Background <p>Although airway pressure release ventilation (APRV) has been extensively studied for hypoxemic respiratory failure, its efficacy in acute hypercapnic respiratory failure is not well established. Conventional APRV settings primarily focus on optimizing oxygenation rather than enhancing carbon dioxide elimination.</p> Objectives <p>To evaluate whether ventilation-driven optimization of APRV, including prolongation of the release phase and promotion of spontaneous breathing, is associated with improvement in carbon dioxide clearance in patients with acute hypercapnic respiratory failure.</p> Methods <p>This prospective physiological study enrolled 40 mechanically ventilated patients with acute hypercapnic respiratory failure who received airway pressure release ventilation (APRV) with an extended T-low interval (0.8 to 1.5 seconds) to facilitate alveolar emptying. Arterial blood gases and ventilator parameters were measured at baseline, 2, 6, 12, and 24 hours, and during weaning..</p> Results <p>PaCO₂ levels decreased significantly within 2 hours (84.3 ± 27.1 to 60.1 ± 19.7 mmHg; p&lt;0.001) and approached near-normal values by 6 hours. Both pH and P/F ratio improved progressively over 24 hours. Successful weaning was achieved in 25 patients (62.5%). A PaCO₂ value of ≤47 mmHg demonstrated excellent predictive performance for successful weaning (AUC 0.951). Early reductions in the mandatory respiratory rate and increases in spontaneous breathing frequency were associated with successful weaning. Parameters indicative of decreased ventilatory demand, rather than static pressure targets, demonstrated the highest discriminative capacity.</p> Conclusion <p>In this exploratory physiological study without a control group, PaCO₂ improved during APRV application, and favorable weaning rates were observed. Early reductions in ventilatory demand may serve as physiological markers of treatment response, though causality cannot be established.</p> Categories <p>Pulmonology, RICU</p>