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Background <p>Acute respiratory distress syndrome (ARDS) requiring veno-venous extracorporeal membrane oxygenation (VV-ECMO) is associated with high mortality. One of the primary challenges in translating preclinical findings into effective clinical treatments lies in developing animal models that accurately replicate clinical scenarios. Thus, we aimed to develop a clinically relevant novel ovine model of severe ARDS with VV-ECMO support, with the primary aim of assessing feasibility through 48-h survival, while monitoring safety and clinical relevance.</p> Methods <p>Six sheep (52.7 ± 1.5&#xa0;kg) were anesthetized and mechanically ventilated. Severe ARDS was induced by oleic acid and lipopolysaccharide (0.5&#xa0;µg/kg). Lung-protective mechanical ventilation commenced once the PaO<sub>2</sub>/FiO<sub>2</sub> ratio deteriorated to less than 150&#xa0;mmHg, with additional doses of oleic acid administered if the PaO<sub>2</sub>/FiO<sub>2</sub> improved. Severe ARDS criteria, triggering ECMO initiation, were defined as PaO<sub>2</sub>/FiO<sub>2</sub> &lt; 100&#xa0;mmHg, PaCO<sub>2</sub> &gt; 60&#xa0;mmHg, or refractory respiratory acidosis (T0) before commencing VV-ECMO (T1), followed by a 48-h observation. The primary outcome was survival at 48&#xa0;h to assess the feasibility of a novel model. All complications were also recorded, and lung tissues were obtained upon autopsy. Assessments followed the American Thoracic Society (ATS) Workshop Report 2022 recommendations, including histological assessments, alveolar–capillary barrier evaluations, and inflammatory and physiological responses. Data were analysed using the Friedman test.</p> Results <p>All sheep survived the 48-h follow-up. No complications were recorded throughout the study. In all sheep, although PaO<sub>2</sub>/FiO<sub>2</sub> reached 126 (interquartile range: IQR 103–149) mmHg, lung-protective mechanical ventilation strategies improved PaO<sub>2</sub>/FiO<sub>2</sub> to 181 (IQR: 167–185) mmHg within 60 min, requiring additional oleic acid doses to reach injury criteria. All sheep developed hallmark features of experimental ARDS including histological evidence (filling of the alveolar space with proteinaceous alveolar fluid and debris and increasing histologic injury score), impaired alveolar–capillary barrier (elevated total protein in bronchoalveolar lavage fluid (BAL) and increased lung wet-to-dry weight ratio), inflammatory response (increase in IL6, IL-8 and neutrophil numbers in BAL), and physiologic dysfunction (e.g., impaired oxygenation, reduction in lung compliance).</p> Conclusions <p>We developed a novel animal model of ARDS that closely replicates ARDS management, including lung-protective mechanical ventilation before the initiation of VV-ECMO, ensuring a prolonged 48-h survival observation without any complications. This model meets all four key features of ARDS as recommended by the latest ATS guidelines and provides an innovative platform to support clinical translation.</p>

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Refining an acute respiratory distress syndrome animal model supported by extracorporeal membrane oxygenator: incorporating clinically relevant mechanical ventilation strategy upon development

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Keibun Liu,
  • Gabriele Fior,
  • Nchafatso Obonyo,
  • Hideaki Nonaka,
  • Angelo Milani,
  • Gabriella Abbate,
  • Sofia Portatadino,
  • Chiara Palmieri,
  • Shinichi Ijuin,
  • Kei Sato,
  • Silver Heinsar,
  • Sun Kyun Ro,
  • Lucia Gandini,
  • Kota Hoshino,
  • Noriko Sato,
  • Samia Farah,
  • Carmen Ainola,
  • Margaret R. Passmore,
  • Rachana Panduru,
  • Mahe Bouquet,
  • Emily S. Wilson,
  • Kieran Hyslop,
  • Molly-rose McInerney,
  • Cheng Zhang,
  • Caitlin McGrath,
  • Joshua Paech,
  • Jacky Y. Suen,
  • John F. Fraser,
  • Gianluigi Li Bassi

摘要

Background

Acute respiratory distress syndrome (ARDS) requiring veno-venous extracorporeal membrane oxygenation (VV-ECMO) is associated with high mortality. One of the primary challenges in translating preclinical findings into effective clinical treatments lies in developing animal models that accurately replicate clinical scenarios. Thus, we aimed to develop a clinically relevant novel ovine model of severe ARDS with VV-ECMO support, with the primary aim of assessing feasibility through 48-h survival, while monitoring safety and clinical relevance.

Methods

Six sheep (52.7 ± 1.5 kg) were anesthetized and mechanically ventilated. Severe ARDS was induced by oleic acid and lipopolysaccharide (0.5 µg/kg). Lung-protective mechanical ventilation commenced once the PaO2/FiO2 ratio deteriorated to less than 150 mmHg, with additional doses of oleic acid administered if the PaO2/FiO2 improved. Severe ARDS criteria, triggering ECMO initiation, were defined as PaO2/FiO2 < 100 mmHg, PaCO2 > 60 mmHg, or refractory respiratory acidosis (T0) before commencing VV-ECMO (T1), followed by a 48-h observation. The primary outcome was survival at 48 h to assess the feasibility of a novel model. All complications were also recorded, and lung tissues were obtained upon autopsy. Assessments followed the American Thoracic Society (ATS) Workshop Report 2022 recommendations, including histological assessments, alveolar–capillary barrier evaluations, and inflammatory and physiological responses. Data were analysed using the Friedman test.

Results

All sheep survived the 48-h follow-up. No complications were recorded throughout the study. In all sheep, although PaO2/FiO2 reached 126 (interquartile range: IQR 103–149) mmHg, lung-protective mechanical ventilation strategies improved PaO2/FiO2 to 181 (IQR: 167–185) mmHg within 60 min, requiring additional oleic acid doses to reach injury criteria. All sheep developed hallmark features of experimental ARDS including histological evidence (filling of the alveolar space with proteinaceous alveolar fluid and debris and increasing histologic injury score), impaired alveolar–capillary barrier (elevated total protein in bronchoalveolar lavage fluid (BAL) and increased lung wet-to-dry weight ratio), inflammatory response (increase in IL6, IL-8 and neutrophil numbers in BAL), and physiologic dysfunction (e.g., impaired oxygenation, reduction in lung compliance).

Conclusions

We developed a novel animal model of ARDS that closely replicates ARDS management, including lung-protective mechanical ventilation before the initiation of VV-ECMO, ensuring a prolonged 48-h survival observation without any complications. This model meets all four key features of ARDS as recommended by the latest ATS guidelines and provides an innovative platform to support clinical translation.