Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial.

Importance: Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption. Objective: To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion. Design, Setting, and Participants: Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021. Interventions: Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines. Main Outcomes and Measures: The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety). Results: Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03). Conclusions and Relevance: Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion. Trial Registration: ClinicalTrials.gov Identifier: NCT03218722.

Time to source control and outcome in community-acquired intra-abdominal infections: The multicentre observational PERICOM study.

BACKGROUND: Optimal management of community-acquired intra-abdominal infections (IAI) requires timely surgical source control and adequate anti-infective treatment. OBJECTIVE: To describe the initial management of community-acquired IAI admitted to the emergency department and assess the association between the length of time to either diagnosis or therapeutic procedures and patient outcomes. DESIGN: A prospective, multicentre, observational study. SETTING: Thirteen teaching hospitals in France between April 2018 and February 2019. PATIENTS: Two hundred and five patients aged at least 18 years diagnosed with community-acquired IAI. MAIN OUTCOME MEASURES: The primary outcome was hospital length of stay. The secondary outcome was hospital mortality. RESULTS: Patients had a mean age of 56 (± 21) years and a median [interquartile] SAPS II of 26 [17 to 34]. Among the study cohort, 18% were postoperatively transferred to intensive care unit and 7% had died by day 28. Median [IQR] time to imaging, antibiotic therapy and surgery were 4 [2 to 6], 7.5 [4 to 12.5] and 9 [5.5 to 17] hours, respectively. The length of time to surgical source control [0.99, 95% confidence interval (CI), 0.98 to 0.99], SOFA greater than 2 [0.36 (95% CI, 0.26 to 0.651)], age greater than 60 years [0.65 (95% CI, 0.45 to 0.94)], generalized peritonitis [0.7 (95% CI, 0.56 to 0.89)] and laparotomy surgery [0.657 (95% CI, 0.42 to 0.78)] were associated with longer hospital length of stay. The duration of time to surgical source control [1.02 (95% CI, 1.01 to 1.04)], generalized peritonitis [2.41 (95% CI, 1.27 to 4.61)], and SOFA score greater than 2 [6.14 (95% CI, 1.40 to 26.88)] were identified as independent risk factors for 28-day mortality. CONCLUSION: This multicentre observational study revealed that the time to surgical source control, patient severity and generalized peritonitis were identified as independent risk factors for increased hospital LOS and mortality in community-acquired IAI. Organisational strategies to reduce the time to surgical management of intra-abdominal infections should be further evaluated. STUDY REGISTRATION: ClinicalTrials.gov on 1 April 2018, NCT03544203.

Withholding and withdrawal of life-sustaining therapy in 8569 trauma patients: A multicentre, analytical registry study.

BACKGROUND: This study aimed to determine the prevalence of withholding or withdrawal of life-sustaining therapy (WLST) decisions in trauma ICU patients, using a large registry. We hypothesised that this prevalence is similar to that of the general population admitted to an ICU. As secondary aims, it sought to describe the trauma patients for whom the decision was made for WLST and the factors associated with this decision. DESIGN: This observational study assessed data from 14 French centres listed in the TraumaBaseTM registry. All trauma patients hospitalised for more than 48 h were pro-spectively included. RESULTS: Data from 8569 trauma patients, obtained from January 2016 to December 2018, were included in this study. A WLST decision was made in 6% of all cases. In the WLST group, 67% of the patients were older men (age: 62 versus 36, P  < 0.001); more often they had a prior medical history and higher median severity scores than the patients in the no WLST decision group; SAPS II 58 (46 to 69) versus 21 (13 to 35) and ISS 26 (22 to 24) versus 12 (5 to 22), P  < 0.001. Neurological status was strongly associated with WLST decisions. The geographic area of the ICUs affected the rate of the WLST decisions. The ICU mortality was 11% (n = 907) of which 47% (n = 422) were preceded by WLST decisions. Fourteen percent of WLST orders were not associated to the death. CONCLUSION: Among 8569 patients, medical history, trauma severity criteria, notably neurological status and geographical areas were associated with WLST. These regional differences deserve to be investigated in future studies.

Gunshot and stab wounds in France: descriptive study from a national trauma registry.

PURPOSE: Severe trauma is a major problem worldwide. In France, blunt trauma (BT) is predominant and few studies are available on penetrating trauma (PT). The purpose of this study was to perform a descriptive analysis of severe gunshot (GSW) and stab wounds (SW) in patients who were treated in French trauma centers. METHODS: Retrospective study on prospectively collected data in a national trauma registry. All adult (> 15 years) trauma patients primarily admitted in 1 of the 17 trauma centers members of the Traumabase between January 2015 to December 2018 were included. Data from patients who had a PT were compared with those who had suffered a BT over the same period. Due to the known differences between GSW and SW, sub-group analyses on data from GSW, SW and BT were also performed. RESULTS: 8128 patients were included. Twelve percent of the study group had a PT. The main mechanism of PT was SW (68.1%). Five hundred and eighty patients with PT (59.4%) required surgery within the first 24 h. Severe hemorrhage was more frequent in penetrating traumas (11.2% vs. 7.8% p < 0.001). Hospital mortality following PT was 8.9% vs 11% for blunt trauma (p = 0.047). Among PT the mortality after GSW was ten times higher than after SW (23.8% vs 2%). CONCLUSION: This work is the largest study to date that has specifically focused on GSW and SW in France, and will help improving knowledge in managing such patients in our country.

Specification and Evaluation of Plasticizer Migration Simulants for Human Blood Products: A Delphi Study.

Potentially toxic plasticizers are commonly added to polyvinyl chloride medical devices for transfusion in order to improve their flexibility and workability. As the plasticizers are not chemically bonded to the PVC, they can be released into labile blood products (LBPs) during storage. Ideally, LBPs would be used in laboratory studies of plasticizer migration from the medical device. However, short supply (i.e., limited stocks of human blood in collection centres) has prompted the development of specific simulants for each type of LBP in the evaluation of new transfusion devices. We performed a Delphi study with a multidisciplinary panel of 24 experts. In the first (qualitative) phase, the panel developed consensus definitions of the specification criteria to be met by each migration simulant. Next, we reviewed the literature on techniques for simulating the migration of plasticizers into LBPs. A questionnaire was elaborated and sent out to the experts, and the replies were synthesized in order to obtain a consensus. The qualitative study established specifications for each biological matrix (whole blood, red blood cell concentrate, plasma, and platelet concentrate) and defined the criteria required for a suitable LBP simulant. Ten criteria were suggested: physical and chemical characteristics, opacity, form, stability, composition, ability to mimic a particular clinical situation, ease and safety of use, a simulant-plastic interaction correlated with blood, and compatibility with analytical methods. The questionnaire data revealed a consensus on the use of natural products (such as pig's blood) to mimic the four LBPs. Opinions diverged with regard to synthetic products. However, an isotonic solution and a rheological property modifier were considered to be of value in the design of synthetic simulants. Consensus reached by the Delphi group could be used as a database for the development of simulants used to assess the migration of plasticizers from PVC bags into LBPs.

Guidelines for the acute care of severe limb trauma patients.

GOAL: To provide healthcare professionals with comprehensive multidisciplinary expert recommendations for the acute care of severe limb trauma patients, both during the prehospital phase and after admission to a Trauma Centre. DESIGN: A consensus committee of 21 experts was formed. A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independently of any industrial funding (i.e., pharmaceutical, medical devices). The authors were advised to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of the quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. Few recommendations remained non-graded. METHODS: The committee addressed eleven questions relevant to the patient suffering severe limb trauma: 1) What are the key findings derived from medical history and clinical examination which lead to the patient's prompt referral to a Level 1 or Level 2 Trauma Centre? 2) What are the medical devices that must be implemented in the prehospital setting to reduce blood loss? 3) Which are the clinical findings prompting the performance of injected X-ray examinations? 4) What are the ideal timing and modalities for performing fracture fixation? 5) What are the clinical and operative findings which steer the surgical approach in case of vascular compromise and/or major musculoskeletal attrition? 6) How to best prevent infection? 7) How to best prevent thromboembolic complications? 8) What is the best strategy to precociously detect and treat limb compartment syndrome? 9) How to best and precociously detect post-traumatic rhabdomyolysis and prevent rhabdomyolysis-induced acute kidney injury? 10) What is the best strategy to reduce the incidence of fat emboli syndrome and post-traumatic systemic inflammatory response? 11) What is the best therapeutic strategy to treat acute trauma-induced pain? Every question was formulated in a PICO (Patient Intervention Comparison Outcome) format and the evidence profiles were produced. The literature review and recommendations were made according to the GRADE® methodology. RESULTS: The experts' synthesis work and the application of the GRADE method resulted in 19 recommendations. Among the formalised recommendations, 4 had a high level of evidence (GRADE 1+/-) and 12 had a low level of evidence (GRADE 2+/-). For 3 recommendations, the GRADE method could not be applied, resulting in an expert advice. After two rounds of scoring and one amendment, strong agreement was reached on all the recommendations. CONCLUSIONS: There was significant agreement among experts on strong recommendations to improve practices for severe limb trauma patients.

National early warning score to predict intensive care unit transfer and mortality in COVID-19 in a French cohort.

BACKGROUND: No risk stratification tool has been validated in hospitalised patients with coronavirus disease 2019 (COVID-19), despite a high rate of intensive care requirement and in-hospital mortality. We aimed to determine whether the National Early Warning Score (NEWS) at admission can accurately predict in-hospital mortality and ICU transfer. METHODS: This was a retrospective cohort study from January 24 to April 16, 2020, at Lille University Hospital. All consecutive adult patients with laboratory-confirmed COVID-19 who were initially admitted to non-ICU wards were included. The primary outcome was a composite criterion consisting of ICU transfer or in-hospital mortality. We evaluated the prognostic performance of NEWS by calculating the area under (AUC) the receiver operating characteristic curve, the optimal threshold value of NEWS, and its association with the primary outcome. RESULTS: Of the 202 COVID-19 patients, the median age was 65 (interquartile range 52-78), 38.6% were women and 136 had at least one comorbidity. The median NEWS was 4 (2-6). A total of 65 patients were transferred to the ICU or died in the hospital. Compared with patients with favourable outcome, these patients were significantly older, had more comorbidities and higher NEWS. The AUC for NEWS was 0.68 (0.60-0.77) and the best cutoff value was 6. Adjusted odds ratio for NEWS ≥ 6 as an independent predictor was 3.78 (1.94-7.09). CONCLUSIONS: In hospitalised COVID-19 patients, NEWS was an independent predictor of ICU transfer and in-hospital death. In daily practice, NEWS ≥ 6 at admission may help to identify patients who are at risk to deteriorate.

Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19.

[Figure: see text].

Impact of High-Dose Prophylactic Anticoagulation in Critically Ill Patients With COVID-19 Pneumonia.

BACKGROUND: Because of the high risk of thrombotic complications (TCs) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent. RESEARCH QUESTION: What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC? STUDY DESIGN AND METHODS: All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight. RESULTS: Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75). INTERPRETATION: High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill patients with COVID-19 without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04405869; URL: www.clinicaltrials.gov.

Study protocol for a multicentre, 2×2 factorial, randomised, controlled trial evaluating the interest of intravenous iron and tranexamic acid to reduce blood transfusion in hip fracture patients (the HiFIT study).

INTRODUCTION: Blood transfusion and anaemia are frequent and are associated with poor outcomes in patients with hip fracture (HF). We hypothesised that preoperative intravenous iron and tranexamic acid (TXA) may reduce the transfusion rate in these patients. METHODS AND ANALYSIS: The HiFIT study is a multicentre, 2×2 factorial, randomised, double-blinded, controlled trial evaluating the effect of iron isomaltoside (IIM) (20 mg/kg) vs placebo and of TXA (intravenously at inclusion and topically during surgery) versus placebo on transfusion rate during hospitalisation, in patients undergoing emergency surgery for HF and having a preoperative haemoglobin between 95 and 130 g/L. 780 patients are expected. The primary endpoint is the proportion of patients receiving an allogenic blood transfusion of packed red blood cells from the day of surgery until hospital discharge (or until D30 if patient is still hospitalised). Enrolment started on March 2017 in 11 French hospitals. The study was stopped between July 2017 and August 2018 (because of investigation of serious AEs with IIM in Spain) and slowed down since March 2020 (COVID-19 crisis). The expected date of final follow-up is May 2022. Analyses of the intent-to-treat and per-protocol populations are planned. ETHICS AND DISSEMINATION: The HiFIT trial protocol has been approved by the Ethics Committee of Comité de Protection des Personnes Ouest II and the French authorities (ANSM). It will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. The HiFIT trial will be the largest study evaluating iron and TXA in patients with HF. TRIAL REGISTRATION NUMBER: clinicalTrials.gov identifier: NCT02972294; EudraCT Number 2016-003087-40.

Early hyperoxemia is associated with lower adjusted mortality after severe trauma: results from a French registry.

BACKGROUND: Hyperoxemia has been associated with increased mortality in critically ill patients, but little is known about its effect in trauma patients. The objective of this study was to assess the association between early hyperoxemia and in-hospital mortality after severe trauma. We hypothesized that a PaO2 ≥ 150 mmHg on admission was associated with increased in-hospital mortality. METHODS: Using data issued from a multicenter prospective trauma registry in France, we included trauma patients managed by the emergency medical services between May 2016 and March 2019 and admitted to a level I trauma center. Early hyperoxemia was defined as an arterial oxygen tension (PaO2) above 150 mmHg measured on hospital admission. In-hospital mortality was compared between normoxemic (150 > PaO2 ≥ 60 mmHg) and hyperoxemic patients using a propensity-score model with predetermined variables (gender, age, prehospital heart rate and systolic blood pressure, temperature, hemoglobin and arterial lactate, use of mechanical ventilation, presence of traumatic brain injury (TBI), initial Glasgow Coma Scale score, Injury Severity Score (ISS), American Society of Anesthesiologists physical health class > I, and presence of hemorrhagic shock). RESULTS: A total of 5912 patients were analyzed. The median age was 39 [26-55] years and 78% were male. More than half (53%) of the patients had an ISS above 15, and 32% had traumatic brain injury. On univariate analysis, the in-hospital mortality was higher in hyperoxemic patients compared to normoxemic patients (12% versus 9%, p < 0.0001). However, after propensity score matching, we found a significantly lower in-hospital mortality in hyperoxemic patients compared to normoxemic patients (OR 0.59 [0.50-0.70], p < 0.0001). CONCLUSION: In this large observational study, early hyperoxemia in trauma patients was associated with reduced adjusted in-hospital mortality. This result contrasts the unadjusted in-hospital mortality as well as numerous other findings reported in acutely and critically ill patients. The study calls for a randomized clinical trial to further investigate this association.

Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19.

BACKGROUND: Hypercoagulability seems to contribute to SARS-CoV-2 pneumonia pathogenesis. However, age and metabolic syndrome are potential confounders when assessing the value of coagulation biomarkers' prediction of COVID-19 outcomes. We assessed whether coagulation biomarkers, including factor VIII (FVIII) and von Willebrand factor (VWF) levels, measured at time of admission, were predictive of COVID-19 adverse outcomes irrespective of age and major comorbidities associated with metabolic syndrome. METHODS: Blood was sampled at admission in 243 adult COVID-19 patients for analysis of coagulation biomarkers including FVIII and VWF on platelet-poor plasma. The association between baseline C-reactive protein (CRP), activated partial thromboplastin time ratio, prothrombin time ratio, D-dimers, fibrinogen, FVIII, VWF antigen (VWF:Ag), and FVIII/VWF:Ag ratio levels and adverse outcomes (increased oxygen requirements, thrombosis, and death at day 30) was assessed by regression analysis after adjustment on age, sex, body mass index (BMI), diabetes, and hypertension. RESULTS: In univariable regression analysis increased CRP (subdistribution hazard ratio [SHR], 1.68; 95% confidence interval [CI], 1.26-2.23), increased fibrinogen (SHR, 1.32; 95% CI, 1.04-1.68), and decreased FVIII/VWF:Ag ratio (SHR, 0.70; 95% CI, 0.52-0.96) levels at admission were significantly associated with the risk of increased oxygen requirement during follow-up. Leucocytes (SHR, 1.36; 95% CI, 1.04-1.76), platelets (SHR,1.71; 95% CI, 1.11-2.62), D-dimers (SHR, 2.48; 95% CI, 1.66-3.78), and FVIII (SHR, 1.78; 95% CI, 1.17-2.68) were associated with early onset of thrombosis after admission. After adjustment for age, sex, BMI, hypertension, and diabetes, these associations were not modified. CONCLUSION: Coagulation biomarkers are early and independent predictors of increased oxygen requirement in COVID-19 patients.

Clinico-Biological Features and Clonal Hematopoiesis in Patients with Severe COVID-19.

Advanced age or preexisting comorbidities have been characterized as risk factors for severe coronavirus disease 2019 (COVID-19) cases requiring hospitalization and intensive care. In recent years, clonal hematopoiesis (CH) of indeterminate potential (CHIP) has emerged as a risk factor for chronic inflammatory background and subsequent aging-associated diseases. The purpose of this study was to identify biological factors (particularly leukocyte subtypes and inflammatory markers) associated with a risk of clinical deterioration (i.e., orotracheal intubation (OTI)) and to determine whether CH was likely to influence clinical and biological behavior in patients with severe COVID-19 requiring hospitalization. Here, we describe clinical and biological features, including the screening of CHIP mutants in a well-annotated cohort of 122 hospitalized patients with a laboratory-confirmed diagnosis of COVID-19 (55% requiring OTI). We showed that elevated white blood cell counts, especially neutrophils and high C-reactive protein (CRP) levels at admission, were associated with an increased requirement of OTI. We noticed a high prevalence of CH (25%, 38%, 56%, and 82% of patients aged <60 years, 60-70 years, 70-80 years, and >80 years) compared to a retrospective cohort of patients free of hematological malignancy explored with the same pipelines (10%, 21%, 37%, and 44%). However, the existence of CH did not significantly impact clinical outcome, including OTI or death, and did not correlate with other laboratory findings.

Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring.

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m2, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 µg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.

Effect of fibrinogen concentrate administration on early mortality in traumatic hemorrhagic shock: A propensity score analysis.

BACKGROUND: Fibrinogen concentrate is widely used in traumatic hemorrhagic shock despite weak evidence in the literature. The aim of the study was to evaluate the effect of fibrinogen concentrate administration within the first 6 hours on 24-hour all-cause mortality in traumatic hemorrhagic shock using a causal inference approach. METHODS: Observational study from a French multicenter prospective trauma registry was performed. Hemorrhagic shock was defined as transfusion of four or more red blood cell units within the first 6 hours after admission. The confounding variables for the outcome (24-hour all-cause mortality) and treatment allocation (fibrinogen concentrate administration within the first 6 hours) were chosen by a Delphi method. The propensity score was specified with a data-adaptive algorithm and a doubly-robust approach with inverse proportionality of treatment weighting allowed to compute the average treatment effect. Sensitivity analyses were performed. RESULTS: Of 14,336 patients in the registry during the study period, 1,027 in hemorrhagic shock were analyzed (758 receiving fibrinogen concentrate within 6 hours and 269 not receiving fibrinogen concentrate). The average treatment effect, expressed as a risk difference, was -0.031 (95% confidence interval, -0.084 to 0.021). All sensitivity analysis confirmed the results. CONCLUSIONS: Fibrinogen concentrate administration within the first 6 hours of a traumatic hemorrhagic shock did not decrease 24-hour all-cause mortality. LEVEL OF EVIDENCE: Prognostic, level III.

Early management of severe abdominal trauma.

OBJECTIVE: To develop French guidelines on the management of patients with severe abdominal trauma. DESIGN: A consensus committee of 20 experts from the French Society of Anaesthesiology and Critical Care Medicine (Société française d'anesthésie et de réanimation, SFAR), the French Society of Emergency Medicine (Société française de médecine d'urgence, SFMU), the French Society of Urology (Société française d'urologie, SFU) and from the French Association of Surgery (Association française de chirurgie, AFC), the Val-de-Grâce School (École du Val-De-Grâce, EVG) and the Federation for Interventional Radiology (Fédération de radiologie interventionnelle, FRI-SFR) was convened. Declaration of all conflicts of interest (COI) policy by all participants was mandatory throughout the development of the guidelines. The entire guideline process was conducted independently of any industry funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for assessment of the available level of evidence with particular emphasis to avoid formulating strong recommendations in the absence of high level. Some recommendations were left ungraded. METHODS: The guidelines are divided in diagnostic and, therapeutic strategy and early surveillance. All questions were formulated according to Population, Intervention, Comparison, and Outcomes (PICO) format. The panel focused on three questions for diagnostic strategy: (1) What is the diagnostic performance of clinical signs to suggest abdominal injury in trauma patients? (2) Suspecting abdominal trauma, what is the diagnostic performance of prehospital FAST (Focused Abdominal Sonography for Trauma) to rule in abdominal injury and guide the prehospital triage of the patient? and (3) When suspecting abdominal trauma, does carrying out a contrast enhanced thoraco-abdominal CT scan allow identification of abdominal injuries and reduction of mortality? Four questions dealt with therapeutic strategy: (1) After severe abdominal trauma, does immediate laparotomy reduce morbidity and mortality? (2) Does a "damage control surgery" strategy decrease morbidity and mortality in patients with a severe abdominal trauma? (3) Does a laparoscopic approach in patients with abdominal trauma decrease mortality or morbidity? and (4) Does non-operative management of patients with abdominal trauma without bleeding reduce mortality and morbidity? Finally, one question was formulated regarding the early monitoring of these patients: In case of severe abdominal trauma, which kind of initial monitoring does allow to reduce the morbi-mortality? The analysis of the literature and the recommendations were conducted following the GRADE® methodology. RESULTS: The SFAR/SFMU Guideline panel provided 15 statements on early management of severe abdominal trauma. After three rounds of discussion and various amendments, a strong agreement was reached for 100% of recommendations. Of these recommendations, five have a high level of evidence (Grade 1±), six have a low level of evidence (Grade 2±) and four are expert judgments. Finally, no recommendation was provided for one question. CONCLUSIONS: Substantial agreement exists among experts regarding many strong recommendations for the best early management of severe abdominal trauma.

Association of Prehospital Time to In-Hospital Trauma Mortality in a Physician-Staffed Emergency Medicine System.

Importance: The association between total prehospital time and mortality in physician-staffed trauma systems remains uncertain. Objective: To describe the association of total prehospital time and in-hospital mortality in prehospital, physician-staffed trauma systems in France, with the hypothesis that total prehospital time is associated with increased mortality. Design, Setting, and Participants: This cohort study was conducted from January 2009 to December 2016. Data for this study were derived from 2 distinct regional trauma registries in France (1 urban and 1 rural) that both have a physician-staffed emergency medical service. Consecutive adult trauma patients admitted to either of the regional trauma referral centers during the study period were included. Data analysis took place from March 2018 to September 2018. Main Outcomes and Measures: The association between death and prehospital time was assessed with a multivariable model adjusted with confounders. Total prehospital time was the primary exposure variable, recorded as the time from the arrival of the physician-led prehospital care team on scene to the arrival at the hospital. The main outcome of interest was all-cause in-hospital mortality. Results: A total of 10 216 patients were included (mean [SD] age, 41 [18] years; 7937 men [78.3%]) affected by predominantly nonpenetrating injuries (9265 [91.5%]), with a mean (SD) Injury Severity Score of 17 (14) points. Of the patients, 6737 (66.5%) had at least 1 body region with an Abbreviated Injury Scale score of 3 or more. A total of 1259 patients (12.4%) presented in shock (with systolic pressure <90 mm Hg) and 2724 (26.9%) with severe head injury (Abbreviated Injury Scale score ≥3 points). On unadjusted analysis, increasing prehospital times (in 30-minute categories) were associated with a markedly and constant increase in the risk of in-hospital death. The odds of death increased by 9% for each 10-minute increase in prehospital time (odds ratio, 1.09 [95% CI, 1.07-1.11]) and after adjustment by 4% (odds ratio, 1.04 [95% CI, 1.01-1.07]). Conclusions and Relevance: In this study, an increase in total prehospital time was associated with increasing in-hospital all-cause mortality in trauma patients at a physician-staffed emergency medical system, after adjustment for case complexity. Prehospital time is a management objective in analogy to physiological targets. These findings plead for a further streamlining of prehospital trauma care and the need to define the optimal intervention-to-time ratio.