Global Protective Ventilator Settings Are Not Regional Protection: A Compartment-Resolved Framework for Personalizing Mechanical Ventilation in Acute Respiratory Distress Syndrome

Background: Lung-protective ventilation in acute respiratory distress syndrome (ARDS) is guided by whole-lung measures, although the same acceptable breath may stabilize regions undergoing repeated alveolar collapse and expansion (RACE) while overdistending tissue already open. Fatigue-Aware Alveolar Stress and Strain Tracking (FAAST) is a clinician-in-the-loop framework designed to make this regional tradeoff observable. Methods: We first constructed a deterministic, twenty-compartment, phenotype-conditioned model from published observations of acute lung injury. With FAAST excluded, the test lung was evaluated controller-blind against nine prespecified correspondence targets under conventional ventilation and frozen after all nine were met. FAAST was then applied in four experiments examining alternative ventilator strategies, regional observability, a recruitment–overdistension crossover, and the interaction between recruitment and tidal-volume reduction. Results: Before FAAST analysis, the frozen phenotype model met all nine prespecified correspondence targets. FAAST analysis then showed that globally acceptable pressures could coexist with suprathreshold regional loading, while a summed-dose controller obscured opposing regional states. At 96 h, median modeled structural-compliance loss was 61.4% at positive end-expiratory pressure (PEEP) 8 cm H2O, 40.7% with the FAAST crossover at mean PEEP 13.5 cm H2O, and 39.3% at fixed PEEP 15. In a fresh virtual cohort, the crossover remained favorable to PEEP 8 in every matched case. Tidal-volume reduction lowered loss by 1.2 points at practice PEEP and 5.9 points after recruitment, with a 4.4-point interaction. No strategy eliminated regional injury. Conclusions: Within this model, global protection did not ensure regional protection. Compartmental analysis preserved information lost through aggregation and generated hypotheses for matching the complete ventilator pattern to lung state. These model-conditional findings do not establish clinical efficacy or a validated PEEP target; external waveform, imaging, physiologic, and outcome validation is required before clinical use.