Predictors of postinjury acute respiratory distress syndrome: Lung injury persists in the era of hemostatic resuscitation.

BACKGROUND: Acute respiratory distress syndrome (ARDS) following trauma is historically associated with crystalloid and blood product exposure. Advances in resuscitation have occurred over the last decade, but their impact on ARDS is unknown. We sought to investigate predictors of postinjury ARDS in the era of hemostatic resuscitation. METHODS: Data were prospectively collected from arrival to 28 days for 914 highest-level trauma activations who required intubation and survived more than 6 hours from 2005 to 2016 at a Level I trauma center. Patients with ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 mmHg or less during the first 8 days were identified. Two blinded expert clinicians adjudicated all chest radiographs for bilateral infiltrates in the first 8 days. Those with left-sided heart failure detected were excluded. Multivariate logistic regression was used to define predictors of ARDS. RESULTS: Of the 914 intubated patients, 63% had a ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 or less, and 22% developed ARDS; among the ARDS cases, 57% were diagnosed early (in the first 24 hours), and 43% later. Patients with ARDS diagnosed later were more severely injured (ISS 32 vs. 20, p = 0.001), with higher rates of blunt injury (84% vs. 72%, p = 0.008), chest injury (58% vs. 36%, p < 0.001), and traumatic brain injury (72% vs. 48%, p < 0.001) compared with the no ARDS group. In multivariate analysis, head/chest Abbreviated Injury Score scores, crystalloid from 0 to 6 hours, and platelet transfusion from 0 to 6 hours and 7 to 24 hours were independent predictors of ARDS developing after 24 hours. CONCLUSIONS: Blood and plasma transfusion were not independently associated with ARDS. However, platelet transfusion was a significant independent risk factor. The role of platelets warrants further investigation but may be mechanistically explained by lung injury models of pulmonary platelet sequestration with peripheral thrombocytopenia. LEVEL OF EVIDENCE: Prognostic study, level IV.

Exposing the bidirectional effects of alcohol on coagulation in trauma: Impaired clot formation and decreased fibrinolysis in rotational thromboelastometry.

BACKGROUND: Alcohol has been associated with altered viscoelastic testing in trauma, indicative of impaired coagulation. Such alterations, however, show no correlation to coagulopathy-related outcomes. Other data suggest that alcohol may inhibit fibrinolysis. We sought to clarify these mechanisms after traumatic injury using thromboelastometry (ROTEM), hypothesizing that alcohol-related clot formation impairment may be counter-balanced by inhibited fibrinolysis. METHODS: Laboratory, demographic, clinical, and outcome data were prospectively collected from 406 critically injured trauma patients at a Level I trauma center. ROTEM and standard coagulation measures were conducted in parallel. Univariate comparisons were performed by alcohol level (EtOH), with subsequent regression analysis. RESULTS: Among 274 (58%) patients with detectable EtOH, median EtOH was 229 mg/dL. These patients were primarily bluntly injured and had lower GCS (p < 0.05) than EtOH-negative patients, but had similar admission pH and injury severity (p = NS). EtOH-positive patients had prolonged ROTEM clotting time and rate of clot formation time (CFT/α); they also had decreased fibrinolysis (max lysis %; all p < 0.05). In linear regression, for every 100 mg/dL increase in EtOH, clotting time increased by 13 seconds and fibrinolysis decreased by 1.5% (both p < 0.05). However, EtOH was not an independent predictor of transfusion requirements or mortality. In high-EtOH patients with coagulopathic ROTEM tracings, transfusion rates were significantly lower than expected, relative to EtOH-negative patients with similar ROTEM findings. CONCLUSION: As assayed by ROTEM, alcohol appears to have a bidirectional effect on coagulation in trauma, both impairing initial clot formation and inhibiting fibrinolysis. This balancing of mechanisms may explain lack of correlation between altered ROTEM and coagulopathy-related outcomes. Viscoelastic testing should be used with caution in intoxicated trauma patients. LEVEL OF EVIDENCE: Epidemiological study, level III.

Characterization of distinct coagulopathic phenotypes in injury: Pathway-specific drivers and implications for individualized treatment.

BACKGROUND: International normalized ratio (INR) and partial thromboplastin time (PTT) are used interchangeably to diagnose acute traumatic coagulopathy but reflect disparate activation pathways. In this study, we identified injury/patient characteristics and coagulation factors that drive contact pathway, tissue factor pathway (TF), and common pathway dysfunction by examining injured patients with discordant coagulopathies. We hypothesized that patients with INR/PTT discordance reflect differing phenotypes representing contact versus tissue factor pathway perturbations and that characterization will provide targets to guide individualized resuscitation. METHODS: Plasma samples were prospectively collected from 1,262 critically injured patients at a single Level I trauma center. Standard coagulation measures and an extensive panel of procoagulant and anticoagulant factors were assayed and analyzed with demographic and outcome data. RESULTS: Fourteen percent of patients were coagulopathic on admission. Among these, 48% had abnormal INR and PTT (BOTH), 43% had isolated prolonged PTT (PTT-CONTACT), and 9% had isolated elevated INR (INR-TF). PTT-CONTACT and BOTH had lower Glasgow Coma Scale score than INR-TF (p < 0.001). INR-TF had decreased factor VII activity compared with PTT-CONTACT, whereas PTT-CONTACT had decreased factor VIII activity compared with INR-TF. All coagulopathic patients had factor V deficits, but activity was lowest in BOTH, suggesting an additive downstream effect of disordered activation pathways. Patients with PTT-CONTACT received half as much packed red blood cell and fresh frozen plasma as did the other groups (p < 0.001). Despite resuscitation, mortality was higher for coagulopathic patients; mortality was highest in BOTH and higher in PTT-CONTACT than in INR-TF (71%, 60%, 41%; p = 0.04). CONCLUSIONS: Discordant phenotypes demonstrate differential factor deficiencies consistent with dysfunction of contact versus tissue factor pathways with additive effects from common pathway dysfunction. Recognition and treatment of pathway-specific factor deficiencies driving different coagulopathic phenotypes in injured patients may individualize resuscitation and improve outcomes. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level II.

Correlation between factor (F)XIa, FIXa and tissue factor and trauma severity.

BACKGROUND: It has been observed that trauma patients often display elevated procoagulant activity that could be caused, in part, by tissue factor (TF). We previously observed that trauma patients with thermal, blunt, and penetrating injuries have active FIXa and FXIa in their plasma. In the current study, we evaluated the effect of injury severity, with or without accompanying shock, on the frequency and concentration of TF, FIXa, and FXIa in plasma from trauma patients. METHODS: Eighty trauma patients were enrolled and divided equally into four groups based on their Injury Severity Score and base deficit:Blood was collected at a 0 time-point (first blood draw upon arrival at hospital) and citrate plasma was prepared, frozen, and stored at -80 °C. FXIa, FIXa, and TF activity assays were based on a response of thrombin generation to corresponding monoclonal inhibitory antibodies. RESULTS: The frequency and median concentrations of TF were relatively low in non-severe injury groups (17.5% and 0 pM, respectively) but were higher in those with severe injury (65% and 0.5 pM, respectively). Although FXIa was observed in 91% of samples and was high across all four groups, median concentrations were highest (by approximately fourfold) in groups with shock. FIXa was observed in 80% of plasma samples and concentrations varied in a relatively narrow range between all four groups. No endogenous activity was observed in plasma from healthy individuals. CONCLUSIONS: (1) Frequency and concentration of TF is higher in patients with a higher trauma severity. (2) Concentration of FXIa is higher in patients with shock. (3) For the first time reported, the vast majority of plasma samples from trauma patients contain active FIXa and FXIa. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level II.

Characterizing the gut microbiome in trauma: significant changes in microbial diversity occur early after severe injury.

BACKGROUND: Recent studies have demonstrated the vital influence of commensal microbial communities on human health. The central role of the gut in the response to injury is well described; however, no prior studies have used culture-independent profiling techniques to characterize the gut microbiome after severe trauma. We hypothesized that in critically injured patients, the gut microbiome would undergo significant compositional changes in the first 72 hours after injury. METHODS: Trauma stool samples were prospectively collected via digital rectal examination at the time of presentation (0 hour). Patients admitted to the intensive care unit (n=12) had additional stool samples collected at 24 hours and/or 72 hours. Uninjured patients served as controls (n=10). DNA was extracted from stool samples and 16S rRNA-targeted PCR amplification was performed; amplicons were sequenced and binned into operational taxonomic units (OTUs; 97% sequence similarity). Diversity was analyzed using principle coordinates analyses, and negative binomial regression was used to determine significantly enriched OTUs. RESULTS: Critically injured patients had a median Injury Severity Score of 27 and suffered polytrauma. At baseline (0 hour), there were no detectable differences in gut microbial community diversity between injured and uninjured patients. Injured patients developed changes in gut microbiome composition within 72 hours, characterized by significant alterations in phylogenetic composition and taxon relative abundance. Members of the bacterial orders Bacteroidales, Fusobacteriales and Verrucomicrobiales were depleted during 72 hours, whereas Clostridiales and Enterococcus members enriched significantly. DISCUSSION: In this initial study of the gut microbiome after trauma, we demonstrate that significant changes in phylogenetic composition and relative abundance occur in the first 72 hours after injury. This rapid change in intestinal microbiota represents a critical phenomenon that may influence outcomes after severe trauma. A better understanding of the nature of these postinjury changes may lead to the ability to intervene in otherwise pathological clinical trajectories. LEVEL OF EVIDENCE: III. STUDY TYPE: Prognostic/epidemiological.

The acute respiratory distress syndrome following isolated severe traumatic brain injury.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is common after traumatic brain injury (TBI) and is associated with worse neurologic outcomes and longer hospitalization. However, the incidence and associated causes of ARDS in isolated TBI have not been well studied. METHODS: We performed a subgroup analysis of 210 consecutive patients with isolated severe TBI enrolled in a prospective observational cohort at a Level 1 trauma center between 2005 and 2014. Subjects required endotracheal intubation and had isolated severe TBI defined by a head Abbreviated Injury Scale (AIS) score of 3 or greater and AIS score lower than 3 in all other categories. ARDS within the first 8 days of admission was rigorously adjudicated using Berlin criteria. Regression analyses were used to test the association between predictors of interest and ARDS. RESULTS: The incidence of ARDS in the first 8 days after severe isolated TBI was 30%. Patients who developed ARDS were administered more crystalloids (4.3 L vs. 3.5 L, p = 0.005) and blood products in the first 12 hours of admission. Patients with ARDS had significantly worse clinical outcomes measured at 28 days, including longer median intensive care unit and hospital stays (4 days vs. 13 days, p < 0.001, and 7.5 days vs. 14.5 days, p < 0.001, respectively). In unadjusted logistic regression analyses, the odds of developing ARDS were significantly associated with head AIS score (odds ratio [OR], 1.8; p = 0.018), male sex (OR, 2.9; p = 0.012), and early transfusion of platelets (OR, 2.8; p = 0.003). These associations were similar in a multivariate logistic regression model. CONCLUSION: In the era of balanced hemostatic resuscitation practices, severity of head injury, male sex, early crystalloids, and early transfusion of platelets are associated with a higher risk of ARDS after severe isolated TBI. Early transfusion of platelets after severe TBI may be a modifiable risk factor for ARDS, and these findings invite further investigation into causal mechanisms driving this observed association. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III.

The Massive Transfusion Score as a decision aid for resuscitation: Learning when to turn the massive transfusion protocol on and off.

BACKGROUND: Previous work proposed a Massive Transfusion Score (MTS) calculated from values obtained in the emergency department to predict likelihood of massive transfusion (MT). We hypothesized the MTS could be used at Hour 6 to differentiate who continues to require balanced resuscitation in Hours 7 to 24 and to predict death at 28 days. METHODS: We prospectively enrolled patients in whom the MT protocol was initiated from 2005 to 2011. Data including timing of blood products were determined at Hours 0, 6, 12, and 24. For each patient, transfusion needs were defined based on either an inappropriately low hemoglobin response to transfusion or a hemoglobin decrease of greater than 1 g/dL if no transfusion. Timing and cause of death were used to account for survivor bias. Multivariate logistic regression was used to determine independent predictors of outcome. RESULTS: A total of 190 MT protocol activations were included, and by Hour 6, 61% required 10 U or greater packed red blood cells. Calculated at initial presentation, a revised MTS (systolic blood pressure < 90 mm Hg, base deficit ≥ 6, temperature < 35.5°C, international normalized ratio > 1.5, hemoglobin < 11 g/dL) was superior to the original MTS (including heart rate ≥ 120 beats per minute, Focused Assessment With Sonography in Trauma [FAST] status, mechanism) or the Assessment of Blood Consumption (ABC) score for predicting MT (area under the curve [AUC] MT at 6 hours, 0.68; 95% confidence interval [CI], 0.57-0.79; at 24 hours, 0.72; 0.61-0.83; p < 0.05). For those alive at Hour 6, the revised MTS was predictive of future packed red blood cell need (AUC, 0.87) in Hours 7 to 12, 24-hour mortality (AUC, 0.95), and 28-day mortality (AUC, 0.77). For each additional positive trigger of the MTS at Hour 6, the odds of death at 24 hours and 28 days were substantially increased (24-hour odds ratio, 4.6; 95% CI, 2.3-9.3; 28-day odds ratio, 2.2; 95% CI, 1.5-3.2; p < 0.0001). CONCLUSION: Early end points of resuscitation adopted from the components of the revised MTS are predictive of ongoing transfusion. Failure to normalize these components by Hour 6 portends a particularly poor prognosis. LEVEL OF EVIDENCE: Prognostic study, level 3.

Discovering the truth about life after discharge: Long-term trauma-related mortality.

BACKGROUND: Outcome after traumatic injury has typically been limited to the determination at time of discharge or brief follow-up. This study investigates the natural history of long-term survival after trauma. METHODS: All highest-level activation patients prospectively enrolled in an ongoing cohort study from 2005 to 2012 were selected. To allow for long-term follow-up, patients had to be enrolled at least 1 year before the latest available data from the National Death Index (NDI, 2013). Time and cause of mortality was determined based on death certificates. Survival status was determined by the latest date of either care in our institution or NDI query. Kaplan-Meier curves were created stratified for Injury Severity Score (ISS). Survival was compared with estimated actuarial survival based on age, sex, and race. RESULTS: A total of 908 highest-level activation patients (median ISS, 18) were followed up for a median 1.7 years (interquartile range 1.0-2.9; maximum, 9.8 years). Survival data were available on 99.8%. Overall survival was 73% (663 of 908). For those with at least 2-year follow-up, survival was only 62% (317 of 509). Severity of injury predicted long-term survival (p < 0.0001) with those having ISS of 25 or greater with the poorest outcome (57% survival at 5 years). For all ISS groups, survival was worse than predicted actuarial survival (p < 0.001). When excluding early deaths (≤30 days), observed survival was still significantly lower than estimated actuarial survival (p < 0.002). Eighteen percent (44 of 245 deaths) of all deaths occurred after 30 days. Among late deaths, 53% occurred between 31 days and 1 year after trauma. Trauma-related mortality was the leading cause of postdischarge death, accounting for 43% of the late deaths. CONCLUSION: Postdischarge deaths represent a significant percentage of total trauma-related mortality. Despite having "survived" to leave the hospital, long-term survival was worse than predicted actuarial survival, suggesting that the mortality from injury does not end at "successful" hospital discharge. LEVEL OF EVIDENCE: Prognostic study, level III.

The found down patient: A Western Trauma Association multicenter study.

BACKGROUND: Unconscious patients who present after being "found down" represent a unique triage challenge. These patients are selected for either trauma or medical evaluation based on limited information and have been shown in a single-center study to have significant occult injuries and/or missed medical diagnoses. We sought to further characterize this population in a multicenter study and to identify predictors of mistriage. METHODS: The Western Trauma Association Multicenter Trials Committee conducted a retrospective study of patients categorized as found down by emergency department triage diagnosis at seven major trauma centers. Demographic, clinical, and outcome data were collected. Mistriage was defined as patients being admitted to a non-triage-activated service. Logistic regression was used to assess predictors of specified outcomes. RESULTS: Of 661 patients, 33% were triaged to trauma evaluations, and 67% were triaged to medical evaluations; 56% of all patients had traumatic injuries. Trauma-triaged patients had significantly higher rates of combined injury and a medical diagnosis and underwent more computed tomographic imaging; they had lower rates of intoxication and homelessness. Among the 432 admitted patients, 17% of them were initially mistriaged. Even among properly triaged patients, 23% required cross-consultation from the non-triage-activated service after admission. Age was an independent predictor of mistriage, with a doubling of the rate for groups older than 70 years. Combined medical diagnosis and injury was also predictive of mistriage. Mistriaged patients had a trend toward increased late-identified injuries, but mistriage was not associated with increased length of stay or mortality. CONCLUSION: Patients who are found down experience significant rates of mistriage and triage discordance requiring cross-consultation. Although the majority of found down patients are triaged to nontrauma evaluation, more than half have traumatic injuries. Characteristics associated with increased rates of mistriage, including advanced age, may be used to improve resource use and minimize missed injury in this vulnerable patient population. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Differences in degree, differences in kind: characterizing lung injury in trauma.

BACKGROUND: Acute lung injury following trauma remains a significant source of morbidity and mortality. Although multiple trauma studies have used hypoxemia without radiographic adjudication as a surrogate for identifying adult respiratory distress syndrome (ARDS) cases, the differences between patients with hypoxemia alone and those with radiographically confirmed ARDS are not well described in the literature. We hypothesized that nonhypoxemic, hypoxemic, and ARDS patients represent distinct groups with unique characteristics and predictors. METHODS: Laboratory, demographic, clinical, and outcomes data were prospectively collected from 621 intubated, critically injured patients at an urban Level 1 trauma center from 2005 to 2013. Hypoxemia was defined as PaO2/FIO2 ratio of 300 or lower. ARDS was adjudicated using Berlin criteria, with blinded two-physician consensus review of chest radiographs. Group comparisons were performed by hypoxemia and ARDS status. Logistic regression analyses were performed to separately assess predictors of hypoxemia and ARDS. RESULTS: Of the 621 intubated patients, 64% developed hypoxemia; 46% of these hypoxemic patients developed ARDS by chest radiograph. Across the three groups (no hypoxemia, hypoxemia, ARDS), there were no significant differences in age, sex, or comorbidities. However, there was an increase in severity of shock, injury, and chest injury by group, with corresponding trends in transfusion requirements and volume of early fluid administration. Outcomes followed a similar stepwise pattern, with pneumonia, multiorgan failure, length of intensive care unit stay, number of ventilator days, and overall mortality highest in ARDS patients. In multiple logistic regression, early plasma transfusion, delayed crystalloid administration, body mass index, and head and chest injury were independent predictors of hypoxemia, while head and chest injury, early crystalloid infusion, and delayed platelet transfusion were independent predictors of ARDS. CONCLUSION: Hypoxemia and ARDS exist on a spectrum of respiratory dysfunction following trauma, with increasing injury severity profiles and resuscitation requirements. However, they also represent distinct clinical states with unique predictors, which require directed research approaches and targeted therapeutic strategies. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III.

Beyond emergency surgery: redefining acute care surgery.

BACKGROUND: Considerable debate exists regarding the definition, skill set, and training requirements for the new specialty of acute care surgery (ACS). We hypothesized that a patient subset could be identified that requires a level of care beyond general surgical training and justifies creation of this new specialty. MATERIALS AND METHODS: Reviewed patient admissions over 1-y to the only general surgical service at a level I trauma center-staffed by trauma and/or critical care trained physicians. Patients classified as follows: trauma, ACS, emergency general (EGS), or elective surgery. ACS patients are nonelective, nontrauma patients with significantly altered physiology requiring intensive care unit admission and/or specific complex operative interventions. Differences in demographics, hospital course, and outcomes were analyzed. RESULTS: In-patient service evaluated approximately 5500 patients, including 3300 trauma patients. A total of 2152 admissions include 37% trauma, 30% elective, 28% EGS, and 4% ACS. ACS and trauma patients were more likely to require multiple operations (ACS relative risk [RR] = 11.5; trauma RR = 5.7, P < 0.0001), have longer hospital and intensive care unit length of stay, and higher mortality (P < 0.0001). They were less likely to be discharged home (ACS RR = 0.75; trauma RR = 0.67, P < 0.0001) compared with that of the EGS group. EGS and elective patients were most similar to each other in multiple areas. CONCLUSIONS: ACS and EGS patients represent distinct patient cohorts, as reflected by significant differences in critical care needs, likelihood of multiple operations, and need for postdischarge rehabilitation. The skills required to care for ACS patients, including ability to rescue from complications and provide critical care, differ from those required for EGS patients and supports development of ACS training and regionalization of care.

The effects of alcohol on coagulation in trauma patients: interpreting thrombelastography with caution.

BACKGROUND: The effects of alcohol on coagulation after trauma remain unclear. In vitro studies show that alcohol may decrease clot strength and inhibit fibrinolysis. Observational data indicate that alcohol leads to altered thrombelastography (TEG) parameters indicative of impaired clot formation. Clinical studies have been inconclusive to date. METHODS: Longitudinal plasma samples were prospectively collected from 415 critically injured trauma patients at a single Level 1 trauma center and were matched with demographic and outcome data. Citrated kaolin TEG and standard coagulation measures were performed in parallel. Univariate and group comparisons were performed by alcohol status, with subsequent linear and logistic regression analysis. RESULTS: A total of 264 patients (63.6%) had detectable blood alcohol levels (EtOH, >10 mg/dL). These patients were primarily male (87% vs. 79%), were bluntly injured (77% vs. 59%), and had lower median Glasgow Coma Scale (GCS) score (9.5 vs. 14, all p < 0.05) than the EtOH-negative patients. There were no notable differences in pH (7.29 vs. 7.31, p = nonsignificant) or injury severity (median Injury Severity Score [ISS], 11 vs. 14; p = nonsignificant) between the groups. The alcohol-positive patients had a prolonged TEG citrated kaolin R-time (reaction time), or time to initial clot formation (5.91 minutes vs. 4.43 minutes, p = 0.013), prolonged K-time (kinetics time), or time to fixed level of clot strength (1.77 minutes vs. 1.43 minutes, p = 0.036), and decreased α angle (66.5 degrees vs. 70.2 degrees, p = 0.001). In multiple linear regression, for every 10-mg/dL increase in EtOH, R-time was prolonged by 3.84 seconds (p = 0.015), and α angle decreased by 0.11 degrees (p = 0.013). However, in multiple logistic regression analyses, EtOH was a negative predictor of coagulopathy by international normalized ratio (>1.3) and was not predictive of transfusion requirements or early or late mortality. CONCLUSION: Patients with elevated EtOH present with impaired clot formation as assayed by TEG, but this does not correlate with standard measures of coagulopathy or with outcome. Reliance on TEG for determining coagulopathy in intoxicated trauma patients may lead to a misperceived hypocoagulable state and inappropriate transfusion. TEG appears to be affected by EtOH in a previously unreported way, warranting further investigation. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III.

The whole is greater than the sum of its parts: hemostatic profiles of whole blood variants.

BACKGROUND: Mounting evidence highlighting the benefits of hemostatic resuscitation has led to a renewed interest in whole blood (WB) and reconstituted WB (RWB). However, few data exist to characterize the clotting profiles of these variants. This study characterizes banked WB variants and RWB in standard 1:1:1 and 2:1:1 transfusion ratios of packed red blood cells, fresh frozen plasma, and platelets (PLTs). We hypothesized that the global hemostatic profile of 1:1:1 RWB is superior to 2:1:1 RWB and that PLT-modified WB (MWB) is superior to 1:1:1 RWB. METHODS: Twenty-three units of packed red blood cells, fresh frozen plasma, and PLTs were obtained from the regional blood collection center and mixed to create 23 1:1:1 and 23 2:1:1 RWB units. Freshly donated WB units were obtained and used to create 11 of each nonmodified WB (NMWB) (room temperature and cooled) and MWB (room temperature and cooled) variants. International normalized ratio (INR)/partial thromboplastin time (PTT), complete blood cell count, functional studies, and an extensive panel of procoagulant and anticoagulant factor assays were performed on all products. RESULTS: The 1:1:1 RWB had significantly lower INR and PTT (1.31 vs. 1.55, p = 0.0029; 42 seconds vs. 50 seconds, p = 0.0008) and higher activity of factors II, V, VII, VIII, IX, and X; antithrombin III, as well as protein C and higher fibrinogen levels than did 2:1:1 RWB (factor IX, 86% vs. 70%, p = 0.0313; fibrinogen, 242 mg/dL vs. 202 mg/dL, p = 0.0385). There were no differences in INR/PTT or factor activity between MWB and NMWB. However, MWB had greater maximum clot firmness (MCF) by rotational thromboelastometry tissue factor-activated extrinsic clotting cascade measures than did NMWB (MCF, 61 mm vs. 50 mm, p = 0.0031). MWB also had greater MCF by rotational thromboelastometry tissue factor-activated extrinsic clotting cascade measures than did 1:1:1 RWB (MCF, 61 mm vs. 45 mm, p = 0.0005). CONCLUSION: Although 1:1:1 RWB had a superior clotting profile relative to 2:1:1 RWB, MWB exhibited even better global hemostasis than did 1:1:1 RWB. Characterization of factor-level and functional clotting differences between WB variants is imperative for understanding the clinical benefits of hemostatic resuscitation.

The natural history and effect of resuscitation ratio on coagulation after trauma: a prospective cohort study.

OBJECTIVE: To investigate the natural history of coagulation factor perturbation after injury and identify longitudinal differences in clotting factor repletion by red blood cell:fresh frozen plasma (RBC:FFP) transfusion ratio. BACKGROUND: Hemostatic transfusion ratios of RBC to FFP approaching 1:1 are associated with a survival advantage in traumatic hemorrhage, even in patients with normal coagulation studies. METHODS: Plasma was prospectively collected from 336 trauma patients during their intensive care unit stay for up to 72 hours from February, 2005, to October, 2011. Standard coagulation studies as well as pro- and anticoagulant clotting factors were measured. RBC:FFP transfusion ratios were calculated at 6 hours after arrival and dichotomized into "low ratio" (RBC:FFP ≤ 1.5:1) and "high ratio" (RBC:FFP > 1.5:1) groups. RESULTS: Factor-level measurements from 193 nontransfused patients provide an early natural history of clotting factor-level changes after injury. In comparison, 143 transfused patients had more severe injury, prolonged prothrombin time and partial thromboplastin time (PTT), and lower levels of both pro- and anticoagulants up to 24 hours. PTT was prolonged up to 12 hours and only returned to admission baseline at 48 hours in "high ratio" patients versus correction by 6 hours in "low ratio" patients. Better repletion of factors V, VIII, and IX was seen longitudinally, and both unadjusted and injury-adjusted survival was significantly improved in "low ratio" versus "high ratio" groups. CONCLUSIONS: Resuscitation with a "low ratio" of RBC:FFP leads to earlier correction of coagulopathy, and earlier and prolonged repletion of some but not all procoagulant factors. This prospective evidence suggests hemostatic resuscitation as an interim standard of care for transfusion in critically injured patients pending the results of ongoing randomized study.

A paradigm shift in trauma resuscitation: evaluation of evolving massive transfusion practices.

IMPORTANCE: The evolution of damage control strategies has led to significant changes in the use of resuscitation after traumatic injury. OBJECTIVE: To evaluate changes in the administration of fluids and blood products, hypothesizing that a reduction in crystalloid volume and a reduced red blood cell (RBC) to fresh frozen plasma (FFP) ratio over the last 7 years would correlate with better resuscitation outcomes. DESIGN: Observational prospective cohort study. SETTING: Urban level I trauma center. PARTICIPANTS: A total of 174 trauma patients receiving a massive transfusion (>10 units of RBCs in 24 hours) or requiring the activation of the institutional massive transfusion protocol from February 2005 to June 2011. EXPOSURE: Patients had to either receive a massive transfusion or require the activation of the institutional massive transfusion protocol. MAIN OUTCOMES AND MEASURES: In-hospital mortality. RESULTS: The mean (SD) Injury Severity Score was 28.4 (16.2), the mean (SD) base deficit was -9.8 (6.3), and median international normalized ratio was 1.3 (interquartile range, 1.2-1.6); the mortality rate was 40.8%. Patients received a median of 6.1 L of crystalloid, 13 units of RBCs, 10 units of FFP, and 1 unit of platelets over 24 hours, with a mean RBC:FFP ratio of 1.58:1. The mean 24-hour crystalloid infusion volume and number of the total blood product units given in the first 24 hours decreased significantly over the study period (P < .05). The RBC:FFP ratio decreased from a peak of 1.84:1 in 2007 to 1.55:1 in 2011 (P = .20). Injury severity and mortality remained stable over the study period. When adjusted for age and injury characteristics using Cox regression, each decrease of 0.1 achieved in the massive transfusion protocol's RBC:FFP ratio was associated with a 5.6% reduction in mortality (P = .005). CONCLUSIONS AND RELEVANCE: There has been a shift toward a reduced crystalloid volume and the recreation of whole blood from component products in resuscitation. These changes are associated with markedly improved outcomes and a new paradigm in the resuscitation of severely injured patients.

Cause and timing of death in massively transfused trauma patients.

BACKGROUND: The purpose of this study was to characterize the cause of death in severely injured trauma patients to define potential responses to resuscitation. METHODS: Prospective analysis of 190 critically injured patients who underwent massive transfusion protocol (MTP) activation or received massive transfusion (>10 U of packed red blood cells [RBC] per 24 hours). Cause of death was adjudicated into one of four categories as follows: (1) exsanguination, (2) early physiologic collapse, (3) late physiologic collapse, and (4) nonsurvivable injury. RESULTS: A total 190 patients underwent massive transfusion or MTP with 76 deaths (40% mortality), of whom 72 deaths were adjudicated to one of four categories: 33.3% died of exsanguination, 16.6% died of early physiologic collapse, 11.1% died of late physiologic collapse, while 38.8% died of nonsurvivable injuries. Patients who died of exsanguination were younger and had the highest RBC/fresh frozen plasma ratio (2.97 [2.24]), although the early physiologic collapse group survived long enough to use the most blood products (p < 0.001). The late physiologic collapse group had significantly fewer penetrating injuries, was older, and had significantly more crystalloid use but received a lower RBC/fresh frozen plasma ratio (1.50 [0.42]). Those who were determined to have a nonsurvivable injury had a lower presenting Glasgow Coma Scale (GCS) score, fewer penetrating injuries, and higher initial blood pressure reflecting a preponderance of nonsurvivable traumatic brain injury. The average survival time for patients with potentially survivable injuries was 2.4 hours versus 18.4 hours for nonsurvivable injuries (p < 0.001). CONCLUSION: Severely injured patients requiring MTP have a high mortality rate. However, no studies to date have addressed the cause of death after MTP. Characterization of cause of death will allow targeting of surgical and resuscitative conduct to allow extension of the physiologic reserve time, therefore rendering previously nonsurvivable injury potentially survivable.

Characterization of platelet dysfunction after trauma.

BACKGROUND: The increased morbidity and mortality associated with coagulopathy and thrombocytopenia after trauma are well described. However, few studies have assessed platelet function after injury. METHODS: Blood samples were prospectively collected from 101 patients with critical injury and trauma on arrival to the emergency department and serially after admission to a Level I urban trauma intensive care unit from November 2010 to October 2011 and functionally assayed for responsiveness to adenosine diphosphate, thrombin receptor-activating peptide, arachidonic acid (AA), and collagen using multiple electrode impedance aggregometry. RESULTS: Of the 101 enrolled patients, 46 (45.5%) had below-normal platelet response to at least one agonist ("platelet hypofunction") at admission, and 92 patients (91.1%) had platelet hypofunction some time during their intensive care unit stay. Admission platelet hypofunction was associated with low Glasgow Coma Scale score and a nearly 10-fold higher early mortality. Logistic regression identified admission Glasgow Coma Scale (odds ratio, 0.819; p = 0.008) and base deficit (odds ratio, 0.872; p = 0.033) as independent predictors of platelet hypofunction. Admission AA and collagen responsiveness were significantly lower for patients who died (p < 0.01), whereas admission platelet counts were similar (p = 0.278); Cox regression confirmed thrombin receptor-activating peptide, AA, and collagen responsiveness as independent predictors of in-hospital mortality (p < 0.05). Receiver operating characteristic analysis identified admission AA and collagen responsiveness as negative predictors of both 24-hour (AA area under the curve [AUC], 0.874; collagen AUC, 0.904) and in-hospital mortality (AA AUC, 0.769; collagen AUC, 0.717). CONCLUSION: In this prognostic study, we identify clinically significant platelet dysfunction after trauma in the presence of an otherwise reassuring platelet count and standard clotting studies, with profound implications for mortality. Multiple electrode impedance aggregometry reliably identifies this dysfunction in injured patients, and admission AA and collagen responsiveness are sensitive and specific independent predictors of both early and late mortality.

Criteria for empiric treatment of hyperfibrinolysis after trauma.

BACKGROUND: Recent studies identify a survival benefit from the administration of antifibrinolytic agents in patients with severe injury and trauma. However, identification of hyperfibrinolysis requires thromboelastography, which is not widely available. We hypothesized that analysis of patients with thromboelastography-diagnosed hyperfibrinolysis would identify clinical criteria for empiric antifibrinolytic treatment in the absence of thromboelastography. METHODS: From November 2010 to March 2012, serial blood samples were collected from 115 patients with critical injury on arrival to the emergency department of an urban Level I trauma center. Rotational thromboelastography was performed to assess viscoelastic properties of clot formation in the presence and absence of aprotinin to identify treatable hyperfibrinolysis. For 20 patients identified with treatable hyperfibrinolysis, clinical predictors were investigated using receiver operating characteristic analysis. RESULTS: Of the 115 patients evaluated, 20% had hyperfibrinolysis, defined as an admission maximal clot lysis of 10% or higher, reversible by aprotinin treatment. Patients with hyperfibrinolysis had significantly lower temperature, pH, and platelet counts and higher international normalized ratio, activated partial thromboplastin time, and D-dimer. Hyperfibrinolysis was associated with multiorgan failure (63.2% vs. 24.6%, p = 0.004) and mortality (52.2% vs. 12.9%, p < 0.001). We then evaluated all non-rotational thromboelastography clinical and laboratory parameters predictive of hyperfibrinolysis using receiver operating characteristic analysis to evaluate potential empiric treatment guidelines. The presence of hypothermia (temperature ≤36.0°C), acidosis (pH ≤7.2), relative coagulopathy (international normalized ratio ≥1.3 or activated partial thromboplastin time ≥30), or relative thrombocytopenia (platelet count ≤200) identified hyperfibrinolysis with 100% sensitivity and 55.4% specificity (area under the curve, 0.777). CONCLUSION: Consideration of empiric antifibrinolytic therapy is warranted for patients with critical injury and trauma who present with acidosis, hypothermia, coagulopathy, or relative thrombocytopenia. These clinical predictors identified hyperfibrinolysis with 100% sensitivity while simultaneously eliminating 46.6% of inappropriate therapy compared with the empiric treatment of all injured patients. These criteria will facilitate empiric treatment of hyperfibrinolysis for clinicians without access to thromboelastography. LEVEL OF EVIDENCE: Prognostic study, level III.