Hyperfibrinolysis: a crucial phenotypic abnormality of posttraumatic fibrinolytic dysfunction.

Background: Traumatic fibrinolytic dysfunction is often categorized into 3 phenotypes based on the result of thromboelastography (TEG) lysis at 30 minutes (LY30): fibrinolysis shutdown, physiologic fibrinolysis, and hyperfibrinolysis. However, the molecular pathophysiology of fibrinolytic dysfunction and the association with clinical outcomes have not been fully evaluated. Objectives: To assess whether posttraumatic fibrinolysis phenotypes identified by TEG correlate with levels of key fibrinolysis-related serum markers and with risk of mortality and hospital complications. Methods: This is a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. Patients were stratified according to the degree of fibrinolysis upon arrival using TEG LY30 values: low LY30, <0.8%; normal LY30, 0.81% to 0.9%; and high LY30, ≥3%. Serial values of molecular markers (0-72 hours after admission) and clinical outcomes were compared between fibrinolysis groups. Results: A total of 547 patients were included (low LY30, 320; normal LY30, 108; high LY30, 119). The high LY30 group had higher tissue plasminogen activator and plasmin-antiplasmin values upon hospital arrival than the low LY30 or normal LY30 groups (P < .001, respectively). There was no significant difference in levels of tissue plasminogen activator, plasmin-antiplasmin, and plasminogen activator inhibitor 1 between the low LY30 and normal LY30 groups. The high LY30 group was associated with an increased risk of 24-hour and 30-day mortality, while there was no significant difference in mortality between the low LY30 and normal LY30 groups. Conclusion: Our results suggest that hyperfibrinolysis is the most common form of traumatic fibrinolytic dysfunction and is associated with worse outcome.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.

INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

RELATIONSHIP BETWEEN TRPM4 RS8104571 GENOTYPE, CIRCULATING TRPM4 AND SUR1, AND CLINICAL OUTCOME FOLLOWING TRAUMATIC BRAIN INJURY.

ABSTRACT: The variant single nucleotide polymorphism rs8104571 has been associated with poor outcomes following traumatic brain injury (TBI) and is most prevalent in those of African ancestry. This single nucleotide polymorphism (SNP) resides within a gene coding for the TRPM4 protein, which complexes with SUR1 protein to create a transmembrane ion channel and is believed to contribute to cellular swelling and cell death in neurological tissue. Our study evaluates the relationship between circulating TRPM4 and SUR1, rs8104571 genotype, and clinical outcome in TBI patients. Trauma patients with moderate to severe TBI were included in this retrospective study. rs8104571 genotyping and admission plasma TRPM4 and SUR1 quantification was performed with real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Adequate plasma for TRPM4 and SUR1 ELISA quantification was available for 289 patients, 54 of whom were African American (AA). Plasma TRPM4 concentration was increased in those with a variant rs8104571 allele compared to wild type when controlling for demographics and injury characteristics in the overall cohort (P = 0.04) and within the AA subgroup (P = 0.01). There was no significant association between plasma TRPM4 or SUR1 and clinical outcome (each P > 0.05). Plasma TRPM4 abundance increased with acute kidney injury severity (P = 0.02). The association between increased plasma TRPM4 and variant rs810457 supports an underlying mechanism involving increased neuroinflammation with a subsequent increase in the leakage of TRPM4 from the central nervous system into circulation. Alternative sources of plasma TRPM4 including the kidney cannot be excluded and may play a significant role in the pathophysiology of trauma as well.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an adult-onset, inherited white matter disorder encompassing two previously identified clinicopathologically similar entities: pigmentary orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with spheroids (HDLS). In this chapter, we discuss how advances in our genetic understanding of the condition have further delineated three distinct clinical entities within ALSP, namely CSF1R-related ALSP, AARS2-related leukoencephalopathy (AARS2-L), and AARS (HDLS-S). We provide descriptions of the clinical, radiologic, pathologic, and pathophysiologic findings in each entity, detailing their similarities and differences, and discuss current and future treatment options where available.

Real-time performance improvement optimizes damage control resuscitation best practice adherence: Results of a pilot prospective observational study.

BACKGROUND: Maintaining balanced blood product ratios during damage control resuscitation (DCR) is independently associated with improved survival. We hypothesized that real-time performance improvement (RT-PI) would increase adherence to DCR best practice. STUDY DESIGN AND METHODS: From December 2020-August 2021, we prospectively used a bedside RT-PI tool to guide DCR in severely injured patients surviving at least 30 min. RT-PI study patients were compared to contemporary control patients at our institution and historic PROMMTT study patients. A subset of patients transfused ≥6 U red blood cells (RBC) in 6 h (MT+) was also identified. The primary endpoint was percentage time in a high ratio range (≥3:4) of plasma (PLAS):RBC and platelet (PLT):RBC over 6 h. Secondary endpoints included time to massive transfusion protocol activation, time to calcium and tranexamic acid (TXA) dosing, and cumulative 6-h ratios. RESULTS: Included patients (n = 772) were 35 (24-51) years old with an Injury Severity Score of 27 (17-38) and 42% had penetrating injuries. RT-PI (n = 10) patients spent 96% of the 6-h resuscitation in a high PLAS:RBC range, no different versus CONTROL (n = 87) (96%) but more than PROMMTT (n = 675) (25%, p < .001). In the MT+ subgroup, optimal PLAS:RBC and PLT:RBC were maintained for the entire 6 h in RT-PI (n = 4) versus PROMMTT (n = 391) patients for both PLAS (p < .001) and PLT ratios (p < .001). Time to TXA also improved significantly in RT-PI versus CONTROL patients (27 min [22-31] vs. 51 min [29-98], p = .035). CONCLUSION: In this prospective study, RT-PI was associated with optimized DCR. Multicenter validation of this novel approach to optimizing DCR implementation is warranted.

CSF1R-Related Disorder: Prevalence of CSF1R Variants and Their Clinical Significance in the UK Population.

Background and Objectives: CSF1R-related disorder (CSF1R-RD) is a devastating neurodegenerative disorder caused by variants in the colony stimulating factor-1 receptor (CSF1R) gene. CSF1R-RD leads to a variable combination of cognitive impairment, movement disorders, upper motor neuron signs, and spasticity with associated imaging abnormalities in brain white matter. Although increasingly recognized, there is evidence that it is significantly underdiagnosed or misdiagnosed, and its true prevalence is unknown. We leveraged the large data set of the UK Biobank to determine the prevalence of CSF1R mutations in the UK population and identify clinical phenotypes associated with these variants. Methods: Pathogenic and likely pathogenic CSF1R variants were identified in UK Biobank whole-exome sequencing data (N = 470,000). Medical history, including neurologic and psychiatric disease, were determined from self-reported and hospital collected codes, and the volume of MRI white matter hyperintensities were compared between variant carriers and controls. Results: We identified 25 individuals carrying 18 unique pathogenic variants and 107 individuals carrying 44 unique likely pathogenic variants-combined prevalence 132 (∼1 in 3,500). Pathogenic CSF1R variant carriers had increased risk of psychiatric disease (OR: 5.15, p = 0.0079), depression (OR: 10.52, p = 0.0015), and Parkinson disease (OR: 19.80, p = 0.0038). Using algorithmically defined diagnosis data, pathogenic or likely pathogenic variants (the combined group) carriers were at higher risk for both dementia (OR: 2.50, p = 0.046) and vascular dementia (OR: 4.72, p = 0.032). Discussion: Damaging variants in CSF1R are more common than expected in the general population and are associated with cognitive, psychiatric, and movement disorder diagnoses, which may reflect clinical manifestation of the disease. This study suggests that CSF1R-RD is either underreported, not diagnosed because of lack of genetic screening or that there is reduced penetrance.

Ketamine for acute pain after trauma: A pragmatic, randomized clinical trial.

BACKGROUND: Non-narcotic intravenous medications may be a beneficial adjunct to oral multimodal pain regimens (MMPRs) which reduce but do not eliminate opioid exposure and prescribing after trauma. We hypothesized that the addition of a subdissociative ketamine infusion (KI) to a standardized oral MMPR reduces inpatient opioid exposure. METHODS: Eligible adult trauma patients admitted to the intermediate or intensive care unit were randomized upon admission to our institutional MMPR per usual care (UC) or UC plus subdissociative KI for 24 hours to 72 hours after arrival. The primary outcome was morphine milligram equivalents per day (MME/d) and secondary outcomes included total MME, discharge with an opioid prescription (OP%), and rates of ketamine side effects. Bayesian posterior probabilities (pp) were calculated using neutral priors. RESULTS: A total of 300 patients were included in the final analysis with 144 randomized to KI and 156 to UC. Baseline characteristics were similar between groups. The Injury Severity Scores for KI were 19 [14, 29] versus UC 22 [14, 29]. The KI group had a lower rate of long-bone fracture (37% vs. 49%) and laparotomy (16% vs. 24%). Patients receiving KI had an absolute reduction of 7 MME/day, 96 total MME, and 5% in OP%. In addition, KI had a relative risk (RR) reduction of 19% in MME/day (RR, 0.81 [0.69-0.95], pp = 99%), 20% in total MME (RR, 0.80 [0.64-0.99], pp = 98%), and 8% in OP% (RR, 0.92 [0.76-1.11], pp = 81%). The KI group had a higher rate of delirium (11% vs. 6%); however, rates of other side effects such as arrythmias and unplanned intubations were similar between groups. CONCLUSION: Addition of a subdissociative ketamine infusion to an oral MMPR resulted in a decrease in opioid exposure in severely injured patients. Subdissociative ketamine infusions can be used as a safe adjunct to decrease opioid exposure in monitored settings. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level I.

Does an early, balanced resuscitation strategy reduce the incidence of hypofibrinogenemia in hemorrhagic shock?

Objectives: Some centers have recommended including concentrated fibrinogen replacement in massive transfusion protocols (MTPs). Given our center's policy of aggressive early balanced resuscitation (1:1:1), beginning prehospital, we hypothesized that our rates of hypofibrinogenemia may be lower than those previously reported. Methods: In this retrospective cohort study, patients presenting to our trauma center November 2017 to April 2021 were reviewed. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography angle <60. Univariate and multivariable analyses assessed risk factors for HYPOFIB. Inverse probability of treatment weighting analyses assessed the relationship between cryoprecipitate administration and outcomes. Results: Of 29 782 patients, 6618 level 1 activations, and 1948 patients receiving emergency release blood, <1%, 2%, and 7% were HYPOFIB. HYPOFIB patients were younger, had higher head Abbreviated Injury Scale value, and had worse coagulopathy and shock. HYPOFIB had lower survival (48% vs 82%, p<0.001), shorter time to death (median 28 (7, 50) vs 36 (14, 140) hours, p=0.012), and were more likely to die from head injury (72% vs 51%, p<0.001). Risk factors for HYPOFIB included increased age (OR (95% CI) 0.98 (0.96 to 0.99), p=0.03), head injury severity (OR 1.24 (1.06 to 1.46), p=0.009), lower arrival pH (OR 0.01 (0.001 to 0.20), p=0.002), and elevated prehospital red blood cell to platelet ratio (OR 1.20 (1.02 to 1.41), p=0.03). Among HYPOFIB patients, there was no difference in survival for those that received early cryoprecipitate (within 2 hours; 40 vs 47%; p=0.630). On inverse probability of treatment weighted analysis, early cryoprecipitate did not benefit the full cohort (OR 0.52 (0.43 to 0.65), p<0.001), nor the HYPOFIB subgroup (0.28 (0.20 to 0.39), p<0.001). Conclusions: Low rates of hypofibrinogenemia were found in our center which treats hemorrhage with early, balanced resuscitation. Previously reported higher rates may be partially due to unbalanced resuscitation and/or delay in resuscitation initiation. Routine empiric inclusion of concentrated fibrinogen replacement in MTPs is not supported by the currently available data. Level of evidence: Level III.

Exposure to statin therapy decreases the incidence of venous thromboembolism after trauma.

INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in trauma patients, despite chemoprophylaxis. Statins have been shown capable of acting upon the endothelium. We hypothesized that statin therapy in the pre- or in-hospital settings leads to a decreased incidence of VTE. METHODS: We conducted a retrospective cohort study of injured patients who received statin therapy pre- or in-hospital. Adult, highest-level trauma activation patients admitted from January 2018 to June 2022 were included. Patients on prehospital anticoagulants, had history of inherited bleeding disorder, and who died within the first 24 hours were excluded. Statin users were matched to nonusers by statin use indications including age, current heart and cardiovascular conditions and history, hyperlipidemia, injury severity, and body mass index. Time to in-hospital statin initiation and occurrence of VTE and other complications within 60 days were collected. Differences between groups were determined by univariate, multivariable logistic regression, and Cox proportional hazard analyses. RESULTS: Of 3,062 eligible patients, 79 were statin users, who were matched to 79 nonusers. There were no differences in admission demographics, vital signs, injury pattern, transfusion volumes, lengths of stay, or mortality between groups. The overall VTE incidence was 10.8% (17 of 158). Incidence of VTE in statin users was significantly lower (3%) than nonusers (19%; p = 0.003). Differences between statin users and nonusers were observed for rates of deep vein thrombosis (0% vs. 9%), pulmonary embolism (3% vs. 15%), and sepsis (0% vs. 5%). Exposure to statins was associated with an 82% decreased risk of developing VTE (hazard ratio, 0.18; 95% confidence interval, 0.04-0.86; p = 0.033). CONCLUSION: Statin exposure was associated with decline in VTE and lower individual rates of deep vein thrombosis, pulmonary embolism, and sepsis. Our findings indicate that statins should be evaluated further as a possible adjunctive therapy for VTE chemoprophylaxis after traumatic injury. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Identifying Age-Specific Risk Factors for Poor Outcomes After Trauma With Machine Learning.

INTRODUCTION: Risk stratification for poor outcomes is not currently age-specific. Risk stratification of older patients based on observational cohorts primarily composed of young patients may result in suboptimal clinical care and inaccurate quality benchmarking. We assessed two hypotheses. First, we hypothesized that risk factors for poor outcomes after trauma are age-dependent and, second, that the relative importance of various risk factors are also age-dependent. METHODS: A cohort study of severely injured adult trauma patients admitted to the intensive care unit 2014-2018 was performed using trauma registry data. Random forest algorithms predicting poor outcomes (death or complication) were built and validated using three cohorts: (1) patients of all ages, (2) younger patients, and (3) older patients. Older patients were defined as aged 55 y or more to maintain consistency with prior trauma literature. Complications assessed included acute renal failure, acute respiratory distress syndrome, cardiac arrest, unplanned intubation, unplanned intensive care unit admission, and unplanned return to the operating room, as defined by the trauma quality improvement program. Mean decrease in model accuracy (MDA), if each variable was removed and scaled to a Z-score, was calculated. MDA change ≥4 standard deviations between age cohorts was considered significant. RESULTS: Of 5489 patients, 25% were older. Poor outcomes occurred in 12% of younger and 33% of older patients. Head injury was the most important predictor of poor outcome in all cohorts. In the full cohort, age was the most important predictor of poor outcomes after head injury. Within age cohorts, the most important predictors of poor outcomes, after head injury, were surgery requirement in younger patients and arrival Glasgow Coma Scale in older patients. Compared to younger patients, head injury and arrival Glasgow Coma Scale had the greatest increase in importance for older patients, while systolic blood pressure had the greatest decrease in importance. CONCLUSIONS: Supervised machine learning identified differences in risk factors and their relative associations with poor outcomes based on age. Age-specific models may improve hospital benchmarking and identify quality improvement targets for older trauma patients.

Weight-based enoxaparin thromboprophylaxis in young trauma patients: analysis of the CLOTT-1 registry.

Introduction: Optimal venous thromboembolism (VTE) enoxaparin prophylaxis dosing remains elusive. Weight-based (WB) dosing safely increases anti-factor Xa levels without the need for routine monitoring but it is unclear if it leads to lower VTE risk. We hypothesized that WB dosing would decrease VTE risk compared with standard fixed dosing (SFD). Methods: Patients from the prospective, observational CLOTT-1 registry receiving prophylactic enoxaparin (n=5539) were categorized as WB (0.45-0.55 mg/kg two times per day) or SFD (30 mg two times per day, 40 mg once a day). Multivariate logistic regression was used to generate a predicted probability of VTE for WB and SFD patients. Results: Of 4360 patients analyzed, 1065 (24.4%) were WB and 3295 (75.6%) were SFD. WB patients were younger, female, more severely injured, and underwent major operation or major venous repair at a higher rate than individuals in the SFD group. Obesity was more common among the SFD group. Unadjusted VTE rates were comparable (WB 3.1% vs. SFD 3.9%; p=0.221). Early prophylaxis was associated with lower VTE rate (1.4% vs. 5.0%; p=0.001) and deep vein thrombosis (0.9% vs. 4.4%; p<0.001), but not pulmonary embolism (0.7% vs. 1.4%; p=0.259). After adjustment, VTE incidence did not differ by dosing strategy (adjusted OR (aOR) 0.75, 95% CI 0.38 to 1.48); however, early administration was associated with a significant reduction in VTE (aOR 0.47, 95% CI 0.30 to 0.74). Conclusion: In young trauma patients, WB prophylaxis is not associated with reduced VTE rate when compared with SFD. The timing of the initiation of chemoprophylaxis may be more important than the dosing strategy. Further studies need to evaluate these findings across a wider age and comorbidity spectrum. Level of evidence: Level IV, therapeutic/care management.

Impact of Intra-Operative Shock and Resuscitation on Surgical Site Infections After Trauma Laparotomy.

Background: Patients undergoing trauma laparotomy experience high rates of surgical site infection (SSI). Although intra-operative shock is a likely contributor to SSI risk, little is known about the relation between shock, intra-operative restoration of physiologic normalcy, and SSI development. Patients and Methods: A retrospective review of trauma patients who underwent emergent definitive laparotomy was performed. Using shock index and base excess at the beginning and end of laparotomy, patients were classified as normal, persistent shock, resuscitated, or new shock. Univariable and multivariable analyses were performed to identify predictors of organ/space SSI, superficial/deep SSI, and any SSI. Results: Of 1,191 included patients, 600 (50%) were categorized as no shock, 248 (21%) as resuscitated, 109 (9%) as new shock, and 236 (20%) as persistent shock, with incidence of any SSI as 51 (9%), 28 (11%), 26 (24%), and 32 (14%), respectively. These rates were similar in organ/space and superficial/deep SSIs. On multivariable analysis, resuscitated, new shock, and persistent shock were associated with increased odds of organ/space SSI (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.5; p < 0.001) and any SSI (OR, 2.0; 95% CI, 1.4-3.2; p < 0.001), but no increased risk of superficial/deep SSI (OR, 1.4; 95% CI, 0.8-2.6; p = 0.331). Conclusions: Although the trajectory of physiologic status influenced SSI, the presence of shock at any time during trauma laparotomy, regardless of restoration of physiologic normalcy, was associated with increased odds of SSI. Further investigation is warranted to determine the relation between peri-operative shock and SSI in trauma patients.

Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia.

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.

Acute respiratory distress syndrome, acute kidney injury, and mortality after trauma are associated with increased circulation of syndecan-1, soluble thrombomodulin, and receptor for advanced glycation end products.

BACKGROUND: Disruption of the vascular endothelium and endothelial glycocalyx (EG) has been described after severe trauma. Plasma has been suggested to restore microvascular integrity by preservation and repair of the EG. We sought to evaluate whether plasma administered in a 1:1:1 ratio was associated with less endothelial marker circulation than a 1:1:2 ratio. METHODS: This is a secondary analysis of the PROPPR trial, which investigated post-traumatic resuscitation with platelets, plasma, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Syndecan-1, soluble thrombomodulin (sTM), and receptor for advanced glycation end products (RAGE) were quantified for each treatment group on admission and at 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours. Patients were excluded if they did not survive longer than 3 hours or had data from fewer than two time points. RESULTS: Three hundred eight patients in the 1:1:1 group and 291 in the 1:1:2 group were analyzed. There were no statistically significant differences in syndecan-1, sTM, or RAGE between treatment groups at any time point ( p > 0.05). Patients who developed acute respiratory distress syndrome, acute kidney injury, and death had significantly elevated biomarker expression at most time points when compared with patients who did not develop these sequelae ( p < 0.05). CONCLUSION: Administration of FFP in a 1:1:1 ratio does not consistently affect circulation of endothelial biomarkers following significant trauma when compared with a 1:1:2 ratio. The development of post-traumatic ARDS, AKI, and death was associated with increased endothelial biomarker circulation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Patient-Reported Outcomes Following Severe Abdominal Trauma: A Secondary Analysis of the Damage Control Laparotomy Trial.

INTRODUCTION: Little is known about patient-reported outcomes (PROs) following abdominal trauma. We hypothesized that patients undergoing definitive laparotomy (DEF) would have better PROs compared to those treated with damage control laparotomy (DCL). METHODS: The DCL Trial randomized DEF versus DCL in abdominal trauma. PROs were measured using the European Quality of Life-5 Dimensions-5 Levels (EQ-5D) questionnaire at discharge and six months postdischarge (1 = perfect health, 0 = death, and <0 = worse than death) and Posttraumatic Stress Disorder (PTSD) Checklist-Civilian. Unadjusted Bayesian analysis with a neutral prior was used to assess the posterior probability of achieving minimal clinically important difference. RESULTS: Of 39 randomized patients (21 DEF versus 18 DCL), 8 patients died (7 DEF versus 1 DCL). Of those who survived, 28 completed the EQ-5D at discharge (12 DEF versus 16 DCL) and 25 at 6 mo (12 DEF versus 13 DCL). Most patients were male (79%) with a median age of 30 (interquartile range (IQR) 21-42), suffered blunt injury (56%), and were severely injured (median injury severity score 33, IQR 21 - 42). Median EQ-5D value at discharge was 0.20 (IQR 0.06 - 0.52) DEF versus 0.31 (IQR -0.03 - 0.43) DCL, and at six months 0.51 (IQR 0.30 - 0.74) DEF versus 0.50 (IQR 0.28 - 0.84) DCL. The posterior probability of minimal clinically important difference DEF versus DCL at discharge and six months was 16% and 23%, respectively. CONCLUSIONS: Functional deficits for trauma patients persist beyond the acute setting regardless of laparotomy status. These deficits warrant longitudinal studies to better inform patients on recovery expectations.

Hypofibrinogenemia following injury in 186 children and adolescents: identification of the phenotype, current outcomes, and potential for intervention.

Objectives: Recent studies evaluating fibrinogen replacement in trauma, along with newly available fibrinogen-based products, has led to an increase in debate on where products such as cryoprecipitate belong in our resuscitation strategies. We set out to define the phenotype and outcomes of those with hypofibrinogenemia and evaluate whether fibrinogen replacement should have a role in the initial administration of massive transfusion. Methods: All patients <18 years of age presenting to our trauma center 11/17-4/21 were reviewed. We then evaluated all patients who received emergency-release and massive transfusion protocol (MTP) products. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography (r-TEG) angle <60 degrees. Our analysis sought to define risk factors for presenting with HYPOFIB, the impact on outcomes, and whether early replacement improved mortality. Results: 4169 patients were entered into the trauma registry, with 926 level 1 trauma activations, of which 186 patients received emergency-release blood products during this time; 1%, 3%, and 10% were HYPOFIB, respectively. Of the 186 patients of interest, 18 were HYPOFIB and 168 were non-HYPOFIB. The HYPOFIB patients were significantly younger, had lower field and arrival Glasgow Coma Scale, had higher head Abbreviated Injury Scale, arrived with worse global coagulopathy, and died from brain injury. Non-HYPOFIB patients were more likely to have (+)focused assessment for the sonography of trauma on arrival, sustained severe abdominal injuries, and die from hemorrhage. 12% of patients who received early cryoprecipitate (0-2 hours) had higher mortality by univariate analysis (55% vs 31%, p=0.045), but no difference on multivariate analysis (OR 0.36, 95% CI 0.07 to 1.81, p=0.221). Those receiving early cryoprecipitate who survived after pediatric intensive care unit (PICU) admission had lower PICU fibrinogen and r-TEG alpha-angle values. Conclusion: In pediatric trauma, patients with hypofibrinogenemia on admission are most likely younger and to have sustained severe brain injury, with an associated mortality of over 80%. Given the absence of bleeding-related deaths in HYPOFIB patients, this study does not provide evidence for the empiric use of cryoprecipitate in the initial administration of a massive transfusion protocol. Level of Evidence: Level III - Therapeutic/Care Management.

Addition of aspirin to venous thromboembolism chemoprophylaxis safely decreases venous thromboembolism rates in trauma patients.

Background: Trauma patients exhibit a multifactorial hypercoagulable state and have increased risk of venous thromboembolism (VTE). Despite early and aggressive chemoprophylaxis (CP) with various heparin compounds ("standard" CP; sCP), VTE rates remain high. In high-quality studies, aspirin has been shown to decrease VTE in postoperative elective surgical and orthopedic trauma patients. We hypothesized that inhibiting platelet function with aspirin as an adjunct to sCP would reduce the risk of VTE in trauma patients. Methods: We performed a retrospective observational study of prospectively collected data from all adult patients admitted to an American College of Surgeons Level I Trauma center from January 2012 to June 2015 to evaluate the addition of aspirin (sCP+A) to sCP regimens for VTE mitigation. Cox proportional hazard models were used to assess the potential benefit of adjunctive aspirin for symptomatic VTE incidence. Results: 10,532 patients, median age 44 (IQR 28 to 62), 68% male, 89% blunt mechanism of injury, with a median Injury Severity Score (ISS) of 12 (IQR 9 to 19), were included in the study. 8646 (82%) of patients received only sCP, whereas 1886 (18%) patients received sCP+A. The sCP+A cohort displayed a higher median ISS compared with sCP (13 vs 11; p<0.01). The overall median time of sCP initiation was hospital day 1 (IQR 0.8 to 2) and the median day for aspirin initiation was hospital day 3 (IQR 1 to 6) for the sCP+A cohort. 353 patients (3.4%) developed symptomatic VTE. Aspirin administration was independently associated with a decreased relative hazard of VTE (HR 0.57; 95% CI 0.36 to 0.88; p=0.01). There were no increased bleeding or wound complications associated with sCP+A (point estimate 1.23, 95% CI 0.68 to 2.2, p=0.50). Conclusion: In this large trauma cohort, adjunctive aspirin was independently associated with a significant reduction in VTE and may represent a potential strategy to safely mitigate VTE risk in trauma patients. Further prospective studies evaluating the addition of aspirin to heparinoid-based VTE chemoprophylaxis regimens should be sought. Level of evidence: Level III/therapeutic.

Volatile anesthetic and outcome in acute trauma care: planned secondary analysis of the PROPPR study.

Background: This retrospective analysis of prospectively collected data from the PROPPR study describes volatile anesthetic use in severely injured trauma patients undergoing anesthesia. Methods: After exclusions, 402 subjects were reviewed of the original 680, and 292 had complete data available for analysis. Anesthesia was not protocolized, so analysis was of contemporary practice. Results: The small group who received no volatile anesthetic (n = 25) had greater injury burden (Glasgow Coma Scale P = 0.05, Injury Severity Score P = 0.001, Revised Trauma Score P = 0.03), higher 6- and 24-hour mortality (P < 0.001), and higher incidence of systemic inflammatory response syndrome (P = 0.003) and ventilator-associated pneumonia (P = 0.02) than those receiving any volatile (n = 267). There were no differences in mortality between volatile agents at 6 hours (P = 0.51) or 24 hours (P = 0.35). The desflurane group was less severely injured than the isoflurane group. Mean minimum alveolar concentration was < 0.6 and lowest in the isoflurane group compared to the sevoflurane and desflurane groups (both P < 0.01). The incidence of systemic inflammatory response syndrome was lower in the desflurane group than in the isoflurane group (P = 0.007). Conclusion: In this acutely injured trauma population, choice of volatile anesthetic did not appear to influence short-term mortality and morbidity. Subjects who received no volatile were more severely injured with greater mortality, representing hemodynamic compromise where volatile agent was limited until stable. As anesthetic was not protocolized, these findings that choice of specific volatile was not associated with short-term survival require prospective, randomized evaluation.