Newer strategies for surfactant delivery

Administration of surfactant to infants on continuous positive airway pressure

A first attempt at overcoming the CPAP-surfactant dilemma was in the form of the technique of intubation, surfactant administration, and extubation (INSURE). This method has been widely practiced, but its advantages over continuation of CPAP have more recently come into question. While some clinical trials have found a reduced need for mechanical ventilation with INSURE, ^, others have not, mostly attributable to difficulty with extubation after the procedure. ^, This limitation, and the difficulty of the intubation itself, has deterred many clinicians from using INSURE in clinical practice.

In view of the difficulties and limitations of the INSURE technique, a number of less invasive means of delivering surfactant to the preterm infant with RDS have been developed and pursued. These newer strategies for surfactant delivery are the subject of this chapter, which will draw upon the published evidence from nonrandomized and randomized studies, as well as reviews ^{, ,} and meta-analyses, to portray the current state of knowledge and bounds of accepted practice, and to highlight the areas of uncertainty in this rapidly changing field.

Aerosolization

While aerosolization is currently used infrequently to deliver medications of any sort to the neonatal lung, it has the attraction of being potentially the least invasive approach to surfactant administration, involving no direct instrumentation of the airway. It is little known that aerosolization was the first method of surfactant therapy in newborn infants with RDS, being first described in 1964. The clinical effects in this and another pioneering clinical study were modest, a testament to the difficulties in effective surfactant delivery and distribution using aerosolized surfactant, but also attributable in these early studies to the surfactant preparation used (pure DPPC with no spreading agents). Even with the advent of third-generation surfactant preparations with enhanced biophysical properties, and the development of sophisticated nebulization devices capable of dispersion of surfactant into droplets <5 μm, surfactant aerosolization for infants with RDS remains in the province of research.

Following on from observational studies and a small clinical trial have come the results of two recent randomized controlled trials (RCTs) in preterm infants with mild-to-moderate RDS. ^, Minocchieri and coworkers investigated the use of a vibrating membrane nebulizer for aerosolization of poractant alfa in infants 29 to 33 weeks’ gestation (n = 64) and reported a clinical benefit in relation to need for subsequent intubation (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.34–0.93). However, the proportion of infants requiring intubation and surfactant therapy in the control group was considerably higher than that usually reported at this gestation. Moreover the degree of RDS as indicated by oxygen requirement at study entry was relatively mild (FiO ₂ 0.22–0.30 at age <4 hours).

More recently, a large multicentre RCT with pragmatic design (the Aero-O2 study) has examined whether, in infants of median gestation 33 weeks (n = 457) with mild-to-moderate RDS, aerosolization of calfactant at a dose of 210 mg/kg phospholipid could reduce the need for intubation for standard surfactant instillation compared with a control group receiving expectant management. Infants were eligible if they had suspected or confirmed RDS and were receiving noninvasive respiratory support. Initially the FiO ₂ entry threshold was set between 0.25 and 0.40 at age 1 to 12 hours, but soon after the start of the trial the lower FiO ₂ limit was altered to room air. Surfactant dosing via aerosolization could be repeated up to a total of three doses (minimum interval 4 hours) as long as there was a positive response to the previous dose. Aerosolization of the surfactant took on average 68 minutes (∼30 minutes per kg body weight), and one-third of infants received two or more doses. The primary outcome of need for intubation followed by liquid surfactant instillation occurred in 26% of the aerosolization group and 50% of the control group (relative risk [RR] 0.48; 95% CI 0.36–0.62; P <0.001). The risk reduction was most apparent at gestations beyond 30 weeks. No difference was noted between groups in secondary outcomes, including pneumothorax and mode of respiratory support on days 3, 7, and 28. The authors concluded that surfactant aerosolization may expand the opportunities for surfactant therapy while avoiding intubation.

Interpretation and translation of the findings of the Aero-O2 study are hampered to a considerable degree by several elements of the study design. The removal of the lower limit on FiO ₂ at study entry meant that many infants with minimal or mild RDS were included. The mean FiO ₂ for the two groups at study entry was relatively low (0.30 and 0.32 in the active treatment and control groups, respectively), especially when considered alongside the median gestation of 33 weeks. Furthermore, the study was not blinded, and no criteria for intubation were imposed on treating clinicians in either group. The study investigators provided an analysis indicating that the lack of intubation criteria had not contributed to treatment bias. It was stated that the intubation rate of 50% in the control group was lower than expected, but no evidence in support of this was provided.

Further well-designed studies of surfactant aerosolization will be needed for this therapy to become accepted as an alternative to more selective intubation for surfactant administration. Ultimately head-to-head trials comparing this technique with other less invasive forms of surfactant therapy will be necessary. Given the relatively low proportional deposition of surfactant within the lung with any form of aerosolization, it is likely that this mode of surfactant administration could only find a place in the management of mild RDS occurring in infants ≥28 weeks’ gestation.

Pharyngeal instillation of surfactant

Although used several decades ago for initial surfactant delivery, the method of pharyngeal surfactant instillation shortly after birth was largely forgotten until rediscovery by Kattwinkel and coworkers, who applied the technique in preterm infants of gestational age 27 to 30 weeks, with some suggestion of an oxygenation response. The approach has also been explored in extremely preterm infants <25 weeks’ gestation, with suggestion of a better transition and lesser need for intubation compared with nonrandomized controls.

More recently, a multicentre RCT focusing on the efficacy of delivery room pharyngeal surfactant administration has been completed in 251 preterm infants ≤28 weeks’ gestation (POPART trial, EudraCT 2016-004198-41). Randomization occurred prenatally, and infants were assigned to receive either oropharyngeal surfactant before cord clamping or standard care. The surfactant dose was 120 mg poractant alfa for infants <26 weeks’ gestation and 240 mg for those at 26 to 28 weeks’ gestation. The primary outcome for the study was the need for intubation in the first 5 days, and clinicians were required to adhere to prespecified criteria regarding intubation in all enrolled infants. Preliminary results indicate that the need for intubation did not differ between groups (oropharyngeal surfactant 63%; control group 65%; P = 0.79). Among secondary outcomes, there was a higher incidence of pneumothorax in infants receiving oropharyngeal surfactant compared to controls (17% vs 7%, P = 0.031) but no other discernible differences in relevant in-hospital outcomes.

The results of the POPART study dampen enthusiasm for oropharyngeal surfactant administration soon after delivery in extremely preterm infants. For more mature infants at gestations beyond 28 weeks, any form of surfactant delivery used unselectively in the delivery room is unlikely to offer an advantage over early rescue therapy in those exhibiting features of RDS not manageable by CPAP alone.

Delivery of surfactant by laryngeal mask airway

The laryngeal mask airway (LMA) is designed to enclose the larynx in a cuffed seal and is increasingly promoted as a tool for facilitating neonatal resuscitation. ^, After initial reports of its use as a conduit for the administration of exogenous surfactant, ^, further studies including a number of clinical trials have been conducted in preterm infants. Interest in surfactant delivery by LMA has been stimulated by the difficulties encountered with airway instrumentation and procedural tolerance associated with other less invasive techniques, especially at more mature gestations. A total of six RCTs have explored surfactant delivery via LMA (reviewed in Roberts et al. ); in four cases this mode of delivery was compared to surfactant therapy after intubation, and in two others LMA surfactant administration was compared to expectant management including continuation of CPAP. ^, All studies have concentrated on infants at 28 weeks’ gestation and above, this being the lower limit of gestation at which the smallest LMA (size 0.5 or 1) can be reliably positioned. Surfactant delivery via LMA has been noted to be relatively easy to perform, with placement achievable in almost all cases. Two of the studies used post-procedure gastric aspiration as a way of confirming surfactant delivery to the lung, although the validity of this method has been questioned. The rate of surfactant redosing has also been rather high after LMA administration (∼38% in two studies combined ^, ). A figure of around 20% might be expected in infants of gestation ≥28 weeks, both with ETT administration and by thin catheter. For the outcome of avoidance of mechanical ventilation, overall the studies have shown a benefit of LMA surfactant administration compared to either continued CPAP (RR 0.57, 95% CI 0.38–0.85) or surfactant administration via ETT (RR 0.43, 95% CI 0.31–0.61). An advantage of LMA surfactant has not been apparent for other outcomes.

Ultimately the role and uptake of the LMA as a conduit for surfactant therapy in preterm infants will depend on the results of further and larger well-designed RCTs comparing LMA surfactant delivery to other forms of less invasive surfactant administration. One such study (SURFSUP trial, ACTRN12620001184965) is now underway and aims to recruit 1000 preterm infants >1250 g with RDS, comparing surfactant delivery via LMA with that via thin catheter placed in the trachea, with a primary outcome of treatment failure, indicated by need for repeat surfactant therapy or need for mechanical ventilation.

Delivery of surfactant via a thin catheter

The alternative of using a thin catheter to deliver surfactant to the trachea rather than an ETT was first reported by Verder et al., with an unstated number of preterm infants treated by this method among 34 preterm infants on CPAP given surfactant therapy in a pilot study. The method was rediscovered and championed by Kribs and colleagues in Cologne, and enthusiasm for tracheal catheterization as a means of surfactant delivery has burgeoned since. Given the wide experience and clinical applicability of this technique, the remainder of this chapter will focus on this approach to surfactant delivery.

Methods of surfactant delivery via thin catheter

Reported techniques for surfactant delivery via thin catheter are shown in Table 7.2 . Some of them involve the use of instrumentation to aid passage of the catheter tip through the vocal cords (e.g., Magill’s forceps); yet others use no internal guide and rely on the skill of the proceduralist to direct the catheter into the trachea. A semi-rigid rather than flexible catheter has generally been used for this latter approach, with the exception of the RCT of Kanmaz et al., in which the trachea was catheterized with a flexible catheter without use of Magill’s forceps. Beyond these original reports, a wide range of different catheters have now been used for surfactant delivery, including umbilical, suction, and urethral catheters, inserted by both oral and nasal routes.

Depth of catheter insertion

As with surfactant instillation via an ETT, the position of the catheter tip in the trachea is critically important, with surfactant reflux into the pharynx, or surfactant delivery preferentially into the right lung, being the potential consequences of an overly shallow or deep tip position, respectively. Reported catheter insertion depth has been 1 to 2 cm beyond vocal cords, depending on gestation. Based on information from a postmortem study of tracheal dimensions, a recommended catheter tip position of 1.5 cm beyond cords at <27 weeks’ gestation, and 2 cm for more mature infants, has been made. Optimal insertion depth for the catheter tip has also been estimated using radiological measurements of carina position, with the following recommendations: <750 g: 1.5 cm; 750–1499 g: 2 cm; 1500–2499 g: 2.5 cm; 2500–3500 g: 3 cm. Note that for many catheters (vascular catheter, feeding tube), a mark has to be drawn near the tip to indicate the required depth; a wax pencil is most suitable for this purpose.

Observational and cohort studies of surfactant delivery

Beyond the first descriptions of tracheal catheterization techniques, numerous single and multicentre experiences with this approach to surfactant delivery have now been reported. The experience of surfactant delivery via thin catheter runs to many thousands of infants. Readers are referred to recent reviews and meta-analyses for discussion of individual studies. ^{, , , , ,}