The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: a subgroup analysis from the prehospital TXA for TBI trial.

BACKGROUND: In the Prehospital Tranexamic Acid (TXA) for TBI Trial, TXA administered within two hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT). METHODS: This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale<13) and systolic blood pressure > =90 mmHg within two hours of injury to a 2-gram out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-gram out-of-hospital TXA bolus/1-gram in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) < = 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors. RESULTS: The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-gram TXA bolus group (17%) compared to the other two groups (1-gram bolus/1-gram infusion 26%, placebo 27%). The estimated adjusted difference between the 2-gram bolus and placebo groups was -8·5 percentage points (95% CI, -15.9 to -1.0) and between the 2-gram bolus and 1-gram bolus/1-gram infusion groups was -10.2 percentage points (95% CI, -17.6 to -2.9). DRS at 6 months was lower in the 2-gram TXA bolus group than the 1-gram bolus/1-gram infusion (estimated difference -2.1 [95% CI, -4.2 to -0.02]) and placebo groups (-2.2 [95% CI, -4.3, -0.2]). Six-month GOSE did not differ among groups. CONCLUSIONS: A 2-gram out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28-day mortality and lower 6-month DRS than placebo and standard TXA dosing. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level II.

Diagnostic Accuracy of a Bacterial and Viral Biomarker Point-of-Care Test in the Outpatient Setting.

Importance: Acute respiratory infections (ARIs) account for most outpatient visits. Discriminating bacterial vs viral etiology is a diagnostic challenge with therapeutic implications. Objective: To investigate whether FebriDx, a rapid, point-of-care immunoassay, can differentiate bacterial- from viral-associated host immune response in ARI through measurement of myxovirus resistance protein A (MxA) and C-reactive protein (CRP) from finger-stick blood. Design, Setting, and Participants: This diagnostic study enrolled adults and children who were symptomatic for ARI and individuals in a control group who were asymptomatic between October 2019 and April 2021. Included participants were a convenience sample of patients in outpatient settings (ie, emergency department, urgent care, and primary care) who were symptomatic, aged 1 year or older, and had suspected ARI and fever within 72 hours. Individuals with immunocompromised state and recent vaccine, antibiotics, stroke, surgery, major burn, or myocardial infarction were excluded. Of 1685 individuals assessed for eligibility, 259 individuals declined participation, 718 individuals were excluded, and 708 individuals were enrolled (520 patients with ARI, 170 patients without ARI, and 18 individuals who dropped out). Exposures: Bacterial and viral immunoassay testing was performed using finger-stick blood. Results were read at 10 minutes, and treating clinicians and adjudicators were blinded to results. Main Outcomes and Measures: Bacterial- or viral-associated systemic host response to an ARI as determined by a predefined comparator algorithm with adjudication classified infection etiology. Results: Among 520 participants with ARI (230 male patients [44.2%] and 290 female patients [55.8%]; mean [SD] age, 35.3 [17.7] years), 24 participants with missing laboratory information were classified as unknown (4.6%). Among 496 participants with a final diagnosis, 73 individuals (14.7%) were classified as having a bacterial-associated response, 296 individuals (59.7%) as having a viral-associated response, and 127 individuals (25.6%) as negative by the reference standard. The bacterial and viral test correctly classified 68 of 73 bacterial infections, demonstrating a sensitivity of 93.2% (95% CI, 84.9%-97.0%), specificity of 374 of 423 participants (88.4% [95% CI, 85.0%-91.1%]), positive predictive value (PPV) of 68 of 117 participants (58.1% [95% CI, 49.1%-66.7%), and negative predictive value (NPV) of 374 of 379 participants (98.7% [95% CI, 96.9%-99.4%]).The test correctly classified 208 of 296 viral infections, for a sensitivity of 70.3% (95% CI, 64.8%-75.2%), a specificity of 176 of 200 participants (88.0% [95% CI, 82.8%-91.8%]), a PPV of 208 of 232 participants (89.7% [95% CI, 85.1%-92.9%]), and an NPV of 176 of 264 participants (66.7% [95% CI, 60.8%-72.1%]). Conclusions and Relevance: In this study, a rapid diagnostic test demonstrated diagnostic performance that may inform clinicians when assessing for bacterial or viral etiology of ARI symptoms.

Tranexamic acid administration in the field does not affect admission thromboelastography after traumatic brain injury.

BACKGROUND: No Food and Drug Administration-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI. METHODS: Data were extracted from a placebo-controlled clinical trial in which patients 15 years or older with TBI (Glasgow Coma Scale, 3-12) and systolic blood pressure of ≥90 mm Hg were randomized prehospital to receive placebo bolus/placebo infusion (placebo), 1 g of TXA bolus/1 g of TXA infusion (bolus maintenance), or 2 g of TXA bolus/placebo infusion (bolus only). Thromboelastography was performed, and coagulation measures including prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, D-dimer, plasmin-antiplasmin (PAP), thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were quantified at admission and 6 hours later. RESULTS: Of 966 patients receiving study drug, 700 had laboratory tests drawn at admission and 6 hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p > 0.05). No differences between prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at 6 hours (p < 0.001). Concentrations of PAP in TXA treatment groups were less than placebo on admission (p < 0.001) and 6 hours (p = 0.02). No differences in D-dimer and PAP were observed between bolus maintenance and bolus only. CONCLUSION: While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared with placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and 6 hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE: Diagnostic test, level III.

Surviving refractory out-of-hospital ventricular fibrillation cardiac arrest: Critical care and extracorporeal membrane oxygenation management.

BACKGROUND: Resuscitation of refractory out-of-hospital ventricular fibrillation/ventricular tachycardia (VF/VT) cardiac arrest using extracorporeal membrane oxygenation (ECMO) establishes a complex patient population. We aimed to describe the critical care strategies and outcomes in this population. METHODS: Between December 1, 2015 and January 1, 2018, 100 consecutive adult patients with refractory VF/VT out-of-hospital cardiac arrest and ongoing CPR were transported to the cardiac catheterization laboratory. ECMO, coronary angiography, and percutaneous coronary intervention were performed. Patients achieving an organized cardiac rhythm were admitted to the cardiac intensive care unit (CICU). All patients were considered eligible for necessary intervention/surgery until declaration of death. RESULTS: Of 100 appropriately transported patients, 83 achieved CICU admission. 40/83 (48%) discharged functionally intact. Multi-system organ failure occurred in all patients. Cardiac, pulmonary, renal, and liver injury improved within 3-4 days. Neurologic injury caused death in 26/37 (70%) patients. Poor neurologic outcomes were associated with anoxic injury or cerebral edema on admission head CT, decline in cerebral oximetry over the first 48 h, and elevated neuron specific enolase on CICU admission. For survivors, mean time to ECMO decannulation was 3.5 ± 0.2 days, following commands at 5.7 ± 0.8 days, and hospital discharge at 21 ± 3.2 days. 41/83 (49%) patients developed infections. CPR caused traumatic injury requiring procedural/surgical intervention in 22/83 (27%) patients. CONCLUSIONS: Multi-system organ failure is ubiquitous but treatable with adequate hemodynamic support. Neurologic recovery was prolonged requiring delayed prognostication. Immediate 24/7 availability of surgical and medical specialty expertise was required to achieve 48% functionally intact survival.

Thrombopoietin receptor agonists protect human cardiac myocytes from injury by activation of cell survival pathways.

Thrombopoietin confers immediate protection against injury caused by ischemia/reperfusion in the rat heart. Eltrombopag is a small molecule agonist of the thrombopoietin receptor, the physiologic target of thrombopoietin. However, the ability of eltrombopag and thrombopoietin to protect human cardiac myocytes against injury and the mechanisms underlying myocyte protection are not known. Human cardiac myocytes (n = 6-10/group) were treated with eltrombopag (0.1-30.0 µM) or thrombopoietin (0.1-30.0 ng/ml) and then subjected to 5 hours of hypoxia (95% N2/5% CO2) and 16 hours of reoxygenation to determine their ability to confer resistance to myocardial injury. The thrombopoietin receptor c-Mpl was detected in unstimulated human cardiac myocytes by Western blotting. Eltrombopag and thrombopoietin confer immediate protection to human cardiac myocytes against injury from hypoxia/reoxygenation by decreasing necrotic and apoptotic cell death in a concentration-dependent manner, with an optimal concentration of 3 µM for eltrombopag and 1.0 ng/ml for thrombopoietin. The extent of protection conferred with eltrombopag is equivalent to that of thrombopoietin. Eltrombopag and thrombopoietin activate multiple prosurvival pathways; inhibition of Janus kinase-2, proto-oncogene tyrosine-protein kinase, protein kinase B/phosphatidylinositol-3 kinase, p44/42 mitogen-activated protein kinase (MAPK), and p38 MAPK abolished cardiac myocyte protection by eltrombopag and thrombopoietin. Eltrombopag and thrombopoietin may represent important and potent agents for immediately and substantially increasing protection of human cardiac myocytes, and may offer a long-lasting benefit through activation of prosurvival pathways during ischemia.

Controlled pauses at the initiation of sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitate neurological and cardiac recovery after 15 mins of untreated ventricular fibrillation.

OBJECTIVE: A multipronged approach to improve vital organ perfusion during cardiopulmonary resuscitation that includes sodium nitroprusside, active compression-decompression cardiopulmonary resuscitation, an impedance threshold device, and abdominal pressure (sodium nitroprusside-enhanced cardiopulmonary resuscitation) has been recently shown to increase coronary and cerebral perfusion pressures and higher rates of return of spontaneous circulation vs. standard cardiopulmonary resuscitation. To further reduce reperfusion injury during sodium nitroprusside-enhanced cardiopulmonary resuscitation, we investigated the addition of adenosine and four 20-sec controlled pauses spread throughout the first 3 mins of sodium nitroprusside-enhanced cardiopulmonary resuscitation. The primary study end point was 24-hr survival with favorable neurologic function after 15 mins of untreated ventricular fibrillation. DESIGN: Randomized, prospective, blinded animal investigation. SETTING: Preclinical animal laboratory. SUBJECTS: Thirty-two female pigs (four groups of eight) 32±2 kg. INTERVENTIONS: After 15 mins of untreated ventricular fibrillation, isoflurane-anesthetized pigs received 5 mins of either standard cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, or controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine. After 4 mins of cardiopulmonary resuscitation, all animals received epinephrine (0.5 mg) and a defibrillation shock 1 min later. Sodium nitroprusside-enhanced cardiopulmonary resuscitation-treated animals received sodium nitroprusside (2 mg) after 1 min of cardiopulmonary resuscitation and 1 mg after 3 mins of cardiopulmonary resuscitation. After 1 min of sodium nitroprusside-enhanced cardiopulmonary resuscitation, adenosine (24 mg) was administered in two groups. MEASUREMENTS AND MAIN RESULTS: A veterinarian blinded to the treatment assigned a cerebral performance category score of 1-5 (normal, slightly disabled, severely disabled but conscious, vegetative state, or dead, respectively) 24 hrs after return of spontaneous circulation. Sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, and controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine resulted in a significantly higher 24-hr survival rate compared to standard cardiopulmonary resuscitation (7 of 8, 8 of 8, and 8 of 8 vs. 2 of 8, respectively p<.05). The mean cerebral performance category scores for standard cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, or controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine were 4.6±0.7, 3±1.3, 2.5±0.9, and 1.5±0.9, respectively (p<.01 for controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine compared to all other groups). CONCLUSIONS: Reducing reperfusion injury and maximizing circulation during cardiopulmonary resuscitation significantly improved functional neurologic recovery after 15 mins of untreated ventricular fibrillation. These results suggest that brain resuscitation after prolonged cardiac arrest is possible with novel, noninvasive approaches focused on reversing the mechanisms of tissue injury.