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Ventilation with an inappropriate tidal volume (Vt) triggers lung inflammation, an important predisposing factor of bronchopulmonary dysplasia. It still remains uncertain what the appropriate starting target Vt should be during the acute phase of respiratory distress syndrome (RDS). Our aim was to evaluate lung inflammation in preterm infants undergoing synchronized intermittent positive-pressure ventilation (SIPPV) with two different tidal volumes Vt during the acute phase of RDS. Thirty preterm infants (gestational age, 25-32 weeks) with acute RDS were randomly assigned to be ventilated with Vt = 5 ml/kg (n = 15) or Vt = 3 ml/kg (n = 15). Proinflammatory cytokines (interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor (TNF)-alpha) were determined in the tracheal aspirate on days 1, 3, and 7 of life. IL-8 and TNF-alpha levels collected on day 7 were significantly higher (P < 0.05), and mechanical ventilation lasted longer in the group with Vt = 3 ml/kg (16.8 +/- 4 vs. 9.2 +/- 4 days; P = 0.05). In conclusion, our data show significantly higher lung inflammation in preterm infants ventilated with Vt = 3 ml/kg, suggesting a role for Vt = 5 ml/kg in reducing both inflammatory response during the acute phase of RDS and the length of ventilation. Whether the use of this starting Vt prevents bronchopulmonary dysplasia requires further study.