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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References
Atz AM, Adatia I, Lock JE, Wessel DL (1999) Combined effects of nitric oxide and oxygen during acute pulmonary vasodilator testing. J Am Coll Cardiol 33:813–819
Badesch DB, Champion HC, Gomez-Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A (2009) Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 54:S55–S66
Balzer DT, Kort HW, Day RW, Corneli HM, Kovalchin JP, Cannon BC, Kaine SF, Ivy DD, Webber SA, Rothman A, Ross RD, Aggarwal S, Takahashi M, Waldman JD (2002) Inhaled nitric oxide as a preoperative test (INOP Test I): the INOP Test Study Group. Circulation 106(12; Suppl 1):I76–I81
Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, Sitbon O, Tapson VF, Galie N (2009) Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 54:S78–S84
Barst RJ, Maislin G, Fishman AP (1999) Vasodilator therapy for primary pulmonary hypertension in children. Circulation 99:1197–1208
Barst RJ (1986) Pharmacologically induced pulmonary vasodilation in children and young adults with primary pulmonary hypertension. Chest 89:497–503
Bennett D, Marcus R, Stokes M (2005) Incidents and complications during pediatric cardiac catheterization. Paediatr Anaesth 15:1083–1088
Cockrill BA, Kacmarek RM, Fifer MA, Bigatello LM, Ginns LC, Zapol WM, Semigran MJ (2001) Comparison of the effects of nitric oxide, nitroprusside, and nifedipine on hemodynamics and right ventricular contractility in patients with chronic pulmonary hypertension. Chest 119:128–136
Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, McGregor K, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P, Sechtem U, Al Attar N, Andreotti F, Aschermann M, Asteggiano R, Benza R, Berger R, Bonnet D, Delcroix M, Howard L, Kitsiou AN, Lang I, Maggioni A, Nielsen-Kudsk JE, Park M, Perrone-Filardi P, Price S, Subirana Domenech MT, Vonk-Noordegraaf A, Zamorano JL (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 30:2493–2537
Houde C, Bohn DJ, Freedom RM, Rabinovitch M (1993) Profile of paediatric patients with pulmonary hypertension judged by responsiveness to vasodilators. Br Heart J 70:461–468
Kieler-Jensen N, Ricksten SE, Stenqvist O, Bergh CH, Lindelov B, Wennmalm A, Waagstein F, Lundin S (1994) Inhaled nitric oxide in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance. J Heart Lung Transplant 13:366–375
Krasuski RA, Warner JJ, Wang A, Harrison JK, Tapson VF, Bashore TM (2000) Inhaled nitric oxide selectively dilates pulmonary vasculature in adult patients with pulmonary hypertension, irrespective of etiology. J Am Coll Cardiol 36:2204–2211
Marshall HW, Swan HJ, Burchell HB, Wood EH (1961) Effect of breathing oxygen on pulmonary artery pressure and pulmonary vascular resistance in patients with ventricular septal defect. Circulation 23:241–252
McLaughlin VM, Archer SA, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ, ACCF/AHA (2009) ACCF/AHA clinical expert consensus document on pulmonary hypertension. Circulation 119:2250–2294
Morales-Blanhir J, Santos S, de Jover L, Sala E, Pare C, Roca J, Rodriguez-Roisin R, Barbera JA (2004) Clinical value of vasodilator test with inhaled nitric oxide for predicting long-term response to oral vasodilators in pulmonary hypertension. Respir Med 98:225–234
Pagano D, Townend JN, Horton R, Smith C, Clutton-Brock T, Bonser RS (1996) A comparison of inhaled nitric oxide with intravenous vasodilators in the assessment of pulmonary haemodynamics prior to cardiac transplantation. Eur J Cardiothorac Surg 10:1120–1126
Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J (1991) Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 338:1173–1174
Rich S, Kaufmann E, Levy PS (1992) The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 327:76–81
Roberts JD Jr, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM (1993) Inhaled nitric oxide in congenital heart disease. Circulation 87:447–453
Rubin LJ (2004) Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126(Suppl 1):7S–10S
Sitbon O, Brenot F, Denjean A, Bergeron A, Parent F, Azarian R, Herve P, Raffestin B, Simonneau G (1995) Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 151(2; Pt 1):384–389
Sitbon O, Humbert M, Jagot JL, Taravella O, Fartoukh M, Parent F, Herve P, Simonneau G (1998) Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 12:265–270
Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Herve P, Simonneau G (2005) Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111:3105–3111
Taylor CJ, Derrick G, McEwan A, Haworth SG, Sury MR (2007) Risk of cardiac catheterization under anaesthesia in children with pulmonary hypertension. Br J Anaesth 98:657–661
Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ (2004) Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation 110:660–665
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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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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DOI: https://doi.org/10.1007/s00246-010-9645-5