Introduction To prevent further lung damage in patients with acute respiratory distress syndrome ( ARDS), it is important to avoid overdistension and cyclic opening and closing of atelectatic alveoli. Previous studies have demonstrated protective effects of using low tidal volume ( VT), moderate positive end-expiratory pressure and low airway pressure. Aspiration of dead space ( ASPIDS) allows a reduction in VT by eliminating dead space in the tracheal tube and tubing. We hypothesized that, by applying goal-orientated ventilation based on iterative computer simulation, VT can be reduced at high respiratory rate and much further reduced during ASPIDS without compromising gas exchange or causing high airway pressure. Methods ARDS was induced in eight pigs by surfactant perturbation and ventilator-induced lung injury. Ventilator resetting guided by computer simulation was then performed, aiming at minimal VT, plateau pressure 30 cmH(2)O and isocapnia, first by only increasing respiratory rate and then by using ASPIDS as well. Results VT decreased from 7.2 +/- 0.5 ml/kg to 6.6 +/- 0.5 ml/kg as respiratory rate increased from 40 to 64 +/- 6 breaths/min, and to 4.0 +/- 0.4 ml/kg when ASPIDS was used at 80 +/- 6 breaths/min. Measured values of arterial carbon dioxide tension were close to predicted values. Without ASPIDS, total positive end-expiratory pressure and plateau pressure were slightly higher than predicted, and with ASPIDS they were lower than predicted. Conclusion In principle, computer simulation may be used in goal-oriented ventilation in ARDS. Further studies are needed to investigate potential benefits and limitations over extended study periods.