Transpulmonary Pressure-Guided Lung-Protective Ventilation Improves Pulmonary Mechanics and Oxygenation Among Obese Subjects on Mechanical Ventilation.

BACKGROUND: Transpulmonary pressure (PL) is used to assess pulmonary mechanics and guide lung-protective mechanical ventilation (LPV). PL is recommended to individualize LPV settings for patients with high pleural pressures and hypoxemia. We aimed to determine whether PL-guided LPV settings, pulmonary mechanics, and oxygenation improve and differ from non-PL-guided LPV among obese patients after 24 h on mechanical ventilation. Secondary outcomes included classification of hypoxemia severity, count of ventilator-free days, ICU length of stay, and overall ICU mortality. METHODS: This is a retrospective analysis of data. Ventilator settings, pulmonary mechanics, and oxygenation were recorded on the initial day of PL measurement and 24 h later. PL-guided LPV targeted inspiratory PL < 20 cm H2O and expiratory PL of 0-6 cm H2O. Comparisons were made to repeat measurements. RESULTS: Twenty subjects (13 male) with median age of 49 y, body mass index 47.5 kg/m2, and SOFA score of 8 were included in our analysis. Fourteen subjects received care in a medical ICU. PL measurement occurred 16 h after initiating non-PL-guided LPV. PL-guided LPV resulted in higher median PEEP (14 vs 18 cm H2O, P = .009), expiratory PL (-3 vs 1 cm H2O, P = .02), respiratory system compliance (30.7 vs 44.6 mL/cm H2O, P = .001), and [Formula: see text] (156 vs 240 mm Hg, P = .002) at 24 h. PL-guided LPV resulted in lower [Formula: see text] (0.53 vs 0.33, P < .001) and lower PL driving pressure (10 vs 6 cm H2O, P = .001). Tidal volume (420 vs 435 mL, P = .64) and inspiratory PL (7 vs 7 cm H2O, P = .90) were similar. Subjects had a median of 7 ventilator-free days, and median ICU length of stay was 14 d. Three of 20 subjects died within 28 d after ICU admission. CONCLUSIONS: PL-guided LPV resulted in higher PEEP, lower [Formula: see text], improved pulmonary mechanics, and greater oxygenation when compared to non-PL-guided LPV settings in adult obese subjects.

Novel inhibitors of the Gardos channel for the treatment of sickle cell disease.

Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium salts. One critical pathway for the regulation of potassium efflux from RBCs is the Gardos channel, a calcium-activated potassium channel. This paper describes the synthesis and biological evaluation of a series of potent inhibitors of the Gardos channel. The goal was to identify compounds that were potent and selective inhibitors of the channel but had improved pharmacokinetic properties compared to 1, Clotrimazole. Several triarylamides such as 10 and 21 were potent inhibitors of the Gardos channel (IC50 of <10 nM) and active in a mouse model of SCD. Compound 21 (ICA-17043) was advanced into phase 3 clinical trials for SCD.