OBJECTIVE: To obtain optimal titration of positive end-expiratory pressure (PEEP) during mechanical ventilation with functional residual capacity and ventilation homogeneity measurements. DESIGN: Experimental human and animal study. INTERVENTIONS: Functional residual capacity and five indices of uneven ventilation (alveolar mean dilution number, mean dilution number, lung clearance index, mixing ratio, and pulmonary clearance delay) were investigated in 22 children aged 0 to 14 yrs with lung disease and in seven rabbits by using a sulfur-hexafluoride wash-out technique. The children and rabbits were exposed to three different levels of PEEP (0, 5, and 10 cm H(2)O for the children and 0, 3 and 6 cm H(2)O for the rabbits). RESULTS: Functional residual capacity of the children increased from 256.9 +/- 178.6 mL (0 PEEP) to 280.0 +/- 201.1 mL (5 PEEP) and to 302.2 +/- 160.4 mL (10 PEEP, p <.001). Ventilation inhomogeneity decreased significantly in all children with increasing PEEP (p <.05). The alveolar mean dilution number decreased from 2.00 +/- 0.29 (0 PEEP) to 1.82 +/- 0.37 (5 PEEP) and to 1.66 +/- 0.34 (10 PEEP), and pulmonary clearance delay decreased from 74.9 +/- 24.2% to 66.6 +/- 38.1% and to 63.9 +/- 24.2%, respectively. The reduction in ventilation inhomogeneity was associated with an improvement in Pao(2) from 101 +/- 42 mm Hg (0 PEEP) to 122 +/- 48 mm Hg (5 PEEP) and to 126 +/- 53 mm Hg (10 PEEP). Functional residual capacity of the rabbits increased from 54.1 +/- 18.7 mL at 0 PEEP to 72.3 +/- 23.4 mL at 3 PEEP and to 93.9 +/- 27.3 mL at 10 PEEP. Alveolar mean dilution number decreased from 2.93 +/- 0.1 (0 PEEP) to 2.20 +/- 0.29 (3 PEEP) and to 1.45 +/- 0.13 (6 PEEP). CONCLUSIONS: In children with lung disease receiving ventilatory support, optimal PEEP titration can be obtained by the measurement of the functional residual capacity and ventilation distribution by using a sulfur-hexafluoride wash-in-wash-out technique.