Randomized, controlled trial of low-dose inhaled nitric oxide in the treatment of term and near-term infants with respiratory failure and pulmonary hypertension.
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.


OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Cornfield
D N
DN
Division of Pulmonary and Critical Care Medicine, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA. cornf001@maroon.tc.umn.edu
Maynard
R C
RC
deRegnier
R A
RA
Guiang
S F
SF
Barbato
J E
JE
Milla
C E
CE
D000280:Administration, Inhalation; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000009:adverse effects; D010100:Oxygen / Q000008:administration & dosage / Q000097:blood; D010313:Partial Pressure; D010547:Persistent Fetal Circulation Syndrome / Q000097:blood / Q000150:complications / Q000628:therapy*; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency / Q000097:blood / Q000150:complications / Q000628:therapy*; D017211:Treatment Failure; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects
D014665:Vasodilator Agents; D009569:Nitric Oxide; D010100:Oxygen