Auxora vs. placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial.

BACKGROUND: Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia. METHODS: CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO2/FiO2 ratio > 75 and ≤ 300. The PaO2/FiO2 was imputed from a SpO2/FiO2 determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early. RESULTS: The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO2/FiO2≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO2/FiO2 ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia. CONCLUSIONS: Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted. Trial registration NCT04345614.

A standardized protocol using clinical adjudication to define true infection status in patients presenting to the emergency department with suspected infections and/or sepsis.

In absence of a "gold standard", a standardized clinical adjudication process was developed for a registrational trial of a transcriptomic host response (HR) test. Two physicians independently reviewed clinical data to adjudicate presence and source of bacterial and viral infections in emergency department patients. Discordant cases were resolved by a third physician. Agreement among 955 cases was 74.1% (708/955) for bacterial, 75.6% (722/955) for viral infections, and 71.2% (680/955) overall. Most discordances were minor (85.2%; 409/480) versus moderate (11.7%; 56/480) or complete (3.3%; 16/480). Concordance levels were lowest for bacterial skin and soft tissue infections (8.2%) and for viral respiratory tract infections (4.5%). This robust adjudication process can be used to evaluate HR tests and other diagnostics by regulatory agencies and for educating clinicians, laboratorians, and clinical researchers. Clinicaltrials.gov NCT04094818. SUMMARY: Without a gold standard for evaluating host response tests, clinical adjudication is a robust reference standard that is essential to determine the true infection status in diagnostic registrational clinical studies.

Initial clinical experience with the Quantra QStat System in adult trauma patients.

BACKGROUND: Whole blood viscoelastic testing (VET) devices are routinely used in a variety of clinical settings to assess hemostasis. The Quantra QStat System is a cartridge-based point of care VET device that measures changes in clot stiffness during coagulation and fibrinolysis using ultrasound detection of resonance. The objective of this study was to assess the ability of the Quantra QStat System to detect coagulopathies in trauma patients. METHODS: A multicenter observational study was conducted on adult subjects at two level 1 trauma centers. For each subject, whole blood samples were drawn upon arrival to the emergency department and again, in some cases, after administration of blood products and/or antifibrinolytics. Samples were analyzed on the Quantra in parallel to ROTEM delta. The QStat cartridge provides measures of Clot Time (CT), Clot Stiffness (CS), Fibrinogen and Platelet Contributions to clot stiffness (FCS and PCS), and Clot Stability to Lysis (CSL). Data analyses included linear regression of Quantra and ROTEM parameters and an assessment of the concordance of the two devices for the assessment of hyperfibrinolysis. RESULTS: A total of 56 patients were analyzed. 42% of samples had a low QStat CS value suggestive of an hypocoagulable state. The low stiffness values could be attributed to either low PCS, FCS or combination. Additionally, 13% of samples showed evidence of hyperfibrinolysis based on the QStat CSL parameter. Samples analyzed with ROTEM assays showed a lower prevalence of low CS and hyperfibrinolysis based on EXTEM and FIBTEM results. The correlation of CS, FCS and CT versus equivalent ROTEM parameters was strong with r-values of 0.83, 0.79 and 0.79, respectively. DISCUSSION: This first clinical experience with the Quantra in trauma patients showed that the QStat Cartridge was strongly correlated with ROTEM parameters and that it could detect coagulopathies associated with critical bleeding. LEVEL OF EVIDENCE: Diagnostic test, Level II.

Emergency Department Time Course for Mild Traumatic Brain Injury Workup.

INTRODUCTION: Mild traumatic brain injury (mTBI) is a common cause for visits to the emergency department (ED). The actual time required for an ED workup of a patient with mTBI in the United States is not well known. National emergency medicine organizations have recommended reducing unnecessary testing, including head computed tomography (CT) for these patients.10. METHODS: To examine this issue, we developed a care map that included each step of evaluation of mTBI (Glasgow Coma Scale Score 13-15) - from initial presentation to the ED to discharge. Time spent at each step was estimated by a panel of United States emergency physicians and nurses. We subsequently validated time estimates using retrospectively collected, real-time data at two EDs. Length of stay (LOS) time differences between admission and discharged patients were calculated for patients being evaluated for mTBI. RESULTS: Evaluation for mTBI was estimated at 401 minutes (6.6 hours) in EDs. Time related to head CT comprised about one-half of the total LOS. Real-time data from two sites corroborated the estimate of median time difference between ED admission and discharge, at 6.3 hours for mTBI. CONCLUSION: Limiting use of head CT as part of the workup of mTBI to more serious cases may reduce time spent in the ED and potentially improve overall ED throughput.

Identification of acute stroke using quantified brain electrical activity.

OBJECTIVES: Acute stroke is a leading cause of brain injury and death and requires rapid and accurate diagnosis. Noncontrast head computed tomography (CT) is the first line for diagnosis in the emergency department (ED). Complicating rapid triage are presenting conditions that clinically mimic stroke. There is an extensive literature reporting clinical utility of brain electrical activity in early diagnosis and management of acute stroke. However, existing technologies do not lend themselves to easily acquired rapid evaluation. This investigation used an independently derived classifier algorithm for the identification of traumatic structural brain injury based on brain electrical activity recorded from a reduced frontal montage to explore the potential clinical utility of such an approach in acute stroke assessment. METHODS: Adult patients (age 18 to 95 years) presenting with stroke-like and/or altered mental status symptoms were recruited from urban academic EDs as part of a large research study evaluating the clinical utility of quantitative brain electrical activity in acutely brain-injured patients. All patients from the parent study who had confirmed strokes, and a control group of stroke mimics (those with final ED diagnoses of migraine or syncope), were selected for this study. All stroke patients underwent head CT scans. Some patients with negative CTs had further imaging with magnetic resonance imaging (MRI). Ten minutes of electroencephalographic data were acquired on a hand-held device in development, from five frontal electrodes. Data analyses were done offline. A Structural Brain Injury Index (SBII) was derived using an independently developed binary discriminant classification algorithm whose input was specified features of brain electrical activity. The SBII was previously found to have high accuracy in the identification of traumatic brain-injured patients who were found to have brain injury on CT (CT+). This algorithm was applied to patients in this study and used to classify patients as CT+ or not CT+. Performance was assessed using sensitivity, specificity, and negative and positive predictive values (NPV, PPV). RESULTS: Forty-eight stroke patients (31 ischemic and 17 hemorrhagic) and 135 stroke mimic controls were included. Within the ischemic population, approximately half were CT- but later confirmed for stroke with MRI (CT-/MRI+). Sensitivity to stroke was 91.7%, specificity 50.4% (to stroke mimic), NPV 94.4%, and PPV 39.6%. Eighty percent of the CT-/MRI+ ischemic strokes were correctly identified at the time of the CT- scan. CONCLUSIONS: Despite a small population and the use of a classifier without the benefit of training on a stroke population, these data suggest that a rapidly acquired, easy-to-use system to assess brain electrical activity at the time of evaluation of acute stroke could be a valuable adjunct to current clinical practice.

Data Elements for Emergency Department Systems, Release 1.0 (DEEDS): A Summary Report.

See editorial, p 274. Variations in the way that data are entered in emergency department record systems impede the use of ED records for direct patient care and deter their reuse for many other legitimate purposes. To foster more uniform ED data, the Centers for Disease Control and Prevention's National Center for Injury Prevention and Control is coordinating a public-private partnership that has developed recommended specifications for many observations, actions, instructions, conclusions, and identifiers that are entered in ED records. The partnership's initial product, Data Elements for Emergency Department Systems, Release 1.0 (DEEDS), is intended for use by individuals and organizations responsible for ED record systems. If the recommended specifications are widely adopted, then problems-such as data incompatibility and high costs of collecting, linking, and using data-can be substantially reduced. The collaborative effort that led to DEEDS, Release 1.0 sets a precedent for future review and revision of the initial recommendations. [DEEDS Writing Committee: Data Elements for Emergency Department Systems, Release 1.0 (DEEDS): A summary report. Ann Emerg Med February 1998;31:264-273.].

A training program in portable fluoroscopy for the detection of glass in soft tissues.

OBJECTIVES: The role of emergency department (ED) bedside fluoroscopy is incompletely defined. One potential application is the evaluation of glass foreign bodies (GFBs). We studied the effect of a training intervention on the ability of emergency physicians to detect GFBs in an established chicken leg model. We also studied performance one week after training. METHODS: Assessment of this teaching intervention involved nine emergency medicine residents with minimal prior hands-on fluoroscopy experience. Zero, one, or two clear glass shards no larger than 1.0 mm in any dimension were inserted into fresh chicken legs. Each subject scanned 12 to 15 legs without being given any feedback to determine baseline accuracy. Next, 27 to 30 more legs were immediately scanned with feedback given after each response. Subjects scanned 15 more legs one week later without feedback as follow-up. Data were analyzed using mixed-model analysis of variance. RESULTS: At baseline, overall sensitivity and specificity were 0.40 and 0.61, respectively. At follow-up, sensitivity and specificity were 0.93 and 0.91, respectively. Subjects were significantly more accurate during training and follow-up than at baseline. This level of proficiency reached during training was maintained and continued to improve one week later. CONCLUSIONS: Emergency medicine residents previously inexperienced in fluoroscopy may, through a brief training intervention, acquire the skill to accurately detect small pieces of glass in a chicken leg model, and maintain proficiency one week later. Further studies of emergency department fluoroscopy in GFB management in humans are warranted.

Use of plasma in the management of central nervous system bleeding: evidence-based consensus recommendations.

INTRODUCTION: Central nervous system (CNS) hemorrhage is a potentially life-threatening condition, especially in patients with acquired coagulopathy. In this setting, treatment of CNS bleeding includes hemostatic therapy to replenish coagulation factors. There is currently a debate over the hemostatic efficacy of plasma in many clinical settings, alongside increasing concern about transfusion-associated adverse events. Despite these concerns, plasma is widely used. Moreover, plasma transfusion practice is variable and there is currently no uniform approach to treatment of traumatic, surgical or spontaneous CNS hemorrhage. This study addresses the need for guidance on the indications and potential risks of plasma transfusion in these settings. An Expert Consensus Panel was convened to develop recommendations guiding the use of plasma to treat bleeding and/or coagulopathy associated with CNS hemorrhage. The panel did not advise on the best treatment available but rather proposed recommendations to be used in the formulation of local procedures to support emergency physicians in their decision-making process. METHODS: Evidence was systematically gathered from the literature and rated using methods established by the Scottish Intercollegiate Guidelines Network. The evidence was used to develop graded consensus recommendations, which are presented along with the evidence-based rationale for each in this report. RESULTS: Sixty-five articles were identified covering both vitamin K antagonist-anticoagulation reversal and treatment of bleeding/coagulopathy in non-anticoagulated patients. Recommendations were then developed in four clinical scenarios within each area, and agreed on unanimously by all members of the panel. CONCLUSION: The Panel considered plasma to be reasonable therapy for CNS hemorrhage requiring urgent correction of coagulopathy, although physicians should be prepared for potential cardiopulmonary complications, and evidence suggests that alternative therapies have superior risk-benefit profiles. Plasma could not be recommended in the absence of hemorrhage or coagulopathy. Consideration of the absolute risks and benefits of plasma therapy before transfusion is imperative.