTIVE: To investigate the role of granulocyte elastase in ischemia/reperfusion injury of liver, the effect of ONO-5046, a granulocyte elastase inhibitor, was examined in ischemia/reperfusion-induced liver injury in rats. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory at a university medical center. SUBJECTS: Male Wistar rats, weighing 220 to 280 g. INTERVENTIONS: Animals receiving continuous intravenous infusion of ONO-5046 (50 mg/kg/hr) were subjected to hepatic ischemia/reperfusion. Hepatic damage was evaluated by effects on bile formation capacity, plasma clearance of indocyanine green, and serum aminotransferase concentrations after ischemia/reperfusion. MEASUREMENTS AND MAIN RESULTS: Hepatic dysfunction, observed after 60 mins of ischemia/reperfusion, led to a reduction in bile flow and to a decrease in the plasma clearance of indocyanine green. These indicators of hepatic dysfunction were prevented, to a large extent, by administration of ONO-5046. Serum concentrations of aminotransferases increased after hepatic ischemia/reperfusion, peaking at 12 hrs of reperfusion. Increases in serum concentrations of aminotransferases were significantly inhibited by ONO-5046. CONCLUSION: Granulocyte elastase derived from activated leukocytes may play a critical role in hepatic dysfunction and the subsequent hepatic injury induced by ischemia/reperfusion.

Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin.

We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.

Gabexate mesilate, a synthetic protease inhibitor, prevents compression-induced spinal cord injury by inhibiting activation of leukocytes in rats.

OBJECTIVE: Gabexate mesilate is a synthetic protease inhibitor capable of inhibiting both coagulation and cytokine production by monocytes. To investigate whether gabexate mesilate is useful for the prevention of posttraumatic spinal cord injury, we examined its effect on compression trauma-induced spinal cord injury in rats. DESIGN: Prospective, randomized, blinded, controlled study. SETTING: Research laboratory at a university medical center. SUBJECTS: Male Wistar rats weighing 300 to 350 g. INTERVENTIONS: Spinal cord injury was induced by applying a 20-g weight extradurally to the spinal cord at the level of the 12th thoracic vertebra for 20 mins. Spinal cord injury was evaluated by assessing the motor function of the rats 24 hrs posttrauma. The accumulation of leukocytes and histologic changes in the injured spinal cord tissue also were examined. Rats received gabexate mesilate (10 or 20 mg/kg i.p.) 30 mins before or after the compressive trauma. The effects of heparin or an inactive derivative of activated factor X (a selective inhibitor of thrombin generation) on compressive trauma-induced spinal cord injury also were examined. Leukocytopenia was induced by the administration of nitrogen mustard. MEASUREMENTS AND MAIN RESULTS: The motor disturbances observed following traumatic spinal cord compression, evaluated by Tarlov's score, and the accumulation of leukocytes in the injured tissue, evaluated by measuring tissue myeloperoxidase activity, were markedly reduced by leukocyte depletion induced by nitrogen mustard and by pre- or posttreatment of animals with gabexate mesilate. Neither heparin nor the inactive derivative of activated factor X prevented the motor disturbances and the accumulation of leukocytes. Histologic examination demonstrated that intramedullary hemorrhages observed 24 hrs after trauma at the 12th thoracic vertebra were significantly attenuated by nitrogen mustard-induced leukocytopenia and the administration of gabexate mesilate. CONCLUSIONS: The compression trauma-induced spinal cord injury demonstrated by this model was mainly mediated by leukocytes. Gabexate mesilate prevented spinal cord injury not by inhibiting coagulation, but by inhibiting the activation of leukocytes.