A new side effect of inhaled nitric oxide in neonates and infants with pulmonary hypertension: Functional impairment of the neutrophil respiratory burst

Introduction. Inhaled nitric oxide (NO) may be beneficial in the treatment of pulmonary hypertension, both of the newborn and in the adult respiratory distress syndrome. Up to now, serious systemic side effects have not been reported. Objective: The effect of inhaled NO on superoxide anion production by neutrophils. Design. Prospective study of a consecutive series of 15 neonates and infants. Setting: Neonatal and paediatric ICUs with a total of 17 beds (university hospital). Measurements and results. Superoxide anion production was determined by a flow cytometric method using dihydrorhodamine 123 (DHR) as an oxidative probe after the priming of neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP) or with Escherichia coli. The generated fluorescence was expressed as relative fluorescence intensity (RFI). Inhalation of NO for more than 24 h reduced the superoxide anion production by neutrophils stimulated with E. coli to below baseline values before NO inhalation (mRFI = 158 +/- 25 vs 222 +/- 24; P = 0.03). This decrease was more pronounced after more than 72 h (mRFI = 133 +/- 17). At this time, superoxide anion production by fMLP-stimulated neutrophils was also decreased (mRFI = 40 +/- 3, vs 57 +/- 5; P = 0.03). The reduced capacity of superoxide production persisted throughout therapy with NO and lasted up to more than 4 days after the end of NO inhalation. Conclusion. The results suggest that inhalation of NO in patients with pulmonary hypertension causes reduced superoxide anion production by neutrophils stimulated with E. coli or with fMLP. To determine the clinical importance of this systemic side effect with respect to bacterial infections, a randomized controlled study is necessary.