Impact of adherence to procalcitonin antibiotic prescribing guideline recommendations for low procalcitonin levels on antibiotic use.

BACKGROUND: The Procalcitonin Antibiotic Consensus Trial (ProACT) found provision of a procalcitonin antibiotic prescribing guideline to hospital-based clinicians did not reduce antibiotic use. Possible reasons include clinician reluctance to follow the guideline, with an observed 64.8% adherence rate. In this study we sought to determine the threshold adherence rate for reduction in antibiotic use, and to explore opportunities to increase adherence. METHODS: This study is a retrospective analysis of ProACT data. ProACT randomized 1656 patients presenting to 14 U.S. hospitals with suspected lower respiratory tract infection to usual care or provision of procalcitonin assay results and an antibiotic prescribing guideline to the treating clinicians. We simulated varying adherence to guideline recommendations for low procalcitonin levels and determined which threshold adherence rate could have resulted in rejection of the null hypothesis of no difference between groups at alpha = 0.05. We also performed sensitivity analyses within specific clinical settings and grouped patients initially prescribed antibiotics despite low procalcitonin into low, medium, and high risk of illness severity or bacterial infection. RESULTS: Our primary outcome was number of antibiotic-days by day 30 using an intention-to-treat approach and a null hypothesis of no difference in antibiotic use. We determined that an 84% adherence rate in the hospital setting (emergency department and inpatient) for low procalcitonin could have allowed rejection of the null hypothesis (3.7 vs 4.3 antibiotic-days, p = 0.048). The threshold adherence rate was 76% for continued guideline adherence after discharge. Even 100% adherence in the emergency department alone failed to reduce antibiotic-days. Of the 218 patients prescribed antibiotics in the emergency department despite low procalcitonin, 153 (70.2%) were categorized as low or medium risk. CONCLUSIONS: High adherence in the hospital setting to a procalcitonin antibiotic prescribing guideline is necessary to reduce antibiotic use in suspected lower respiratory tract infection. Continued guideline adherence after discharge and withholding of antibiotics in low and medium risk patients with low procalcitonin may offer impactful potential opportunities for antibiotic reduction. Trial registration Procalcitonin Antibiotic Consensus Trial (ProACT), ClinicalTrials.gov Identifier: NCT02130986. First posted May 6, 2014.

Evaluation of Bebtelovimab for Treatment of Covid-19 During the SARS-CoV-2 Omicron Variant Era.

Background: Monoclonal antibody (mAb) treatment is associated with decreased risk of hospitalization and death in high-risk outpatients with mild to moderate coronavirus disease 2019 (COVID-19) caused by early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Bebtelovimab exhibits in vitro activity against the Omicron variant and its sublineages; however, clinical data are lacking. Methods: A retrospective cohort study was conducted comparing bebtelovimab-treated patients with propensity score-adjusted and matched nontreated control groups. Participants included high-risk outpatients eligible for bebtelovimab treatment under Emergency Use Authorization with a positive SARS-CoV-2 test from March 30 to May 28, 2022. Treated patients received single-dose intravenous treatment with bebtelovimab. The primary outcome was hospitalization or death over 28 days. Results: Before matching/statistical adjustment, mAb-treated patients were, on average, 10 years older than nontreated patients (61.6 vs 51.3 years) and had higher prevalence of obstructive sleep apnea, hypertension, chronic kidney disease, cancer, organ or cell transplant, and immunocompromised status (standardized mean differences ≥0.20). The adjusted odds ratio (OR) of hospitalization or death comparing 1006 treated with 2023 nontreated patients was 0.50 (95% CI, 0.31-0.80). Among 930 treated and 930 propensity score-matched nontreated patients, the incidence of hospitalization or death was 3.1% vs 5.5%, respectively (conditional OR, 0.53; 95% CI, 0.32-0.86). The lower odds ratio of hospitalization or death associated with bebtelovimab treatment was most evident in older patients, those with immunocompromised status, and fully vaccinated patients. Conclusions: Monoclonal antibody treatment with bebtelovimab among COVID-19 outpatients is associated with lower odds of hospitalization or death, particularly among immunocompromised and older patients.

Association of Subcutaneous or Intravenous Administration of Casirivimab and Imdevimab Monoclonal Antibodies With Clinical Outcomes in Adults With COVID-19.

Importance: Monoclonal antibody (mAb) treatment decreases hospitalization and death in high-risk outpatients with mild to moderate COVID-19; however, only intravenous administration has been evaluated in randomized clinical trials of treatment. Subcutaneous administration may expand outpatient treatment capacity and qualified staff available to administer treatment, but the association with patient outcomes is understudied. Objectives: To evaluate whether subcutaneous casirivimab and imdevimab treatment is associated with reduced 28-day hospitalization and death compared with nontreatment among mAb-eligible patients and whether subcutaneous casirivimab and imdevimab treatment is clinically and statistically similar to intravenous casirivimab and imdevimab treatment. Design, Setting, and Participants: This prospective cohort study evaluated high-risk outpatients in a learning health system in the US with mild to moderate COVID-19 symptoms from July 14 to October 26, 2021, who were eligible for mAb treatment under emergency use authorization. A nontreated control group of eligible patients was also studied. Exposures: Subcutaneous injection or intravenous administration of the combined single dose of 600 mg of casirivimab and 600 mg of imdevimab. Main Outcomes and Measures: The primary outcome was the 28-day adjusted risk ratio or adjusted risk difference for hospitalization or death. Secondary outcomes included 28-day adjusted risk ratios and differences in hospitalization, death, a composite end point of emergency department admission and hospitalization, and rates of adverse events. Among 1959 matched adults with mild to moderate COVID-19, 969 patients (mean [SD] age, 53.8 [16.7] years; 547 women [56.4%]) who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization or death of 3.4% (22 of 653 patients) compared with 7.0% (92 of 1306 patients) in nontreated controls (risk ratio, 0.48; 95% CI, 0.30-0.80; P = .002). Among 2185 patients treated with subcutaneous (n = 969) or intravenous (n = 1216; mean [SD] age, 54.3 [16.6] years; 672 women [54.4%]) casirivimab and imdevimab, the 28-day rate of hospitalization or death was 2.8% vs 1.7%, which resulted in an adjusted risk difference of 1.5% (95% CI, -0.6% to 3.5%; P = .16). Among all infusion patients, there was no difference in intensive care unit admission (adjusted risk difference, 0.7%; 95% CI, -3.5% to 5.0%) or need for mechanical ventilation (adjusted risk difference, 0.2%; 95% CI, -5.8% to 5.5%). Conclusions and Relevance: In this cohort study of high-risk outpatients with mild to moderate COVID-19 symptoms, subcutaneously administered casirivimab and imdevimab was associated with reduced hospitalization and death when compared with no treatment. These results provide preliminary evidence of potential expanded use of subcutaneous mAb treatment, particularly in areas that are facing treatment capacity and/or staffing shortages.

Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days.

Outpatient treatments that limit progression to severe coronavirus disease 2019 (COVID-19) are of vital importance to optimise patient outcomes and public health. Monoclonal antibodies (mAb) demonstrated ability to decrease hospitalizations in randomized, clinical trials. However, there are many barriers to mAb treatment such as patient access and clinician education. There are no data comparing efficacy or safety of available mAbs. We sought to rapidly launch an adaptive platform trial with the goals of enhancing access to treatment, regardless of geography and socioeconomic status, and evaluating comparative efficacy and safety of available mAbs. Within 21 days from idea genesis, we allocated mAb treatment to all patients within the context of this clinical trial. Within 2 months, we closed the gap of the likelihood of receiving mAb, conditional on background positivity rate, between Black and White patients (Black patients 0.238; White patients 0.241). We describe trial infrastructure, lessons learned, and future directions for a culture of learning while doing.

Outcomes of end-stage renal disease patients in the PROCESS trial.

OBJECTIVE: Intravenous fluid administration is a main component of sepsis therapy, but physicians are cautious about giving fluids to end-stage renal disease (ESRD) patients out of concern for causing volume overload. We compared the outcomes of septic shock patients with and without ESRD and evaluated the association between early intravenous fluid administration and outcomes. METHODS: We analyzed patients enrolled in the Protocolized Care for Early Septic Shock (PROCESS) trial, which studied different resuscitation strategies for early septic shock. Stratifying for ESRD, we compared patient characteristics, course of care, and outcomes between ESRD and non-ESRD. Using multivariable logistic regression, we determined the association between 6-hour total fluid volume (> = 30 mL/kg vs < 30 mL/kg) from preenrollment and outcomes. RESULTS: There were 84 ESRD and 1257 non-ESRD patients. ESRD patients had a higher median Charlson Comorbidity score (5 vs 2, P < .001), higher median acute physiology and chronic health evaluation (APACHE) II score (26.5 vs 20.0, P < .001), and lower 6-hour intravenous fluid administration (54.7 vs 68.3 mL/kg, P < .001). Ninety-day mortality (33.3% vs 29.3%, P = .43) and intubation rate (31.0% vs 33.4%, P = .64) did not differ between groups. Fewer ESRD received > = 30 mL/kg (66.6% vs 86.7% P < .001). For ESRD, receipt of > = 30 mL/kg intravenous fluid did not alter any outcome. For non-ESRD patients, receiving   ≥30 mL/kg of intravenous fluid was associated with increased 90-day mortality (adjusted odds ratio = 1.64; 95% confidence interval, 1.03-2.61). CONCLUSIONS: In the PROCESS trial, ESRD patients had similar outcomes to non-ESRD patients. Although ESRD patients received less intravenous fluid administration, most received over 30 mL/kg in the first 6 hours. In contrast to non-ESRD patients, receiving  ≥30 mL/kg of intravenous fluid was not associated with worse outcomes in ESRD.

Inter-facility transfer of patients with traumatic intracranial hemorrhage and GCS 14-15: The pilot study of a screening protocol by neurosurgeon to avoid unnecessary transfers.

We sought to evaluate feasibility and cost-reduction potential of a pilot screening program involving neurosurgeon tele-consultation for inter-facility transfer decisions in TBI patients with GCS 14-15 and abnormal CT head at a community hospital. The authors performed a retrospective comparative analysis of two patient cohorts during the pilot at a large hospital system from 2015 to 2017. In "screened" patients (n = 85), images and examination were reviewed remotely by a neurosurgeon who made recommendations regarding transfer to a level 1 trauma center. In the "unscreened" group (n = 39), all patients were transferred. Baseline patient characteristics, outcomes, and costs were reviewed. Patient demographics were similar between cohorts. Traumatic subarachnoid hemorrhage was more common in screened patients (29.4% vs 12.8%, P = 0.02). The presence of midline shift >5 mm was comparable between groups. Among screened patients, 5 were transferred (5.8%) and one required evacuation of chronic subdural hematoma. In unscreened patients, 7 required evacuation of subdural hematoma. None of the screened patients who were not transferred deteriorated. Screened patients had significantly reduced average total cost compared to unscreened patients ($2,003 vs. $4,482, P = 0.03) despite similar lengths of stay (2.6 vs. 2.7 days, P = 0.85). In non-surgical patients, costs were less in the screened group ($2,025 vs. $2,939), although statistically insignificant (P = 0.38). In this pilot study, remote review of images and examination by a neurosurgeon was feasible to avoid unnecessary transfer of patients with traumatic intracranial hemorrhage and GCS 14-15. The true potential in cost-reduction will be realized in system-wide large-scale implementation.

Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial.

IMPORTANCE: In-hospital administration of tranexamic acid after injury improves outcomes in patients at risk for hemorrhage. Data demonstrating the benefit and safety of the pragmatic use of tranexamic acid in the prehospital phase of care are lacking for these patients. OBJECTIVE: To assess the effectiveness and safety of tranexamic acid administered before hospitalization compared with placebo in injured patients at risk for hemorrhage. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, phase 3, multicenter, double-blind, placebo-controlled, superiority randomized clinical trial included injured patients with prehospital hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110/min) before arrival at 1 of 4 US level 1 trauma centers, within an estimated 2 hours of injury, from May 1, 2015, through October 31, 2019. INTERVENTIONS: Patients received 1 g of tranexamic acid before hospitalization (447 patients) or placebo (456 patients) infused for 10 minutes in 100 mL of saline. The randomization scheme used prehospital and in-hospital phase assignments, and patients administered tranexamic acid were allocated to abbreviated, standard, and repeat bolus dosing regimens on trauma center arrival. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. RESULTS: In all, 927 patients (mean [SD] age, 42 [18] years; 686 [74.0%] male) were eligible for prehospital enrollment (460 randomized to tranexamic acid intervention; 467 to placebo intervention). After exclusions, the intention-to-treat study cohort comprised 903 patients: 447 in the tranexamic acid arm and 456 in the placebo arm. Mortality at 30 days was 8.1% in patients receiving tranexamic acid compared with 9.9% in patients receiving placebo (difference, -1.8%; 95% CI, -5.6% to 1.9%; P = .17). Results of Cox proportional hazards regression analysis, accounting for site, verified that randomization to tranexamic acid was not associated with a significant reduction in 30-day mortality (hazard ratio, 0.81; 95% CI, 0.59-1.11, P = .18). Prespecified dosing regimens and post-hoc subgroup analyses found that prehospital tranexamic acid were associated with significantly lower 30-day mortality. When comparing tranexamic acid effect stratified by time to treatment and qualifying shock severity in a post hoc comparison, 30-day mortality was lower when tranexamic acid was administered within 1 hour of injury (4.6% vs 7.6%; difference, -3.0%; 95% CI, -5.7% to -0.3%; P < .002). Patients with severe shock (systolic blood pressure ≤70 mm Hg) who received tranexamic acid demonstrated lower 30-day mortality compared with placebo (18.5% vs 35.5%; difference, -17%; 95% CI, -25.8% to -8.1%; P < .003). CONCLUSIONS AND RELEVANCE: In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02086500.

Association Between Intravenous Fluid Bolus and Biomarker Trajectory During Prehospital Care.

Background: Patients with acute illness who receive intravenous (IV) fluids prior to hospital arrival may have a lower in-hospital mortality. To better understand whether this is a direct treatment effect or epiphenomenon of downstream care, we tested the association between a prehospital fluid bolus and the change in inflammatory cytokines measured at prehospital and emergency department timepoints in a sample of non-trauma, non-cardiac arrest patients at risk for critical illness. Methods: In a prospective cohort study, we screened 4,013 non-trauma, non-cardiac arrest encounters transported by City of Pittsburgh Emergency Medical Services (EMS) to 2 hospitals from August 2013 to February 2014. In 345 patients, we measured prehospital biomarkers (IL-6, IL-10, and TNF) at 2 time points: the time of prehospital IV access placement by EMS and at ED arrival. We determined the relative change for marker X as: ([XED - XEMS]/XEMS). We determined the risk-adjusted association between prehospital IV fluid bolus and relative change for each marker using multivariable linear regression. Results: Among 345 patients, 88 (26%) received a prehospital IV fluid bolus and 257 (74%) did not. Compared to patients who did not receive prehospital fluids, median prehospital IL-6 was greater initially in subjects receiving a prehospital IV fluid bolus (22.3 [IQR 6.4-113] vs. 11.5 [IQR 5.5-47.6]). Prehospital IL-10 and TNF were similar in both groups (IL-10: 3.5 [IQR 2.2-25.6] vs. 3.0 [IQR 1.9-9.0]; TNF: 7.5 [IQR 6.4-10.4] vs. 6.9 [IQR 6.0-8.3]). After adjustment for demographics, illness severity, and prehospital transport time, we observed a relative decrease in IL-6 at hospital arrival in those receiving a prehospital fluid bolus (adjusted ß = -10.0, 95% CI: -19.4, -0.6, p = 0.04), but we did not detect a significant change in IL-10 (p = 0.34) or TNF (p = 0.53). Conclusions: Among non-trauma, non-cardiac arrest patients at risk for critical illness, a prehospital IV fluid bolus was associated with a relative decrease in IL-6, but not IL-10 or TNF.

Association of Practitioner Interfacility Triage Performance With Outcomes for Severely Injured Patients With Fee-for-Service Medicare Insurance.

Importance: Despite evidence that treatment of severely injured patients at trauma centers is associated with reduced mortality, nearly half of all such patients are treated at nontrauma centers (undertriaged). Little is known about whether interfacility undertriage occurs because of practitioner decision-making or institutional and regional factors. Objectives: To assess the associations between variation in triage practitioners at nontrauma centers and between practitioner-level variation and patient outcomes after injury. Design, Setting, and Participants: This retrospective cohort study used Medicare claims data from severely injured patients presenting to nontrauma centers and the practitioners who evaluated them in the emergency department from January 1, 2010, to October 15, 2015. Data analysis was performed from January 15, 2018, to March 21, 2019. Main Outcomes and Measures: Proportion of variation in undertriage associated with practitioners, practitioner rates of undertriage, practitioner characteristics associated with undertriage, and 30-day case-fatality rate. Results: A total of 124 008 severely injured patients (mean [SD] age, 81 [8.4] years; 67 253 [54.2%] female) and the 25 376 practitioners (5564 [21.9%] female) who evaluated the patients in the emergency department of nontrauma centers were included in the study. Undertriage occurred among 85 403 patients (68.9%), with 40.6% of total variation associated with practitioners, 37.8% with hospitals, and 6.7% with regions. Compared with physicians with National Provider Identification (NPI) enumeration before 2007, those with an NPI enumerated between 2007 and 2010 had an undertriage risk ratio (RR) of 0.98 (95% CI, 0.97-0.99), and those with an NPI enumerated after 2010 had an undertriage RR of 0.96 (95% CI, 0.94-0.99). Hospitals with neurosurgeons had an undertriage RR of 1.51 (95% CI, 1.45-1.57) compared with those that did not; hospitals with spine surgeons had an undertriage RR of 1.10 (95% CI, 1.06-1.13); hospitals with general surgeons had an undertriage RR of 1.13 (95% CI, 1.09-1.17). Compared with practitioners who undertriaged 25% or less of patients, a statistically significant increase was found in the odds of death for patients treated by practitioners with a triage rate of less than 25% to 50% (odds ratio [OR], 1.08; 95% CI, 1.05-1.20) and less than 50% to 75% undertriage (OR, 1.12; 95% CI, 1.09-1.26) but not undertriage at greater than 75% (OR, 1.03, 95% CI, 1.00-1.18). In sensitivity analyses to adjust for unmeasured confounding, the association between triage practices and the case fatality rate became monotonic; compared with patients treated by practitioners with an undertriage rate of 25% or less, the odds of case fatality were 1.13 (95% CI, 1.05-1.21; P = .001) among patients treated by practitioners with undertriage rates less than 25% to 50%, 1.22 (95% CI, 1.13-1.32; P < .001) for patients treated by practitioners with undertriage rates less than 50% to 75%, and 1.20 (95% CI, 1.10-1.30; P < .001) for patients treated by practitioners with undertriage rates greater than 75%. Conclusions and Relevance: The findings suggest that individual practitioner practices are an important source of variation in triage and represent a potential locus of intervention to reduce preventable deaths after injury.

Intravenous fluid resuscitation is associated with septic endothelial glycocalyx degradation.

BACKGROUND: Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. Preclinical models suggest that fluid resuscitation degrades the endothelial glycocalyx, a heparan sulfate-enriched structure necessary for vascular homeostasis. We hypothesized that endothelial glycocalyx degradation is associated with the volume of intravenous fluids administered during early sepsis resuscitation. METHODS: We used mass spectrometry to measure plasma heparan sulfate (a highly sensitive and specific index of systemic endothelial glycocalyx degradation) after 6 h of intravenous fluids in 56 septic shock patients, at presentation and after 24 h of intravenous fluids in 100 sepsis patients, and in two groups of non-infected patients. We compared plasma heparan sulfate concentrations between sepsis and non-sepsis patients, as well as between sepsis survivors and sepsis non-survivors. We used multivariable linear regression to model the association between volume of intravenous fluids and changes in plasma heparan sulfate. RESULTS: Consistent with previous studies, median plasma heparan sulfate was elevated in septic shock patients (118 [IQR, 113-341] ng/ml 6 h after presentation) compared to non-infected controls (61 [45-79] ng/ml), as well as in a second cohort of sepsis patients (283 [155-584] ng/ml) at emergency department presentation) compared to controls (177 [144-262] ng/ml). In the larger sepsis cohort, heparan sulfate predicted in-hospital mortality. In both cohorts, multivariable linear regression adjusting for age and severity of illness demonstrated a significant association between volume of intravenous fluids administered during resuscitation and plasma heparan sulfate. In the second cohort, independent of disease severity and age, each 1 l of intravenous fluids administered was associated with a 200 ng/ml increase in circulating heparan sulfate (p = 0.006) at 24 h after enrollment. CONCLUSIONS: Glycocalyx degradation occurs in sepsis and septic shock and is associated with in-hospital mortality. The volume of intravenous fluids administered during sepsis resuscitation is independently associated with the degree of glycocalyx degradation. These findings suggest a potential mechanism by which intravenous fluid resuscitation strategies may induce iatrogenic endothelial injury.

Relationship Between Alternative Resuscitation Strategies, Host Response and Injury Biomarkers, and Outcome in Septic Shock: Analysis of the Protocol-Based Care for Early Septic Shock Study.

OBJECTIVES: The Protocol-based Care for Early Septic Shock trial found no differences across alternative resuscitation strategies in all-cause mortality. A separate aim was to determine whether differences in resuscitation strategies affected trajectories of biomarkers of key pathways associated with downstream clinical outcomes of sepsis and whether there were differences in survival across treatment arms for patients with different baseline biomarker profiles. DESIGN: Secondary analysis of a large randomized clinical trial. SETTING: Thirty-one U.S. hospitals. PATIENTS: Six hundred twenty-eight patients with septic shock. INTERVENTIONS: Two resuscitation protocols versus usual care. MEASUREMENTS AND MAIN RESULTS: We measured a panel of biomarkers representing four pathophysiologic domains: "inflammation" (tumor necrosis factor, interleukin-6, and -10); "coagulation" (D-dimers, thrombin-antithrombin complex); "oxidative stress" (urine isoprostane); and "tissue hypoxia" (lactate) at 0, 6, 24, and 72 hours after treatment. We analyzed whether alternative resuscitation strategies affected biomarker trajectories over 72 hours and whether effects on 90-day hospital mortality varied by baseline (time 0) biomarker profiles-both using regression models with interaction terms for treatment arms. For all baseline biomarkers, higher concentrations were associated with increased risk of death by 90 days. However, there was no significant effect of treatment assignment on subsequent biomarker trajectories. We did find evidence for heterogeneity of treatment effect of protocol-based care on mortality for patients with different baseline [interleukin-6] and [interleukin-6] × [interleukin-10] profiles, whereas patients with the lowest quartiles fared better with protocol-based care (odds ratios, 0.32 [0.13-075]; p = 0.01 and 0.32 [0.14-0.73]; p = 0.01, respectively). CONCLUSIONS: In patients with septic shock, alterations in inflammation, coagulation, oxidative stress, and tissue hypoxia are common and associated with adverse outcomes but are not influenced by protocol-based resuscitation compared with usual care. However, contrary to expectation, protocol-based resuscitation appeared to be superior in patients with lower concentrations of inflammatory biomarkers. The mechanisms responsible for this effect are unclear.

Endothelial Permeability and Hemostasis in Septic Shock: Results From the ProCESS Trial.

BACKGROUND: We studied patients from the Protocolized Care in Early Septic Shock (ProCESS) trial to determine the effects of alternative resuscitation strategies on circulating markers of endothelial cell permeability and hemostasis and the association between biomarkers and mortality. METHODS: This was a prospective study of biomarkers of endothelial cell permeability (vascular endothelial growth factor [VEGF], soluble fms-like tyrosine kinase 1 [sFLT-1], angiopoietin 2 [Ang-2]) and biomarkers of hemostasis (von Willebrand factor [vWF], thrombomodulin [TM], tissue plasminogen activator [tPA] in 605 of the 1,341 ProCESS participants in a derivation cohort and 305 participants in a validation cohort. Analyses assessed (1) the impact of varying resuscitation strategies on biomarker profiles and (2) the association of endothelial biomarkers with 60-day in-hospital mortality. The study was conducted in 31 US EDs in adult patients with septic shock. Patients were randomly assigned to one of three resuscitation strategies. Blood samples were collected at enrollment, at 6 h, and at 24 h. RESULTS: There were 116 (19.2%) and 52 (17.0%) deaths in the derivation and validation cohorts, respectively. There was no significant association between treatment strategy and any biomarker levels. Permeability (Ang-2 and sFLT-1) and hemostasis (vWF, TM, tPA) biomarkers were higher and VEGF levels were lower in nonsurvivors (P < .05 for all). At baseline, sFLT-1 had the highest point estimate for mortality discrimination (derivation area under the curve [AUC], 0.74; validation, 0.70), similar to lactate (AUC, 0.74) and Sequential Organ Failure Assessment score (AUC, 0.73). In an analysis including all time points and adjusted for age, presence of cancer, and Charlson comorbidity score, the adjusted AUC for sFLT-1 was 0.80. CONCLUSIONS: We found no relationship between different resuscitation strategies and biomarker profiles in sepsis, but we did find that elevated levels of endothelial cell biomarkers of permeability and hemostasis were associated with increased mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00510835 and NCT00793442; URL: www.clinicaltrials.gov.

A Novel Artificial Intelligence System for Endotracheal Intubation.

OBJECTIVE: Adequate visualization of the glottic opening is a key factor to successful endotracheal intubation (ETI); however, few objective tools exist to help guide providers' ETI attempts toward the glottic opening in real-time. Machine learning/artificial intelligence has helped to automate the detection of other visual structures but its utility with ETI is unknown. We sought to test the accuracy of various computer algorithms in identifying the glottic opening, creating a tool that could aid successful intubation. METHODS: We collected a convenience sample of providers who each performed ETI 10 times on a mannequin using a video laryngoscope (C-MAC, Karl Storz Corp, Tuttlingen, Germany). We recorded each attempt and reviewed one-second time intervals for the presence or absence of the glottic opening. Four different machine learning/artificial intelligence algorithms analyzed each attempt and time point: k-nearest neighbor (KNN), support vector machine (SVM), decision trees, and neural networks (NN). We used half of the videos to train the algorithms and the second half to test the accuracy, sensitivity, and specificity of each algorithm. RESULTS: We enrolled seven providers, three Emergency Medicine attendings, and four paramedic students. From the 70 total recorded laryngoscopic video attempts, we created 2,465 time intervals. The algorithms had the following sensitivity and specificity for detecting the glottic opening: KNN (70%, 90%), SVM (70%, 90%), decision trees (68%, 80%), and NN (72%, 78%). CONCLUSIONS: Initial efforts at computer algorithms using artificial intelligence are able to identify the glottic opening with over 80% accuracy. With further refinements, video laryngoscopy has the potential to provide real-time, direction feedback to the provider to help guide successful ETI.

A Mobile Alert System for Preparing the Delivery of Radiation Mitigators.

BACKGROUND/AIM: A mobile system allowing hospital medical personnel to prepare for the administration of radiation mitigators prior to receiving casualties is desirable. MATERIALS AND METHODS: We evaluated a portable spectroscopic personal radiation detector for use as an ambulance-based unit for early detection and identification of gamma radiation. We tested the sensitivity, time-to-identification, and radionuclide identification accuracy rates, change in detector response to vehicle operation, interference from cardiac equipment, and internal versus external radiation source location. RESULTS: We detected radiation sources in each of 119 trials using a humanoid phantom in a moving ambulance with a primary radionuclide identification accuracy of 96%. Typical identification time was around two minutes (149±95 s). CONCLUSION: Our observations suggest this mobile system is a potential pre-hospital arrival tool allowing for rapid preparation of radiation mitigators.

A comparative assessment of adverse event classification in the out-of-hospital setting.

OBJECTIVES: We sought to test reliability of two approaches to classify adverse events (AEs) associated with helicopter EMS (HEMS) transport. METHODS: The first approach for AE classification involved flight nurses and paramedics (RN/Medics) and mid-career emergency physicians (MC-EMPs) independently reviewing 50 randomly selected HEMS medical records. The second approach involved RN/Medics and MC-EMPs meeting as a group to openly discuss 20 additional medical records and reach consensus-based AE decision. We compared all AE decisions to a reference criterion based on the decision of three senior emergency physicians (Sr-EMPs). We designed a study to detect an improvement in agreement (reliability) from fair (kappa = 0.2) to moderate (kappa = 0.5). We calculated sensitivity, specificity, percent agreement, and positive and negative predictive values (PPV/NPV). RESULTS: For the independent reviews, the Sr-EMP group identified 26 AEs while individual clinician reviewers identified between 19 and 50 AEs. Agreement on the presence/absence of an AE between Sr-EMPs and three MC-EMPs ranged from κ = 0.20 to κ = 0.25. Agreement between Sr-EMPs and three RN/Medics ranged from κ = 0.11 to κ = 0.19. For the consensus/open-discussion approach, the Sr-EMPs identified 13 AEs, the MC-EMP group identified 18 AEs, and RN/medic group identified 36 AEs. Agreement between Sr-EMPs and MC-EMP group was (κ = 0.30 95%CI -0.12, 0.72), whereas agreement between Sr-EMPs and RN/medic group was (κ = 0.40 95%CI 0.01, 0.79). Agreement between all three groups was fair (κ = 0.33, 95%CI 0.06, 0.66). Percent agreement (58-68%) and NPV (63-76%) was moderately dissimilar between clinicians, while sensitivity (25-80%), specificity (43-97%), and PPV (48-83%) varied. CONCLUSIONS: We identified a higher level of agreement/reliability in AE decisions utilizing a consensus-based approach for review rather than independent reviews.

Measuring adverse events in helicopter emergency medical services: establishing content validity.

INTRODUCTION: We sought to create a valid framework for detecting adverse events (AEs) in the high-risk setting of helicopter emergency medical services (HEMS). METHODS: We assembled a panel of 10 expert clinicians (n = 6 emergency medicine physicians and n = 4 prehospital nurses and flight paramedics) affiliated with a large multistate HEMS organization in the Northeast US. We used a modified Delphi technique to develop a framework for detecting AEs associated with the treatment of critically ill or injured patients. We used a widely applied measure, the content validity index (CVI), to quantify the validity of the framework's content. RESULTS: The expert panel of 10 clinicians reached consensus on a common AE definition and four-step protocol/process for AE detection in HEMS. The consensus-based framework is composed of three main components: (1) a trigger tool, (2) a method for rating proximal cause, and (3) a method for rating AE severity. The CVI findings isolate components of the framework considered content valid. CONCLUSIONS: We demonstrate a standardized process for the development of a content-valid framework for AE detection. The framework is a model for the development of a method for AE identification in other settings, including ground-based EMS.

Multidisciplinary acute care research organization (MACRO): if you build it, they will come.

BACKGROUND: Clinical research will increasingly play a core role in the evolution and growth of acute care surgery program development across the country. What constitutes an efficient and effective clinical research infrastructure in the current fiscal and academic environment remains obscure. We sought to characterize the effects of implementation of a multidisciplinary acute care research organization (MACRO) at a busy tertiary referral university setting. METHODS: In 2008, to minimize redundancy and cost as well as to maximize existing resources promoting acute care research, MACRO was created, unifying clinical research infrastructure among the Departments of Critical Care Medicine, Emergency Medicine, and Surgery. During the periods 2008 to 2012, we performed a retrospective analysis and determined volume of clinical studies, patient enrollment for both observational and interventional trials, and staff growth since MACRO's origination and characterized changes over time. RESULTS: From 2008 to 2011, the volume of patients enrolled in clinical studies, which MACRO facilitates has significantly increased more than 300%. The percentage of interventional/observational trials has remained stable during the same period (50-60%). Staff has increased from 6 coordinators to 10, with an additional 15 research associates allowing 24/7 service. With this significant growth, MACRO has become financially self-sufficient, and additional outside departments now seek MACRO's services. CONCLUSION: Appropriate organization of acute care clinical research infrastructure minimizes redundancy and can promote sustainable, efficient growth in the current academic environment. Further studies are required to determine if similar models can be successful at other acute care surgery programs.

Trauma triage in the emergency departments of nontrauma centers: an analysis of individual physician caseload on triage patterns.

BACKGROUND: Treatment at Level I/II trauma centers improves outcomes for patients with severe injuries. Little is known about the role of physicians' clinical judgment in triage at outlying hospitals. We assessed the association between physician caseload, case mix, and the triage of trauma patients presenting to nontrauma centers. METHODS: A retrospective cohort analysis of patients evaluated between January 1, 2007, and December 31, 2010, by emergency physicians working in eight community hospitals in western Pennsylvania. We linked billing records to hospital charts, summarized physicians' caseloads, and calculated rates of undertriage (proportion of patients with moderate-to-severe injuries not transferred to a trauma center), and overtriage (proportion of patients transferred with a minor injury). We measured the correlation between physician characteristics, caseload, and rates of triage. RESULTS: Of 50 eligible physicians, 29 (58%) participated in the study. Physicians had a mean (SD) of 16.8 (10.1) years of postresidency clinical experience; 21 (72%) were board certified in emergency medicine. They evaluated a median of 2,423 patients per year, of whom 148 (6%) were trauma patients and 3 (0.1%) had moderate-to-severe injuries. The median undertriage rate was 80%; the median overtriage rate was 91%. Physicians' caseload of patients with moderate-to-severe injuries was inversely associated with rates of undertriage (correlation coefficient, -0.42; p = 0.03). Compared with physicians in the lowest quartile, those in the highest quartile undertriaged 31% fewer patients. CONCLUSION: Emergency physicians working in nontrauma centers rarely encounter patients with moderate-to-severe injuries. Caseload was strongly associated with compliance with American College of Surgeons' Committee on Trauma guidelines. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Emergency medicine journal impact factor and change compared to other medical and surgical specialties.

OBJECTIVES: A journal impact factor represents the mean number of citations per article published. Designed as one tool to measure the relative importance of a journal, impact factors are often incorporated into academic evaluation of investigators. The authors sought to determine how impact factors of emergency medicine (EM) journals compare to journals from other medical and surgical specialties and if any change has taken place over time. METHODS: The 2010 impact factors and 5-year impact factors for each journal indexed by the Thomson Reuters ISI Web of Knowledge Journal Citation Reports (JCR) were collected, and EM, medical, and surgical specialties were evaluated. The maximum, median, and interquartile range (IQR) of the current impact factor and 5-year impact factor in each journal category were determined, and specialties were ranked according to the summary statistics. The "top three" impact factor journals for each specialty were analyzed, and growth trends from 2001 through 2010 were examined with random effects linear regression. RESULTS: Data from 2,287 journals in 31 specialties were examined. There were 23 EM journals with a current maximum impact factor of 4.177, median of 1.269, and IQR of 0.400 to 2.176. Of 23 EM journals, 57% had a 5-year impact factor available, with a maximum of 4.531, median of 1.325, and IQR of 0.741 to 2.435. The top three EM journals had a mean standard deviation (±SD) impact factor of 3.801 (±0.621) and median of 4.142 and a mean (±SD) 5-year impact factor of 3.788 (±1.091) and median of 4.297, with a growth trend of 0.211 (95% confidence interval [CI] = 0.177 to 0.245; p < 0.001). By any criterion analyzed, EM journals ranked no higher than 24th among 31 specialties. CONCLUSIONS: Emergency medicine journals rank low in impact factor summary statistics and growth trends among 31 medical and surgical specialties.