Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population.

Endobronchial Phenylephrine in Airway Bleeding During Bronchoscopy Does not Cause Hypertension: A Retrospective Observational Study.

Background: Bleeding is a known complication during bronchoscopy, with increased incidence in patients undergoing a more invasive procedure. Phenylephrine is a potent vasoconstrictor that can control airway bleeding when applied topically and has been used as an alternative to epinephrine. The clinical effects of endobronchial phenylephrine on systemic vasoconstriction have not been clearly evaluated.

Early Mobility Index and Patient Outcomes: A Retrospective Study in Multiple Intensive Care Units.

Background: Early mobility interventions in intensive care units (ICUs) are safe and improve outcomes in subsets of critically ill adults. However, implementation varies, and the optimal mobility dose remains unclear.

Objective: To test for associations between daily dose of out-of-bed mobility and patient outcomes in different ICUs.

Using the ROX Index to Predict Treatment Outcome for High-Flow Nasal Cannula and/or Noninvasive Ventilation in Patients With COPD Exacerbations.

Background: The ratio of oxygen saturation index (ROX index; or S /F /breathing frequency) has been shown to predict risk of intubation after high-flow nasal cannula (HFNC) support among adults with acute hypoxemic respiratory failure primarily due to pneumonia. However, its predictive value for other subtypes of respiratory failure is unknown. This study investigated whether the ROX index predicts liberation from HFNC or noninvasive ventilation (NIV), intubation with mechanical ventilation, or death in adults admitted for respiratory failure due to an exacerbation of COPD.

Modeling current practices in critical care comparative effectiveness research.

To determine whether contemporaneous practices are adequately represented in recent critical care comparative effectiveness research studies. All critical care comparative effectiveness research trials published in the from April 2019 to March 2020 were identified. To examine studies published in other high impact medical journals during the same period, such trials were subsequently also identified in the and All cited sources were reviewed, and the medical literature was searched to find studies describing contemporary practices.

Cross-cultural adaptation of the FRAIL scale for critically ill patients in Spain.

Aim: To translate and culturally adapt the FRAIL scale into Spanish and perform a preliminary test of diagnostic accuracy in patients admitted to intensive care units.

Design: Cross-sectional diagnostic study.

Methods: Five intensive care units (ICU) in Spain were participated.

Controls, comparator arms, and designs for critical care comparative effectiveness research: It's complicated.

Background: Comparative effectiveness research is meant to determine which commonly employed medical interventions are most beneficial, least harmful, and/or most costly in a real-world setting. While the objectives for comparative effectiveness research are clear, the field has failed to develop either a uniform definition of comparative effectiveness research or an appropriate set of recommendations to provide standards for the design of critical care comparative effectiveness research trials, spurring controversy in recent years. The insertion of non-representative control and/or comparator arm subjects into critical care comparative effectiveness research trials can threaten trial subjects' safety.

Work of Breathing During Proportional Assist Ventilation as a Predictor of Extubation Failure.

Background: Despite decades of research on predictors of extubation success, use of ventilatory support after extubation is common and 10-20% of patients require re-intubation. Proportional assist ventilation (PAV) mode automatically calculates estimated total work of breathing (total WOB). Here, we assessed the performance of total WOB to predict extubation failure in invasively ventilated subjects.

Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections.

Polyunsaturated fatty acids are metabolized into regulatory lipids important for initiating inflammatory responses in the event of disease or injury and for signaling the resolution of inflammation and return to homeostasis. The epoxides of linoleic acid (leukotoxins) regulate skin barrier function, perivascular and alveolar permeability and have been associated with poor outcomes in burn patients and in sepsis. It was later reported that blocking metabolism of leukotoxins into the vicinal diols ameliorated the deleterious effects of leukotoxins, suggesting that the leukotoxin diols are contributing to the toxicity.

Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative.

This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids (EpFA), which are natural mediators that reduce pain, resolve inflammation, and maintain normal blood pressure. EC5026 is a slow-tight binding transition-state mimic that inhibits the soluble epoxide hydrolase (sEH) at picomolar concentrations.

Use of Machine Learning to Screen for Acute Respiratory Distress Syndrome Using Raw Ventilator Waveform Data.

Unlabelled: To develop and characterize a machine learning algorithm to discriminate acute respiratory distress syndrome from other causes of respiratory failure using only ventilator waveform data.

Design: Retrospective, observational cohort study.

Setting: Academic medical center ICU.

Leveraging IoTs and Machine Learning for Patient Diagnosis and Ventilation Management in the Intensive Care Unit.

Future healthcare systems will rely heavily on clinical decision support systems (CDSS) to improve the decision-making processes of clinicians. To explore the design of future CDSS, we developed a research-focused CDSS for the management of patients in the intensive care unit that leverages Internet of Things (IoT) devices capable of collecting streaming physiologic data from ventilators and other medical devices. We then created machine learning (ML) models that could analyze the collected physiologic data to determine if the ventilator was delivering potentially harmful therapy and if a deadly respiratory condition, acute respiratory distress syndrome (ARDS), was present.

Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?

Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production.

Individualized Care Is Superior to Standardized Care for the Majority of Critically Ill Patients.

Tools for standardizing patient care can take many forms, including but not limited to, bundles, quality improvement and performance measures, guidelines, and protocols. Each is intended to improve compliance with interventions believed to be supported by the best available evidence, ensuring consistency of management across all patients with the ultimate goal of improving outcomes. However, in the ICU, patients typically present with complex acute illnesses and accompanying comorbidities, requiring careful tailoring of interventions and treatments for each individual patient.

In canine bacterial pneumonia circulating granulocyte counts determine outcome from donor cells.

Background: In experimental canine septic shock, depressed circulating granulocyte counts were associated with a poor outcome and increasing counts with prophylactic granulocyte colony-stimulating factor (G-CSF) improved outcome. Therapeutic G-CSF, in contrast, did not improve circulating counts or outcome, and therefore investigation was undertaken to determine whether transfusing granulocytes therapeutically would improve outcome.

Study Design And Methods: Twenty-eight purpose-bred beagles underwent an intrabronchial Staphylococcus aureus challenge and 4 hours later were randomly assigned to granulocyte (40-100 × 10 cells) or plasma transfusion.

Haptoglobin therapy has differential effects depending on severity of canine septic shock and cell-free hemoglobin level.

Background: During sepsis, higher plasma cell-free hemoglobin (CFH) levels portend worse outcomes. In sepsis models, plasma proteins that bind CFH improve survival. In our canine antibiotic-treated Staphylococcus aureus pneumonia model, with and without red blood cell (RBC) exchange transfusion, commercial human haptoglobin (Hp) concentrates bound and compartmentalized CFH intravascularly, increased CFH clearance, and lowered iron levels, improving shock, lung injury, and survival.

Inhaled nebulized nitrite and nitrate therapy in a canine model of hypoxia-induced pulmonary hypertension.

Dysfunction in the nitric oxide (NO) signaling pathway can lead to the development of pulmonary hypertension (PH) in mammals. Discovery of an alternative pathway to NO generation involving reduction from nitrate to nitrite and to NO has motivated the evaluation of nitrite as an alternative to inhaled NO for PH. In contrast, inhaled nitrate has not been evaluated to date, and potential benefits include a prolonged half-life and decreased risk of methemoglobinemia.

Impact of different standard red blood cell storage temperatures on human and canine RBC hemolysis and chromium survival.

Background: Storage temperature is a critical factor for maintaining red-blood cell (RBC) viability, especially during prolonged cold storage. The target range of 1 to 6°C was established decades ago and may no longer be optimal for current blood-banking practices.

Study Design And Methods: Human and canine RBCs were collected under standard conditions and stored in precision-controlled refrigerators at 2°C, 4°C, or 6°C.

Haptoglobin improves shock, lung injury, and survival in canine pneumonia.

During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity.

Parenteral irons versus transfused red blood cells for treatment of anemia during canine experimental bacterial pneumonia.

Background: No studies have been performed comparing intravenous (IV) iron with transfused red blood cells (RBCs) for treating anemia during infection. In a previous report, transfused older RBCs increased free iron release and mortality in infected animals when compared to fresher cells. We hypothesized that treating anemia during infection with transfused fresh RBCs, with minimal free iron release, would prove superior to IV iron therapy.

Usual Care and Informed Consent in Clinical Trials of Oxygen Management in Extremely Premature Infants.

Objective: The adequacy of informed consent in the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) has been questioned. SUPPORT investigators and publishing editors, heads of government study funding agencies, and many ethicists have argued that informed consent was adequate because the two oxygen saturation target ranges studied fell within a range commonly recommended in guidelines. We sought to determine whether each oxygen target as studied in SUPPORT and four similar randomized controlled trials (RCTs) was consistent with usual care.

In a canine pneumonia model of exchange transfusion, altering the age but not the volume of older red blood cells markedly alters outcome.

Background: Massive exchange transfusion of 42-day-old red blood cells (RBCs) in a canine model of Staphylococcus aureus pneumonia resulted in in vivo hemolysis with increases in cell-free hemoglobin (CFH), transferrin-bound iron (TBI), non-transferrin-bound iron (NTBI), and mortality. We have previously shown that washing 42-day-old RBCs before transfusion significantly decreased NTBI levels and mortality, but washing 7-day-old RBCs increased mortality and CFH levels. We now report the results of altering volume, washing, and age of RBCs.