Amanda S. Conroy

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.

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.

Individual clotting factor contributions to mortality following trauma.

BACKGROUND Acute traumatic coagulopathy affects 20% to 30% of trauma patients, but the extensive collinearity of the coagulation cascade complicates attempts to clarify global clotting factor dysfunction. This study aimed to characterize phenotypes of clotting factor dysfunction and their contributions to mortality after major trauma. METHODS This prospective cohort study examines all adult trauma patients of the highest activation level presenting to San Francisco General Hospital between February 2005 and February 2015. Factors II, V, VII, VIII, IX, and X and protein C activity on admission and mortality status at 28 days were assessed. Predictors of 28-day mortality in univariate analysis were included in multiple logistic regression controlling for traumatic brain injury (TBI), acidosis, age, and mechanism of injury. Principal component analysis was utilized to identify phenotypic coagulation. RESULTS Complete coagulation factor data were available for 876 (61%) of 1,429 patients. In multiple logistic regression, factors V (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.76–0.97), VIII (OR, 0.97; 95% CI, 0.95–0.99), and X (OR, 0.79; 95% CI, 0.68–0.92) and protein C (OR, 1.17; 95% CI, 1.05–1.30) significantly predicted 28-day mortality after controlling for age, base deficit, mechanism of injury, and TBI. Principal component analysis identified two significant principal components (Phenotypes 1 and 2) that accounted for 66.3% of the total variance. Phenotype 1 (factors II, VII, IX, and X and protein C abnormalities) explained 49.3% and was associated with increased injury, coagulopathy, TBI, and mortality. Phenotype 2 (factors V and VIII abnormalities) explained 17.0% and was associated with increased coagulopathy, blunt injury, and mortality. Only Phenotype 2 remained significantly associated with 28-day mortality in multiple logistic regression. CONCLUSIONS Principal component analysis identified two distinct phenotypes within the entirety of global clotting factor abnormalities, and these findings substantiate the crucial association of factors V and VIII on mortality following trauma. This may be the first step toward identifying unique phenotypes after injury and personalizing hemostatic resuscitation. LEVEL OF EVIDENCE Prognostic study, level III.

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

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.

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.

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: Group 1: Non-severe injury, no shock Group 2: Non-severe injury, with shock Group 3: Severe injury, no shock Group 4: Severe injury, with shock 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.

Elevated plasma levels of TIMP-3 are associated with a higher risk of acute respiratory distress syndrome and death following severe isolated traumatic brain injury

Background Complications after injury, such as acute respiratory distress syndrome (ARDS), are common after traumatic brain injury (TBI) and associated with poor clinical outcomes. The mechanisms driving non-neurologic organ dysfunction after TBI are not well understood. Tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) is a regulator of matrix metalloproteinase activity, inflammation, and vascular permeability, and hence has plausibility as a biomarker for the systemic response to TBI. Methods In a retrospective study of 182 patients with severe isolated TBI, we measured TIMP-3 in plasma obtained on emergency department arrival. We used non-parametric tests and logistic regression analyses to test the association of TIMP-3 with the incidence of ARDS within 8 days of admission and in-hospital mortality. Results TIMP-3 was significantly higher among subjects who developed ARDS compared with those who did not (median 2810 pg/mL vs.2260 pg/mL, p=0.008), and significantly higher among subjects who died than among those who survived to discharge (median 2960 pg/mL vs.2080 pg/mL, p<0.001). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of ARDS increased significantly, OR 1.5 (95% CI 1.1 to 2.1). This association was only attenuated in multivariate models, OR 1.4 (95% CI 1.0 to 2.0). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of death increased significantly, OR 1.7 (95% CI 1.2 to 2.3). The magnitude of this association was greater in a multivariate model adjusted for markers of injury severity, OR 1.9 (95% CI 1.2 to 2.8). Discussion TIMP-3 may play an important role in the biology of the systemic response to brain injury in humans. Along with clinical and demographic data, early measurements of plasma biomarkers such as TIMP-3 may help identify patients at higher risk of ARDS and death after severe isolated TBI. Level of evidence III.