Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review.

OBJECTIVES: Cell-free hemoglobin (CFH) is a potent mediator of endothelial dysfunction, organ injury, coagulopathy, and immunomodulation in hemolysis. These mechanisms have been demonstrated in patients with sepsis, hemoglobinopathies, and those receiving transfusions. However, less is known about the role of CFH in the pathophysiology of trauma, despite the release of equivalent levels of free hemoglobin. DATA SOURCES: Ovid MEDLINE, Embase, Web of Science Core Collection, and BIOSIS Previews were searched up to January 21, 2023, using key terms related to free hemoglobin and trauma. DATA EXTRACTION: Two independent reviewers selected studies focused on hemolysis in trauma patients, hemoglobin breakdown products, hemoglobin-mediated injury in trauma, transfusion, sepsis, or therapeutics. DATA SYNTHESIS: Data from the selected studies and their references were synthesized into a narrative review. CONCLUSIONS: Free hemoglobin likely plays a role in endothelial dysfunction, organ injury, coagulopathy, and immune dysfunction in polytrauma. This is a compelling area of investigation as multiple existing therapeutics effectively block these pathways.

A Delphi consensus statement for digital surgery.

The use of digital technology is increasing rapidly across surgical specialities, yet there is no consensus for the term 'digital surgery'. This is critical as digital health technologies present technical, governance, and legal challenges which are unique to the surgeon and surgical patient. We aim to define the term digital surgery and the ethical issues surrounding its clinical application, and to identify barriers and research goals for future practice. 38 international experts, across the fields of surgery, AI, industry, law, ethics and policy, participated in a four-round Delphi exercise. Issues were generated by an expert panel and public panel through a scoping questionnaire around key themes identified from the literature and voted upon in two subsequent questionnaire rounds. Consensus was defined if >70% of the panel deemed the statement important and <30% unimportant. A final online meeting was held to discuss consensus statements. The definition of digital surgery as the use of technology for the enhancement of preoperative planning, surgical performance, therapeutic support, or training, to improve outcomes and reduce harm achieved 100% consensus agreement. We highlight key ethical issues concerning data, privacy, confidentiality and public trust, consent, law, litigation and liability, and commercial partnerships within digital surgery and identify barriers and research goals for future practice. Developers and users of digital surgery must not only have an awareness of the ethical issues surrounding digital applications in healthcare, but also the ethical considerations unique to digital surgery. Future research into these issues must involve all digital surgery stakeholders including patients.

Growing the next generation of trauma surgeon-scientists: Reflections on 20 years of research investment.

INTRODUCTION: The Eastern Association for the Surgery of Trauma mission includes fostering research and providing career development opportunities. Eastern Association for the Surgery of Trauma has awarded for 20 years a research scholarship to a promising young investigator. The research mentorship efforts were expanded 5 years ago with the INVEST-C Hack-a-thon. INVEST-C provides an intensive, short-term engagement to propel junior faculty toward establishing research independence. This study investigates the impact of these programs on academic productivity. METHODS: Pubmed records, National Institutes of Health (NIH) Reporter data, and SCOPUS h-index were acquired for all scholarship (SCH) awardees from 2002 to 2021 (n = 20) and all INVEST-C (INV) participants (2017-2020, n = 19). Current type of practice, total number of funding awards, and timing of first award were ascertained. INVEST-C participants were also surveyed on an annual basis to track their progress. Medians (interquartile range [IQR]) are reported and compared (analysis of variance). RESULTS: Median publications (PUBs) of SCH awardees were 56 (IQR, 33-88), h-index was 16 (IQR, 12-21), and 25% of awardees have ≥1 NIH grant since their SCH. Among the last 10 awardees with a minimum of 2 years from SCH, 40% have received an NIH award compared with a mean NIH funding rate of 18.5% over the same period. For those remaining in academics (90% SCH), PUBs were higher for those >5 years (66 [IQR, 51-115]) versus <5 years from their SCH (33 [22-59]; p = 0.05), but there was no difference in h-index (16 [IQR, 14-25] vs. 15 [9-19], p = NS). Comparing the most recent 5 years of SCH to INV group, there was no difference in academic productivity as measured by total PUBs (SCH, 33 [IQR, 22-59] vs. INV, 34 [IQR, 18-44]; p = 0.7) or h-index (INV, 9 [IQR, 5-14]; p = 0.1). However, no attendee held research funding before INV, but 31.6% (6 of 19 attendees) have subsequently acquired ≥1 funding award (11 non-NIH, 1 NIH) in the short interval since participation. CONCLUSION: Investments in research activities have translated to significant extramural funding. Those in the last 5 years have been particularly fruitful with INV participants already achieving equal median academic productivity to SCH recipients. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III.

Importance of catecholamine signaling in the development of platelet exhaustion after traumatic injury.

BACKGROUND: Impaired ex vivo platelet aggregation is common in trauma patients. The mechanisms driving these impairments remain incompletely understood, but functional platelet exhaustion due to excessive in vivo activation is implicated. Given platelet adrenoreceptors and known catecholamine surges after injury, impaired ex vivo platelet aggregation in trauma patients may be linked to catecholamine-induced functional platelet exhaustion. OBJECTIVE: To determine the relationship of catecholamines with platelet-dependent hemostasis after injury and to model catecholamine-induced functional platelet exhaustion in healthy donor platelets. PATIENTS/METHODS: Whole blood was collected from 67 trauma patients as part of a prospective cohort study. Platelet aggregometry and rotational thromboelastometry were performed, and plasma epinephrine (EPI) and norepinephrine (NE) concentrations were measured. The effect of catecholamines on healthy donor platelets was examined in a microfluidic model, with platelet aggregometry, and by flow cytometry examining surface markers of platelet activation. RESULTS: In trauma patients, EPI and NE were associated with impaired platelet aggregation (both p < 0.05), and EPI was additionally associated with decreased viscoelastic clot strength, increased fibrinolysis, and mortality (all p < 0.05). In healthy donors, short duration incubation with EPI enhanced platelet aggregation, platelet adhesion under flow, and increased glycoprotein IIb/IIIa activation, while weaker effects were observed with NE. Compared with short incubation, longer incubation with EPI resulted in decreased platelet adhesion, platelet aggregation, and surface expression of glycoprotein IIb/IIIa. CONCLUSIONS: These findings suggest sympathoadrenal activation in trauma patients contributes to impaired ex vivo platelet aggregation, which mechanistically may be explained by a functionally exhausted platelet phenotype under prolonged exposure to high plasma catecholamine levels.

Postinjury platelet aggregation and venous thromboembolism.

BACKGROUND: Posttraumatic venous thromboembolism (VTE) remains prevalent in severely injured patients despite chemoprophylaxis. Importantly, although platelets are central to thrombosis, they are not routinely targeted in prevention of posttraumatic VTE. Furthermore, platelets from injured patients show ex vivo evidence of increased activation yet impaired aggregation, consistent with functional exhaustion. However, the relationship of this platelet functional phenotype with development of posttraumatic VTE is unknown. We hypothesized that, following injury, impaired ex vivo platelet aggregation (PA) is associated with the development of posttraumatic VTE. METHODS: We performed a secondary analysis of 133 severely injured patients from a prospective observational study investigating coagulation and inflammation (2011-2019). Platelet aggregation in response to stimulation with adenosine diphosphate (ADP), collagen, and thrombin was measured at presentation (preresuscitation) and 24 hours (postresuscitation). Viscoelastic clot strength and lysis were measured in parallel by thromboelastography. Multivariable regression examined relationships between PA at presentation, 24 hours, and the change (δ) in PA between presentation and 24 hours with development of VTE. RESULTS: The 133 patients were severely injured (median Injury Severity Score, 25), and 14% developed VTE (all >48 hours after admission). At presentation, platelet count and PA were not significantly different between those with and without incident VTE. However, at 24 hours, those who subsequently developed VTE had significantly lower platelet counts (126 × 10 9 /L vs. 164 × 10 9 /L, p = 0.01) and lower PA in response to ADP ( p < 0.05), collagen ( p < 0.05), and thrombin ( p = 0.06). Importantly, the magnitude of decrease in PA (δ) from presentation to 24 hours was independently associated with development of VTE (adjusted odds ratios per 10 aggregation unit decrease: δ-ADP, 1.31 [ p = 0.03]; δ-collagen, 1.36 [ p = 0.01]; δ-thrombin, 1.41 [ p < 0.01]). CONCLUSION: Severely injured patients with decreasing ex vivo measures of PA despite resuscitation have an increased risk of developing VTE. This may have implications for predicting development of VTE and for studying platelet targeted chemoprophylaxis regimens. LEVEL OF EVIDENCE: Prognostic/Epidemiological; Level III.

Development and Validation of a Deep Learning Strategy for Automated View Classification of Pediatric Focused Assessment With Sonography for Trauma.

OBJECTIVE: Pediatric focused assessment with sonography for trauma (FAST) is a sequence of ultrasound views rapidly performed by clinicians to diagnose hemorrhage. A technical limitation of FAST is the lack of expertise to consistently acquire all required views. We sought to develop an accurate deep learning view classifier using a large heterogeneous dataset of clinician-performed pediatric FAST. METHODS: We developed and conducted a retrospective cohort analysis of a deep learning view classifier on real-world FAST studies performed on injured children less than 18 years old in two pediatric emergency departments by 30 different clinicians. FAST was randomly distributed to training, validation, and test datasets, 70:20:10; each child was represented in only one dataset. The primary outcome was view classifier accuracy for video clips and still frames. RESULTS: There were 699 FAST studies, representing 4925 video clips and 1,062,612 still frames, performed by 30 different clinicians. The overall classification accuracy was 97.8% (95% confidence interval [CI]: 96.0-99.0) for video clips and 93.4% (95% CI: 93.3-93.6) for still frames. Per view still frames were classified with an accuracy: 96.0% (95% CI: 95.9-96.1) cardiac, 99.8% (95% CI: 99.8-99.8) pleural, 95.2% (95% CI: 95.0-95.3) abdominal upper quadrants, and 95.9% (95% CI: 95.8-96.0) suprapubic. CONCLUSION: A deep learning classifier can accurately predict pediatric FAST views. Accurate view classification is important for quality assurance and feasibility of a multi-stage deep learning FAST model to enhance the evaluation of injured children.

Prehospital end-tidal carbon dioxide is predictive of death and massive transfusion in injured patients: An Eastern Association for Surgery of Trauma multicenter trial.

BACKGROUND: Prehospital identification of the injured patient likely to require emergent care remains a challenge. End-tidal carbon dioxide (ETCO2) has been used in the prehospital setting to monitor respiratory physiology and confirmation of endotracheal tube placement. Low levels of ETCO2 have been demonstrated to correlate with injury severity and mortality in a number of in-hospital studies. We hypothesized that prehospital ETCO2 values would be predictive of mortality and need for massive transfusion (MT) in intubated patients. METHODS: This was a retrospective multicenter trial with 24 participating centers. Prehospital, emergency department, and hospital values were collected. Receiver operating characteristic curves were created and compared. Massive transfusion defined as >10 U of blood in 6 hours or death in 6 hours with at least 1 U of blood transfused. RESULTS: A total of 1,324 patients were enrolled. ETCO2 (area under the receiver operating characteristic curve [AUROC], 0.67; confidence interval [CI], 0.63-0.71) was better in predicting mortality than shock index (SI) (AUROC, 0.55; CI, 0.50-0.60) and systolic blood pressure (SBP) (AUROC, 0.58; CI, 0.53-0.62) (p < 0.0005). Prehospital lowest ETCO2 (AUROC, 0.69; CI, 0.64-0.75), SBP (AUROC, 0.75; CI, 0.70-0.81), and SI (AUROC, 0.74; CI, 0.68-0.79) were all predictive of MT. Analysis of patients with normotension demonstrated lowest prehospital ETCO2 (AUROC, 0.66; CI, 0.61-0.71), which was more predictive of mortality than SBP (AUROC, 0.52; CI, 0.47-0.58) or SI (AUROC, 0.56; CI, 0.50-0.62) (p < 0.001). Lowest prehospital ETCO2 (AUROC, 0.75; CI, 0.65-0.84), SBP (AUROC, 0.63; CI, 0.54-0.74), and SI (AUROC, 0.64; CI, 0.54-0.75) were predictive of MT in normotensive patients. ETCO2 cutoff for MT was 26 mm Hg. The positive predictive value was 16.1%, and negative predictive value was high at 98.1%. CONCLUSION: Prehospital ETCO2 is predictive of mortality and MT. ETCO2 outperformed traditional measures such as SBP and SI in the prediction of mortality. ETCO2 may outperform traditional measures in predicting need for transfusion in occult shock. LEVEL OF EVIDENCE: Diagnostic test, level III.

Multi-center validation of the Bowel Injury Predictive Score (BIPS) for the early identification of need to operate in blunt bowel and mesenteric injuries.

INTRODUCTION: The Bowel Injury Prediction Score (BIPS) is a tool for identifying patients at risk for blunt bowel and mesenteric injury (BBMI) requiring surgery. BIPS is calculated by assigning one point for each of the following: (1) WBC ≥ 17,000, (2) abdominal tenderness, and (3) injury grade ≥ 4 (mesenteric contusion or hematoma with bowel wall thickening or adjacent interloop fluid collection) on CT scan. A total score ≥ 2 is associated with BBMI requiring surgery. We aimed to validate the BIPS as a predictor for patients with BBMIs requiring operative intervention in a multi-center prospective study. MATERIALS AND METHODS: Patients were prospectively enrolled at 15 U.S. trauma centers following blunt trauma with suspicion of BBMI on CT scan between July 1, 2018 and July 31, 2019. The BIPS was calculated for each patient enrolled in the study. RESULTS: Of 313 patients, 38% had BBMI requiring operative intervention. Patients were significantly more likely to require surgery in the presence of abdominal tenderness (OR, 3.6; 95% CI, 1.6-8.0) and CT grade ≥ 4 (OR, 11.7; 95% CI, 5.7-23.7). Patients with a BIPS ≥ 2 were more than ten times more likely to require laparotomy than those with a BIPS < 2 (OR, 10.1; 95% CI, 5.0-20.4). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a BIPS ≥ 2 for BBMI requiring surgery was 72% (CI 0.6-0.8), 78% (CI 0.7-0.8), 67% (CI 0.6-0.8), and 82% (CI 0.8-0.9), respectively. The AUROC curve for BIPS ≥ 2 was 0.75. The sensitivity, specificity, PPV, and NPV of a BIPS ≥ 2 for BBMI requiring surgery in patients with severe alteration in mental status (GCS 3-8) was 70% (CI 0.5-0.9), 92% (CI 0.8-1.0), 82% (CI 0.6-1.0), and 86% (CI 0.7-1.0), respectively. CONCLUSION: This prospective multi-center trial validates BIPS as a predictor of BBMI requiring surgery. Calculation of BIPS during the initial evaluation of trauma patients is a useful adjunct to help general surgeons taking trauma call determine operative versus non-operative management of patients with BBMI including those with severe alteration in mental status.

Internal and External Validation of an Alcohol Biomarker for Screening in Trauma.

OBJECTIVE: We aimed to examine biomarkers for screening unhealthy alcohol use in the trauma setting. SUMMARY AND BACKGROUND DATA: Self-report tools are the practice standard for screening unhealthy alcohol use; however, their collection suffers from recall bias and incomplete collection by staff. METHODS: We performed a multi-center prospective clinical study of 251 adult patients who arrived within 24 hours of injury with external validation in another 60 patients. The Alcohol Use Disorders Identification Test served as the reference standard. The following biomarkers were measured: (1) PEth; (2) ethyl glucuronide; (3) ethyl sulfate; (4) gamma-glutamyl-transpeptidase; (5) carbohydrate deficient transferrin; and (6) blood alcohol concentration (BAC). Candidate single biomarkers and multivariable models were compared by considering discrimination (AUROC). The optimal cutpoint for the final model was identified using a criterion for setting the minimum value for specificity at 80% and maximizing sensitivity. Decision curve analysis was applied to compare to existing screening with BAC. RESULTS: PEth alone had an AUROC of 0.93 [95% confidence interval (CI): 0.92-0.93] in internal validation with an optimal cutpoint of 25 ng/mL. A 4- variable biomarker model and the addition of any single biomarker to PEth did not improve AUROC over PEth alone ( P > 0.05). Decision curve analysis showed better performance of PEth over BAC across most predicted probability thresholds. In external validation, sensitivity and specificity were 76.0% (95% CI: 53.0%-92.0%) and 73.0% (95% CI: 56.0%-86.0%), respectively.Conclusion and Relevance: PEth alone proved to be the single best biomarker for screening of unhealthy alcohol use and performed better than existing screening systems with BAC. PEth may overcome existing screening barriers.

Emergency Department Length of Stay and Mortality in Critically Injured Patients.

OBJECTIVE: Multicenter data from 2 decades ago demonstrated that critically ill and injured patients spending more than 6 hours in the emergency department (ED) before transfer to the intensive care unit (ICU) had higher mortality rates. A contemporary analysis of ED length of stay in critically injured patients at American College of Surgeons' Trauma Quality Improvement Program (ACS-TQIP) centers was performed to test whether prolonged ED length of stay is still associated with mortality. METHODS: This was an observational cohort study of critically injured patients admitted directly to ICU from the ED in ACS-TQIP centers from 2010-2015. Spending more than 6 hours in the ED was defined as prolonged ED length of stay. Patients with prolonged ED length of stay were matched to those with non-prolonged ED length of stay and mortality was compared. MAIN RESULTS: A total of 113,097 patients were directly admitted from the ED to the ICU following injury. The median ED length of stay was 167 minutes. Prolonged ED length of stay occurred in 15,279 (13.5%) of patients. Women accounted for 29.4% of patients with prolonged ED length of stay but only 25.8% of patients with non-prolonged ED length of stay, P < 0.0001. Mortality rates were similar after matching-4.5% among patients with prolonged ED length of stay versus 4.2% among matched controls. Multivariable logistic regression of the matched cohorts demonstrated prolonged ED length of stay was not associated with mortality. However, women had higher adjusted mortality compared to men Odds Ratio = 1.41, 95% Confidence Interval 1.28 -1.61, P < 0.0001. CONCLUSION: Prolonged ED length of stay is no longer associated with mortality among critically injured patients. Women are more likely to have prolonged ED length of stay and mortality.

A Parallel Pandemic: Increased Firearm Injuries at Five Northern California Trauma Centers During the COVID-19 Pandemic: An Interrupted Time-series Analysis.

OBJECTIVE: This study aimed to characterize changes in firearm injuries at 5 level 1 trauma centers in Northern California in the 12 months following the start of the COVID-19 pandemic compared with the preceding 4 years, accounting for regional variations and seasonal trends. SUMMARY AND BACKGROUND DATA: Increased firearm injuries have been reported during the early peaks of the COVID-19 pandemic despite shelter-in-place restrictions. However, these data are overwhelmingly from singlecenter studies, during the initial phase of the pandemic prior to lifting of shelter-in-place restrictions, or do not account for seasonal trends. METHODS: An interrupted time-series analysis (ITSA) of all firearm injuries presenting to 5 adult level 1 trauma centers in Northern California was performed (January 2016to February 2021). ITSA modeled the association of the onset of the COVID-19 pandemic (March 2020) with monthly firearm injuries using the ordinary least-squares method, included month indicators to adjust for seasonality, and specified lags of up to 12 months to account for autocorrelation. RESULTS: Prior to the start of COVID-19, firearm injuries averaged (±SD) of 86 (±16) and were decreasing by 0.5/month (P < 0.01). The start of COVID- 19 (March 2020) was associated with an alarming increase of 39 firearm injuries/month (P < 0.01) followed by an ongoing rise of 3.5/mo (P < 0.01). This resulted in an average of 130 (±26) firearm injuries/month during the COVID-19 period and included 8 of the 10 highest monthly firearm injury rates in the past 5 years. CONCLUSIONS: These data highlight an alarming escalation in firearm injuries in the 12 months following the onset of the COVID-19 pandemic in Northern California. Additional studies and resources are needed to better understand and address this parallel public health crisis.

Trauma and COVID-Induced Severe Rhabdomyolysis.

The novel coronavirus COVID-19 has been implicated in a number of extra-pulmonary manifestations including rhabdomyolysis. It is hypothesized to be secondary to direct muscle damage from the virus. The usual treatment of rhabdomyolysis is resuscitation with aggressive fluid management to prevent acute renal failure. However, the combination of blunt thoracic trauma and COVID pneumonia has posed additional challenges for critical care management. A 68-year-old male presented to our institution after being found down for an unknown duration of time. He was diagnosed symptomatic COVID pneumonia. His traumatic injuries included 4 rib fractures, a rectus sheath hematoma, and rhabdomyolysis with a creatinine kinase (CK) level of 16,716 U/L. He was initially treated with steroids, prone positioning, and aggressive fluid administration. Despite treatment his CK level peaked at 146,328 U/L. Here we present the case of trauma and COVID-induced rhabdomyolysis with an extremely elevated CK level.

A new trauma frontier: Exploratory pilot study of platelet transcriptomics in trauma patients.

BACKGROUND: The earliest measurable changes to postinjury platelet biology may be in the platelet transcriptome, as platelets are known to carry messenger ribonucleic acids (RNAs), and there is evidence in other inflammatory and infectious disease states of differential and alternative platelet RNA splicing in response to changing physiology. Thus, the aim of this exploratory pilot study was to examine the platelet transcriptome and platelet RNA splicing signatures in trauma patients compared with healthy donors. METHODS: Preresuscitation platelets purified from trauma patients (n = 9) and healthy donors (n = 5) were assayed using deep RNA sequencing. Differential gene expression analysis, weighted gene coexpression network analysis, and differential alternative splicing analyses were performed. In parallel samples, platelet function was measured with platelet aggregometry, and clot formation was measured with thromboelastography. RESULTS: Differential gene expression analysis identified 49 platelet RNAs to have differing abundance between trauma patients and healthy donors. Weighted gene coexpression network analysis identified coexpressed platelet RNAs that correlated with platelet aggregation. Differential alternative splicing analyses revealed 1,188 splicing events across 462 platelet RNAs that were highly statistically significant (false discovery rate <0.001) in trauma patients compared with healthy donors. Unsupervised principal component analysis of these platelet RNA splicing signatures segregated trauma patients in two main clusters separate from healthy controls. CONCLUSION: Our findings provide evidence of finetuning of the platelet transcriptome through differential alternative splicing of platelet RNA in trauma patients and that this finetuning may have relevance to downstream platelet signaling. Additional investigations of the trauma platelet transcriptome should be pursued to improve our understanding of the platelet functional responses to trauma on a molecular level.

External validation of a novel signature of illness in continuous cardiorespiratory monitoring to detect early respiratory deterioration of ICU patients.

OBJECTIVE: The goal of predictive analytics monitoring is the early detection of patients at high risk of subacute potentially catastrophic illnesses. An excellent example of a targeted illness is respiratory failure leading to urgent unplanned intubation, where early detection might lead to interventions that improve patient outcomes. Previously, we identified signatures of this illness in the continuous cardiorespiratory monitoring data of intensive care unit (ICU) patients and devised algorithms to identify patients at rising risk. Here, we externally validated three logistic regression models to estimate the risk of emergency intubation developed in Medical and Surgical ICUs at the University of Virginia. APPROACH: We calculated the model outputs for more than 8000 patients in the University of California-San Francisco ICUs, 240 of whom underwent emergency intubation as determined by individual chart review. MAIN RESULTS: We found that the AUC of the models exceeded 0.75 in this external population, and that the risk rose appreciably over the 12 h before the event. SIGNIFICANCE: We conclude that there are generalizable physiological signatures of impending respiratory failure in the continuous cardiorespiratory monitoring data.

Outcomes after ultramassive transfusion in the modern era: An Eastern Association for the Surgery of Trauma multicenter study.

BACKGROUND: Despite the widespread institution of modern massive transfusion protocols with balanced blood product ratios, survival for patients with traumatic hemorrhage receiving ultramassive transfusion (UMT) (defined as ≥20 U of packed red blood cells [RBCs]) in 24 hours) remains low and resource consumption remains high. Therefore, we aimed to identify factors associated with mortality in trauma patients receiving UMT in the modern resuscitation era. METHODS: An Eastern Association for the Surgery of Trauma multicenter retrospective study of 461 trauma patients from 17 trauma centers who received ≥20 U of RBCs in 24 hours was performed (2014-2019). Multivariable logistic regression and Classification and Regression Tree analysis were used to identify clinical characteristics associated with mortality. RESULTS: The 461 patients were young (median age, 35 years), male (82%), severely injured (median Injury Severity Score, 33), in shock (median shock index, 1.2; base excess, -9), and transfused a median of 29 U of RBCs, 22 U of fresh frozen plasma (FFP), and 24 U of platelets (PLT). Mortality was 46% at 24 hours and 65% at discharge. Transfusion of RBC/FFP ≥1.5:1 or RBC/PLT ≥1.5:1 was significantly associated with mortality, most pronounced for the 18% of patients who received both RBC/PLT and RBC/FFP ≥1.5:1 (odds ratios, 3.11 and 2.81 for mortality at 24 hours and discharge; both p < 0.01). Classification and Regression Tree identified that age older than 50 years, low initial Glasgow Coma Scale, thrombocytopenia, and resuscitative thoracotomy were associated with low likelihood of survival (14-26%), while absence of these factors was associated with the highest survival (71%). CONCLUSION: Despite modern massive transfusion protocols, one half of trauma patients receiving UMT are transfused with either RBC/FFP or RBC/PLT in unbalanced ratios ≥1.5:1, with increased associated mortality. Maintaining focus on balanced ratios during UMT is critical, and consideration of advanced age, poor initial mental status, thrombocytopenia, and resuscitative thoracotomy can aid in prognostication. LEVEL OF EVIDENCE: Prognostic, level III.

Good Platelets Gone Bad: The Effects of Trauma Patient Plasma on Healthy Platelet Aggregation.

BACKGROUND: Altered postinjury platelet behavior is recognized in the pathophysiology of trauma-induced coagulopathy (TIC), but the mechanisms remain largely undefined. Studies suggest that soluble factors released by injury may inhibit signaling pathways and induce structural changes in circulating platelets. Given this, we sought to examine the impact of treating healthy platelets with plasma from injured patients. We hypothesized that healthy platelets treated ex-vivo with plasma from injured patients with shock would impair platelet aggregation, while treatment with plasma from injured patients with significant injury burden, but without shock, would enhance platelet aggregation. METHODS: Plasma samples were isolated from injured patients (pretransfusion) and healthy donors at a Level I trauma center and stored at -80°C. Plasma samples from four separate patients in each of the following stratified clinical groups were used: mild injury/no shock (injury severity score [ISS] 2-15, base excess [BE]>-6), mild injury/with shock (ISS 2-15, BE≤-6), severe injury/no shock (ISS>25, BE>-6), severe injury/with shock (ISS>25, BE≤-6), minimal injury (ISS 0/1, BE>-6), and healthy. Platelets were isolated from three healthy adult males and were treated with plasma for 30 min. Aggregation was stimulated with a thrombin receptor agonist and measured via multiple-electrode platelet aggregometry. Data were normalized to HEPES Tyrode's (HT) buffer-only treated platelets. Associations of plasma treatment groups with platelet aggregation measures were tested with Mann-Whitney U tests. RESULTS: Platelets treated with plasma from patients with shock (regardless of degree of injury) had significantly impaired thrombin-stimulated aggregation compared with platelets treated with plasma from patients without shock (P = 0.002). Conversely, platelets treated with plasma from patients with severe injury, but without shock, had amplified thrombin-stimulated aggregation (P = 0.030). CONCLUSION: Shock-mediated soluble factors impair platelet aggregation, and tissue injury-mediated soluble factors amplify platelet aggregation. Future characterization of these soluble factors will support development of novel treatments of TIC.

Dynamic effects of calcium on in vivo and ex vivo platelet behavior after trauma.

BACKGROUND: Mobilization of intra and extracellular calcium is required for platelet activation, aggregation, and degranulation. However, the importance of alterations in the calcium-platelet axis after injury is unknown. We hypothesized that in injured patients, in vivo initial calcium concentrations (pretransfusion) predict ex vivo platelet activation and aggregation, viscoelastic clot strength, and transfusion of blood products. We additionally hypothesized that increasing calcium concentrations ex vivo increases the expression of platelet activation surface receptors and platelet aggregation responses to agonist stimulation in healthy donor blood. METHODS: Blood samples were collected from 538 trauma patients on arrival to the emergency department. Standard assays (including calcium), platelet aggregometry (PA) and thromboelastometry (ROTEM) were performed. In PA, platelet activation (prestimulation impedance [Ω]) and aggregation responses to agonist stimulation (area under the aggregation curve [AUC]) with adenosine diphosphate (ADP), thrombin receptor-activating peptide, arachidonic acid (AA), and collagen (COL) were measured. Multivariable regression tested the associations of calcium with PA, ROTEM, and transfusions. To further examine the calcium-platelet axis, calcium was titrated in healthy blood. Platelet aggregometry and ROTEM were performed, and expression of platelet glycoprotein IIb/IIIa and P-selectin was measured by flow cytometry. RESULTS: The patients were moderately injured with normal calcium and platelet counts. Higher calcium on arrival (pretransfusion) was independently associated with increased platelet activation (prestimulation, Ω; p < 0.001), aggregation (ADP-stimulated, AUC; p = 0.002; thrombin receptor-activating peptide-stimulated, AUC; p = 0.038), and clot strength (ROTEM max clot firmness; p < 0.001), and inversely associated with 24-hour transfusions of blood, plasma, and platelets (all p < 0.005). Up-titrating calcium in healthy blood increased platelet activation (prestimulation, Ω; p < 0.001), aggregation (ADP, AA, COL-stimulated AUCs; p < 0.050), and expression of P-selectin (p = 0.003). CONCLUSION: Initial calcium concentrations (pretransfusion) are independently associated with platelet activation, aggregation, clot-strength, and transfusions after injury. These changes may be mediated by calcium driven expression of surface receptors necessary for platelet activation and aggregation. However, the therapeutic benefit of early, empiric calcium repletion in trauma patients remains undefined. LEVEL OF EVIDENCE: Prognostic, level V.

Gender distribution and leadership trends in trauma surgery societies.

INTRODUCTION: Women are under-represented in the surgical disciplines and gender bias is believed to play a factor. We aimed to understand the gender distribution of membership, leadership opportunities, and scientific contributions to annual trauma professional meetings as a case study of gender issues in trauma surgery. METHODS: Retrospective collection of membership, leadership, presentation and publication data from 2016 to 2018 Trauma/Acute Care Surgery/Surgical Critical Care (TACSCC) Annual Meetings. Gender was assigned based on self-identification in demographic information, established relationships, or public sources. RESULTS: Women remain under-represented with only 28.1% of those ascertaining American Board of Surgery certification in critical care self-identifying as female. The proportion of female members in Eastern Association for the Surgery of Trauma (EAST) was comparable (29.4%), slightly lower for Western Trauma Association (WTA) (19.0%), and lowest for American Association for the Surgery of Trauma (AAST) (12.8%, p<0.05). In contrast, AAST had the highest proportion of female participants in executive leadership (AAST 32.5%, WTA 19.0%, EAST 18.8%) and WTA the highest for committee chairs (WTA 33.3%, AAST 27.8%, EAST 20.5%). AAST had the most significant increase in executive leadership during the last 3 years (AAST 28.6% to 41.6%). Invited lectureships, masters, panelists and senior author scientific contributions demonstrated the largest gap of academic representation of female TACSCC surgeons. CONCLUSION: Fewer women than men pursue careers in the trauma field. Continuing to provide mentorship, leadership, and scientific recognition will increase gender diversity in TACSCC. We must continue to promote, sponsor, recognize, invite, and elect 'her'. LEVEL OF EVIDENCE: III, Epidemiology.

Cost-effectiveness evaluation of the PROPPR trial transfusion protocols.

BACKGROUND: There have been no prior investigations of the cost effectiveness of transfusion strategies for trauma resuscitation. The Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) study was a Phase III multisite, randomized trial in 680 subjects comparing the efficacy of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with the 1:1:2 ratio. We hypothesized that 1:1:1 transfusion results in an acceptable incremental cost-effectiveness ratio, when estimated using patients' age-specific life expectancy and cost of care during the 30-day PROPPR trial period. STUDY DESIGN AND METHODS: International Classification of Diseases, Ninth Revision codes were prospectively collected, and subjects were matched 1:2 to subjects in the Healthcare Utilization Program State Inpatient Data to estimate cost weights. We used a decision tree analysis, combined with standard costs and estimated years of expected survival to determine the cost effectiveness of the two treatments. RESULTS: The 1:1:1 group had higher overall costs for the blood products but were more likely to achieve hemostasis and decreased hemorrhagic death by 24 hours (p = 0.006). For every 100 patients treated in the 1:1:1 group, eight more achieved hemostasis than in the 1:1:2 group. At 30 days, the total hospital cost per 100 patients was $5.6 million in the 1:1:1 group compared with $5.0 million in the 1:1:2 group. For each 100 patients, the 1:1:1 group had 218.5 more years of life expectancy. This was at a cost of $2994 per year gained. CONCLUSION: The 1:1:1 transfusion ratio in severely injured hemorrhaging trauma patients is a very cost-effective strategy for increasing hemostasis and decreasing trauma deaths.

A journey upstream: Fluctuating platelet-specific genes in cell-free plasma as proof-of-concept for using ribonucleic acid sequencing to improve understanding of postinjury platelet biology.

BACKGROUND: The mechanisms of aberrant circulating platelet behavior following injury remain unclear. Platelets retain megakaryocyte immature ribonucleic acid (RNA) splicing and protein synthesis machinery to alter their functions based on physiologic signals. We sought to identify fluctuating platelet-specific RNA transcripts in cell-free plasma (CFP) from traumatic brain injury (TBI) patients as proof-of-concept for using RNA sequencing to improve our understanding of postinjury platelet behavior. We hypothesized that we could identify differential expression of activated platelet-specific spliced RNA transcripts from CFP of patients with isolated severe fatal TBI (fTBI) compared with minimally injured trauma controls (t-controls), filtered by healthy control (h-control) data sets. METHODS: High-read depth RNA sequencing was applied to CFP from 10 patients with fTBI (Abbreviated Injury Scale [AIS] for head ≥3, AIS for all other categories <3, and expired) and five t-controls (Injury Severity Score ≤1, and survived). A publicly available CFP RNA sequencing data set from 23 h-controls was used to determine the relative steady state of splice-form RNA transcripts discoverable in CFP. Activated platelet-specific spliced RNA transcripts were derived from studies of ex vivo platelet activation and identified by splice junction presence greater than 1.5-fold or less than 0.67-fold ex vivo nonactivated platelet-specific RNA transcripts. RESULTS: Forty-two differentially spliced activated platelet-specific RNA transcripts in 34 genes were altered in CFP from fTBI patients (both upregulated and downregulated). CONCLUSION: We have discovered differentially expressed activated platelet-specific spliced RNA transcripts present in CFP from isolated severe fTBI patients that are upregulated or downregulated compared with minimally injured trauma controls. This proof-of-concept suggests that a pool of immature platelet RNAs undergo splicing events after injury for presumed modulation of platelet protein products involved in platelet function. This validates our exploration of injury-induced platelet RNA transcript modulation as an upstream "liquid biopsy" to identify novel postinjury platelet biology and treatment targets for aberrant platelet behavior. LEVEL OF EVIDENCE: Diagnostic tests, level V.