Early restrictive fluid strategy impairs the diaphragm force in lambs with acute respiratory distress syndrome

Background: The effect of fluid management strategies in critical illness–associated diaphragm weakness are unknown. This study hypothesized that a liberal fluid strategy induces diaphragm muscle fiber edema, leading to reduction in diaphragmatic force generation in the early phase of experimental pediatric acute respiratory distress syndrome in lambs. Methods: Nineteen mechanically ventilated female lambs (2 to 6 weeks old) with experimental pediatric acute respiratory distress syndrome were randomized to either a strict restrictive fluid strategy with norepinephrine or a liberal fluid strategy. The fluid strategies were maintained throughout a 6-h period of mechanical ventilation. Transdiaphragmatic pressure was measured under different levels of positive end-expiratory pressure (between 5 and 20 cm H ₂O). Furthermore, diaphragmatic microcirculation, histology, inflammation, and oxidative stress were studied. results: Transdiaphragmatic pressures decreased more in the restrictive group (–9.6 cm H ₂O [95% CI, –14.4 to –4.8]) compared to the liberal group (–0.8 cm H ₂O [95% CI, –5.8 to 4.3]) during the application of 5 cm H ₂O positive end-expiratory pressure (P = 0.016) and during the application of 10 cm H ₂O positive end-expiratory pressure (–10.3 cm H ₂O [95% CI, –15.2 to –5.4] vs. –2.8 cm H ₂O [95% CI, –8.0 to 2.3]; P = 0.041). In addition, diaphragmatic microvessel density was decreased in the restrictive group compared to the liberal group (34.0 crossings [25th to 75th percentile, 22.0 to 42.0] vs. 46.0 [25th to 75th percentile, 43.5 to 54.0]; P = 0.015). The application of positive end-expiratory pressure itself decreased the diaphragmatic force generation in a dose-related way; increasing positive end-expiratory pressure from 5 to 20 cm H ₂O reduced transdiaphragmatic pressures with 27.3% (17.3 cm H ₂O [95% CI, 14.0 to 20.5] at positive end-expiratory pressure 5 cm H ₂O vs. 12.6 cm H ₂O [95% CI, 9.2 to 15.9] at positive end-expiratory pressure 20 cm H ₂O; P < 0.0001). The diaphragmatic histology, markers for inflammation, and oxidative stress were similar between the groups. Conclusions: Early fluid restriction decreases the force-generating capacity of the diaphragm and diaphragmatic microcirculation in the acute phase of pediatric acute respiratory distress syndrome. In addition, the application of positive end-expiratory pressure decreases the force-generating capacity of the diaphragm in a dose-related way. These observations provide new insights into the mechanisms of critical illness–associated diaphragm weakness.