Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn,☆☆,

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Abstract

Background: Although inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in newborn infants with persistent pulmonary hypertension, its effects are variable. We hypothesized (1) that the response to iNO therapy is dependent on the primary disease associated with persistent pulmonary hypertension of the newborn (PPHN) and (2) that the combination of high-frequency oscillatory ventilation (HFOV) with iNO would be efficacious in patients for whom either therapy alone had failed.

Methods: To determine the relative roles of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neonates in a randomized, multicenter clinical trial. Patients were stratified by predominant disease category: respiratory distress syndrome ( n = 70), meconium aspiration syndrome ( n = 58), idiopathic PPHN or pulmonary hypoplasia (excluding congenital diaphragmatic hernia) (“other”: n = 43), and congenital diaphragmatic hernia ( n = 34); they were then randomly assigned to treatment with iNO and conventional ventilation or to HFOV without iNO. Treatment failure (partial pressure of arterial oxygen [Pa o 2 ] <60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treatment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained Pa o 2 of 60 mm Hg or greater.

Results: Baseline oxygenation index and Pa o 2 were 48 ± 2 and 41 ± 1 mm Hg, respectively, during treatment with conventional ventilation. Ninety-eight patients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initially assigned therapy without crossover (30 with iNO [28%] and 23 with HFOV [23%]; p = 0.33). Within this group, survival was 100% and there were no differences in days of mechanical ventilation, air leak, or supplemental oxygen requirement at 28 days. Of patients whose initial treatment failed, crossover treatment with the alternate therapy was successful in 21% and 14% for iNO and HFOV, respectively ( p = not significant). Of 125 patients in whom both treatment strategies failed, 32% responded to combination treatment with HFOV plus iNO. Overall, 123 patients (60%) responded to either treatment alone or combination therapy. By disease category, response rates for HFOV plus iNO in the group with respiratory syndrome and the group with meconium aspiration syndrome were better than for HFOV alone or iNO with conventional ventilation ( p <0.05). Marked differences in outcomes were noted among centers (percent death or treatment with extracorporeal membrane oxygenation = 29% to 75%).

Conclusions: We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN. Differences in responses are partly related to the specific disease associated with PPHN. (J Pediatr 1997;131:55-62)

Section snippets

Organization and Eligibility Criteria

Eight clinical centers with experience in the use of HFOV participated in this trial. The study was approved by the institutional review board at each center and by the U.S. Food and Drug Administration under an investigator-initiated Investigational New Drug exemption. Criteria for enrollment included the following: gestational age 34 weeks or more; severe hypoxemia despite mechanical ventilation with high fraction of inspired oxygen (partial pressure of arterial oxygen < 80 mm Hg in F io 2 =

Study Subjects

Data were analyzed from a total of 205 newborn infants in this trial. Ninety-eight patients were randomly assigned to treatment with HFOV, and 107 patients to iNO (Fig. 1).

. Flow diagram for study design, showing percentage of responders to initial assignment, crossover ( X-OVER ), and combined treatment ( TX ) with HFOV and iNO.

Enrollments by disease category were as follows: RDS, n = 70; MAS, n = 58; “other,” n = 43; and CDH, n = 34. Cyanotic congenital heart disease (total anomalous pulmonary

Discussion

We found that treatment with HFOV plus iNO is more successful than HFOV or iNO alone in severe PPHN and that differences in responses are related to the specific disease associated with the complex disorders of PPHN. For patients with PPHN complicated by severe lung disease, response rates for HFOV plus iNO were better than HFOV alone or iNO with conventional ventilation. In contrast, for patients without significant parenchymal lung disease, both iNO therapy and HFOV-plus-iNO therapy were more

Acknowledgements

We gratefully acknowledge the support and contributions of Reese H. Clark, MD, Bradley A. Yoder, MD, Donald M. Null Jr., MD, J. Schmidt, RRT, J. Griebel, RRT, and L. Fashaw, RN.

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Supported in part by National Institutes of Health grants HL41012 and 46481 (Dr. Abman); the General Clinical Research Centers Program (M01 RR00069), National Center for Research Resources; the March of Dimes Birth Defects Foundation (Dr. Kinsella); the American Heart Association Established Investigator Award (Dr. Abman); the Bugher Physician-Scientist Training Program (Dr. Kinsella); the Children’s Hospital Research Institute (Dr. Kinsella); the Hastings Foundation (Dr. deLemos), and the Children’s Mercy Hospital Physician Scientist Award (Dr. Truog).

☆☆

Reprint requests: John P. Kinsella, MD, Division of Neonatology, Box B-070, Children’s Hospital, 1056 E. 19th Ave., Denver, CO 80218-1088.

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