Cigarette Smoke Exposure and Acute Respiratory Distress Syndrome in Sepsis: Epidemiology, Clinical Features, and Biologic Markers.

Rationale: Cigarette smoke exposure is associated with an increased risk of developing acute respiratory distress syndrome (ARDS) in trauma, transfusion, and nonpulmonary sepsis. It is unknown whether this relationship exists in the general sepsis population. Furthermore, it is unknown if patients with ARDS have differences in underlying biology based on smoking status. Objectives: To assess the relationship between cigarette smoke exposure and ARDS in sepsis and identify tobacco-related biomarkers of lung injury. Methods: We studied a prospective cohort of 592 patients with sepsis from 2009 to 2017. Plasma cotinine and urine NNAL [urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] were measured to categorize smoking status. Plasma biomarkers of inflammation and lung injury were measured, including in a smaller cohort of trauma patients with ARDS to increase generalizability. Measurements and Main Results: Passive and active smoking were associated with increased odds of developing ARDS in patients with sepsis. Among patients with sepsis and ARDS, active cigarette smokers were younger and had lower severity of illness than nonsmokers. Patients with ARDS with cigarette smoke exposure had lower plasma levels of IL-8 (P = 0.01) and sTNFR-1 (soluble tumor necrosis factor 1; P = 0.01) compared with those without exposure. Similar biomarker patterns were observed in blunt trauma patients with ARDS. Conclusions: Passive and active smoking are associated with an increased risk of developing ARDS in patients with pulmonary and nonpulmonary sepsis. Among patients with ARDS, those with cigarette smoke exposure have less systemic inflammation, while active smokers also have lower severity of illness compared with nonsmokers, suggesting that smoking contributes to biological heterogeneity in ARDS.

Cigarette Smoking and ARDS After Blunt Trauma: The Influence of Changing Smoking Patterns and Resuscitation Practices.

BACKGROUND: Cigarette smoking is associated with an increased risk of developing ARDS. However, whether changes in smoking patterns or processes of care impact this relationship is unclear. RESEARCH QUESTION: Are changes in smoking and resuscitation patterns associated with changes in the relationship between smoking and ARDS? STUDY DESIGN AND METHODS: We conducted a prospective cohort study of critically injured adults with blunt trauma from 2005 to 2015. Plasma cotinine, a tobacco biomarker, was measured to categorize patients by smoking status. We used regression to assess the relationship between smoking, resuscitation practices, and ARDS over time. RESULTS: In the overall cohort, active (OR, 1.9; 95% CI, 1.0-3.5; P = .046) and passive (OR, 2.6; 95% CI, 1.4-4.8; P = .002) smoking were associated with an increased risk of developing ARDS in multivariate analyses. In contrast to the dose-response relationship in patients enrolled from 2005 to 2008, passive cigarette smoke exposure was associated with the highest risk of developing ARDS in patients enrolled from 2009 to 2015, suggesting a threshold effect. Packed RBC (pRBC) and fresh frozen plasma (FFP) transfusions were associated with an increased risk of developing ARDS, particularly in active smokers (pRBC: OR, 5.6; P < .001; FFP: OR, 4.5; P < .001) compared with passive smokers or nonsmokers. Blood product transfusion and smoking patterns changed over time. INTERPRETATION: Despite changes in resuscitation and smoking patterns, cigarette smoking remains associated with an increased risk of developing ARDS. However, this relationship changed over time, with passive smokers at particularly increased risk of developing ARDS in later years, which may be related to changes in smoking patterns or transfusion practices over time. These findings highlight the need for additional mechanistic and epidemiologic studies of the effects of low levels of cigarette smoke exposure on lung health.

End-tidal carbon dioxide underestimates plasma carbon dioxide during emergent trauma laparotomy leading to hypoventilation and misguided resuscitation: A Western Trauma Association Multicenter Study.

BACKGROUND: End-tidal carbon dioxide (ETCO2) is routinely used during elective surgery to monitor ventilation. The role of ETCO2 monitoring in emergent trauma operations is poorly understood. We hypothesized that ETCO2 values underestimate plasma carbon dioxide (pCO2) values during resuscitation for hemorrhagic shock. METHODS: Multicenter trial was performed analyzing the correlation between ETCO2 and pCO2 levels. RESULTS: Two hundred fifty-six patients resulted in 587 matched pairs of ETCO2 and pCO2. Correlation between these two values was very poor with an R of 0.04. 40.2% of patients presented to the operating room acidotic and hypercarbic with a pH less than 7.30 and a pCO2 greater than 45 mm Hg. Correlation was worse in patients that were either acidotic or hypercarbic. Forty-five percent of patients have a difference greater than 10 mm Hg between ETCO2 and pCO2. A pH less than 7.30 was predictive of an ETCO2 to pCO2 difference greater than 10 mm Hg. A difference greater than 10 mm Hg was predictive of mortality independent of confounders. CONCLUSION: Nearly one half (45%) of patients were found to have an ETCO2 level greater than 10 mm Hg discordant from their PCO2 level. Reliance on the discordant values may have contributed to the 40% of patients in the operating room that were both acidotic and hypercarbic. Early blood gas analysis is warranted, and a lower early goal of ETCO2 should be considered. LEVEL OF EVIDENCE: Therapeutic, level IV.

It's About Time: Transfusion effects on postinjury platelet aggregation over time.

BACKGROUND: Impaired postinjury platelet aggregation is common, but the effect of transfusion on this remains unclear. Data suggest that following injury platelet transfusion may not correct impaired platelet aggregation, and impaired platelet aggregation may not predict the need for platelet transfusion. We sought to further investigate platelet aggregation responses to transfusions, using regression statistics to isolate the independent effects of transfusions given in discrete time intervals from injury on both immediate and longitudinal platelet aggregation. We hypothesized that platelet aggregation response to platelet transfusion increases over time from injury. METHODS: Serial (0-96 hours) blood samples were collected from 248 trauma patients. Platelet aggregation was assessed in vitro with impedance aggregometry stimulated by adenosine diphosphate, collagen, and thrombin receptor-activating peptide-6. Using regression, transfusion exposure was modeled against platelet aggregation at each subsequent timepoint and adjusted for confounders (Injury Severity Score, international normalized ratio (INR), base deficit, platelet count, and interval transfusions). The expected change in platelet aggregation at each timepoint under the intervention of transfusion exposure was calculated and compared with the observed platelet aggregation. RESULTS: The 248 patients analyzed were severely injured (Injury Severity Score, 21 ± 19), with normal platelet counts (mean, 268 × 10/L ± 90), and 62% were transfused in 24 hours. The independent effect of transfusions on subsequent platelet aggregation over time was modeled with observed platelet aggregation under hypothetical treatment of one unit transfusion of blood, plasma, or platelets. Platelet transfusions had increasing expected effects on subsequent platelet aggregation over time, with the maximal expected effect occurring late (4-5 days from injury). CONCLUSION: Controversy exists on whether transfusions improve impaired postinjury platelet aggregation. Using regression modeling, we identified that expected transfusion effects on subsequent platelet aggregation are maximal with platelet transfusion given late after injury. This is critical for tailored resuscitation, identifying a potential early period of resistance to platelet transfusion that resolves by 96 hours. LEVEL OF EVIDENCE: Therapeutic, level V.

Dynamic multi-outcome prediction after injury: Applying adaptive machine learning for precision medicine in trauma.

OBJECTIVE: Machine learning techniques have demonstrated superior discrimination compared to conventional statistical approaches in predicting trauma death. The objective of this study is to evaluate whether machine learning algorithms can be used to assess risk and dynamically identify patient-specific modifiable factors critical to patient trajectory for multiple key outcomes after severe injury. METHODS: SuperLearner, an ensemble machine-learning algorithm, was applied to prospective observational cohort data from 1494 critically-injured patients. Over 1000 agnostic predictors were used to generate prediction models from multiple candidate learners for outcomes of interest at serial time points post-injury. Model accuracy was estimated using cross-validation and area under the curve was compared to select among predictors. Clinical variables responsible for driving outcomes were estimated at each time point. RESULTS: SuperLearner fits demonstrated excellent cross-validated prediction of death (overall AUC 0.94-0.97), multi-organ failure (overall AUC 0.84-0.90), and transfusion (overall AUC 0.87-0.9) across multiple post-injury time points, and good prediction of Acute Respiratory Distress Syndrome (overall AUC 0.84-0.89) and venous thromboembolism (overall AUC 0.73-0.83). Outcomes with inferior data quality included coagulopathic trajectory (AUC 0.48-0.88). Key clinical predictors evolved over the post-injury timecourse and included both anticipated and unexpected variables. Non-random missingness of data was identified as a predictor of multiple outcomes over time. CONCLUSIONS: Machine learning algorithms can be used to generate dynamic prediction after injury while avoiding the risk of over- and under-fitting inherent in ad hoc statistical approaches. SuperLearner prediction after injury demonstrates promise as an adaptable means of helping clinicians integrate voluminous, evolving data on severely-injured patients into real-time, dynamic decision-making support.

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.

The why and how our trauma patients die: A prospective Multicenter Western Trauma Association study.

BACKGROUND: Historically, hemorrhage has been attributed as the leading cause (40%) of early death. However, a rigorous, real-time classification of the cause of death (COD) has not been performed. This study sought to prospectively adjudicate and classify COD to determine the epidemiology of trauma mortality. METHODS: Eighteen trauma centers prospectively enrolled all adult trauma patients at the time of death during December 2015 to August 2017. Immediately following death, attending providers adjudicated the primary and contributing secondary COD using standardized definitions. Data were confirmed by autopsies, if performed. RESULTS: One thousand five hundred thirty-six patients were enrolled with a median age of 55 years (interquartile range, 32-75 years), 74.5% were male. Penetrating mechanism (n = 412) patients were younger (32 vs. 64, p < 0.0001) and more likely to be male (86.7% vs. 69.9%, p < 0.0001). Falls were the most common mechanism of injury (26.6%), with gunshot wounds second (24.3%). The most common overall primary COD was traumatic brain injury (TBI) (45%), followed by exsanguination (23%). Traumatic brain injury was nonsurvivable in 82.2% of cases. Blunt patients were more likely to have TBI (47.8% vs. 37.4%, p < 0.0001) and penetrating patients exsanguination (51.7% vs. 12.5%, p < 0.0001) as the primary COD. Exsanguination was the predominant prehospital (44.7%) and early COD (39.1%) with TBI as the most common later. Penetrating mechanism patients died earlier with 80.1% on day 0 (vs. 38.5%, p < 0.0001). Most deaths were deemed disease-related (69.3%), rather than by limitation of further aggressive care (30.7%). Hemorrhage was a contributing cause to 38.8% of deaths that occurred due to withdrawal of care. CONCLUSION: Exsanguination remains the predominant early primary COD with TBI accounting for most deaths at later time points. Timing and primary COD vary significantly by mechanism. Contemporaneous adjudication of COD is essential to elucidate the true understanding of patient outcome, center performance, and future research. LEVEL OF EVIDENCE: Epidemiologic, level II.

Is it time to measure complications from the National Trauma Data Bank? A longitudinal analysis of recent reporting trends.

BACKGROUND: Payers have approached select complications as never events, yet there is rationale that achieving a zero incidence of these events is impractical. Prior 2005 National Trauma Data Bank (NTDB) analysis showed high rates (37%) of centers reporting no complications data making national estimates for determining standardized complication rates difficult to ascertain. METHODS: The 2008-2012 NTDB National Sample Program nationally weighted files were used to calculate yearly national estimates. Rates were compared in all centers and those reporting complications data. Hospital characteristics were compared using Student t test. In 2011, an other complication category was introduced; overall rates were calculated with and without this category. Yearly estimates were reported for patients receiving care within centers reporting complications data. RESULTS: From 2008-2012 NTDB, there were raw data on 3,657,884 patients. A total of 594,894 patients (16.3%) experienced one or more complications (82.7% one complication; 17.3% two or more complications). Excluding the other complication category, the overall weighted rate was 8.4% to 9.2%. Pneumonia was the most common complication (2.7-3.0%), occurring at twice the 2005 rate. The number of centers reporting no complications data dropped to 8.1% in 2011 (2008, 14.5%; 2009, 18.2%; 2010, 15.9%; 2012, 8.9%). By 2012, nearly all level I centers reported complications, whereas 46.4% of level IVs reported none (I 0.5%, II 2.7%, III 8.5%, p = 0.04). Data were reported the least frequently in nonteaching hospitals (15.8%, p = 0.007), those in the South (19.6%, p = 0.007), and those with less than 200 beds (23.6%, p = 0.005). CONCLUSION: Overall rates of complications from 2008 to 2012 were nearly twofold higher than 2005 data. Reporting has increased, and NTDB may provide a valuable platform for establishing rational and achievable measures for specific complications. LEVEL OF EVIDENCE: Prognostic and epidemiological, level IV.

Dynamic coagulability after injury: Is delaying venous thromboembolism chemoprophylaxis worth the wait?

BACKGROUND: Severely injured patients often progress from early hypocoagulable to normal and eventually hypercoagulable states, developing increased risk for venous thromboembolism (VTE). Prophylactic anticoagulation can decrease this risk, but its initiation is frequently delayed for extended periods due to concerns for bleeding. To facilitate timely introduction of VTE chemoprophylaxis, we characterized the transition from hypo- to hypercoagulability and hypothesized that trauma-induced coagulopathy resolves within 24 hours after injury. METHODS: Serial blood samples were collected prospectively from critically injured patients for 120 hours after arrival at an urban Level I trauma center. Extrinsic thromboelastometry maximum clot firmness was used to classify patients as hypocoagulable (HYPO, <49 mm), normocoagulable (NORM, 49-71 mm), or hypercoagulable (HYPER, >71 mm) at each time point. Changes in coagulability over hospital course, VTE occurrence, and timing of prophylaxis initiation were analyzed. RESULTS: 898 patients (median Injury Severity Score, 13; mortality, 12%; VTE, 8%) were enrolled. Upon arrival, 3% were HYPO (90% NORM, 7% HYPER), which increased to 9% at 6 hours before down-trending. Ninety-seven percent were NORM by 24 hours, and 53% were HYPER at 120 hours. Median maximum clot firmness began in the NORM range, up-trended gradually, and entered the HYPER range at 120 hours. Patients with traumatic brain injury (TBI) followed a similar course and were not more HYPO at any time point than those without TBI. Failure to initiate prophylaxis by 72 hours was predicted by TBI and associated with VTE development (27% vs 16%, p < 0.05). CONCLUSIONS: Regardless of injury pattern, trauma-induced coagulopathy largely resolves within 24 hours, after which hypercoagulability becomes increasingly more prevalent. Deferring initiation of chemoprophylaxis, which is often biased toward patients with intracranial injuries, is associated with VTE development. LEVEL OF EVIDENCE: Prognostic study, level III; Therapeutic, level IV.

Citrated kaolin thrombelastography (TEG) thresholds for goal-directed therapy in injured patients receiving massive transfusion.

INTRODUCTION: Goal-directed hemostatic resuscitation based on thrombelastography (TEG) has a survival benefit compared with conventional coagulation assays such as international normalized ratio, activated partial thromboplastin time, fibrinogen level, and platelet count. While TEG-based transfusion thresholds for patients at risk for massive transfusion (MT) have been defined using rapid TEG, cutoffs have not been defined for TEG using other activators such as kaolin. The purpose of this study was to develop thresholds for blood product transfusion using citrated kaolin TEG (CK-TEG) in patients at risk for MT. METHODS: CK-TEG was assessed in trauma activation patients at two Level 1 trauma centers admitted between 2010 and 2017. Receiver operating characteristic (ROC) curve analyses were performed to test the predictive performance of CK-TEG measurements in patients requiring MT, defined as >10 units of red blood cells or death within the first 6 hours. The Youden Index defined optimal thresholds for CK-TEG-based resuscitation. RESULTS: Of the 825 trauma activations, 671 (81.3%) were men, 419 (50.8%) suffered a blunt injury, and 62 (7.5%) received a MT. Patients who had a MT were more severely injured, had signs of more pronounced shock, and more abnormal coagulation assays. CK-TEG R-time was longer (4.9 vs. 4.4 min, p = 0.0084), angle was lower (66.2 vs. 70.3 degrees, p < 0.0001), maximum amplitude was lower in MT (57 vs. 65.5 mm, p < 0.0001), and LY30 was greater (1.8% vs. 1.2%, p = 0.0012) in patients with MT compared with non-MT. To predict MT, R-time yielded an area under the ROC curve (AUROC) = 0.6002 and a cut point of >4.45 min. Angle had an AUROC = 0.6931 and a cut point of <67 degrees. CMA had an AUROC = 0.7425, and a cut point of <60 mm. LY30 had an AUROC = 0.623 with a cut point of >4.55%. CONCLUSION: We have identified CK-TEG thresholds that can guide MT in trauma. We propose plasma transfusion for R-time >4.45 min, fibrinogen products for an angle <67 degrees, platelet transfusion for MA <60 mm, and antifibrinolytics for LY30 >4.55%. LEVEL OF EVIDENCE: Therapeutic study, level V.

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.

Perhaps it's not the platelet: Ristocetin uncovers the potential role of von Willebrand factor in impaired platelet aggregation following traumatic brain injury.

BACKGROUND: Injury to the blood-brain barrier exposes endothelium rich in von Willebrand factor (vWF), which may play a role in altered platelet aggregation following traumatic brain injury (TBI). Ristocetin is an antimicrobial substance that induces vWF-mediated aggregation of platelets. We examined these mechanisms in injured patients by measuring the aggregation response of platelets to stimulating agonists (including ristocetin) via whole-blood multiple-electrode platelet aggregometry. We hypothesized that patients with TBI have an altered platelet aggregation response to ristocetin stimulation compared with patients without TBI. METHODS: Blood was collected from 233 trauma patients without thrombocytopenia. Platelet aggregation was assessed using multiple-electrode platelet aggregometry (Multiplate). Platelet aggregation response to stimulating agonists collagen, thrombin receptor-activating peptide 6, adenosine diphosphate, arachidonic acid, and ristocetin was measured. Factor activity was measured. RESULTS: Of the 233 patients, 23% had TBI. There were no differences in platelet aggregation responses to any agonists between TBI and non-TBI patients except ristocetin. Platelet aggregation response to ristocetin stimulation was significantly lower in TBI patients (p = 0.03). Patients with TBI also had higher factor VIII activity (215% vs. 156%, p = 0.01). In multivariate analysis, there was a significant independent association of impaired platelet aggregation response to ristocetin stimulation with TBI (odds ratio, 3.05; p = 0.04). CONCLUSIONS: Given the importance of platelets in hemostasis, understanding the mechanisms of impaired platelet aggregation following injury is critical. The impaired platelet aggregation response to ristocetin stimulation and corresponding increase in factor VIII activity in TBI patients may be secondary to a TBI-induced effect on vWF quantity (due to injury-driven consumption of vWF) or vWF function with resultant increase in circulating factor VIII activity (due to impaired carrying capacity of vWF). Given there are multiple known therapies for vWF deficits including desmopressin, purified and recombinant vWF, and estrogens, these lines of investigation are particularly compelling in patients with TBI and hemorrhage. LEVEL OF EVIDENCE: Prognostic study, level II.

Health care utilization and the cost of posttraumatic acute respiratory distress syndrome care.

BACKGROUND: Posttraumatic acute respiratory distress syndrome (ARDS) is associated with prolonged mechanical ventilation and longer hospitalizations. The relationship between posttraumatic ARDS severity and financial burden has not been previously studied. We hypothesized that increasing ARDS severity is associated with incrementally higher health care costs. METHODS: Adults arriving as the highest level of trauma activation were enrolled in an ongoing prospective cohort study. Patients who survived 6 hours or longer are included in the analysis. Blinded review of chest radiographs was performed by two independent physicians for any intubated patient with PaO2:FIO2 ratio of 300 mmHg or lower during the first 8 days of admission. The severity of ARDS was classified by the Berlin criteria. Hospital charge data were used to perform standard costing analysis. RESULTS: Acute respiratory distress syndrome occurred in 13% (203 of 1,586). The distribution of disease severity was 33% mild, 42% moderate, and 25% severe. Patients with ARDS were older (41 years vs. 35 years, p < 0.01), had higher median Injury Severity Score (30 vs. 10, p < 0.01), more chest injury (Abbreviated Injury Scale score, ≥ 3: 51% vs. 21%, p < 0.01), and blunt mechanisms (85% vs. 53%, p < 0.01). By ARDS severity, there was no significant difference in age, mechanism, or rate of traumatic brain injury. Increasing ARDS severity was associated with higher Injury Severity Score and higher mortality rates. Standardized total hospital charges were fourfold higher for patients who developed ARDS compared with those who did not develop ARDS (US $434,000 vs. US $96,000; p < 0.01). Furthermore, the daily hospital charges significantly increased across categories of worsening ARDS severity (mild, US $20,451; moderate, US $23,994; severe, US $33,316; p < 0.01). CONCLUSION: The development of posttraumatic ARDS is associated with higher health care costs. Among trauma patients who develop ARDS, total hospital charges per day increase with worsening severity of disease. Prevention, early recognition, and treatment of ARDS after trauma are potentially important objectives for efforts to control health care costs in this population. LEVEL OF EVIDENCE: Economic and value-based evaluations, level IV.

Reduction in oral mucositis severity using a topical vasoconstrictor: A case report of three bone marrow transplant patients.

BACKGROUND: Grade 3 oral mucositis (OM) is historically observed in >90% of bone marrow transplant patients who received the cyclophosphamide + total body irradiation (CY+TBI) conditioning regimen. It was previously shown that orotopically applied adrenergic vasoconstrictor prevented up to 100% of radiation-induced oral mucositis in two preclinical animal models. METHODS: Adrenergic vasoconstrictor (i.e., phenylephrine in an aqueous-alcohol NG11-1 formulation) was orotopically applied to three patients (ages 24-29) who received the CY+TBI conditioning regimen; they were compared to five matched controls who received no orotopical vasoconstrictor. All patients received the CY+TBI conditioning regimen for acute lymphoblastic leukemia within the University of Wisconsin Adult Bone Marrow Transplant Program. Over the seven-day Cy+TBI conditioning regimen, 20 min before each treatment, either radiation or chemotherapy, vasoconstrictor was applied topically to the oral cavity, and patients then received either 1.5 Gy whole-body radiation or IV cyclophosphamide. RESULTS: OM severity was scored over a three-week period using: i) physican assessments, ii) daily photos of the oral cavity, iii) oral pain and oral function score sheets, and iv) recorded narcotic consumption. Both "Grade 3 OM" duration and "any OM" duration in vasoconstrictor-treated patients were substantially lower than for the five control patients. Though nasogastric tube or total parenteral nutrition were used in 3 out of 5 control patients, there was no use of these supportive care measures in the three vasoconstrictor-treated patients. CONCLUSION: Orotopically applied NG11-1 vasoconstrictor formulation substantially reduced the incidence and severity of "Grade 3" and "any" oral mucositis when compared to matched control patients, all of whom received the same CY+TBI conditioning regimen. The liquid orotopical formulation was easily tolerated by patients both in its ease of use and lack of side effects.

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.

Platelet aggregation after blunt trauma is associated with the acute respiratory distress syndrome and altered by cigarette smoke exposure.

BACKGROUND: The risk of the acute respiratory distress syndrome (ARDS) is increased in passive and active smokers after blunt trauma. However, the mechanisms responsible, including the role of platelet aggregation, for this association are unknown. METHODS: We analyzed 215 patients with severe blunt trauma from a prospective observational cohort at a Level I trauma center between 2010 and 2015. Subjects underwent impedance-based platelet aggregometry in response to platelet agonists arachidonic acid, adenosine diphosphate, collagen, and thrombin receptor activating peptide-6. Acute respiratory distress syndrome within the first 8 days of admission was adjudicated using Berlin criteria. Plasma cotinine was measured to assess cigarette smoke exposure. Regression analyses were used to assess the relationship between (1) platelet aggregation and ARDS and (2) cigarette smoke exposure and platelet aggregation. RESULTS: At both 0 hour and 24 hours, impaired platelet aggregation was associated with increased odds of developing ARDS. Cigarette smoke exposure was associated with increased platelet aggregation upon arrival to the emergency department. However, at 24 hours, cigarette smoke exposure was associated with increased impairment in platelet aggregation, reflecting a statistically significant decline in platelet aggregation over the initial 24 hours after trauma. The relationship between this decline in platelet aggregation and ARDS differed by cigarette smoke exposure status, suggesting that impaired platelet activation differentially affects the risk of ARDS in those with cigarette smoke exposure (arachidonic acid, p for interaction: 0.005, collagen p for interaction: 0.02, adenosine diphosphate, p for interaction: 0.05). CONCLUSION: Impaired platelet aggregation at 0 hour and 24 hours is associated with an increased risk of developing ARDS after severe blunt trauma. Cigarette smoke-exposed patients are more likely to develop impaired platelet aggregation over the first 24 hours of admission, which may contribute to their increased risk of ARDS. LEVEL OF EVIDENCE: Prognostic/Epidemiological, 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.

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.