HFOV often is used to treat infants with PPHN and may reduce the number of infants who require extracorporeal membrane oxygenation (ECMO). Widespread use of HFOV, however, may prevent timely transfers of critically ill infants to ECMO centers. The purpose of this study is to determine which infants with PPHN are most likely to respond and how quickly the response to HFOV is observed. Design: Descriptive study of infants who received HFOV without NO in a clinical trial of inhaled nitric oxide (NO) therapy.Subjects: All 40 infants born 9/92-10/95 who were at least 34 weeks' gestation, had a clinical and echocardiographic diagnosis of severe PPHN (PaO2< 100 at FiO2 1.0), and were treated with HFOV. Results: HFOV treatment occurred prior to randomization for infants who later received NO(N=8), after failure of conventional ventilation with NO (N=6), and at any point before or after randomization for infants in the conventional treatment group (N=26). Nonresponse was defined by the clinician's decision to discontinue HFOV in favor of either ECMO therapy or randomization to NO therapy. All HFOV responders and 20(87%) of nonresponders survived. Responders and nonresponders to HFOV were not significantly different in gestational age, birth weight, gender ratio, or Apgar scores. However, compared with responders, nonresponders were more likely to be born at Level I or II (54% vs. 17%) (P=.03) than Level III hospitals. Although infants in both groups showed similar oxygenation (median PaO2 44 vs. 41 mmHg) at initiation of HFOV, responders showed rapid and progressive improvements in cardiorespiratory measures over the first six hours, including: oxygen saturation, oxygenation index, arterial/alveolar oxygen ratio, alveolar-arterial oxygen gradient, alveolar-arterial oxygen difference, PaO2/FiO2 ratio, and maximum blood pressure (each with P<.05). The likelihood of HFOV treatment success in this population varied with associated diagnoses: pneumonia 60%, sepsis 43%, and meconium aspiration syndrome (MAS) 29% (P=.11 for MAS vs. other diagnoses). Conclusion: Among infants with PPHN, it is unclear whether associated respiratory conditions influence the response to HFOV. Once initiated, the failure to achieve prompt and sustained improvement in respiratory parameters with HFOV identifies infants who are most likely to require ECMO therapy. These data will assist treatment and transfer decision making for infants with PPHN. Funded by: Wyeth Pediatric Neonatology Research Fund.