Inhalational nitric oxide (INO)therapy, which results in selective pulmonary vasodilation and possibly bronchodilation, is efficacious in the management of newborns with severe respiratory failure and PPHN. Inactivation of NO occurs when NO binds to hemoglobin, resulting in methemoglobin (MetHb) formation. We investigated whether acute changes in blood MetHb levels, or changes in paCO2, might be used to predict response to INO therapy. The purpose of our investigation was threefold: 1) To determine whether baseline MetHb levels or baseline pCO2 levels could predict NO efficacy, 2) To determine whether baseline MetHb levels vary with underlying disease, and 3) To determine the relationship between the effects of INO on pulmonary gas exchange and changes in blood MetHb for the purpose of predicting NO efficacy. Forty-three of 205 patients who took part in a prospective, randomized multicenter trial comparing NO and HFOV were evaluated (Kinsella et al., Pediatr Res 1996, 39:222A). Patients were randomized initially to NO or HFOV, with the potential for crossover in the case of failure, and stratified by disease. The 43 patients were selected based on availability of paired blood MetHb levels and corresponding blood gas tension measurements, which were obtained at baseline and 4 hours. We found that the change in MetHb levels after 4 hours of INO showed no correlation with the change in AaDO2 at 4 hours(r=.02). The change in pCO2 at 4 hours also did not correlate with the change in AaDO2(r=.12). The comparison of both baseline MetHb levels and baseline pCO2 to the change in gas exchange also revealed no significant correlation(r=.25 and r=.12 respectively). Seven patients with culture-proven sepsis were evaluated separately. We found no significant difference between the sepsis group (S) and other disease categories (O) for average baseline MetHb (S=.91+/- 0.4% vs. 1.1 +/- 0.5%). Although both baseline MetHb and the change in MetHb at 4 hours appeared to be better predictors of response to INO therapy in the sepsis group (r=0.53 and r=0.78 for AaDO2), the n was small (n=7). Based on these data, we conclude that methemoglobin levels and pCO2 are not adequate predictors of response to inhaled NO therapy.