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BACKGROUND AND OBJECTIVE: Pulmonary problems are vitally important in newborns. Increased intense and mucoid secretions may lead to atelectasis, pulmonary infections, respiratory distress, prolonged mechanical ventilation or even death. The aim of this study was to evaluate the safety of recombinant human deoxyribonuclease (rhDNase) in the management of persistent atelectasis in term and preterm newborns, unresponsive to the conventional treatment. DESIGN AND SETTING: Prospective study of patients admitted to a general community setting of a neonatal intensive care unit between December 2007 and December 2009. PATIENTS AND METHODS: The study included 22 patients (12 premature and 10 term) who were admitted to the neonatal intensive care unit because of respiratory distress and developed atelectasis, and were unresponsive to conventional treatment. Nebulized rhDNase was administered to all patients at a dose of 1 mg/m2 twice daily for 3 days. In patients who did not respond to 3 days of treatment, endotracheal rhDNase was administered at a dose of 1 mg/m2. We assessed the clinical (respiratory rate and oxygen requirement) and radiologic responses (chest radiographic score), recurrence of atelectasis, the need for a repetitive treatment, and mortality rate. RESULTS: A clinical and radiologic improvement of atelectasis was observed in 18 of 22 patients following 3 days of nebulized rhDNase treatment. Atelectasis relapsed in 4 patients. Following the administration of combined endotracheal and nebulized rhDNase treatment, an improvement of atelectasis was noted in all four recurrent cases. No adverse events were observed in patients because of the rhDNase treatment. CONCLUSIONS: rhDNase treatment is a safe option and may be used as an effective method for the management of persistent atelectasis in newborns, which is resistant to other conventional treatment methods.