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Vasodilator Testing with Nitric Oxide and/or Oxygen in Pediatric Pulmonary Hypertension

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Abstract

The objective of this study was to determine whether a combination of inhaled nitric oxide (iNO) and O2 is more effective than 100% O2 or iNO alone for acute vasodilator testing in children. An open, prospective, randomized, controlled trial was conducted at 16 centers. Subjects were children 4 weeks to 18 years of age with pulmonary hypertension (PH) and increased pulmonary vascular resistance (PVR) undergoing right heart catheterization for acute vasodilator testing. All patients were tested with each of three agents (80 ppm iNO, 100% O2, combination of 80 ppm iNO/100% O2) in three 10-min treatment periods, and hemodynamic measurements obtained. Primary outcome measures were percentages of acute responders with O2 alone vs. iNO/O2 and iNO alone vs. iNO/O2. More patients on the combination were acute responders compared with O2 or iNO alone (26% vs. 14%, P = 0.019, and 27% vs. 24%, P = 0.602, respectively). Changes in PVR index and mean pulmonary arterial pressure vs. baseline were greater with iNO/O2 vs. either O2 or iNO alone (P < 0.001). Survival at 1-year follow-up included (1) 90.9% of acute responders to the combination, compared with 77.8% of nonresponders to the combination, and (2) 85.7% of acute responders to O2 alone, compared with 80.6% of nonresponders to O2. Key conclusions are as follows. In children with PH and increased PVR, more acute responders were identified with the iNO/O2 combination vs. O2 alone. While there was no significant difference in acute responder rate with iNO alone vs. iNO/O2, the combination improved pulmonary hemodynamics acutely better than iNO alone. One-year survival data show similar rates between the iNO/O2 and the O2 alone groups; however, the combination may be more effective than O2 alone in discriminating survivors versus nonsurvivors at long-term follow-up.

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Acknowledgments

This study was sponsored by INO Therapeutics/Ikaria, Clinton, New Jersey, USA. Investigators are as follows. France: Prof. D. Sidi, Dr. G. Agnoletti, Hôpital Necker Enfants Malades, Paris; Dr. A. Fraisse, Dr. A. Dragulescu, CHU la Timone–Hôpital d’Enfants, Marseille; Dr. Marçon, Hôpital d’Enfants, Nancy. Spain: Dr. F. Gutierrez Larraya, Dr. A. Mendoza, Hospital Materno-Infantil XII de Octubre, Madrid; Dr. J. L. Zunzunegui Martinez, Hospital Gregorio Maranon, Madrid; Dr. J. J. Bartrons Casas, Dr. F. Prada Hermógenes, Hospital Sant Joan de Deu, Barcelona; Dr. J. Girona Comas, Hospital Infantil Vall d’Hebron, Barcelona. The Netherlands: Prof. Dr. R. Berger, Beatrix Children’s Hospital, University Hospital, Groningen. United Kingdom: Dr. A. Magee, L. Davies Shaughnessy, RN, The Royal Brompton Hospital, London. United States: Dr. R. Barst, Columbia University, New York; Dr. S. Abman, Donna Parker, RRT, The Children’s Hospital, Denver, CO; Dr. D. Balzer, Washington University, St. Louis, MO; Dr. Andrew Atz, Teresa Atz, RN, Children’s Hospital Medical University of South Carolina, Charleston; Dr. J. A. Feinstein, Val Scott, RN, Lucile Salter Packard Children’s Hospital—Stanford, Palo Alto, CA; Dr. C. Daniels, Ohio State University Medical Center & Columbus Children’s Hospital, Columbus; Dr. R. Hirsch, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

Competing Interests

Dr. Robyn J. Barst has served as a consultant to, and received research support from, Actelion, Eli Lilly, Gilead, GSK, INO/Ikaria, Novartis, and Pfizer. Dr. Gabriella Agnoletti was reimbursed for attending an investigator meeting (Edinburgh) and was paid to include 10 more patients in the study. Dr. Alain Fraisse was reimbursed for attending two investigator meetings for this study (Miami and Edinburgh) and is a consultant to Sanofi-Aventis. Dr. James Baldassarre is an employee of Ikaria. Dr. David L. Wessel serves as a consultant to Ikaria and has received research funds from Pfizer.

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Correspondence to Robyn J. Barst.

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Clinical Trials Identifier: NCT00626028. Institutions where work was completed are as follows. France : Hôpital Necker Enfants Malades, Paris; CHU la Timone–Hôpital d’Enfants, Marseille; Hôpital d’Enfants, Nancy. Spain : Hospital Materno-Infantil XII de Octubre, Madrid; Hospital Gregorio Maranon, Madrid; Hospital Sant Joan de Deu, Barcelona; Hospital Infantil Vall d’Hebron, Barcelona. The Netherlands : Beatrix Children’s Hospital, University Hospital, Groningen. United Kingdom : The Royal Brompton Hospital, London. United States : Columbia University, New York; The Children’s Hospital, Denver, CO; Washington University, St. Louis, MO; Children’s Hospital Medical University of South Carolina, Charleston; Children’s Hospital—Stanford, Palo Alto, CA; Ohio State University Medical Center & Columbus Children’s Hospital, Columbus; Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

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Barst, R.J., Agnoletti, G., Fraisse, A. et al. Vasodilator Testing with Nitric Oxide and/or Oxygen in Pediatric Pulmonary Hypertension. Pediatr Cardiol 31, 598–606 (2010). https://doi.org/10.1007/s00246-010-9645-5

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