Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock.

BACKGROUND: We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC. METHODS: We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction. RESULTS: Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients. CONCLUSION: Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed.

Massive amounts of tissue factor induce fibrinogenolysis without tissue hypoperfusion in rats.

Trauma-induced tissue factor (TF) release into the systemic circulation is considered to play an important role in the development of disseminated intravascular coagulation (DIC) immediately after severe trauma. However, the relationship between TF and hyperfibrinolysis, especially fibrinogenolysis, has been unclear. A total of 18 rats were divided into three groups: (a) the control group was infused with normal saline; (b) the low-dose group was infused with 4 U/kg TF; and (c) the high-dose group was infused with 16 U/kg TF. Arterial blood was drawn immediately and 2 and 4 h after the start of TF infusion. At each sampling point, arterial blood gases, platelet counts, and coagulation variables were measured. The fibrinogen degradation products were evaluated by a Western blot analysis. Hypotension, hypoxemia, and lactic acidosis were not observed in any of the three groups. In proportion to the doses of TF, the platelet counts, coagulation, and fibrinolysis variables deteriorated in line with DIC. The α2-plasmin inhibitor levels significantly decreased in the high-dose group compared with the other groups. The amounts of fibrinogen degradation products increased in proportion to the doses of TF. The plasmin-α2-plasmin inhibitor complex level in the high-dose group increased more than that of the other groups. In conclusion, TF can induce DIC associated with fibrinolysis and fibrinogenolysis without tissue hypoperfusion. The decrease in the α2-plasmin inhibitor level and the significant increase in the plasmin level may be the two main factors underlying the pathogenesis of hyperfibrin(ogen)olysis after TF administration.

Effectiveness of end-expiratory lung volume measurements during the lung recruitment maneuver for patients with atelectasis.

PURPOSE: The aim of this study was to determine whether the relative change in the end-expiratory lung volume (EELV) obtained by the recruitment maneuver (RM) can serve as an indicator of the change in the P/F ratio. MATERIALS AND METHODS: The effects of the intermittent stepwise increases in the RM (peak inspiratory pressure, 45, 50, and 55 cm H2O) were compared in 21 patients with atelectasis under mechanical ventilation. The EELV, the ratio of arterial oxygen concentration to the fraction of inspired oxygen P/F ratio, and relative change rate (Δ) in these parameters were evaluated after each RM. RESULTS: A greater improvement in the EELV (1157 ± 344 mL vs 1469 ± 396 mL) and P/F ratio (250 ± 99 vs 320 ± 92) was observed after the RM. The ΔEELV was correlated with the ΔP/F ratio (ρ = 0.73, P < .01) and was identified as an accurate predictor of the improvement of the ΔP/F ratio by the receiver operating characteristic curve (the area under the curve, 0.93; P < .01). CONCLUSIONS: These results suggest that the ΔEELV obtained by intermittent stepwise RM can serve as an indicator of the change in the P/F ratio.

Pharmacokinetics and pharmacodynamics of recombinant soluble thrombomodulin in disseminated intravascular coagulation patients with renal impairment.

Recombinant human soluble thrombomodulin (TM-α) was recently developed as an anticoagulant for patients with disseminated intravascular coagulation (DIC). However, the pharmacokinetics and pharmacodynamics of TM-α in DIC patients with severe renal impairment have not yet been elucidated. We investigated the pharmacokinetics and pharmacodynamics of TM-α in DIC patients with severe renal impairment. Eleven DIC patients with severe renal impairment (creatinine clearance <30 mL/min) and 10 DIC patients without severe renal impairment (creatinine clearance ≥30 mL/min) were included in this study. In all patients, a dose of 380 U/kg of TM-α was administered during a 30-min infusion. Blood samples were taken before the start of the first TM-α administration, and at 0.5, 2, 4, 8, and 24 h after the start of administration. Although the clearance of TM-α in the patients with renal impairment was 80% of that in the patients without renal impairment, none of the pharmacokinetic values were significantly different between the groups. In the pharmacokinetic simulation, however, the trough levels of TM-α increased gradually in the patients with renal impairment when the same dose of TM-α was repeatedly administered. After the administration of TM-α, the prothrombinase activities in the patients in both groups were sufficiently inhibited during the observation period. Although the pharmacokinetic values in DIC patients with severe renal impairment were only slightly different from those in DIC patients without severe renal impairment, we need to pay attention to the elevation of the trough levels of TM-α when the same dose of TM-α is repeatedly administered.

Disseminated intravascular coagulation (DIC) at an early phase of trauma continuously proceeds to DIC at a late phase of trauma.

The data from 254 patients with severe trauma were retrospectively analyzed. The patients were subdivided into disseminated intravascular coagulation (DIC) and non-DIC. There was a difference in the incidence of the continuous progression from the early to late phase of DIC between the patients with and without DIC on day 0. While 2 of 9 patients who newly developed late-phase DIC were complicated with sepsis, none of the 32 patients who showed a continuous progression of DIC from the early to late phase of trauma developed sepsis. The DIC and Sequential Organ Failure Assessment scores on day 0 were independent factors that predicted the continuous progression of the DIC from the early to late phase of trauma. Trauma itself, but not sepsis, contributes to the continuous progression of DIC from the early to late phase of trauma. The severity of DIC and organ dysfunction are involved in the pathogenesis of this continuous progression.

Improved detection of heat stroke-induced brain injury by high b-value diffusion-weighted imaging.

We report a case of heat stroke in which detection of brain injury was improved by high b-value diffusion-weighted imaging (DWI). High b-value DWI revealed moderate to marked hyperintensity at/around bilateral dentate nuclei and part of thalami. Apparent diffusion coefficient maps revealed apparent diffusion coefficient decrease of the dentate lesions. Routine DWI showed only mild hyperintensity of part of dentate lesions. High b-value DWI could be valuable for improved detection of heat stroke-induced brain injury.

Dramatic changes of the gut flora immediately after severe and sudden insults.

BACKGROUND: The gut flora is crucially involved in host homeostasis. However, the changes in the gut flora during the early phase of a critical illness are unknown. AIMS: We investigated the changes in the gut flora at an early phase of severe insult in critically ill patients. METHODS: Fifteen patients who experienced a sudden and severe insult were studied, along with 12 healthy volunteers as the control group. Fecal samples were acquired from the subjects by swabs of the rectum within 6 h after admission to the emergency room (day 0). Samples were serially collected from patients until day 14. Samples were also collected from control subjects. RESULTS: On day 0, total bacterial counts were decreased to one-thousandth the number of the control subjects, in particular, obligate anaerobes and Lactobacillus were significantly decreased. In addition, on day 0, the major short-chain fatty acids of the patients were significantly lower than those of the control subjects. The gut flora and the concentrations of major short-chain fatty acids did not recover to normal levels. In contrast, Enterococcus and Pseudomonas increased during the study period. CONCLUSIONS: The gut flora in critically ill patients changed immediately after a severe insult. The concentrations of the three major short-chain fatty acids were immediately decreased in tandem with the destruction of the gut flora. The gut flora and the concentration of major short-chain fatty acids did not improve during the first 2 weeks after hospital admission. At the same time, the number of harmful bacteria gradually increased.

Imbalance between macrophage migration inhibitory factor and cortisol induces multiple organ dysfunction in patients with blunt trauma.

Migration inhibitory factor (MIF) is associated with multiple organ dysfunction syndrome (MODS) in patients with systemic inflammatory response syndrome (SIRS). Our purposes were to determine the serum MIF, cortisol, and tumor narcosis factor-α (TNF-α) and to investigate the influences of the balance between the levels of MIF and cortisol in patients with blunt trauma. The cortisol levels were identical between the patients with and without MODS. However, the MIF and TNF-α levels in the patients with MODS were statistically higher than those of the patients without MODS. The cortisol/MIF ratios in the patients with MODS were statistically higher than those of the patients without MODS. The results show that MIF and TNF-α play an important role together in posttraumatic inflammatory response. An excessive serum MIF elevation overrides the anti-inflammatory effects of cortisol and leads to persistent SIRS followed by MODS in blunt trauma patients.

Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase.

BACKGROUND: The aims of the present study were to confirm the consumption coagulopathy of disseminated intravascular coagulation with the fibrinolytic phenotype at an early phase of trauma and to test the hypothesis that thrombin-activatable fibrinolysis inhibitor, neutrophil elastase, and plasmin contribute to the increased fibrinolysis of this type of disseminated intravascular coagulation. Furthermore, we hypothesized that disseminated intravascular coagulation at an early phase of trauma progresses dependently to disseminated intravascular coagulation with a thorombotic phenotype from 3 to 5 days after injury. METHODS: Fifty-seven trauma patients, including 30 patients with disseminated intravascular coagulation and 27 patients without disseminated intravascular coagulation, were studied prospectively. Levels of thrombin-activatable fibrinolysis inhibitor, tissue-type plasminogen activator plasminogen activator inhibitor-1 complex, plasmin alpha2 plasmin inhibitor complex, D-dimer, neutrophil elastase, and fibrin degradation product by neutrophil elastase were measured on days 1, 3, and 5 after trauma. The prothrombin time, fibrinogen, fibrin/fibrinogen degradation product, antithrombin, and lactate also were measured. RESULTS: Independent of the lactate levels, disseminated intravascular coagulation patients showed a prolonged prothrombin time, lesser fibrinogen and antithrombin levels, and increased levels of fibrin/fibrinogen degradation product on day 1. Disseminated intravascular coagulation diagnosed on day 1 continued to late-phase disseminated intravascular coagulation on days 3 and 5 after trauma. Increased levels of tissue-type plasminogen activator plasminogen activator inhibitor-1 complex, plasmin alpha2 plasmin inhibitor complex, D-dimer, neutrophil elastase, and fibrin degradation product by neutrophil elastase but not thrombin-activatable fibrinolysis inhibitor were observed in the disseminated intravascular coagulation patients. No correlation was observed between plasmin alpha2 plasmin inhibitor complex and fibrin degradation product by neutrophil elastase in disseminated intravascular coagulation patients. Multiple regression analysis showed the disseminated intravascular coagulation score and the tissue-type plasminogen activator plasminogen activator inhibitor-1 complex levels on day 1 to correlate with the total volume of transfused blood. Patient prognosis deteriorated in accordance with the increasing disseminated intravascular coagulation severity. CONCLUSION: Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase independent of hypoperfusion and continues to disseminated intravascular coagulation at a late phase of trauma. Increased fibrinolysis requires more blood transfusions, contributing to a poor patient outcome.

Shortening of cardiopulmonary resuscitation time before the defibrillation worsens the outcome in out-of-hospital VF patients.

OBJECTIVE: The purpose of the study is to investigate the influence of cardiopulmonary resuscitation (CPR) time before the first defibrillation. METHODS: The present study retrospectively analyzed the Utstein template records from April 1, 2002, to June 30, 2005. Patients who had out-of-hospital-witnessed cardiac arrest caused by cardiac disease and who presented with ventricular fibrillation (VF) as the initial cardiac rhythm were included in the study. Before April 1, 2003, the emergency medical technician (EMT) needed to obtain telephone permission before attempting defibrillation, and CPR was continued until permission was received (CPR first). On and after April 1, 2003, the EMT was immediately able to attempt a defibrillation without obtaining permission (shock first). RESULTS: In 143 patients who had out-of-hospital-witnessed VF, 43 patients and 100 patients were treated with the CPR-first strategy and the shock-first strategy, respectively. The duration of CPR before the first defibrillation was longer in the CPR-first group than that in the shock-first group. The CPR-first group showed a higher rate of favorable neurologic outcome 30 days after (28% vs 14%; P = .048) and 1 year after cardiac arrest (26% vs 11%; P = .033) than those of the shock-first group. In the patients with witnessed VF, a stepwise multiple logistic regression analysis showed the CPR-first strategy to improve the neurologic outcome. CONCLUSIONS: In patients with out-of-hospital-witnessed VF, sufficient CPR before the first defibrillation is considered to improve the neurologic outcome in comparison to the performance of immediate defibrillation.

Early detection of global cerebral anoxia: improved accuracy by high-b-value diffusion-weighted imaging with long echo time.

BACKGROUND AND PURPOSE: Early and accurate detection of global cerebral anoxia is important for determination of prognosis and further management. We evaluated whether accuracy in early detection of global cerebral anoxia was improved by high-b-value diffusion-weighted imaging (DWI) with long echo time (TE). METHODS: Routine DWI (b = 1000 s/mm(2); TE = 139 ms), high-b-value DWI (b = 3000 s/mm(2); TE = 190 ms), T2-weighted imaging (T2WI), and fluid-attenuated inversion recovery (FLAIR) imaging were acquired in six patients who experienced cardiopulmonary arrest within 24 hours and six volunteers. Region of interest-based analysis was performed. Regions of interest of patients showing significant decrease in apparent diffusion coefficient (ADC) values than volunteers were considered abnormal. Three neuroradiologists independently assessed images of the patients for conspicuity of hyperintensity within regions of interest. Receiver operating characteristic (ROC) analysis was performed, and the area under the curve (Az) was compared among sequences and observers. Average contrast and contrast-to-noise ratios between abnormal regions of interest and regions of interest of normal surrounding parenchyma were calculated. RESULTS: For all observers, high-b-value DWIs achieved the largest Az, and FLAIR imaging the lowest Az. Az of routine DWI and T2WI were between these values. High-b-value DWI and FLAIR imaging showed no significant interobserver variation in Az, whereas routine DWI and T2WI did. High-b-value DWI also achieved the largest contrast and contrast-to-noise ratios. CONCLUSION: High-b-value DWI with long TE improved accuracy in early detection of global cerebral anoxia. Application of the sequence would facilitate early diagnosis.

Three-dimensional conformal setup (3D-CSU) of patients using the coordinate system provided by three internal fiducial markers and two orthogonal diagnostic X-ray systems in the treatment room.

PURPOSE: To test the accuracy of a system for correcting for the rotational error of the clinical target volume (CTV) without having to reposition the patient using three fiducial markers and two orthogonal fluoroscopic images. We call this system "three-dimensional conformal setup" (3D-CSU). METHODS AND MATERIALS: Three 2.0-mm gold markers are inserted into or adjacent to the CTV. On the treatment couch, the actual positions of the three markers are calculated based on two orthogonal fluoroscopies crossing at the isocenter of the linear accelerator. Discrepancy of the actual coordinates of gravity center of three markers from its planned coordinates is calculated. Translational setup error is corrected by adjustment of the treatment couch. The rotation angles (alpha, beta, gamma) of the coordinates of the actual CTV relative to the planned CTV are calculated around the lateral (x), craniocaudal (y), and anteroposterior (z) axes of the planned CTV. The angles of the gantry head, collimator, and treatment couch of the linear accelerator are adjusted according to the rotation of the actual coordinates of the tumor in relation to the planned coordinates. We have measured the accuracy of 3D-CSU using a static cubic phantom. RESULTS: The gravity center of the phantom was corrected within 0.9 +/- 0.3 mm (mean +/- SD), 0.4 +/- 0.2 mm, and 0.6 +/- 0.2 mm for the rotation of the phantom from 0-30 degrees around the x, y, and z axes, respectively, every 5 degrees. Dose distribution was shown to be consistent with the planned dose distribution every 10 degrees of the rotation from 0-30 degrees. The mean rotational error after 3D-CSU was -0.4 +/- 0.4 (mean +/- SD), -0.2 +/- 0.4, and 0.0 +/- 0.5 degrees around the x, y, and z axis, respectively, for the rotation from 0-90 degrees. CONCLUSIONS: Phantom studies showed that 3D-CSU is useful for performing rotational correction of the target volume without correcting the position of the patient on the treatment couch. The 3D-CSU will be clinically useful for tumors in structures such as paraspinal diseases and prostate cancers not subject to large internal organ motion.