Aerosolized drugs have been used routinely in the NICU for several decades; however, the results of clinical studies have been generally disappointing. Aerosolized agents were first used in critically ill infants more than 40 years ago by Robilliard et al. [
59] who administered aerosolized dipalmitoyl-phosphatidylcholine directly into the incubators of premature infants with established respiratory distress syndrome (RDS). In this non-controlled study, they found that respiratory effort decreased in 8 of 11 infants. In contrast, investigators at the University of California, San Francisco, and the University of Singapore were unable to demonstrate a physiological benefit with aerosolized phosphatidylcholine [
13]. Other studies in which dipalmitoyl lecithin aerosol was administered to infants with RDS were also “negative” and discouraged the use of aerosolized surfactant therapy for many years [
39,
64]. However, in the 1990 s, clinicians once again became interested in aerosolized surfactant therapy as noninvasive mechanical ventilation became more prevalent in the neonatal population. The first study in neonates, using nasal continuous positive airway pressure (nCPAP) in combination with aerosolized surfactant for treatment of RDS, was conducted in 1997. This was a pilot feasibility study in which preterm newborns with moderate RDS requiring pharyngeal CPAP received nebulized SF-RI1 (Alveofact
®, Boehringer Ingelheim, Ingelheim, Germany) [
42]. The procedure was shown to be safe and the study demonstrated that ventilation and oxygenation improved once nebulization of surfactant was initiated. The following year, Arroe et al. [
5] tested the efficacy and safety of nebulized colfosceril palmitate (Exosurf
®, GlaxoSmithKline, Brentford, UK) delivered via nCPAP in preterm newborns. The study reported no adverse effects, but did not demonstrate any improvement in clinical efficacy variables as a result of the treatment. Berggren et al. [
8] treated 34 newborns (28–33 weeks post-conceptional age and 1,015–2,370 g) with RDS using nCPAP and aerosolized poractant alfa (Curosurf
®, Chiesi Pharmaceutici SpA, Parma, Italy). The investigators were also unable to demonstrate the superiority of aerosolized surfactant delivery over nCPAP alone. Finer et al. [
26], in a recent clinical study with aerosolized lucinactant (Aerosurf
®, Discovery Laboratories Inc., Warrington, PA, USA), tested the feasibility and safety of delivering a peptide-containing synthetic surfactant to newborns with early signs of RDS within 1 h of birth. This study used a clinically approved vibrating mesh nebulizer, the Aeroneb
® Pro (Aerogen, Dangan, Galway, Ireland), with a specially designed CPAP adaptor which allows for aerosol administration just below the “Y” connector. The procedure was shown to be safe with a low occurrence of “peridosing events” but lack of efficacy as there was not control group included.
A wide variety of other aerosolized medications have been studied in critically ill infants, demonstrating little to no benefit. Shah et al. [
63] published a review in the Cochrane Library on the early administration of inhaled corticosteroids for preventing chronic lung disease (CLD) in ventilated very low-birth-weight infants. The meta-analysis of seven trials found no evidence that the early use of inhaled steroids prevents the development of CLD. All of the studies included in this meta-analysis utilized metered-dose inhalers (MDI), except one study by Jonsson et al. [
41] which used a dosimetric jet nebulizer for corticosteroid aerosol generation.
The Cochrane Library also reviewed the use of aerosolized bronchodilators for the prevention and treatment of CLD. Only one study, in which CLD was a key clinical outcome, met the criteria for inclusion in the analysis. This double-blinded, multicenter randomized trial compared inhaled beclomethasone in combination with salbutamol vs. beclomethasone alone. There were no statistically significant differences in mortality, CLD, need for parenteral dexamethasone, respiratory infections, or positive blood cultures between the combination with salbutamol and beclomethasone alone. Furthermore, there were no statistically significant differences in the duration of ventilatory support, duration of oxygen supply, or age of weaning from respiratory support (defined as assisted ventilation or oxygen supplementation) between the two treatment groups [
53].
Inhaled prostacyclin (PGI
2) has been administered to newborns with persistent pulmonary hypertension (PPHN) [
10,
43,
66] and to infants with PPHN following surgical repair of congenital heart disease [
12]. These studies showed improvement in oxygenation due to the decrease of intrapulmonary shunt after treatment with aerosolized PGI
2. Nevertheless, these observations were never confirmed by subsequent large multicenter randomized trials.