Kenji Inaba

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma: The PROPPR Randomized Clinical Trial

IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01545232.

Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients

BACKGROUND Blood loss and uncontrollable bleeding are major factors affecting survival in trauma patients. Because treatment with antifibrinolytic drugs may be effective, early detection of hyperfibrinolysis with rotation thrombelastography (ROTEM may be beneficial. METHODS Eighty-seven trauma patients were included in this prospective observational study. Blood samples were collected at admission. After in vitro activation with tissue factor (EXTEM) and inhibition with aprotinin (APTEM), ROTEM parameters including maximal clot firmness (MCF) and clot lysis index at 30 min (CLI(30)) were determined. Hyperfibrinolysis was defined as a euglobulin lysis time (ELT) <90 min. Threshold for ROTEM parameters were determined with receiver-operating characteristic curves (ROC) analysis according to the ELT results. RESULTS ELT was determined in a subgroup of 23 patients. In this group of patients, ROC analysis showed that for a threshold of 18 mm (MCF-EXTEM), 71% (CLI(30)) and 7% (increase of MCF-APTEM), sensitivity was, respectively, 100%, 75%, and 80% with a specificity of 100%. With the application of these thresholds to the whole trauma cohort, ROTEM analysis detected hyperfibrinolysis in five patients [6%, 95% confidence interval (CI): 2-13%]. As expected, patients with hyperfibrinolysis were more severely injured (median Injury Severity Score: 75 vs 20, P<0.05), had greater coagulation abnormalities [international normalized ratio (INR): 8.2 vs 1.3, P<0.05; fibrinogen: 0.0 vs 2.2 g litre(-1), P<0.05], and a higher mortality rate (100%, CI: 48-100% vs 11% CI: 5-20%, P<0.05). CONCLUSIONS ROTEM provided rapid and accurate detection of hyperfibrinolysis in severely injured trauma patients.

Preventable or potentially preventable mortality at a mature trauma center.

OBJECTIVE The objective of this study was to analyze the preventable and potentially preventable deaths occurring at a mature Level I trauma center. METHODS All trauma patients that died during their initial hospital admission during an 8-year period (January, 1998 to December, 2005) were analyzed. The deaths were initially reviewed at a weekly Morbidity and Mortality (M&M) conference followed by a multidisciplinary (Trauma Surgery, Critical Care, Emergency Medicine, Neurosurgery, Nursing, and Coroner) Combined Trauma Death Review Committee, and were classified into nonpreventable, potentially preventable, and preventable deaths. All preventable and potentially preventable deaths were identified for the purpose of the study. Quality improvement death forms included data on epidemiology, vital signs, injury severity, type of injury, probability of survival with Trauma and Injury Severity Score methodology, preventability (nonpreventable, potentially preventable, and preventable deaths), errors in the evaluation and management of the patient, and classification of errors (system, judgment, knowledge). Additional injury details, clinical course, circumstances leading to the death and autopsy findings were abstracted from the trauma registry and individual chart review. RESULTS During the study period, 35,311 patients meeting trauma registry criteria were admitted and a total of 2,081 (5.9%) deaths occurred. Fifty-one deaths were classified as preventable or potentially preventable deaths (0.1% of admissions, 2.5% of deaths). Eleven of them (0.53% of deaths) were classified as preventable and 40 (1.92% of deaths) as potentially preventable deaths. Mean age was 40 years, 66.7% were men, mean Injury Severity Score was 27, 74.5% were blunt. The most common cause of death was bleeding (20, 39.2%) followed by multiple organ dysfunction syndrome (14, 27.5%) and cardiorespiratory arrest (8, 15.6%). This was caused by a delay in treatment (27, 52.9%), clinical judgment error (11, 21.6%), missed diagnosis (6, 11.8%), technical error (4, 7.8%), and other (3, 5.9%). The deaths peaked at two time periods: 26 (51.1%) during the first 24 hours and 16 (31.4%) after 7 days. Only one patient (2.0%) died in the first hour. The most common location of death was the intensive care unit (28, 54.9%), operating room (13, 25.5%), and emergency room (5, 9.8%). CONCLUSION Preventable or potentially preventable deaths are rare but do occur at an academic Level I trauma center. Delay in treatment and error in judgment are the leading causes of preventable and potentially preventable deaths.

Crystal Structure of the DsbB-DsbA Complex Reveals a Mechanism of Disulfide Bond Generation

Oxidation of cysteine pairs to disulfide requires cellular factors present in the bacterial periplasmic space. DsbB is an E. coli membrane protein that oxidizes DsbA, a periplasmic dithiol oxidase. To gain insight into disulfide bond formation, we determined the crystal structure of the DsbB-DsbA complex at 3.7 A resolution. The structure of DsbB revealed four transmembrane helices and one short horizontal helix juxtaposed with Cys130 in the mobile periplasmic loop. Whereas DsbB in the resting state contains a Cys104-Cys130 disulfide, Cys104 in the binary complex is engaged in the intermolecular disulfide bond and captured by the hydrophobic groove of DsbA, resulting in separation from Cys130. This cysteine relocation prevents the backward resolution of the complex and allows Cys130 to approach and activate the disulfide-generating reaction center composed of Cys41, Cys44, Arg48, and ubiquinone. We propose that DsbB is converted by its specific substrate, DsbA, to a superoxidizing enzyme, capable of oxidizing this extremely oxidizing oxidase.

Selective Nonoperative Management of Penetrating Abdominal Solid Organ Injuries

Objective:To assess the feasibility and safety of selective nonoperative management in penetrating abdominal solid organ injuries. Background:Nonoperative management of blunt abdominal solid organ injuries has become the standard of care. However, routine surgical exploration remains the standard practice for all penetrating solid organ injuries. The present study examines the role of nonoperative management in selected patients with penetrating injuries to abdominal solid organs. Patients and Methods:Prospective, protocol-driven study, which included all penetrating abdominal solid organ (liver, spleen, kidney) injuries admitted to a level I trauma center, over a 20-month period. Patients with hemodynamic instability, peritonitis, or an unevaluable abdomen underwent an immediate laparotomy. Patients who were hemodynamically stable and had no signs of peritonitis were selected for further CT scan evaluation. In the absence of CT scan findings suggestive of hollow viscus injury, the patients were observed with serial clinical examinations, hemoglobin levels, and white cell counts. Patients with left thoracoabdominal injuries underwent elective laparoscopy to rule out diaphragmatic injury. Outcome parameters included survival, complications, need for delayed laparotomy in observed patients, and length of hospital stay. Results:During the study period, there were 152 patients with 185 penetrating solid organ injuries. Gunshot wounds accounted for 70.4% and stab wounds for 29.6% of injuries. Ninety-one patients (59.9%) met the criteria for immediate operation. The remaining 61 (40.1%) patients were selected for CT scan evaluation. Forty-three patients (28.3% of all patients) with 47 solid organ injuries who had no CT scan findings suspicious of hollow viscus injury were selected for clinical observation and additional laparoscopy in 2. Four patients with a “blush” on CT scan underwent angiographic embolization of the liver. Overall, 41 patients (27.0%), including 18 cases with grade III to V injuries, were successfully managed without a laparotomy and without any abdominal complication. Overall, 28.4% of all liver, 14.9% of kidney, and 3.5% of splenic injuries were successfully managed nonoperatively. Patients with isolated solid organ injuries treated nonoperatively had a significantly shorter hospital stay than patients treated operatively, even though the former group had more severe injuries. In 3 patients with failed nonoperative management and delayed laparotomy, there were no complications. Conclusions:In the appropriate environment, selective nonoperative management of penetrating abdominal solid organ injuries has a high success rate and a low complication rate.

Impact of Plasma Transfusion in Trauma Patients Who Do Not Require Massive Transfusion

BACKGROUND For trauma patients requiring massive blood transfusion, aggressive plasma usage has been demonstrated to confer a survival advantage. The aim of this study was to evaluate the impact of plasma administration in nonmassively transfused patients. STUDY DESIGN Trauma patients admitted to a Level I trauma center (2000-2005) requiring a nonmassive transfusion (<10 U packed RBC [PRBC] within 12 hours of admission) were identified retrospectively. Propensity scores were calculated to match and compare patients receiving plasma in the first 12 hours with those who did not. RESULTS The 1,716 patients (86.1% of 1,933 who received PRBC transfusion) received a nonmassive transfusion. After exclusion of 31 (1.8%) early deaths, 284 patients receiving plasma were matched to patients who did not. There was no improvement in survival with plasma transfusion (17.3% versus 14.1%; p = 0.30) irrespective of the plasma-to-PRBC ratio achieved. However, the overall complication rate was significantly higher for patients receiving plasma (26.8% versus 18.3%, odds ratio [OR] = 1.7; 95% CI, 1.1-2.4; p = 0.016). As the volume of plasma increased, an increase in complications was seen, reaching 37.5% for patients receiving >6 U. The ARDS rate specifically was also significantly higher in patients receiving plasma (9.9% versus 3.5%, OR = 3.0; 95% CI, 1.4-6.2; p = 0.004]. Patients receiving >6 U plasma had a 12-fold increase in ARDS, a 6-fold increase in multiple organ dysfunction syndrome, and a 4-fold increase in pneumonia and sepsis. CONCLUSIONS For nonmassively transfused trauma patients, plasma administration was associated with a substantial increase in complications, in particular ARDS, with no improvement in survival. An increase in multiple organ dysfunction, pneumonia, and sepsis was likewise seen as increasing volumes of plasma were transfused. The optimal trigger for initiation of a protocol for aggressive plasma infusion warrants prospective evaluation.

FIBTEM provides early prediction of massive transfusion in trauma

IntroductionPrediction of massive transfusion (MT) among trauma patients is difficult in the early phase of trauma management. Whole-blood thromboelastometry (ROTEM®) tests provide immediate information about the coagulation status of acute bleeding trauma patients. We investigated their value for early prediction of MT.MethodsThis retrospective study included patients admitted to the AUVA Trauma Centre, Salzburg, Austria, with an injury severity score ≥16, from whom blood samples were taken immediately upon admission to the emergency room (ER). ROTEM® analyses (extrinsically-activated test with tissue factor (EXTEM), intrinsically-activated test using ellagic acid (INTEM) and fibrin-based extrinsically activated test with tissue factor and the platelet inhibitor cytochalasin D (FIBTEM) tests) were performed. We divided patients into two groups: massive transfusion (MT, those who received ≥10 units red blood cell concentrate within 24 hours of admission) and non-MT (those who received 0 to 9 units).ResultsOf 323 patients included in this study (78.9% male; median age 44 years), 78 were included in the MT group and 245 in the non-MT group. The median injury severity score upon admission to the ER was significantly higher in the MT group than in the non-MT group (42 vs 27, P < 0.0001). EXTEM and INTEM clotting time and clot formation time were significantly prolonged and maximum clot firmness (MCF) was significantly lower in the MT group versus the non-MT group (P < 0.0001 for all comparisons). Of patients admitted with FIBTEM MCF 0 to 3 mm, 85% received MT. The best predictive values for MT were provided by hemoglobin and Quick value (area under receiver operating curve: 0.87 for both parameters). Similarly high predictive values were observed for FIBTEM MCF (0.84) and FIBTEM A10 (clot amplitude at 10 minutes; 0.83).ConclusionsFIBTEM A10 and FIBTEM MCF provided similar predictive values for massive transfusion in trauma patients to the most predictive laboratory parameters. Prospective studies are needed to confirm these findings.

Impact of plasma transfusion in massively transfused trauma patients.

OBJECTIVE The objective of this study was to determine the optimal use of fresh-frozen plasma (FFP) in trauma. Our hypothesis was that a higher FFP: packed red blood cells (PRBC) ratio is associated with improved survival. METHODS This is a 6-year retrospective trauma registry and blood bank database study in a level I trauma center. All massively transfused patients (> or =10 PRBC during 24 hours) were analyzed. Patients with severe head trauma (head Abbreviated Injury Severity score > or =3) were excluded from the analysis. Patients were classified into four groups according to the FFP:PRBC ratio received: low ratio (< or =1:8), medium ratio (>1:8 and < or =1:3), high ratio (>1:3 and < or =1:2), and highest ratio (>1:2). RESULTS Of 25,599 trauma patients, 4,241 (16.6%) received blood transfusion. Massive transfusion occurred in 484 (11.4%) of the transfused. After exclusion of 101 patients with severe head injury 383 patients were available for analysis. The mortality rate decreased significantly with increased FFP transfusion. However, there does not seem to be a survival advantage after a 1:3 FFP:PRBC ratio has been reached. Using the highest ratio group as a reference, the relative risk of death was 0.97 (p = 0.97) for the high ratio group, 1.90 (p < 0.01) for the medium ratio group, and 3.46 (p < 0.01) for the low ratio group. There was an increasing trend toward more FFP use during time with the mean units per patient increasing 83% from 6.3 +/- 4.6 in 2000 to 11.5 +/- 9.7 in 2005. CONCLUSION Higher FFP:PRBC ratio is an independent predictor of survival in massively transfused patients. Aggressive early use of FFP may improve outcome in massively transfused trauma patients.

The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock: a randomized, controlled, double-blinded trial.

Objective:To investigate the potential immunologic and anti-inflammatory effects of hypertonic saline plus dextran (HSD) in hemorrhagic trauma patients. Background:Unbalanced inflammation triggered by shock has been linked to multiorgan dysfunction (MOD) and death. In animal and cellular models, HSD alters the inflammatory response to shock, attenuating MOD and improving outcome. It remains untested whether HSD has similar effects in humans. Methods:A single 250-mL dose of either HSD (7.5% NaCl, 6% dextran-70) or placebo (0.9% NaCl) was administered to adult blunt trauma patients in hemorrhagic shock. The primary outcome was to measure changes in immune/inflammatory markers, including neutrophil activation, monocyte subset redistribution, cytokine production, and neuroendocrine changes. Patient demographics, fluid requirements, organ dysfunction, infection, and death were recorded. Results:A total of 27 patients were enrolled (13 HSD) with no significant differences in clinical measurements. Hyperosmolarity was modest and transient, whereas the immunologic/anti-inflammatory effects persisted for 24 hours. HSD blunted neutrophil activation by abolishing shock-induced CD11b up-regulation and causing CD62L shedding. HSD altered the shock-induced monocyte redistribution pattern by reducing the drop in “classic” CD14++ and the expansion of the “pro-inflammatory” CD14+CD16+ subsets. In parallel, HSD significantly reduced pro-inflammatory tumor necrosis factor (TNF)-α production while increasing anti-inflammatory IL-1ra and IL-10. HSD prevented shock-induced norepinephrine surge with no effect on adrenal steroids. Conclusions:This first human trial evaluating the immunologic/anti-inflammatory effects of hypertonic resuscitation in trauma patients demonstrates that HSD promotes a more balanced inflammatory response to hemorrhagic shock, raising the possibility that similar to experimental models, HSD might also attenuate post-trauma MOD.

Coagulopathy in severe traumatic brain injury: a prospective study.

BACKGROUND The incidence and risk factors for traumatic brain injury (TBI)-associated coagulopathy after severe TBI (sTBI) and the effect of this complication on outcomes have not been evaluated in any large prospective studies. METHODS Prospective study of all patients admitted to the surgical intensive care unit (ICU) of an urban, Level I trauma center from June 2005 through May 2007 with sTBI (head Abbreviated Injury Scale score of >or=3). Criteria for TBI-coagulopathy included a clinical condition consistent with coagulopathy, i.e. sTBI, in conjunction with a platelet count <100,000 mm3 and/or elevated international normalized ratio and/or activated partial thromboplastin time. The following potential risk factors with p < 0.2 on bivariate analysis were included in a stepwise logistic regression analysis to identify independent risk factors for TBI coagulopathy and its association with mortality: age, mechanism of injury (blunt [B] or penetrating [P]), presence of hypotension upon admission, Injury Severity Score (ISS), Glasgow Coma Scale (GCS), head and other body area Abbreviated Injury Scale, isolated head injury, diffuse axonal injury, cerebral edema, intracranial hemorrhage (intraventricular, parenchymal, subarachnoid, or subdural), pneumocephalus, and presence of midline shift. RESULTS A total of 436 patients (392 blunt, 44 penetrating) met study criteria, of whom 387 patients had isolated SHI. TBI coagulopathy occurred in 36% of all patients (B: 33%, P: 55%; p < 0.0075) and in 34% of patients with isolated head injury (B: 32%, P: 54%; p = 0.0062). Independent risk factors for TBI-coagulopathy in isolated sTBI were found to include a GCS score of <or=8, ISS >or=16, presence of cerebral edema, subarachnoid hemorrhage, and midline shift. ICU lengths of stay were significantly longer in SHI patients who developed TBI coagulopathy (12.7 vs. 8.8 days; p = 0.006). The development of TBI coagulopathy in SHI was associated with increased mortality, adjusted odds ratio (95% confidence interval): 9.61 (4.06-25.0); p < 0.0001. CONCLUSION The incidence of TBI coagulopathy in SHI is high, especially in penetrating injuries. Independent risk factors for coagulopathy in isolated head injuries include GCS score of <or=8, ISS >or=16, hypotension upon admission, cerebral edema, subarachnoid hemorrhage, and midline shift. The development of TBI coagulopathy is associated with longer ICU length of stay and an almost 10-fold increased risk of death.