Improved gas exchange has been observed during spontaneous breathing with airway pressure release ventilation (APRV) as compared with controlled mechanical ventilation. This study was designed to determine whether use of APRV with spontaneous breathing as a primary ventilatory support modality better prevents deterioration of cardiopulmonary function than does initial controlled mechanical ventilation in patients at risk for acute respiratory distress syndrome (ARDS). Thirty patients with multiple trauma were randomly assigned to either breathe spontaneously with APRV (APRV Group) (n = 15) or to receive pressure-controlled, time-cycled mechanical ventilation (PCV) for 72 h followed by weaning with APRV (PCV Group) (n = 15). Patients maintained spontaneous breathing during APRV with continuous infusion of sufentanil and midazolam (Ramsay sedation score [RSS] of 3). Absence of spontaneous breathing (PCV Group) was induced with sufentanil and midazolam (RSS of 5) and neuromuscular blockade. Primary use of APRV was associated with increases (p < 0.05) in respiratory system compliance (CRS), arterial oxygen tension (PaO2), cardiac index (CI), and oxygen delivery (DO2), and with reductions (p < 0.05) in venous admixture (QVA/QT), and oxygen extraction. In contrast, patients who received 72 h of PCV had lower CRS, PaO2, CI, DO2, and Q VA/Q T values (p < 0.05) and required higher doses of sufentanil (p < 0.05), midazolam (p < 0.05), noradrenalin (p < 0.05), and dobutamine (p < 0.05). CRS, PaO2), CI and DO2 were lowest (p < 0.05) and Q VA/Q T was highest (p < 0.05) during PCV. Primary use of APRV was consistently associated with a shorter duration of ventilatory support (APRV Group: 15 +/- 2 d [mean +/- SEM]; PCV Group: 21 +/- 2 d) (p < 0.05) and length of intensive care unit (ICU) stay (APRV Group: 23 +/- 2 d; PCV Group: 30 +/- 2 d) (p < 0.05). These findings indicate that maintaining spontaneous breathing during APRV requires less sedation and improves cardiopulmonary function, presumably by recruiting nonventilated lung units, requiring a shorter duration of ventilatory support and ICU stay.