Comparison of Pre- and Post-inhaled Nitric Oxide (iNO) Therapy 691 rates of the two periods by Kaplan-Meier curve analysis, des- pite the fact that the survival rate obtained after the intro- duction of iNO therapy was higher than during the previ- ous period. Thus, additional evaluation was necessary because ranges of severity and clinical variability in CDH at the time of birth made it difficult to simply compare the survival rates of the two periods. Therefore, we compared period survival rates after adjusting for initial clinical characteristics related to the survival rate, i.e., sex, gestational age, birth weight (4), Apgar score at 5 min (4), significant associated anoma- lies (7, 12-14), prenatal diagnosis, inborn delivery (12, 15), polyhydramnios (16), and liver herniation (17). Among the above initial clinical characteristics, birth weight and Apgar score at 5 min were found to be the most important predic- tors to estimate the severity of CDH in the first 5 min of life by the Congenital Diaphragmatic Hernia Study Group (4). The lung-to-head ratio (18), one of the reliable predictors to help determine postnatal survival in CDH, was excluded from survival analysis because the rate of outborn delivery without prenatal diagnosis was very high at our institution. However, we considered that the significance of the lung- to-head ratio could be reflected to some degree by initial clin- ical characteristics such as Apgar score at 5 min. We also excluded clinical characteristics such as pneumothorax caused by CDH management from survival analysis. According to this analysis, the survival rate of P2 was significantly higher than that of P1. This result suggests that the survival rate difference observed between the two periods is likely to have been influenced by the change of management strategy rather than due to differences between the above initial clinical characteristics, including prenatal diagnosis and inborn deliv- ery, which were significantly different between P1 and P2. The significant differences in the management strategy between the two periods in this study were the introduction of iNO therapy and the longer duration of preoperative res- piratory management in P2. Preoperative HFOV therapy was excluded from evaluation of further management strat- egy because the number of patients who received HFOV therapy preoperatively was not significantly different between the two periods. The most important aspect of the postnatal management of neonates with CDH is PPH management (7). NO, originally identified as endothelial derived relaxing factor, has been used successfully to treat PPH because it is a potent vasodilator (19). Some investigators have tried iNO therapy in neonates with PPH complicating the course of CDH (20, 21). However, a multicenter randomized controll- ed trial of iNO therapy in CDH patients failed to demon- strate any reduction in the need for ECMO or in mortality (5). These results are consistent with previous observations by another group, who found that early iNO therapy was not associated with significant improvements in oxygena- tion in neonates with CDH (22). On the other hand, other studies favor the effect of iNO therapy in neonates with CDH, although these were not controlled studies (15, 23). Recent- ly, Downard et al. suggested that iNO therapy could be an important adjunct for treating PPH in neonates with CDH, when used in concert with echo- cardiography (7). The results of our study seem to support those of previous studies, which found that iNO therapy is effective in the management of CDH. In the present study, the postoperative survival rate in the P2 group was significantly higher. Among the 12 pa- tients who received iNO therapy as a rescue therapy for PPH and refractory hypoxemia in P2, seven patients survived post- operatively. It is possible that the survival of these seven pa- tients in P2 was partly attribu- table to the introduction of iNO therapy. We mentioned above that a reduction in the oxygenation index to 30% or more within 24 hr of iNO ther- apy was defined as a clinical response (8). This definition is meaningful in that most of the clinical responders (6 of 7) in P2 survived after operation, and thus contributed to im- proved survival in P2. Another significant difference in man- agement strategies in this study was the longer duration of preoperative respiratory management in P2. Several resear- chers have suggested that delayed operation for CDH after prolonged stabilization for at least 24 hr has a beneficial effect on survival rate for patients with CDH (2, 7, 24). In our study, we believe that iNO therapy is one of the factors that made delayed operation possible in P2, although more severe preoperative respiratory conditions may have been responsible for these delays. Some recent studies similar to our own allow comparisons of the survival rates of neonates with CDH with historical controls (23, 25-27). Three of these studies reported dramati- cally improved survival rates in neonates with CDH during 1988-2000, 1978-2001, and 1996-2001, respectively (23, 26, 27). However, only Okazaki et al. reported that the sur- vival rate of neonates with CDH was improved significantly after the introduction of iNO therapy with a delayed opera- tion (26). One of the most important limitations of the above studies, including the present study, concerns the use of a historical control, which may mislead investigators believe that changes in survival rate over a period is the direct result of a new therapy. All of the above studies did not prove statis- tically that the improved survival rate observed in the later period was not related to a less severe clinical condition. As mentioned above, the spectrum of severity of CDH is very wide, and the determination of effects of some specified treat- ment for this disease is very difficult. In this study, we tried to adjust for some initial clinical characteristics that might have influenced survival rates mainly, and to minimize con- founding features of a study using a historical control. How- ever, present study also has some limitations to adjust for all initial clinical characteristics due to its retrospective nature as other previous studies. Further prospective studies will be required to overcome these limitations and to confirm our hypothesis raised in this study. In summary, a significant improvement in the survival rate of neonates with CDH after the introduction of iNO thera-