BACKGROUND: Chest wall loading has been shown to paradoxically improve respiratory system compliance (C(RS)) in patients with moderate to severe acute respiratory distress syndrome (ARDS). The most likely, albeit unconfirmed, mechanism is relief of end-tidal overdistension in 'baby lungs' of low-capacity. The purpose of this study was to define how small changes of tidal volume (V(T)) and positive end-expiratory pressure (PEEP) affect C(RS) (and its associated airway pressures) in patients with ARDS who demonstrate a paradoxical response to chest wall loading. We hypothesized that small reductions of V(T) or PEEP would alleviate overdistension and favorably affect C(RS) and conversely, that small increases of V(T) or PEEP would worsen C(RS). METHODS: Prospective, multi-center physiologic study of seventeen patients with moderate to severe ARDS who demonstrated paradoxical responses to chest wall loading. All patients received mechanical ventilation in volume control mode and were passively ventilated. Airway pressures were measured before and after decreasing/increasing V(T) by 1 ml/kg predicted body weight and decreasing/increasing PEEP by 2.5 cmH(2)O. RESULTS: Decreasing either V(T) or PEEP improved C(RS) in all patients. Driving pressure (DP) decreased by a mean of 4.9 cmH(2)O (supine) and by 4.3 cmH(2)O (prone) after decreasing V(T), and by a mean of 2.9 cmH(2)O (supine) and 2.2 cmH(2)O (prone) after decreasing PEEP. C(RS) increased by a mean of 3.1 ml/cmH(2)O (supine) and by 2.5 ml/cmH(2)O (prone) after decreasing V(T.) C(RS) increased by a mean of 5.2 ml/cmH(2)O (supine) and 3.6 ml/cmH(2)O (prone) after decreasing PEEP (P < 0.01 for all). Small increments of either V(T) or PEEP worsened C(RS) in the majority of patients. CONCLUSION: Patients with a paradoxical response to chest wall loading demonstrate uniform improvement in both DP and C(RS) following a reduction in either V(T) or PEEP, findings in keeping with prior evidence suggesting its presence is a sign of end-tidal overdistension. The presence of 'paradox' should prompt re-evaluation of modifiable determinants of end-tidal overdistension, including V(T), PEEP, and body position.