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Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial.

ABSTRACT: BACKGROUND:High-permeability pulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS) and is frequently accompanied by impaired alveolar fluid clearance (AFC). AP301 enhances AFC by activating epithelial sodium channels (ENaCs) on alveolar epithelial cells, and we investigated its effect on extravascular lung water index (EVLWI) in mechanically ventilated patients with ARDS. METHODS:Forty adult mechanically ventilated patients with ARDS were included in a randomized, double-blind, placebo-controlled trial for proof of concept. Patients were treated with inhaled AP301 (n?=?20) or placebo (0.9% NaCl; n?=?20) twice daily for 7 days. EVLWI was measured by thermodilution (PiCCO®), and treatment groups were compared using the nonparametric Mann-Whitney U test. RESULTS:AP301 inhalation was well tolerated. No differences in mean baseline-adjusted change in EVLWI from screening to day 7 were found between the AP301 and placebo group (p?=?0.196). There was no difference in the PaO2/FiO2 ratio, ventilation pressures, Murray lung injury score, or 28-day mortality between the treatment groups. An exploratory subgroup analysis according to severity of illness showed reductions in EVLWI (p?=?0.04) and ventilation pressures (p?

SUBMITTER: Krenn K

PROVIDER: S-EPMC5531100 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial.

Krenn Katharina K Lucas Rudolf R Croizé Adrien A Boehme Stefan S Klein Klaus Ulrich KU Hermann Robert R Markstaller Klaus K Ullrich Roman R

Critical care (London, England) 20170727 1

<h4>Background</h4>High-permeability pulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS) and is frequently accompanied by impaired alveolar fluid clearance (AFC). AP301 enhances AFC by activating epithelial sodium channels (ENaCs) on alveolar epithelial cells, and we investigated its effect on extravascular lung water index (EVLWI) in mechanically ventilated patients with ARDS.<h4>Methods</h4>Forty adult mechanically ventilated patients with ARDS were included in a random ...[more]

PMID: 28750677

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Project description:Experimental acute lung injury models are often used to increase our knowledge on the acute respiratory distress syndrome (ARDS), however, existing animal models often do not take into account the impact of specific fluid strategies on the development of lung injury. In contrast, the current literature strongly suggests that fluid management strategies have a significant impact on clinical outcome of patients with ARDS. Thus, it is important to characterize the role of fluid management strategies in experimental models of lung injury. In this study we investigated the effect of two different fluid strategies on commonly used outcome variables in a short-term model of acute lung injury, in relation to age. Infant (2-3 weeks) and adult (3-4 months) Wistar rats received intratracheal instillations of lipopolysaccharide and 24 hours later were mechanically ventilated for 6 hours. During mechanical ventilation, rats from both age groups were randomized to either a standard or conservative intravenous fluid strategy. We found that the hemodynamic response in infant and adult rats was similar in both fluid strategies. Lung wet-to-dry ratios were lower in adult, but not in infant rats receiving the conservative fluid strategy as compared to the standard fluid strategy. There were age-related differences in markers of alveolar capillary barrier disruption and alveolar fluid clearance, yet these were unaffected by fluid strategy. Finally, we found significantly higher IL-1? and TNF-? concentrations in the adult rats treated with the conservative as compared to the standard fluid regimen. In conclusion, the choice of fluid strategy in mechanically ventilated rats with experimental LPS-induced acute lung injury has a significant effect on pulmonary extravascular water, an important and well-recognized lung injury marker, and on the local pro-inflammatory cytokine profiles. We advocate the use of a more uniform, conservative, fluid strategy regimen in experimental models of acute lung injury.

Project description:BACKGROUND:Clinical and epidemiological differences between acute respiratory distress syndrome (ARDS) that presents at the initiation of mechanical ventilation [MV] (ARDS at MV onset) and that which develops during the course of MV (ARDS after MV onset) are not well understood. We conducted an observational study in five Peruvian ICUs to characterize differences between ARDS at MV onset and after MV onset and identify risk factors for the development of ARDS after MV onset. METHODS:We consecutively enrolled critically ill patients with acute respiratory failure requiring at least 24?h of mechanical ventilation and followed them prospectively during the first 28?days and compared baseline characteristics and clinical outcomes by ARDS status. RESULTS:We enrolled 1657 participants on MV (mean age 60.0?years, 55% males) of whom 334 (20.2%) had ARDS at MV onset and 180 (10.9%) developed ARDS after MV onset. Average tidal volume at the initiation of MV was 8.7?mL/kg of predicted body weight (PBW) for participants with ARDS at MV onset, 8.6?mL/kg PBW for those who developed ARDS after MV onset, and 8.5?mL/kg PBW for those who never developed ARDS (p =?0.23). Overall, 90-day mortality was 56% and 55% for ARDS after MV onset and ARDS at MV onset, respectively, as compared to 46% among those who never developed ARDS (p <?0.01). Adults with ARDS had a higher body mass index (BMI) than those without ARDS (27.3 vs 26.5?kg/m2, p <?0.01). Higher peak pressure (adjusted interquartile OR?=?1.51, 95% CI 1.21-1.88), higher mean airway pressure (adjusted interquartile OR?=?1.41, 95% CI 1.13-1.76), and higher positive end-expiratory pressure (adjusted interquartile OR?=?1.29, 95% CI 1.10-1.50) at MV onset were associated with a higher odds of developing ARDS after MV onset. CONCLUSIONS:In this study of mechanically ventilated patients, 31% of study participants had ARDS at some point during their ICU stay. Optimal lung-protective ventilation was not used in a majority of patients. Patients with ARDS after MV onset had a similar 90-day mortality as those with ARDS at MV onset. Higher airway pressures at MV onset, higher PEEP, and higher BMI were associated with the development of ARDS after MV onset.

Dataset Information

Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial.

Publications

Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial.

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