Randomized, prospective study of low-dose versus high-dose inhaled nitric oxide in the neonate with hypoxic respiratory failure.
OBJECTIVE
There is little information on the response to very low doses of inhaled nitric oxide (iNO) in hypoxic near-term infants. The potential toxicities of iNO are dose related; thus, the ability to use lower doses safely and effectively may be advantageous. We hypothesized that there is no difference in the acute improvement in oxygenation between treatment with inhaled nitric oxide at 1 to 2 parts per million (ppm) or 10 to 20 ppm.


METHODS
We randomized near-term and term infants with hypoxic respiratory failure with oxygenation indices (OIs) of >/=10 and PaO(2) <100 on 2 separate blood gases taken at least 30 minutes apart. Infants with congenital diaphragmatic hernia were excluded. After parental consent was obtained, patients were randomized to receive a starting nitric oxide (iNO) dose of either 1 to 2 ppm (low-dose group, n = 15) or 10 to 20 ppm (high-dose group, n = 21). The response to iNO was assessed according to the increase in arterial PaO(2) and decrease in OI 30 to 60 minutes after exposure to the initial starting concentration. A response of <10% increase on PaO(2) and a <10% decrease in OI resulted in a doubling of iNO within the dose range protocol (1, 2, 4, and 8 ppm for the low-dose group; 10, 20, 40, and 80 ppm for the high-dose group).


RESULTS
Thirty minutes after the study gas was initiated, PaO(2) increased significantly overall in the low-dose (90.7 +/- 41 torr to 166.8 +/- 95.6 torr) and high-dose (76.2 +/- 32.7 torr to 198.7 +/- 142.8 torr) groups; the maximal increase was seen in the infants who initially were treated with 10 ppm. The OI also decreased significantly overall and also was significant in the high-dose group (21.0 +/- 13.7 to 11.4 +/- 10.4; low-dose: 18.3 +/- 7.1 to 13.2 +/- 12.3). There was a nonsignificant fall of PaCO(2) with iNO treatment (low dose 35 +/- 7.3 to 30 +/- 8.5 torr vs high dose 35.2 +/- 9.9 to 32.4 +/- 10.7 torr). A sustained response (ie, maintaining a PaO(2) and OI gain greater than 20% for the duration of the study gas administration) was greater in the high-dose group (53.3% vs 30.0%). In addition, dose increases were required more often in the low-dose group than in the high-dose group (80.0% vs 57.1%). Among patients who did not respond to the initial iNO dose, 100.0% and 83.3% responded at higher doses of iNO for the low- and high-dose groups, respectively. There were no differences for death, need for extracorporeal membrane oxygenation, or other outcomes between the groups.


CONCLUSIONS
We did not find any significant difference in response to low- versus high-dose iNO. An initial exposure to low-dose iNO does not compromise the response to higher doses if required and may result in less toxicity.
Finer
N N
NN
University of California, San Diego Medical Center, San Diego, California, USA. nfiner@ucsd.edu
Sun
J W
JW
Rich
W
W
Knodel
E
E
Barrington
K J
KJ
D000280:Administration, Inhalation; D001784:Blood Gas Analysis / Q000706:statistics & numerical data; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015199:Extracorporeal Membrane Oxygenation / Q000706:statistics & numerical data; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000188:drug therapy*; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000097:blood / Q000188:drug therapy; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D010100:Oxygen / Q000097:blood; D011446:Prospective Studies; D012127:Respiratory Distress Syndrome, Newborn / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome; D014692:Ventilation-Perfusion Ratio / Q000187:drug effects
D009569:Nitric Oxide; D010100:Oxygen