PEDIATRICS Vol. 104 No. 5 November 1999, pp. 1089-1094

Randomized, Controlled Trial of Low-dose Inhaled Nitric Oxide in the Treatment of Term and Near-term Infants With Respiratory Failure and Pulmonary Hypertension

Received Nov 23, 1998; accepted Apr 9, 1999.

David N. Cornfield^*, Roy C. Maynard^{, §}, Raye-Ann O. deRegnier^{, §}, Sixto F. Guiang III, Joel E. Barbato^*, and Carlos E. Milla^*

From the Divisions of ^* Pulmonary and Critical Care Medicine and  Neonatology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; and ^§ Children's Hospitals and Clinics, Minneapolis, Minnesota.

Recent reports indicate that inhaled nitric oxide (iNO) causes selective pulmonary vasodilation, increases arterial oxygen tension, and may decrease the use of extracorporeal membrane oxygenation (ECMO) in infants with persistent pulmonary hypertension of the newborn (PPHN). Despite these reports, the optimal dose and timing of iNO administration in PPHN remains unclear.

Objectives.  To test the hypotheses that in PPHN 1) iNO at 2 parts per million (ppm) is effective at acutely increasing oxygenation as measured by oxygenation index (OI); 2) early use of 2 ppm of iNO is more effective than control (0 ppm) in preventing clinical deterioration and need for iNO at 20 ppm; and 3) for those infants who fail the initial treatment protocol (0 or 2 ppm) iNO at 20 ppm is effective at acutely decreasing OI.

Study Design.  A randomized, controlled trial of iNO in 3 nurseries in a single metropolitan area. Thirty-eight children, average gestational age of 37.3 weeks and average age <1 day were enrolled. Thirty-five of 38 infants had echocardiographic evidence of pulmonary hypertension. On enrollment, median OI in the control group, iNO at 0 ppm, (n = 23) was 33.1, compared with 36.9 in the 2-ppm iNO group (n = 15).

Results.  Initial treatment with iNO at 2 ppm for an average of 1 hour was not associated with a significant decrease in OI. Twenty of 23 (87%) control patients and 14 of 15 (92%) of the low-dose iNO group demonstrated clinical deterioration and were treated with iNO at 20 ppm. In the control group, treatment with iNO at 20 ppm decreased the median OI from 42.6 to 23.8, whereas in the 2-ppm iNO group with a change in iNO from 2 to 20 ppm, the median OI did not change (42.6 to 42.0). Five of 15 patients in the low-dose nitric oxide group required ECMO and 2 died, compared with 7 of 23 requiring ECMO and 5 deaths in the control group.

Conclusion.  In infants with PPHN, iNO 1): at 2 ppm does not acutely improve oxygenation or prevent clinical deterioration, but does attenuate the rate of clinical deterioration; and 2) at 20 ppm acutely improves oxygenation in infants initially treated with 0 ppm, but not in infants previously treated with iNO at 2 ppm. Initial treatment with a subtherapeutic dose of iNO may diminish the clinical response to 20 ppm of iNO and have adverse clinical sequelae.

This article has been cited by other articles:

				G. G. Konduri, A. Solimano, G. M. Sokol, J. Singer, R. A. Ehrenkranz, N. Singhal, L. L. Wright, K. Van Meurs, E. Stork, H. Kirpalani, et al. A Randomized Trial of Early Versus Standard Inhaled Nitric Oxide Therapy in Term and Near-Term Newborn Infants With Hypoxic Respiratory Failure Pediatrics, March 1, 2004; 113(3): 559 - 564. [Abstract] [Full Text] [PDF]

				R. S. Frey and A. B. Malik Oxidant signaling in lung cells Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L1 - L3. [Full Text] [PDF]

				R. T. Lightfoot, S. Khov, and H. Ischiropoulos Transient injury to rat lung mitochondrial DNA after exposure to hyperoxia and inhaled nitric oxide Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L23 - L29. [Abstract] [Full Text] [PDF]

				H. Gerlach, D. Keh, A. Semmerow, T. Busch, K. Lewandowski, D. M. Pappert, R. Rossaint, and K. J. Falke Dose-Response Characteristics during Long-Term Inhalation of Nitric Oxide in Patients with Severe Acute Respiratory Distress Syndrome: A Prospective, Randomized, Controlled Study Am. J. Respir. Crit. Care Med., April 1, 2003; 167(7): 1008 - 1015. [Abstract] [Full Text] [PDF]

				A. N. MacRitchie, K. H. Albertine, J. Sun, P. S. Lei, S. C. Jensen, A. A. Freestone, P. M. Clair, M. J. Dahl, E. A. Godfrey, D. P. Carlton, et al. Reduced endothelial nitric oxide synthase in lungs of chronically ventilated preterm lambs Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L1011 - L1020. [Abstract] [Full Text] [PDF]

				N. N. Finer, J. W. Sun, W. Rich, E. Knodel, and K. J. Barrington Randomized, Prospective Study of Low-Dose Versus High-Dose Inhaled Nitric Oxide in the Neonate With Hypoxic Respiratory Failure Pediatrics, October 1, 2001; 108(4): 949 - 955. [Abstract] [Full Text] [PDF]

				S. Jaillard, Y. Riou, S. Klosowski, F. Cneude, P. Fialdes, X. Codaccioni, P. Lequien, and L. Storme Effects of inhaled nitric oxide on gas exchange and acute lung injury in premature lambs with moderate hyaline membrane disease Eur. J. Cardiothorac. Surg., September 1, 2000; 18(3): 334 - 341. [Abstract] [Full Text] [PDF]