Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonaryhypertension of the newborn

Objective. Because of case reports describing hypoxemia on withdrawal of in haled nitric oxide (I-NO), we prospectively examined this safety issue in n ewborns with persistent pulmonary hypertension who were classified as treat ment successes or failures during a course of I-NO therapy. Methods. Randomized, placebo-controlled, double-masked, dose-response clini cal trial at 25 tertiary centers from April 1994 to June 1996. Change in ox ygenation and outcome (death and/or extracorporeal membrane oxygenation) du ring or immediately after withdrawing I-NO were the principal endpoints. Pa tients (n = 155) were term infants, <3 days old at study entry with echocar diographic evidence of persistent pulmonary hypertension of the newborn. Ex clusion criteria included previous surfactant treatment, high-frequency ven tilation, or lung hypoplasia. Withdrawal from treatment gas (0, 5, 20, or 8 0 ppm) started once treatment success or failure criteria were met. Withdra wal of treatment gas occurred at 20% decrements at <4 hours between steps. Results. The patient profile was similar for placebo and I-NO groups. Treat ment started at an oxygenation index (OI) of 25 +/- 10 (mean +/- SD) at 26 +/- 18 hours after birth. For infants classified as treatment successes (me an duration of therapy = 88 hours, OI <10), decreases in the arterial parti al pressure of oxygen (PaO2) were observed only at the final step of withdr awal. On cessation from 1, 4, and 16 ppm, patients receiving I-NO demonstra ted a dose-related reduction in PaO2 (-11 +/- 23, -28 +/- 24, and -50 +/- 4 8 mm Hg, respectively). For infants classified as treatment failures (mean duration of therapy = 10 hours), no change in OI occurred for the placebo g roup (-13 +/- 36%, OI of 31 +/- 11 after the withdrawal process); however a 42 +/- 101% increase in OI to 46 +/- 21 occurred for the pooled nitric oxi de doses. One death was possibly related to withdrawal of I-NO. Conclusion. For infants classified as treatment successes, a dose response between the I-NO dose and decrease in PaO2 after discontinuing I-NO was fou nd. A reduction in I-NO to 1 ppm before discontinuation of the drug seems t o minimize the decrease in PaO2 seen. For infants failing treatment, discon tinuation of I-NO could pose a life-threatening reduction in oxygenation sh ould extracorporeal membrane oxygenation not be readily available or I-NO c annot be continued on transport.