RANDOMIZED, MULTICENTER TRIAL OF INHALED NITRIC-OXIDE AND HIGH-FREQUENCY OSCILLATORY VENTILATION IN SEVERE, PERSISTENT PULMONARY-HYPERTENSION OF THE NEWBORN

Background: Although inhaled nitric oxide (iNO) causes selective pulmo nary vasodilation and improves oxygenation in newborn infants with per sistent pulmonary hypertension, its effects are variable. We hypothesi zed (1) that the response to iNO therapy is dependent on the primary d isease associated with persistent pulmonary hypertension of the newbor n (PPHN) and (2) that the combination of high-frequency oscillatory ve ntilation (HFOV) with iNO would be efficacious in patients for whom ei ther therapy alone had failed. Methods: To determine the relative role s of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neo nates in a randomized, multicenter clinical trial. Patients were strat ified by predominant disease category: respiratory distress syndrome ( n = 70), meconium aspiration syndrome (n = 58), idiopathic PPHN or pul monary hypoplasia (excluding congenital diaphragmatic hernia) (''other '': n = 43), and congenital diaphragmatic hernia (n = 34); they were t hen randomly assigned to treatment with iNO and conventional ventilati on or to HFOV without iNO. Treatment failure (partial pressure of arte rial oxygen [PaO2] <60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treat ment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained PaO2 of 60 mm Hg or greater. Results: Baselin e oxygenation index and PaO2 were 48 +/- 2 and 41 +/- 1 mm Hg, respect ively, during treatment with conventional ventilation. Ninety-eight pa tients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initial ly assigned therapy without crossover (30 with iNO [28%] and 23 with H FOV [23%]; p = 0.33). Within this group, survival was 100% and there w ere no differences in days of mechanical ventilation, air leak, or sup plemental oxygen requirement at 28 days. Of patients whose initial tre atment failed, crossover treatment with the alternate therapy was succ essful in 21% and 14% for iNO and HFOV, respectively (p = not signific ant). Of 125 patients in whom both treatment strategies failed, 32% re sponded to combination treatment with HFOV plus iNO. Overall, 123 pati ents (60%) responded to either treatment alone or combination therapy. BS disease category, response rates for HFOV plus iNO in the group wi th respiratory syndrome and the group with meconium aspiration syndrom e were better than for HFOV alone or iNO with conventional ventilation (p <0.05). Marked differences in outcomes were noted among centers (p ercent death or treatment with extracorporeal membrane oxygenation = 2 9% to 75%). Conclusions: We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in sev ere PPHN. Differences in responses are partly related to the specific disease associated with PPHN.