Inhaled nitric oxide does not improve outcome in pediatric patients with acute hypoxemic resperatory failure following bone marrow transplantation

Introduction; Pediatric patients who undergo bone marrow transplantation (BMT) and develop acute hypoxemic respiratory failure (AHRF) have a mortality rate as high as 0.88.¹ Since 1995, BMT patients with AHRF have received inhaled nitric oxide (iNO) in an attempt to improve survival. Methods; A prospective, non-randomized, unblinded trial in which mechanically ventilated patients with AHRF were enrolled if the oxygenation index (OI) became ≥ 15 (OI = 100 × FiO₂ × mean airway pressure/PaO₂). A dose-response trial with sequential dosages of 5, 20, 40, 60, & 80 ppm iNO was followed by iNO administered at the maximal therapeutic dose. A clinical response (CR) was defined as a 20% decrease in OI from the pre-iNO baseline. Mortality was the primary outcome measure with CR as a secondary variable. Using 0.88 as the historical mortality¹ and 0.50 as a goal for significant improvement, a N of 15 provides a power of > 0.80 with a = 0.05 for detecting a difference. Results: Between 1995 and 1999, 15 patients (age 13 ± 3 yrs)(mean ± 95% CI), 60 ± 28 days post-BMT with an OI = 36 ± 9 and PaOa/FiO₂ = 97 ± 18 received iNO. Hematologic malignancy was the primary diagnosis in 13/15 with 14/15 allogeneic and 1 autologous BMT. Preparative regimens consisted of total body irradiation in 12/15, cyclophosphamide in 13 and thiotepa in 7. A response to iNO was demonstrated in 11/15 patients (73%). Inhaled NO was administered for 12 ± 8 days at a maximum sustained dose of 42 ± 9 ppm. Repeated measures ANOVA with Dunnett's post hoc test showed a decrease in OI compared with baseline at 20, 40, 60 and 80 ppm of iNO. The mortality rate was 1.0 with 14/15 receiving iNO when they expired. Conclusions: Despite 73% of subjects showing a clinical response to iNO, there was no decrease in mortality compared with historical controls. The absence of a clear survival advantage indicates that investigation of iNO therapy in this population by large multicenter, randomized trials may not be helpful.