A Data-Adaptive Targeted Learning Approach of Evaluating Viscoelastic Assay Driven Trauma Treatment Protocols

Estimating the impact of trauma treatment protocols is complicated by the high dimensional yet finite sample nature of trauma data collected from observational studies. Viscoelastic assays are highly predictive measures of hemostasis. However, the effectiveness of thromboelastography(TEG) based treatment protocols has not been statistically evaluated.To conduct robust and reliable estimation with sparse data, we built an estimation "machine" for estimating causal impacts of candidate variables using the collaborative targeted maximum loss-based estimation(CTMLE) framework.The computational efficiency is achieved by using the scalable version of CTMLE such that the covariates are pre-ordered by summary statistics of their importance before proceeding to the estimation steps.To extend the application of the estimator in practice, we used super learning in combination with CTMLE to flexibly choose the best convex combination of algorithms. By selecting the optimal covariates set in high dimension and reducing constraints in choosing pre-ordering algorithms, we are able to construct a robust and data-adaptive model to estimate the parameter of interest.Under this estimation framework, CTMLE outperformed the other doubly robust estimators(IPW,AIPW,stabilized IPW,TMLE) in the simulation study. CTMLE demonstrated very accurate estimation of the target parameter (ATE). Applying CTMLE on the real trauma data, the treatment protocol (using TEG values immediately after injury) showed significant improvement in trauma patient hemostasis status (control of bleeding), and a decrease in mortality rate at 6h compared to standard care.The estimation results did not show significant change in mortality rate at 24h after arrival

Trauma Early Mortality Prediction Tool (TEMPT) for assessing 28-day mortality.

Background:Prior mortality prediction models have incorporated severity of anatomic injury quantified by Abbreviated Injury Severity Score (AIS). Using a prospective cohort, a new score independent of AIS was developed using clinical and laboratory markers present on emergency department presentation to predict 28-day mortality. Methods:All patients (n=1427) enrolled in an ongoing prospective cohort study were included. Demographic, laboratory, and clinical data were recorded on admission. True random number generator technique divided the cohort into derivation (n=707) and validation groups (n=720). Using Youden indices, threshold values were selected for each potential predictor in the derivation cohort. Logistic regression was used to identify independent predictors. Significant variables were equally weighted to create a new mortality prediction score, the Trauma Early Mortality Prediction Tool (TEMPT) score. Area under the curve (AUC) was tested in the validation group. Pairwise comparison of Trauma Injury Severity Score (TRISS), Revised Trauma Score, Glasgow Coma Scale, and Injury Severity Score were tested against the TEMPT score. Results:There was no difference between baseline characteristics between derivation and validation groups. In multiple logistic regression, a model with presence of traumatic brain injury, increased age, elevated systolic blood pressure, decreased base excess, prolonged partial thromboplastin time, increased international normalized ratio (INR), and decreased temperature accurately predicted mortality at 28 days (AUC 0.93, 95% CI 0.90 to 0.96, P<0.001). In the validation cohort, this score, termed TEMPT, predicted 28-day mortality with an AUC 0.94 (95% CI 0.92 to 0.97). The TEMPT score preformed similarly to the revised TRISS score for severely injured patients and was highly predictive in those having mild to moderate injury. Discussion:TEMPT is a simple AIS-independent mortality prediction tool applicable very early following injury. TEMPT provides an AIS-independent score that could be used for early identification of those at risk of doing poorly following even minor injury. Level of evidence:Level II

Blunt trauma induced splenic blushes are not created equal

<p>Abstract</p> <p>Background</p> <p>Currently, evidence of contrast extravasation on computed tomography (CT) scan is regarded as an indication for intervention in splenic injuries. In our experience, patients transferred from other institutions for angioembolization have often resolved the blush upon repeat imaging at our hospital. We <it>hypothesized </it>that not all splenic blushes require intervention.</p> <p>Methods</p> <p>During a 10-year period, we reviewed all patients transferred with blunt splenic injuries and contrast extravasation on initial postinjury CT scan.</p> <p>Results</p> <p>During the study period, 241 patients were referred for splenic injuries, of whom 16 had a contrast blush on initial CT imaging (88% men, mean age 35 ± 5, mean ISS 26 ± 3). Eight (50%) patients were managed without angioembolization or operation. Comparing patients with and without intervention, there was a significant difference in admission heart rate (106 ± 9 <it>vs </it>83 ± 6) and decline in hematocrit following transfer (5.3 ± 2.0 <it>vs </it>1.0 ± 0.3), but not in injury grade (3.9 ± 0.2 <it>vs </it>3.5 ± 0.3), systolic blood pressure (125 ± 10 <it>vs </it>115 ± 6), or age (38.5 ± 8.2 <it>vs </it>30.9 ± 4.7). Of the 8 observed patients, 3 underwent repeat imaging immediately upon arrival with resolution of the blush. In the intervention group, 4 patients had ongoing extravasation on repeat imaging, 2 patients underwent empiric embolization, and 2 patients underwent splenectomy for physiologic indications.</p> <p>Conclusions</p> <p>For blunt splenic trauma, evidence of contrast extravasation on initial CT imaging is not an absolute indication for intervention. A period of observation with repeat imaging could avoid costly, invasive interventions and their associated sequelae.</p

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

Trauma-induced coagulopathy

Acknowledgements E.E.M. and A.S. appreciate the generous support from the National Institutes of Health for their inflammation and coagulation research over the past 35 years (NIGMS: 1-6 P50 GM49222, 1-6 T32 GM08315, 1-2 U54 GM 62119, RM1 GM 131968 and NHLBI: UM1 HL120877). H.B.M. acknowledges the generous support from the National Institutes of Health (NHBLI: K99HL1518870) L.Z.K. acknowledges the generous support from the National Institutes of Health for her platelet biology research (NIGMS: K23GM130892-01). M.D.N. acknowledges the generous support by the National Institutes of Health (NIGMS: R35 GM119526 and NHLBI R01 HL141080).Peer reviewedPostprin

Early Cold Stored Platelet Transfusion Following Severe Injury: A Randomized Clinical Trial

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock. BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury. METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus standard care resuscitation. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was 24-hour mortality. RESULTS: Mortality at 24 hours was 5.9% in patients who were randomized to early cold stored platelet transfusion compared with 10.2% in the standard care arm (difference, -4.3%; 95% CI, -12.8% to 3.5%; P =0.26). No significant differences were found for any of the prespecified ancillary outcomes. Rates of arterial and/or venous thromboembolism and adverse events did not differ across treatment groups. CONCLUSIONS AND RELEVANCE: In severely injured patients, early cold stored platelet transfusion is feasible, safe and did not result in a significant lower rate of 24-hour mortality. Early cold stored platelet transfusion did not result in a higher incidence of arterial and/or venous thrombotic complications or adverse events. The storage age of the cold stored platelet product was not associated with significant outcome differences

Association of SARS-CoV-2 nucleocapsid viral antigen and the receptor for advanced glycation end products with development of severe disease in patients presenting to the emergency department with COVID-19

IntroductionThere remains a need to better identify patients at highest risk for developing severe Coronavirus Disease 2019 (COVID-19) as additional waves of the pandemic continue to impact hospital systems. We sought to characterize the association of receptor for advanced glycation end products (RAGE), SARS-CoV-2 nucleocapsid viral antigen, and a panel of thromboinflammatory biomarkers with development of severe disease in patients presenting to the emergency department with symptomatic COVID-19.MethodsBlood samples were collected on arrival from 77 patients with symptomatic COVID-19, and plasma levels of thromboinflammatory biomarkers were measured.ResultsDifferences in biomarkers between those who did and did not develop severe disease or death 7 days after presentation were analyzed. After adjustment for multiple comparisons, RAGE, SARS-CoV-2 nucleocapsid viral antigen, interleukin (IL)-6, IL-10 and tumor necrosis factor receptor (TNFR)-1 were significantly elevated in the group who developed severe disease (all p&lt;0.05). In a multivariable regression model, RAGE and SARS-CoV-2 nucleocapsid viral antigen remained significant risk factors for development of severe disease (both p&lt;0.05), and each had sensitivity and specificity &gt;80% on cut-point analysis.DiscussionElevated RAGE and SARS-CoV-2 nucleocapsid viral antigen on emergency department presentation are strongly associated with development of severe disease at 7 days. These findings are of clinical relevance for patient prognostication and triage as hospital systems continue to be overwhelmed. Further studies are warranted to determine the feasibility and utility of point-of care measurements of these biomarkers in the emergency department setting to improve patient prognostication and triage

Heparin Dose Intensity and Organ Support-Free Days in Patients Hospitalized for COVID-19.

BACKGROUND Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation. OBJECTIVES The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin. METHODS Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21. RESULTS Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low. CONCLUSIONS Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis

Heparin Dose Intensity and Organ Support-Free Days in Patients Hospitalized for COVID-19

Background: Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation. Objectives: The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin. Methods: Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21. Results: Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low. Conclusions: Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis